Dissertations / Theses: 'Drug-herb interactions'

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Blackwelder, Reid B. "Drug-Herb Interactions." Digital Commons @ East Tennessee State University, 2005. https://dc.etsu.edu/etsu-works/6913.

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Shams, Tahiatul. "Solute Carrier Transporters in drug-drug/herb interactions and their molecular regulation in disease." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20342.

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Solute Carrier Transporters (SLCs) are a group of influx transporters responsible for the cellular uptake of endogenous substances and exogenous molecules including a number of clinically important drugs. They are widely expressed in epithelium throughout the body, where they play essential roles in determining the disposition and elimination of these substances. They have been recognized as the crucial determinants to drug pharmacokinetics in humans. The dysfunction of SLC transporters contributes to the pathophysiology of several diseases, as well as largely impacts on drug pharmacokinetic performance, which in turn alters drug efficacy and toxicity. SLCs can also mediate the transport of various herbal compounds and dietary substances. Due to the wide substrate specificity of SLC transporters there is a possibility of potential drug-drug, drug-herb or drug-food interactions that might compromise therapeutic outcomes. Therefore, understanding the structure, expression, function and molecular regulation of SLCs is required to optimise therapeutic outcomes and drug development. The studies presented in this thesis were aimed to explore the physiological and pharmacological role of SLCs, understand the mechanisms through which drug-drug/herb interactions may occur and study the potential molecular regulation of the function and expression of SLCs. The inhibitory effects of five clinically relevant alkaloids were investigated using HEK293 cell line over-expressing essential SLCs. The study indicated that, tryptanthrin significantly inhibited the transport activity of OAT3, whereas, chelerythrine acted as a potent inhibitor of OATP1A2, OCT1 and OCT2. The inhibitory effects of these two natural alkaloids suggested the potential interactions of tryptanthrin and chelerythrine with OAT3, OATP1A2 and OCTs drug substrates, leading to altered pharmacokinetic profiles of these drugs. Therefore, precautions are warranted on the coadministration of these compounds with OAT3, OATP1A2 or OCT substrates due to unexpected toxicity or undesirable therapeutic outcomes. In the second study, we reported that Wnt/β-catenin pathway is involved in the molecular regulation of OATP1A2 function and expression. Transporter functional assays showed that OATP1A2 transport activity was impaired when cells were treated with Wnt-specific inhibitors FH535, 21H7; Wnt specific activator HLY78 and Wnt agonist. Treatment with FH535 reduced the transport activity of OATP1A2 by decreasing the apparent affinity of OATP1A2 for its substrate (Km), without changing the Vmax. On the other hand, 21H7, HLY78 and Wnt agonist treatments showed a reduced Vmax of E3S transport by OATP1A2, without affecting the affinity of the transporter for its substrate (Km). Immunoblotting analysis showed that 21H7, HLY78 and Wnt agonist significantly impaired the plasma membrane expression of OATP1A2. In addition, OATP1A2 overexpressing HEK293T cells co-transfected with β-catenin silencing siRNA showed significant reduction in OATP1A2 function as well as cell surface expression. Overall, Wnt modulators down-regulated the function and cell surface expression of OATP1A2, which can potentially impact the disposition of drugs that are transported by this transporter. In the third study we found that Wnt pathway is also involved in the regulation of OATs. Transporter functional assays showed that Wnt inhibitors FH535 and 21H7 reduced the transport activity of OAT1. FH535 also impaired the function of OAT4. The Wnt inhibitors did not affect the total cell and plasma membrane expression of OAT1 and OAT4. The transport function of OAT3 was impaired by Wnt-specific modulators FH535, 21H7 and HLY78. Kinetic analysis suggested that the impaired transport activity of OAT3 following FH535 treatment was due to the decreased Vmax for substrate transport, while the apparent affinity remained unchanged. FH535 treatment decreased the plasma membrane expression of OAT3. Therefore, modulation of OAT function by Wnt pathway might impact the pharmacokinetics of its drug substrates. Finally, an update on the interactions of anticancer drugs with OATPs has been discussed in chapter 5. OATPs play an important role in the disposition of anticancer drugs. Modulation of OATPs function and expression by genetic polymorphism and drug-drug/herb interactions significantly impacts the PK of anticancer drugs. Because of their abundant expression in various tumour cells and their ability to transport numerous anticancer drugs, OATPs can be considered as important therapeutic targets in anticancer drug design. Due to their physiological and pharmacological importance, SLC transporters play a significant role in human health and disease. Further research on SLC transporters is necessary to comprehensively understand their involvement in human diseases and drug development.

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Sachdeva, Karuna. "Regulation of cytochrome P450-3A (CYP3A) and pregnane X receptor (PXR) : implications to drug-drug interactions /." View online ; access limited to URI, 2005. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3186919.

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Ezuruike, U. F. "Evaluation of herb-drug interactions in Nigeria with a focus on medicinal plants used in diabetes management." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1465961/.

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Studies have shown an increasing use of herbal medicines alongside conventional drugs by patients in their disease management especially for chronic diseases, with the attendant risks of herb-drug interactions. In order to forestall this, adequate information about the pharmacological and toxicological profile of herbal medicines and how these would in turn affect the bioavailability of the co-administered drug is required. To evaluate potential herb-drug interactions that could occur in diabetes management in Nigeria- (a) An assessment of available data on the pharmacological and toxicological effects of plants used in diabetes management was conducted as a means of mapping those with identified potential risks for herb-drug interactions; (b) A field work study was carried out in different localities in Nigeria to identify potential pharmacokinetic interactions based on the prescription drugs and herbal medicines co-administered by diabetic patients; and (c) Experimental analysis of plant samples collected during the field work was done to assess their effects on known cell detoxification mechanisms and pharmacokinetic parameters. The results of the research have confirmed the continued use of a wide range of medicinal plants in diabetes management, many of which have not been thoroughly investigated. In addition, 50% of diabetic patients visiting healthcare facilities in Nigeria routinely manage their diabetes or existing co-morbidities with herbal medicines alongside prescription drugs. Even more worrying is the frequent use of unlabeled herbal preparations which would constitute a huge challenge in the proper identification of herb-drug interactions when they occur. Based on previously available data and the experimental results of this research, a number of these herbal medicines have been identified as having overlapping interactions with prescription drugs. There is therefore a need for better regulation of herbal medicine use alongside pharmacovigilance monitoring in Nigeria in order to forestall the occurrence of clinically relevant untoward herb-drug interactions.

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Lundahl, Anna. "In vivo Pharmacokinetic Interactions of Finasteride and Identification of Novel Metabolites." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-129362.

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The general aim of this thesis was to improve the understanding of the in vivo pharmacokinetics and, in particular, the metabolism of finasteride, a 5α-reductase inhibitor used in the treatment of enlarged prostate glands and male pattern baldness. CYP3A4 has been identified as the major enzyme involved in the sequential metabolism of finasteride to ω-OH finasteride (M1) and ω-COOH finasteride (M3). The consequences of induced and inhibited metabolism on the pharmacokinetics of finasteride and its metabolites were investigated in humans and pigs. Both studies included bile collection. The collected human and pig samples were used for the metabolite identification. As expected, induced metabolism led to reduced plasma exposure of finasteride and inhibited metabolism had the opposite effect. The interactions were investigated in detail and included examination of the biliary pharmacokinetics of finasteride and its metabolites. In pigs, the study included monitoring of the hepatic extraction over time, deconvolution and the development of a semi-physiological model for comparison of the effects on the gut wall and liver metabolism. For M3, the concentration ratios of bile to plasma and the renal clearance indicated that carrier-mediated processes are involved in the biliary and urinary excretion. This was not, however, the case for finasteride. The metabolite, M1, could not be quantified either in humans or pigs. Instead, two other OH metabolites, M1 isomers, were identified in humans. These metabolites were found to undergo glucuronide conjugation. In humans, one glucuronide was identified intact and in pigs, both glucuronides were identified intact in bile and in urine. In addition, a glucuronide of M3 was identified in human bile. In conclusion, advances have been made in the understanding of the pharmacokinetics of finasteride, in particular in relation to the metabolism. Hopefully, the findings of this comprehensive investigation can be applied to other drugs and novel chemical entities.

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Fang, Yuan Yuan. "In vitro drug-herb interaction potential of African medicinal plant products used by Type II diabetics." Thesis, Nelson Mandela Metropolitan University, 2011. http://hdl.handle.net/10948/1341.

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In Africa, use of medicinal plants for the treatment of diabetes is very common. However, efficacy on co-administering of medicinal plants with therapeutic drugs hasn't been fully determined, especially for African medicinal plants. The current study focused on assessing the in vitro modulation effects of three popular African medicinal plants, namely: Aloe ferox, Sutherlandia frutescens and Prunus africana (including five commercial preparations containing these medicinal plants) on two of the most important anti-diabetic drug metabolising enzymes, Cytochrome P450 (CYP450) 2C9 and CYP3A4 and a key drug efflux transporter, P-glycoprotein (P-gp). Vivid® microsome-based screening kits were used to assess inhibitory potency of plants preparations on CYP2C9 and CYP3A4 enzymes activities. The study showed that P. africana was a more potent inhibitor of CYP2C9 and CYP3A4 activity than the corresponding positive controls Ginkgo biloba and St. John's wort, which are known to cause clinically significant drug-herb interactions. S. frutescens leaf extract demonstrated potent to moderate inhibition on both the tested CYP activities, while its commercial products (Promune® and Probetix®) possessed moderate to mild inhibitory effects on the activities of both CYPs. Potent inhibitory effect on CYP2C9 and CYP3A4 was seen with Aloe Ferox®. Prosit® and Aloes powder® showed potent to moderate inhibition on CYP2C9 activity and moderate to mild inhibition on CYP3A4 activity. In addition to CYP450 activity, the present study also investigated the effects of the selected medicinal plant products on the activity of the main drug efflux protein, P-gp. A screening assay was specifically developed to assess the potential for herbal remedies to interact with P-gp mediated drug absorption. The assay is based on the principle of the reversal of drug resistance in modified Caco-2 cells specifically altered to express high iv efflux protein activity. These cells display a multidrug resistance phenotype and the addition of a plant extract containing a P-gp inhibitor or substrate will inhibit or compete with any cytotoxic drug and consequently reverse the drug resistance. The suitability of the assay was confirmed using a known P-gp inhibitor. The study observed that the anti-proliferation effect of vinblastine was significantly enhanced in vinblastine-resistant Caco-2 cells, which have high P-gp expression, when they were exposed to the selected African herbal preparations. This observation indicates that the studied plant preparations may alter P-gp functionality and therefore lead to interference with the absorption of co-administered drugs. The outcomes of this study provide useful information on whether there are any potential drug-herb interactions between the commonly used African medicinal plants and oral anti-diabetic drugs, at the level of CYP and P-gp drug metabolism and could contribute to better therapeutic management of Type II diabetics. However these predicted interactions will need to be verified in a clinical setting.

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Mazhar, Hajra. "The Use of Complementary and Integrative Medicines and Exploring Natural Health Product-Drug Interactions In Vitro in the Management of Pediatric Attention-Deficit Hyperactivity Disorder." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40653.

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This thesis applied a novel interdisciplinary approach for pharmacovigilance to examine the use of complementary and integrative medicine (CIM), focusing on herbal remedies, to manage pediatric attention-deficit hyperactivity disorder (ADHD). The safety and potential risk of herb-drug interactions in ADHD management were first evaluated through an assessment of available information on the safety and efficacy of natural health products (NHPs) commonly used by ADHD patients as a means of identifying knowledge gaps. A clinical questionnaire was administered to caregivers of pediatric patients with ADHD to determine the factors and related outcomes of CIM use, including adverse events. A systematic search was conducted to further identify clinical adverse events involving herbal remedies and ADHD drugs to determine causal links to herb-drug interactions. In vitro analysis of identified herbal remedies was conducted to determine their potential for pharmacokinetic interactions, specifically on carboxylesterase-1 (CES1) mediated metabolism. The presented research builds on otherwise scarce evidence of the safety of herbal remedies for ADHD, particularly with respect to herb-drug interactions and adverse events (AEs) associated with concurrent use of NHPs and ADHD prescription drugs. Beyond studies conducted on the pharmacokinetic safety of herbal remedies through the cytochrome P450 pathways that metabolize some ADHD drugs, including amphetamine, atomoxetine and guanfacine, few data were available for CES1, which metabolizes methylphenidate, the first line of drug used to manage ADHD. The clinical questionnaire revealed that 40% of patients had used CIM and confirmed the use of a variety of CIM. Moreover, the majority of CIM users were also concurrently taking ADHD medication, and eight mild adverse events were self-reported. The systematic search on the adverse event reporting system highlighted a potential NHP-drug interaction between methylphenidate and St. John’s wort, and the overall poor quality of NHP-related adverse event reports. As a follow-up from the adverse event results, various commercial St. John’s wort products showed variable inhibition of recombinant human CES1 in vitro. Although the concentration of marker phytochemicals was not correlated to inhibition, hyperforin showed stronger activity than hypericin and quercetin. The preliminary in vitro investigation revealed that the herbal remedies used by ADHD patients have the potential to interact with CES1 mediated metabolism, with Rhodiola rosea identified as the most potent inhibitor. Further investigation on various commercial products of Rhodiola rosea revealed both reversible and irreversible inhibition of recombinant CES1. However, the inhibition was not dependent on the concentration of marker phytochemicals, and rosarin, rosavin, rosin, and salidroside were not potent inhibitors of recombinant CES1. Moreover, a commercial Rhodiola rosea extract showed concentration-dependent inhibition of human liver microsome meditated metabolism of methylphenidate. Overall, results from this thesis suggest potential risk from use of NHPs concurrently with conventional medicine used to manage ADHD. Improved evidence and pharmacovigilance for the use of NHPs in a pediatric population is warranted.

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Dias, Araujo Mazzari A. L. "In vitro effects of selected medicinal plants shortlisted for clinical use in the Brazilian public health system in CYP3A4 mRNA gene expression, glutathione levels and P-glycoprotein activity and their implications for herb-drug interactions." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1535229/.

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The Brazilian Unified Public Health System (SUS) shortlisted various plant species of interest (RENISUS) for future clinical use. However, very little is known about their effects on metabolic and transporter proteins, which could potentially lead to herb-drug interactions (HDI). To evaluate this, we conducted in vitro preclinical studies on twenty-four plant extracts to disclose their effects on CYP3A4 mRNA gene expression, intracellular glutathione (GSH) levels, inhibition of γ-glutamyl transferase (GGT) in HepG2 cells and P- glycoprotein (P-gp) activity in vincristine resistant Caco-2 (Caco-2 VCR) cells. We also investigated whether four Brazilian native species were able to activate the human pregnane X receptor (hPXR) in transiently co-transfected HeLa cells. This preclinical research showed that all but two plant extracts were able to modulate at least one of the selected targets. CYP3A4 mRNA gene expression in HepG2 cells was significantly affected by half of the extracts. The antagonistic effect of Solanum paniculatum L. on hPXR could explain its ability to inhibit CYP3A4. GSH levels were affected by 80% of the extracts. There was depletion of intracellular GSH levels by Cordia verbenacea A. DC., Costus spicatus (Jacq.) Sw., Persea americana Mill., Salix alba L., Schinus terebinthifolia Raddi and Syzygium jambolanum (Lam.) DC. accompanied because of the inhibition of GGT activity. P-gp activity was modulated in a significant manner by 17% of the extracts. The approaches used for the conduction of in vitro preclinical studies in herbal medicines revealed a series of challenges faced especially by academics in order to anticipate cases of HDI. Clinicians have also to consider the presence of intrinsic factors such as genetic polymorphisms in each patient. The possible presence of undesirable interactions between RENISUS herbal medicines and essential drugs in SUS need eventually be clinically confirmed to attest our observed in vitro effects.

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Maja, Kvrgić. "Farmakološki efekti sirupa i tinkture timijana." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2016. http://www.cris.uns.ac.rs/record.jsf?recordId=101065&source=NDLTD&language=en.

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Poslednjih godina je prisutan trend povratka prirodi i upotrebi biljnih lekova, kako u prevenciji tako i u lecenju razlicitih bolesti. Timijan (Thymus vulgaris L.) se u narodnoj medicini koristio u lecenju respiratornih oboljenja kao &scaron;to su ka&scaron;alj, bronhitis i astma. Rezultati novijih istraživanja pokazuju da timijan poseduje i druga potencijalno korisna farmakolo&scaron;ka svojstva (antimikrobna, antiinflamatorna, antioksidativna, spazmoliticka, antidijabetesna i anksioliticka). Ciljevi ovog istraživanja su bili da se ispitaju farmakodinamske osobine preparata timijana, njihove interakcije sa lekovima koji deluju na centralni nervni sistem, uticaj na funkciju jetre i parametrem oksidativnog stresa kod životinja izloženih ugljentetrahloridu, kao sadržaj karvakrola i timola u sirupu timijna, pri razlicitim uslovima cuvanja. U farmakodinamskim ispitivanjima kao eksperimentalne životinje kori&scaron;ceni su mi&scaron;evi soja NMRI, a u svim drugim ispitivanjima pacovi soja Wistar. Tinktura timijana je primenjena u dozi od 0,4mk/kg, a sirup u dozi od 12,08 ml/kg, na mi&scaron;evima. Primenjene doze na pacovima su bile 0,18 ml/kg za tinkturu i 5,6 ml/kg za sirup timijana. Za ispitivanje analgetickog dejstva kori&scaron;ceni su metod vrele ploce i test sircetne kiseline. Za procenu motorne koordinacije kori&scaron;cen je test rotirajuceg &scaron;tapa, a za procenu hipnotickog delovanja mereno je vreme spavanja. Prilikom ispitivanja uticaja preparata timijana na farmakokinetiku paracetamola, odre_ivana je koncentracija ovog leka HPLC metodom, a nakon toga su odreeni farmakokinetski parametri paracetamola. Antioksidantna aktivnost preparata timijana odre_ivana je pomocu in vitro i in vivo testova. Nakon žrtvovanja životinja ra_ena je histopatolo&scaron;ka analiza jetrenog tkiva, a u serumu su odre_ivani biohemijski parametri, kao i pokazatelji bubrežene i jetrene funkcije. Sadržaj timola i karvakrola i sirupu timijana odre_en je GC/MS metodom. Sirup i tinktura timijana su pokazali analgeticki efekat u testu vrele ploce, kao i smanjenje broja grceva izazvano primenom sircetne kiseline. Sedmodnevna primena preparata timijana smanjila je analgeticko dejstvo kodeina, a pojacala analgeticki efekat paracetamola. Sirup timijana je potencirao diazepamom izazvan poremecaj motorne koordinacije. Ispitivanjem uticaja preparata timijana na hipnoticko delovanje pentobarbitala, postignuti su razliciti rezultati u zavisnosti od dužine trajanja pretremana. Sedmodnevna primena timijana je produžila vreme trajanja spavanja, dok je jednokratna primena timijana skratila vreme trajanja spavanja. Nakon i intravenske i peroralne primene paracetamola, grupe životinja koje su bile pretretirane preparatima timijana imale su krace poluvreme eliminacije i vecu konstantu eliminacije. Upotreba samo preparata timijana nije imala uticaj na biohemijske i histolo&scaron;ke promene jetrene funkcije. S druge strane, upotreba tincture timijana u kombinaciji sa ugljen-tetrahloridom dovela je do porasta vrednosti AST i ALT enzima u serumu, dok je sirup timijana u kombinaciji sa ugljentetrahloridom smanjio aktivnost aminotransferaza. Najvece odstupanje u koncentracijama aktivnih komponenti timola i karavkrola, pokazali su sirupi cuvani na sobnoj temperaturi (20°C), u sekundarnoj ambalaži i na svetlom mestu. Rezultati dobijeni u toku ovog istraživanja ukazuju da preparati timijana uticu na farmakodinamske osobine kodeina, paracetamola, diazepama i pentobarbitala, kao i na farmakokinetiku paracetamola. Upotreba preparata timijana ispoljila je analgeticki efekat i umanjila posledice izloženosti oksidativnom stresu. Uslovi cuvanja sirupa timijana uticali su na njegovu stabilnost. In recent years is present trend of return to nature and the use of herbal medicines in prevention and treatment of different diseases. Thyme (Thymus vulgaris L.) was used in folk medicine in the treatment of respiratory diseases such as cough, bronchitis and asthma. The new research results have demonstrated that thyme has many others potentially useful pharmacological properties (antimicrobial, antiinflammatory, antioxidant, antispasmodic, antidiabetic and anxiolytic). The aims of this research were to determine the pharmacodynamic properties of thyme preparations and their interactions with central nervous system drugs, influence on liver function and oxidative stress parameters of animals exposed to carbon tetrachloride, as well as concentration of thymol and carvacrol in thyme syrup, at different storage conditions. In pharmacodynamics examination as experimental animals were used NMRI mice, while in all other test were used Wistar rats. Applied dose of thyme tincture was 0.4 ml/kg and of syrup 12.08 ml/kg, for mice. For rats, applied doses of tincture and syrup were 0.18 ml/kg and 5.6 ml/kg, respectively. The analgesic activity was examined by the hot plate test and acetic acid test. The Rotarod test was used to evaluate the motor coordination and to evaluate hypnotic activity sleeping time was mesaured. In order to examine the influence of thyme preparations on pharmacokinetics of paracetamol, the concentracion of this drug was measured by HPLC metods, and after that pharmocokinetic parameters of paracetamol were determined.The antioxidant acivity of thyme preparations was determined by using in vitro and in vivo tests. After animals sacrificing, histopathological analysis of liver tissue were peroformed, in serum were determined biochemical parameters and renal and hepatic function parameters. Quantification of thymol and carvacrol in syrup was carried out by GC/MS method. Thyme syrup and thyme tincture exhibited analgesic activity in hot plate test and reduced the number of writhes induced by acetic acid. Seven-day pretreatment with thyme preparations reduced analgesic activity of codeine and increased analgesic effect of paracetamol. Thyme syrup potentiated diazepam induced motor coordination impairment. Examining the impact of thyme preparations on hypnotic effect induced by pentobarbital, different results were achieved depending on the duration of pretreatment. Seven-day pretreatment with thyme had prolonged the sleeping time, while after single dose of thyme the sleeping time was decreased. After intravenous and after oral administration of paracetamol, groups pretreated with thyme preparations had decreased elimination half-life and increased elimination constant rate. Administration of thyme preparations alone did not change biochemical nor histological markers of hepatic function. On the other hand, co-administration of thyme tincture and carbon tetrachloride resulted in exacerbation of AST and ALT values in serum, while thyme syrup in coadministration with carbon tetrachloride managed to reduce activities of aminotransferases. The concentration of major active compounds, thymol and carvacrol, was mostly changed when syrups were stored at room temperature (20°C), in secondary containers and in light place. Results obtained in this study demonstrated that thyme preparations do affect pharmacodynamic properties of codeine, paracetamol, diazepam and pentobarbital and pharmacokinetics of paracetamol. Administration of thyme preparations exhibited analgesic activity and reduced the effects of exposure to oxidative stress. Storage conditions of thyme syrup did affect its stability.

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Fasinu, Pius Sedowhe. "In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85850.

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Thesis (PhD)--Stellenbosch University, 2013. ENGLISH ABSTRACT: Introduction Earlier studies have shown the popularity of herbal products among people as traditional, complementary or alternative medication. One of the major clinical risks in the concomitant administration of herbal products and prescription medicine is pharmacokinetic herb-drug interaction (HDI). This is brought about by the ability of phytochemicals to inhibit or induce the activity of metabolic enzymes and transport proteins. The aim of this study was to investigate the potential of the crude extracts of popular medicinal herbs used in South Africa to inhibit major cytochrome P450 (CYP) enzymes and transport proteins through in vitro assessment. Methods Medicinal herbs were obtained from traditional medical practitioners and 15 were selected for this study. The selected herbal products were extracted and incubated with human liver microsomes to monitor the following reactions as markers for the metabolic activities of the respective CYP: phenacetin O-deethylation (CYP1A2), diclofenac 4‟-hydroxylation (CYP2C9), S-mephenytoin 4‟- hydroxylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In addition, the influence of Lessertia frutescens (formerly Sutherlandia frutescens) and Hypoxis hemerocallidea was investigated on more isozymes: coumarin 7-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), paclitaxel 6α-hydroxylation (CYP2C8), bufuralol 1‟-hydroxylation (CYP2D6), chlorzoxazone 6- hydroxylation (CYP2E1) and midazolam 1‟-hydroxylation (CYP3A4/5). The generation of the CYPspecific substrates/metabolites were monitored and quantified with the aid of LC-MS/MS. The metabolic clearance of midazolam using cryopreserved hepatocytes was monitored in the presence of Lessertia frutescens and Hypoxis hemerocallidea. The potential of both to inhibit human ATP-binding cassette (ABC) transporter activity was assessed using recombinant MDCKII and LLC-PK1 cells overexpressing human breast cancer resistant protein (BCRP) and human P-glycoprotein (P-gp), respectively. Similarly, the potential for interactions with human organic anion transporting polypeptide (OATP1B1 and OATP1B3) was assessed using recombinant HEK293 cells over-expressing OATP1B1 and OATP1B3, respectively. Results Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (methanolic extract), Hypoxis hemerocallidea, Spirostachys africana and Lessertia frutescens (aqueous extract), in ascending order of potency demonstrated strong inhibition of CYP1A2 activity (IC50 = 1-100 g/mL). Similarly, Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana and Pentanisia prunelloides inhibited CYP2C9 with IC50 less than 100 g/mL. The following demonstrated strong inhibition of CYP2C19 with IC50 values less than 100 g/mL: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens and Zantedeschia aethiopica. CYP3A4 was inhibited by Lessertia frutescens, Hypoxis hemerocallidea, Spirostachys Africana, Bowiea volubilis, Zantedeschia aethiopica, Chenopodium album, Kedrostis Africana, Acacia karroo, Emex australis, Pachycarpus concolor, Ranunculus multifidus, Capparis sepiaria and Pentanisia prunelloides. Time-dependent (irreversible) inhibition of CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) and delay in the production of midazolam metabolites in the human hepatocytes, leading to a 40% decreased midazolam upscaled in vivo clearance, was observed with Lessertia frutescens. Further, Lessertia frutescence inhibited the activity of P-gp (IC50 = 324.8 μg/mL), OATP1B1 (IC50 = 10.4 μg/mL) and OATP1B3 (IC50 = 6.6 μg/mL). Hypoxis hemerocallidea inhibited the activity of OATP1B1 (IC50 = 118.7 μg/mL) and OATP1B3 (IC50 = 290.1 μg/mL) with no potent inhibitory effects on P-gp. None of the two inhibited the activity of BCRP within the tested concentrations. Conclusion The result indicates the potential for HDI between the selected medicinal herbs and the substrates of the enzymes investigated in this study, if sufficient in vivo concentrations are achieved. AFRIKAANSE OPSOMMING: Inleiding Vroeëre studies het aangedui dat die gebruik van plantaardige produkte as tradisionele, aanvullende en alternatiewe medikasie baie gewild is. Een van die grootste kliniese risiko‟s geassosieer met die gelyktydige gebruik van plantaardige produkte met voorskrifmedikasie is farmakokinetiese kruiegeneesmiddel interaksies (HDI). Hierdie interaksies word veroorsaak deur die vermoë van plantchemikalieë om die aktiwiteit van metaboliese ensieme en transportproteïene te inhibeer of te induseer. Die doel van hierdie studie is om ondersoek in te stel na die moontlikheid van onsuiwer ekstrakte van gewilde Suid-Afrikaanse medisinale kruie om die belangrikste sitochroom P450 (CYP)- ensieme en transportproteïene te inhibeer. Hierdie ondersoek sal plaasvind deur middel van in vitrostudies. Metodes Medisinale kruie is verkry vanaf tradisionele genesers, waaruit ŉ totaal van 15 kruie geselekteer is vir gebruik tydens hierdie studie. Die geselekteerde kruie is geëkstraheer en met menslike lewermikrosome geïnkubeer om die volgende reaksies as merkers vir die metaboliese aktiwiteit van die onderskeie CYP-ensieme te moniteer: fenasetien-O-deëtilasie (CYP1A2), diklofenak-4‟- hidroksilasie (CYP2C9), S-mefenitoïen-4‟-hidroksilasie (CYP2C19) en testosteroon-6β-hidroksilasie (CYP3A4). Afgesien van die voorafgaande, is ook die invloed van Lessertia frutescens en Hypoxis hemerocallidea op verskeie ander iso-ensieme ondersoek. Hierdie iso-ensieme is soos volg: koumarien-7-hidroksilasie (CYP2A6), bupropioonhidroksilasie (CYP2B6), paklitaksiel-6α-hidroksilasie (CYP2C8), bufuralol-1‟-hidroksilasie (CYP2D6), chloorsoksasoon-6-hidroksilasie (CYP2E1) en midasolaam-1‟- hidroksilasie (CYP3A4/5). Die produksie van CYP-spesifieke substrate/metaboliete is gemoniteer en deur middel van LC-MS/MS-analises gekwantifiseer. Die metaboliese opruiming van midasolaam deur middel van krio-gepreserveerde hepatosiete is gemoniteer in die teenwoordigheid van Lessertia frutescens en Hypoxis hemerocallidea. Die moontlikheid van beide om menslike ATPbindingskasset (ABC)-transporteerderaktiwiteit te inhibeer is bepaal deur die gebruik van rekombinante MDCKII- en LLC-PK1-selle wat onderskeidelik menslike borskanker-weerstandige proteïen (BCRP) en menslike P-glikoproteïen (P-gp) potensieel. Op ŉ soortgelyke wyse is die moontlikheid vir interaksies met menslike organiese anion-transportpolipeptiede (OATP1B1 en OATP1B3) bepaal deur rekombinante HEK293-selle te gebruik wat onderskeidelik OATP1B1 en OATP1B3 potensieel. Resultate Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (metanol-ekstrak), Hypoxis hemerocallidea, Spirostachys africana en Lessertia frutescens (water-ekstrak), in toenemende potensie, het sterk inhibisie van CYP1A2-aktiwiteit (IC50 = 1-100 g/mL) getoon. In ooreenstemming met die voorafgaande resultate het Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana en Pentanisia prunelloides CYP2C9 met IC50–waardes van minder as 100 g/mL geïnhibeer. Die volgende het sterk inhibisie van CYP2C19 met IC50-waardes van minder as 100 g/mL getoon: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens en Zantedeschia aethiopica. CYP3A4 is deur Lessertia frutescens, Hypoxis hemerocallidea, Spirostachys Africana, Bowiea volubilis, Zantedeschia aethiopica, Chenopodium album, Kedrostis Africana, Acacia karroo, Emex australis, Pachycarpus concolor, Ranunculus multifidus, Capparis sepiaria en Pentanisia prunelloides geïnhibeer. Tydafhanklike (onomkeerbare) inhibisie van CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) en vertraging in die produksie van midasolaammetaboliete in menslike hepatosiete wat aanleiding gee tot ŉ 40% afname in midasolaam bepaal in vivo opruiming, is waargeneem met Lessertia frutescens. Lessertia frutescens het ook die aktiwiteit van P-gp (IC50 = 324.8 μg/mL), OATP1B1 (IC50 = 10.4 μg/mL) en OATP1B3 (IC50 = 6.6 μg/mL) geïnhibeer. Hypoxis hemerocallidea het die aktiwiteit van OATP1B1 (IC50 = 118.7 μg/mL) en OATP1B3 (IC50 = 290.1 μg/mL) geïnhibeer met geen betekenisvolle effekte op P-gp nie. Geen een van die twee het die aktiwiteit van BCRP geïnhibeer binne die konsentrasies waarin getoets is nie. Gevolgtrekking Die resultate van hierdie studie dui aan dat wanneer voldoende in vivo-konsentrasies bereik word, die moontlikheid vir kruie-geneesmiddel interaksies tussen die geselekteerde medisinale kruie en ensiemsubstrate ŉ werklikheid word.

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11

Jiang, Xuemin. "Effect of herbal medicines on the pharmacokinetics and pharmacodynamics of Warfarin in healthy subjects." University of Sydney. Pharmacy, 2004. http://hdl.handle.net/2123/651.

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Herbal medicines are widely used in our community. A survey of Australian consumers indicated that 60% had used complementary and/or alternative medicines in the past year with the majority not informing their doctor that they were using herbal medicines. Little is known about the potentially serious consequences of interactions between herbal and conventional medicines. Warfarin has an important role in treating people with heart disease, yet it has a narrow therapeutic range, is highly bound to plasma proteins, and is metabolised by cytochrome P450. This creates the potential for life-threatening interactions with other drugs and foods leading to excessive bleeding. Hence, warfarin is one of the most frequently investigated drugs for interaction studies. Early clinical reports suggest that there exists the potential for an interaction between warfarin and four herbal medicines: St John�s wort, ginseng, ginkgo and ginger. However, these herb-drug combinations have never been conclusively studied. The two clinical studies conducted as part of this research had an identical study design. Twenty-four healthy male subjects were recruited into the two separate studies. This was an open label, three-way crossover randomised study in twelve healthy male subjects, who received a single 25 mg dose of warfarin alone or after 14 days pre-treatment with St John�s wort, or 7 days pre-treatment with ginseng. Dosing with St John�s wort or ginseng was continued for 7 days after administration of the warfarin dose in study I or who received a single 25 mg dose of warfarin alone or after 7 days pre-treatment with recommended doses of ginkgo or ginger from single ingredient products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose in study II. Platelet aggregation, international normalised ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured in both studies. Statistical comparisons were made using ANOVA and 95% confidence interval (CI) for mean value and 90% CI for geometric mean ratio value are reported. n study I, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone or with St John�s wort or ginseng were, respectively, 198 (174 � 223) ml/h, 269 (241 � 297) ml/h and 220 (201 � 238) ml/h. The respective apparent clearances of R-warfarin were 110 (94 � 126) ml/h, 142 (123 � 161) ml/h and 119 (106 � 131) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.29 (1.16-1.46) and for R-warfarin was 1.23 (1.11-1.37) when St John�s wort was co-administered. The mean ratio of AUC0-168 of INR was 0.79 (0.70 - 0.95) when St John�s wort was co-administered. The urinary excretion ratio of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.06) mg/h and there was no significant difference following treatment with either St John�s wort 0.03 (0.02 � 0.04) mg/h or ginseng 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 0.82 (0.61-1.12) for St John�s wort, and 0.68 (0.50-0.91) for ginseng. St John�s wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. In study II, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167 � 210) ml/h, 200 (173 � 227) ml/h and 201 (171 � 231) ml/h, respectively. The respective apparent clearances of R-warfarin were 127 (106 � 149) ml/h, 126 (111 � 141) ml/h and 131 (106 � 156) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.98 -1.12) and for R-warfarin was 1.00 (0.93 -1.08) when co-administered with ginkgo. The mean ratio of AUC0-168 of INR was 0.93 (0.81 -1.05) when co-administered with ginkgo. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.97 -1.13) and for R-warfarin was 1.02 (0.95 -1.10) when co-administered with ginger. The mean ratio of AUC0-168 of INR was 1.01 (0.93 -1.15) when co-administered with ginger. The urinary excretion ratio (UER) of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.05) mg/h and there was no significant difference following treatment with either ginkgo 0.04 (0.03 � 0.04) mg/h or ginger 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 1.07 (0.69-1.67) for ginkgo, and 1.00 (0.64-1.56) for ginger. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. In conclusion, St John�s wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Ginseng, ginkgo and ginger at recommended doses affect neither clotting status, nor the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin in healthy subjects.

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12

Liu, Rui. "Pharmacology and Toxiclogy of Echinacea, Souroubea and Platanus spp." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39309.

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The research presented in this thesis addressed knowledge gaps for three medicinal plant taxa, Souroubea spp. (Marcgraviaceae) and Platanus (Platanaceae) as well as Echinacea spp. (Asteraceae). The primary pharmacological mechanism of Souroubea sympetala and Platanus occidentalis were well established, with pentacyclic triterpenes identified as major active principles. My results indicate that major triterpenoids, and crude plant extracts, selectively inhibited monoacyglycerol lipase (MAGL) activity but not fatty acid amide hydrolase (FAAH) activity. These data suggest a possible secondary anxiolytic mechanism of action through the endocannabinoid system (ECS). My study of herb-drug interactions of Souroubea and Plantanus products showed some potential risk when combined with a classic benzodiazepine class drug, diazepam, and I proposed a mechanism through in vitro CYP450 enzyme inhibition. The pharmacokinetic study revealed the difficulty of detecting betulinic acid in animal blood. To support the development a commercial botanical composed of these medicinal plants, an extraction method and a highly sensitive and selectivity HPLC-APCI-MS based quantification method was successfully developed and validated. Part II of this thesis focused on the impact of phytochemical variation and hepatic metabolism on the ECS activity of Echinacea spp. and explored the potential for new applications of Echinacea spp. as a natural health product. My research indicated that considerable variability in the content of phenolic and alkylamide (AKA) compounds reflected similar variability in in vitro bioactivity at ECS-related pharmacological targets. Following biochemometric analysis, several phenolic compounds and AKAs in Echinacea spp. were found to be significant independent variables determining FAAH inhibition and CB receptor activation. Hepatic metabolism was also found to affect the FAAH inhibition of AKA, as increased FAAH inhibitory effects were observed after CYP450-mediated metabolism of both individual AKAs and crude extracts of E angustifolia and E. purpurea, suggesting a “pro-drug” mechanism. Dose dependent activities were observed with oral administration of both E angustifolia and E. purpurea root extract in rat paw model of inflammation and pain. Further tests indicated these activities can be partially blocked by co-administration of CB1 and CB2 receptor antagonists AM251 and AM630, respectively. This evidence suggests activity for peripheral pain was at least partially mediated through the ECS.

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13

Isidora, Milanović. "Farmakološki efekti etarskog ulja ruzmarina Rosmarinus officinalis, L. (Lamiaceae), na miševima soja NMRI-Haan i pacovima soja Wistar." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2015. http://www.cris.uns.ac.rs/record.jsf?recordId=94338&source=NDLTD&language=en.

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Ruzmarin Rosmarinus officinalis L. (Lamiaceae) je biljka koja se u tradicionalnoj medicini na na&scaron;em području koristi za postizanje analgetičkog, holeretičkog i hepatoprotektivnog delovanja. Prema Evropskoj agenciji za lekove (2010 godine), indikacije za sistemsku primenu etarskog ulja ruzmarina su lečenje dispepsije i spazama gastrointestinalnog trakta, a za spolja&scaron;nju primenu se preporučuje u lečenju umereno jakih bolova u zglobovima i mi&scaron;ićima i u lečenju poremećaja periferne cirkulacije. Imajući u vidu da komponente etarskog ulja ruzmarina ispoljavaju i druga, potencijalno korisna farmakolo&scaron;ka svojstva, postoji potreba da se ova delovanja detaljnije ispitaju. Ciljevi ispitivanja su bili da se utvrdi: 1) analgetički efekat etarskog ulja ruzmarina i njegov uticaj na farmakodinamske osobine paracetamola, kodeina, diazepama i pentobarbitala kao i na farmakokinetske osobine paracetamola; 2) antioksidativni i hepatoprotektivni efekat u uslovima hemijski izazvanog oksidativnog stresa. Metodom gasne hromatografije (GC/MS i GC/FID) utvrđen je kvantitativni sastav etarskog ulja. Najzastupljenije komponente ulja koje je kori&scaron;ćeno u na&scaron;em ispitivanju su oksidovani monoterpeni 1,8-cineol (43.77%) i kamfor (12.53%) i monoterpenski ugljovodonik α-pinen (11.51%). Suspenzija etarskog ulja ruzmarina primenjivana je mi&scaron;evima u dozama 10 i 20 mg/kg tm tokom sedam dana i jednokratno u farmakodinamskim testovima: test vrele ploče, test &bdquo;uvijanja“ (posle intraperitonealne primene sirćetne kiseline), test za procenu motorne koordinacije životinja na rotirajućem &scaron;tapu i test merenja vremena trajanja spavanja. Za ispitivanje uticaja etarskog ulja ruzmarina na farmakokinetske osobine paracetamola i za biohemijska i toksikolo&scaron;ka ispitivanja, kori&scaron;ćeni su pacovi koji su tokom sedam dana tretirani suspenzijom etarskog ulja ruzmarina u dozi 5 i 10 mg/kg tm, a sedmog dana su primili paracetamol i.v. ili p.o.. Za praćenje farmakokinetskih parametara kori&scaron;ćeni su uzorci krvi dobijeni iz repne vene pacova u kojima su HPLC metodom merene koncentracije paracetamola, na osnovu kojih su potom određeni farmakokinetski parametri ovog leka. Antioksidativna aktivnost etarskog ulja ruzmarina je određivana in vitro (DPPH i Folin-Ciocaulteu testovima) i in vivo. Nakon žrtvovanja životinja iz prikupljenih uzoraka krvi određivani su iz seruma biohemijski parametri, pokazatelji bubrežne i jetrene funkcije, a u homogenatu tkiva jetre određivani su parametri oksidativnog stresa. Samo etarsko ulje ruzmarina ispoljava analgetičko delovanje i smanjuje visceralnu bol izazvanu sirćetnom kiselinom. Pored toga, potencira analgetički efekat kodeina i paracetamola. Etarsko ulje ruzmarina značajno smanjuje hipnotičko delovanje pentobarbitala i sprečava poremećaj motorne koordinacije nakon primene diazepama. Etarsko ulje ruzmarina ne utiče značajnije na oralnu biolo&scaron;ku raspoloživost paracetamola. Vi&scaron;ekratna primena različitih doza etarskog ulja ruzmarina ne izaziva toksične promene u krvi i jetri ispitivanih životinja. Primena etarskog ulja ruzmarina &scaron;titi životinje od reaktivnih kiseoničnih vrsta, umanjuje posledice izloženosti oksidativnom stresu i ispoljava značajno hepatoprotektivno delovanje. Rosemary Rosmarinus officinalis, L.(Lamiaceae) is traditionally used in folk medicine for its analgetic, choleretic and hepatoprotective properties. According to the recommendation of European Medicines Agency from 2010, rosemary essential oil can be used for treating dyspepsia and mild spasmodic disorders of the gastrointestinal tract, and also externally as an adjuvant in the relief of minor muscular and articular pain and minor peripheral circulatory disorders. Different studies conducted with rosemary essential oil show other pharmacological effects of main components of the oil. The aim of this study was to examine: 1) analgetic effects of rosemary essential oil and its influence on the pharmacodynamic properties of paracetamol, codeine, diazepam and pentobarbital, and also its influence on the pharmacokinetic properties of paracetamol; 2) antioxidant and hepatoprotective effects on the parameters of chemicaly induced oxidative stress. The quantification of chemical constituents of the essential oil was carried out by gas chromatography (GC/FID and GC/MS). The major compounds that were identified and quantitated by GC-FID and GC-MS were oxygenated monoterpens 1,8-cineole (43.77%), camphor (12.53%) and monoterpene hydrocarbon α-pinene (11.51%). The suspension of rosemary essential oil was applied to mice orally (doses: 10 and 20 mg/kg b.w.) for seven days and in single dose for the pharmacodynamic tests: hot plate, writhing, rotharod and sleeping time. Rats treated with suspension of rosemary essential oil for seven days orally (doses: 5 and 10 mg/kg b.w.) were used for the examination of influence of essential oil on the pharmacokinetic properties of paracetamol. Then on the 7th day the paracetamol was applied to them p.o. or i.v.. The parameters of pharmacokinetic were analyzed in blood samples obtained from rats tail veins. The HPLC method was used for measurement of concentration of paracetamol in blood samples. Those concentrations were used for calculation of the pharmacokinetic parameters. The antioxidant activity of the rosemary essential oil was evaluated in vitro (with DPPH and Folin-Ciocaulteu tests) and in vivo. The animals were sacrificed and the samples of blood and liver were taken. The obtained serum was used for determination of standard biochemical parameters and the parameters of oxidative stress were analyzed in obtained liver homogenates. The essential oil of rosemary shows analgetic properties and it decreases visceral pain induced with intraperitoneally injected acetic acid. The rosemary essential oil increases pharmacological effects of codeine and paracetamol. Also, this oil reduces pentobarbital-induced sleeping time and diminishes diazepam-induced disorder of psychomotor coordination. The essential oil of rosemary does not change paracetamol bioavailability. The rosemary essential oil applied in multiple doses does not induce toxic changes in blood and liver samples obtained from animals. The use of rosemary essential oil protects animals from reactive oxygen species, decreases the effects caused by oxidative stress and shows significant hepatoprotective effect.

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14

Awortwe, Charles. "Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS." Thesis, Stellenbosch : Stellenbosch University, 2015. http://hdl.handle.net/10019.1/96796.

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Thesis (DMed)--Stellenbosch University, 2015 ENGLISH ABSTRACT: Introduction The increasing intake of traditional medicines among HIV/AIDS patients in sub-Saharan Africa needs urgent consideration by clinicians and other healthcare providers since the safety of such medications are unknown. The pharmacokinetic parameters - Absorption, Distribution, Metabolism and Elimination (ADME) play important role in the safety evaluation of drugs, thus implicating drug metabolizing enzymes and transporters as critical indicators for herb-drug interactions. The objective of this study was to evaluate the risk potential of seven herbal medicines commonly consumed by HIV/AIDS patients for drug interactions applying in vitro models. In this study, inhibition and induction effects of the herbal medicines on cytochrome P450s (CYPs) 1A2, 2C9, 2C19, 2D6 and 3A4 as well as P-glycoprotein (P-gp) were investigated. Methods Herbal medicines – Lessertia frutescens, Hypoxis hemerocallidea, Kalanchoe integra and Taraxacum officinale were sourced from Medico Herbs, South Africa were identified by experts from Compton Herbarium, South African National Biodiversity Institute, Cape Town. Moringa oleifera, Echinacea purpurea and Kalanchoe crenata were obtained from the repository of the National Centre for Natural Product Research (NCNPR), University of Mississippi, USA. Reversible inhibitory effect of aqueous and methanol herbal extracts were evaluated in recombinant CYPs applying the fluorescent metabolites at specified excitation/emission wavelengths; CYP1A2 (3-cyano-7-hydroxycoumarin (CHC); 405/460 nm), CYP2C9, CYP2C19 and CYP3A4 (7-hydroxy-4-(trifluoromethyl)-coumarin (HFC); 405/535 nm) and CYP2D6 (7-hydroxy-4-(aminomethyl)-coumarin (HAMC); 390/460 nm). Comparative studies in human liver microsomes (HLM) and recombinant CYPs were conducted to investigate the inhibitory effect of methanol herbal extracts and fractions on 6β testosterone hydroxylation activity. Time dependent inhibitory (TDI) effect of the herbal extracts were evaluated applying the IC50 shift fold, normalized ratio and the NADPH-, time- and concentration-dependent approaches. Influence of herbal extracts on metabolic clearance of testosterone was assessed in both HLM and human hepatocytes. The effects of each herbal extract on expression of CYP1A2, CYP3A4 and MDR1 genes were evaluated in activated human pregnane X receptor (PXR) co-transfected HepG2 cells. Finally, the inhibitory effect of herbal extracts on P-gp was assessed using the calcein-acetoxymethyl ester (calcein-AM) uptake and the digoxin radiolabelled substrates in MDCKII-MDRI cells. Results The aqueous extracts of Moringa oleifera, Kalanchoe integra, Kalanchoe crenata, Echinacea purpurea and Lessertia frutescens demonstrated high risk of in vivo inhibition on CYPs 3A4 and 1A2 with Cmax/Ki >1.0. Methanol extracts of these herbal medicines also indicated potential risk of reversible drug interaction. The methanol extracts of M. oleifera, K. crenata and L. frutescens showed strong TDI effect on CYP3A4 with IC50 shift fold >1.5 and normalised ratio <0.7. Moringa oleifera intermediately reduced intrinsic clearance of testosterone in human hepatocytes (2 ≤ AUC ratio ≤ 5) when scaled up to humans. Methanol extracts of Echinacea purpurea up-regulated the expression of CYP1A2, CYP3A4 and MDR1 genes in activated PXR. Kalanchoe crenata and Echinacea purpurea indicated strong inhibition on P-gp by reducing transport of digoxin across hMDR1-MDCKII cell monolayer from basolateral to apical with IC50 values of 18.24 ± 2.52 μg/mL and 24.47 ± 4.97 μg/mL, respectively. Conclusion The herbal medicines especially M. oleifera, K. integra and E. purpurea have the potential to cause herb-drug interaction in vivo if sufficient hepatic concentration is achieved in humans. AFRIKAANSE OPSOMMING: Inleiding Die verhoogde inname van tradisionele medisynes onder MIV/VIGS-pasiënte in sub-Sahara-Afrika verg dringend oorweging deur klinici en ander gesondheidsorgverskaffers, aangesien die veiligheid van sodanige medikasies onbekend is. Die farmakokinetiese parameters – Absorpsie, Distribusie, Metabolisme en Eliminasie (ADME) – speel ’n belangrike rol by die veiligheidsevaluering van geneesmiddels, en impliseer gevolglik geneesmiddel-metaboliserende ensieme en vervoerders as kritiese indikators vir krui-geneesmiddel-interaksies (HDI). Die oogmerk van hierdie studie is om die risikopotensiaal van sewe kruiemedisynes wat algemeen deur MIV/VIGS-pasiënte geneem word, vir geneesmiddel-interaksies te evalueer deur in vitro-modelle te gebruik. In hierdie studie is die inhiberings- en induseringsuitwerkings van die kruiemedisynes op sitochroom P450’s (verkort na CYP’s) 1A2, 2C9, 2C19, 2D6 en 3A4, sowel as P-glikoproteïen (P-gp), ondersoek. Metodes Kruiemedisynes – Lessertia frutescens, Hypoxis hemerocallidea, Kalanchoe integra en Taraxacum officinale – is van Medico Herbs, Suid-Afrika, bekom en deur kundiges van die Compton-herbarium, by die Suid-Afrikaanse Nasionale Biodiversiteitsinstituut, Kaapstad, geïdentifiseer. Moringa oleifera, Echinacea purpurea en Kalanchoe crenata is van die bewaarplek van die Nasionale Sentrum vir Natuurlike Produknavorsing (NCNPR) aan die Universiteit van Mississippi in die VSA verkry. Die omkeerbare inhiberende uitwerking van kruie-ekstrakte in water en metanol is in rekombinante CYP’s geëvalueer deur die gebruik van die fluoresserende metaboliete op gespesifiseerde opwekkings-/emissiegolflengtes; CYP1A2 (3-siaan-7-hidroksikumarien (CHC); 405/460 nm), CYP2C9, CYP2C19 en CYP3A4 (7-hidroksi-4-(trifluoormetiel)-kumarien (HFC); 405/535 nm) en CYP2D6 (7-hidroksi-4-(aminometiel)-kumarien (HAMC); 390/460 nm). Vergelykende studies van menslikelewermikrosome (HLM) en rekombinante CYP’s is uitgevoer om die inhiberende uitwerking van metanolkruie-ekstrakte en -fraksies op 6β-testosteroonhidroksileringsaktiwiteit te ondersoek. Die tydafhanklike inhiberende uitwerking (TDI) van die kruie-ekstrakte is geëvalueer deur gebruikmaking van die IC50-verskuiwingsvou-, die genormaliseerdeverhoudings- en die NADPH-, tyd- en konsentrasieafhanklike benaderings. Die invloed van kruie-ekstrakte op metaboliese testosteroonverheldering is in beide HLM en menslike hepatosiete geëvalueer. Die uitwerkings van elke kruie-ekstrak op die uitdrukking van CYP1A2-, CYP3A4- en MDR1-gene is in geaktiveerde menslike pregnaan-X-reseptor(PXR)-, ko-getransfekteerde HepG2-selle geëvalueer. Laastens is die inhiberende uitwerking van kruie-ekstrakte op P-gp geëvalueer, met gebruikmaking van die kalsien-asetoksimetiel-ester (kalsien-AM)-opname en die digoksien- radiogemerkte substrate in MDCKII-MDRI-selle. Resultate Die ekstrakte in water van M. oleifera, K. integra, K. crenata, E. purpurea en L. frutescens het ’n hoë risiko van in vivo-inhibering op CYP’s 3A4 en 1A2 met Cmaks/Ki >1.0 getoon. Ekstrakte van hierdie kruiemedisynes in metanol het verder potensiële risiko van omkeerbare geneesmiddelinteraksie getoon. Die ekstrakte van M. oleifera, K. crenata en L. frutescens in metanol het sterk TDI-uitwerking op CYP3A4 met IC50-verskuiwingsvou >1.5 en genormaliseerde verhouding <0.7 getoon. M. oleifera het intermediêre vermindering van intrinsieke testosteroonverheldering in menslike hepatosiete (2 ≤ AUC verhouding ≤ 5) tot gevolg wanneer die skaal na mense verhoog word. Ekstrakte van E. purpurea in metanol het die uitdrukking van CYP1A2-, CYP3A4- en MDR1-gene in geaktiveerde PXR opgereguleer. K. crenata en E. purpurea het sterk inhibering van P-gp getoon deur die vervoer van digoksien deur die hMDR1-MDCKII-selmonolaag van basolateraal tot apikaal met IC50-waardes van onderskeidelik 18.24 ± 2.52 μg/mL en 24.47 ± 4.97 μg/mL te verminder. Gevolgtrekking Kruiemedisynes, veral M. oleifera, K. integra en E. purpurea, het die potensiaal om HDI in vivo te veroorsaak indien voldoende hepatiese konsentrasie by mense bereik word.

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Nensén, Nord Maria. "Användandet av naturmedel som egenvård och kommunikationen mellan vårdgivare och patient : En litteraturstudie." Thesis, Uppsala universitet, Vårdvetenskap, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-347214.

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Bakgrund: I Sverige har naturläkemedel huvudsakligen använts på patienters eget initiativ och utan kontakt med vårdgivare. Många tror att naturmedel inte är mediciner utan säkra och naturliga i tillägg till en hälsosam diet. Precis som konventionella läkemedel kan naturmedel ge upphov till både biverkningar och interaktioner. Det finns få rapporterade biverkningar av godkända naturläkemedel och växtbaserade läkemedel. Syfte: Syftet med studien är att undersöka användandet av naturmedel som egenvård, hur vårdgivare och patienter kommunicerar om naturmedel som egenvård samt kunskapen om naturmedel hos vårdpersonal. Metod: Litteraturstudie baserad på kvantitativa studier. Resultat: Resultatet i denna studie visar på ett varierat användande av naturmedel. Det som framkommer är att det är mer kvinnor och framförallt högutbildade personer som använder det i högre utsträckning. Det är få som väljer att diskutera sin användning av naturmedel med läkare eller annan vårdpersonal. Vårdpersonal frågar å sin sida heller inte om patienter använder sig av naturmedel. Slutsats: Vårdpersonal skattar sin kunskap om naturmedel som låg eller obetydlig men att många ville lära sig mer om naturmedel. För att undvika biverkningar och interaktioner bör användandet av naturmedel uppmärksammas inom vården. Background: Natural remedies have mostly been used on the initiative of the patient without contact with healthcare staff in Sweden. Many people believe that natural remedies are a safe and natural supplement to healthy living and not a medicine. Just like ordinary drugs, natural remedies can cause side effect and interactions with other medicines. There are few reported adverse effects of herbal medicine and traditional medicine. Aim: The aim of this study was to examine the use of natural remedies as a selfcare treatment, to study the communication between healthcare staff and patients and to study the knowledge of natural remedies among healthcare staff. Method: The study is in form of a literature review based on quantitative studies. Results: The result indicates a range of uses of natural remedies. It is predominantly women and especially highly educated people who use natural remedies. Only a few choose to discuss their use of natural remedies with their doctor or healthcare staff. Healthcare staff do not tend to ask the patients about their use of natural remedies. Conclusion: Healthcare staff rate their knowledge about natural remedies as being low or insignificant, but many would like to learn more about them to avoid adverse effect or interactions, the use of natural remedies needs to be highlighted within the health service.

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Corte, Cristiane Lenz Dalla. "Avaliação dos efeitos do tratamento crônico com neurolépticos e sua interação com substâncias potencialmente antioxidantes sobre parâmetros de estresse oxidativo no fígado e rim de ratos." Universidade Federal de Santa Maria, 2008. http://repositorio.ufsm.br/handle/1/11086.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Treatment with neuroleptic drugs has been associated to side effects like tardive diskynesia and hepatic damage. In spite of the several reports of hepatotoxicity after neuroleptic administration, few data are available in the literature about these effects and the precise mechanisms by which neuroleptics induce hepatotoxicity remain unclear. In the same way, there are few studies about the effects of neuroleptics on kidney. In this way, the first aim of the present work was to assess the effects of chronic exposure to fluphenazine in liver and kidney of rats, as well as the protective effect of diphenyl diselenide on the fluphenazine-induced damage (article 1). Long-term treatment with fluphenazine caused an increase in lipid peroxidation levels in liver and kidney homogenates, a decrease in hepatic SOD activity, and an increase in hepatic CAT activity. Diphenyl diselenide was able to protect liver and kidney from lipid peroxidation, ameliorate SOD activity in liver, and prevent the increase in hepatic CAT activity. Diphenyl diselenide treatment did not affect δ-ALA-D activity, but fluphenazine and/or in combination with diphenyl diselenide showed an inhibitory effect on δ-ALA-D activity in liver and kidney. The second objective of this study was to determine whether the treatment with haloperidol (HP), valerian or both in association impairs liver or kidney functions (article 2). Valerian did not affect oxidative stress parameters in the liver or kidney of rats. HP only increased glutathione (GSH) depletion in liver, but not in kidney. However, when HP was associated with valerian, an increase in lipid peroxidation levels and reactive species production was observed in the hepatic tissue. HP and valerian when administered independently did not affect the activity of hepatic and renal δ-ALA-D, however, these drugs administered concomitantly provoked an inhibition of hepatic δ-ALA-D activity. Serum aspartate aminotransferase (AST) activity was not altered by any treatment. However, serum alanine aminotransferase (ALT) activity was higher in the HP group and HP plus valerian group. Taken together, these results indicate the relationship between the treatment with flufenazine and the oxidative stress, and also point to the protective role of diphenyl diselenide on the oxidative damage induced by fluphenazine in liver. Our data also suggest adverse interactions between haloperidol and valerian treatments causing hepatic damage related to oxidative stress. O tratamento com drogas neurolépticas tem sido associado a efeitos colaterais como a discinesia tardia (DT) e o dano hepático. Apesar dos inúmeros casos de hepatotoxicidade após a administração de neurolépticos, são escassos os dados na literatura a respeito desses efeitos e o mecanismo exato pelo qual neurolépticos induzem hepatotoxicidade permanece incerto. Da mesma forma, existem poucos estudos relatando os efeitos dos neurolépticos sobre o rim. Dessa forma, o primeiro objetivo deste trabalho foi avaliar os efeitos da exposição crônica à flufenazina em fígado e rim de ratos bem como o efeito protetor do disseleneto de difenila sobre o dano induzido por flufenazina (artigo 1). O tratamento prolongado com flufenazina causou um aumento na peroxidação lipídica no fígado e no rim, uma diminuição na atividade da SOD hepática, e um aumento na atividade da CAT hepática. O disseleneto de difenila foi capaz de proteger o fígado e o rim da peroxidação lipídica, melhorou a atividade da SOD no fígado, e preveniu o aumento na atividade da CAT no fígado. O tratamento com disseleneto de difenila não afetou a atividade da δ-ALA-D, mas a flufenazina e/ou em combinação com disseleneto de difenila demonstrou ter efeito inibitório sobre a atividade da δ-ALA-D no fígado e no rim. O segundo objetivo deste estudo foi determinar se o tratamento com haloperidol (HP), valeriana ou a associação de ambas as drogas pode alterar as funções hepáticas e renais (artigo 2). A valeriana não afetou nenhum parâmetro de estresse oxidativo no fígado e no rim dos ratos. O HP apenas aumentou a depleção de glutationa (GSH) no fígado, mas não no rim. Entretanto, quando o HP foi associado com a valeriana, um aumento na peroxidação lipídica e produção de espécies reativas foram observados no tecido hepático. HP e valeriana quando administrados independentemente não afetaram a atividade da δ-ALA-D hepática e renal, contudo, quando estas drogas foram administradas concomitantemente provocaram uma inibição da atividade da δ-ALA-D hepática. A atividade da aspartato aminotransferase (AST) do soro não foi alterada por nenhum dos tratamentos. No entanto, a atividade da alanina aminotransferase (ALT) do soro estava aumentada nos grupos tratados com HP e HP mais flufenazina. Juntos estes resultados indicam uma relação entre o tratamento com flufenazina e o estresse oxidativo, e também apontam para o papel protetor do disseleneto de difenila no dano oxidativo induzido por flufenazina no fígado. Nossos dados também sugerem interações adversas no tratamento com haloperidol e valeriana, ocasionando dano hepático associado ao estresse oxidativo.

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Chen, Bi-Wen, and 陳碧雯. "Drug-Herb and Diet Supplement Interactions." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/28376785684561932588.

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碩士 國立臺灣海洋大學 食品科學系 96 Recently, the average human life-span in the developed country prolonged because of better medication, hygiene and nutrient conditions. The chronic diseases also increase as well. Therefore, alternate medicine and diet supplements which claimed to have the abilities of prevention or/and treatments of diseases attract more and more attention. Some popular mistaken believes about the diet supplement are: they are safe and less side effects comparing to medicine because they are from the nature. Thus, most of the people treat the diet supplement as food. In fact, the nature herbs may cause toxic side effect and it may cause the interaction with drugs if both are administered together. However, most people do not know about the drug-herb interactions. In addition, the medical health professionals do not provide this information to the consumers. Thus, the users consider that nature material are safe and neglect the interaction between diet supplement and medicine. There are few clinical reports about interactions between drug and herb/diet supplement. Nevertheless, many serious consequences, such as death, caused by the interaction between drug and herb/diet supplement have been reported. The objective of this study is to review and analysis of drug-herb/diet supplement interactions based on reported literatures and books. Since the case reports of drug-herb/diet supplement interactions were not published extensively, a grading system was used to reflect the level of available scientific evidence in support of the interactions.

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Chiang, Hsiu-Mei, and 江秀梅. "From biopharmaceutical studies of Pueraria lobata to herb - drug interactions." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/12663185352616140107.

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博士 中國醫藥大學 藥物化學研究所 93 Pueraria Radix (PR), the roots of Pueraria lobata OWHI is an isoflavone-rich Chinese herb and also a food in oriental countries. Puerarin, daidzin and daidzein are bioactive isoflavone constituents of PR. The aims of this study were (1) to investigate the metabolic pharmacokinetics of isoflavones after oral administrations of commercial and ethanol extract of PR in rats, (2) to measure the effects of PR decoction on the pharmacokinetics of methotrexate (MTX) and valproic acid (VPA), and (3) to measure the effect of PR in extracellular acetylcholine release on rat hippocampus. Rats were given commercial and ethanol extract of PR and blood samples were withdrawn via cardiopuncture and assayed by HPLC method after enzymatic hydrolysis with β-glucuronidase and sulfatase, respectively. Daidzein sulfates were found predominantly in the bloodstream, whereas daidzein glucuronides presented in less amount. Microdialysis technique was used for pharmacodynamic study of PR, the effect of PR after oral dosing on the extracellular acetylcholine release in rat hippocampus was not significant. MTX and VPA are two western medicines with narrow therapeutic index, and thus were used as model drugs to explore the herb - drug interaction which is an important public health issue in Taiwan. MTX and VPA are carboxylic acids and being substrates of multidrug resistance proteins (MRPs) and organic anion transporters (OATs). The isoflavones of PR were metabolized into sulfates and glucuronides in the body, both metabolites are also reported as substrates of MRPs and OATs. These metabolites may compete the transporters with MTX and VPA. This study investigated the effects of PR decoction on the pharmacokinetics of MTX and VPA in rats. The blood concentrations of MTX and VPA were determined by monoclonal fluorescence polarization immunoassay (FPIA) method. The systemic exposure of MTX and VPA were significantly increased after oral coadministration of PR decoction. In addition, when MTX and VPA were given intravenously, the coadministration of PR decoction significantly decreased the clearance of MTX and VPA. Therefore, the enhanced of exposure of MTX and VPA by coadministration of PR can be ascribed to the decreased elimination of MTX and VPA. In order to ensure safety, concurrent intake of MTX or VPA with PR should be discouraged. Cyclosporin (CsA) is a widely used immunosuppressant with narrow therapeutic range. CsA was used as a model drug, representing CYP3A4/P-gp substrates, to investigate interactions with herbs including ginseng, American ginseng, notoginseng, cordyceps and ginger juice. Our results showed that all the herbs except notoginseng significantly decreased the bioavalibility of CsA. However, the pharmacokineties of intravenous CsA were not altered. This suggested that the interactions occurred at the absorption site. For the sake of efficacy, the coadiministraction of these herbs with CsA should be avoided. In summary, using pharmacokinetic approach can better understand the biological fate of herbal contents, and furthermore, the hidden risk of herb - drug interactions can be explored.

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Lin, Ying-Ku, and 林盈谷. "Predicting Herb-drug Interactions by HPLC Analysis: Furanocoumarin-based Metabolic Interactions with CYP3A4." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/30464789411389774172.

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博士 臺北醫學大學 藥學系(博士班) 96 An attempt made in this study was to predict the potential for metabolic interactions of herbal extracts of drugs based on their chromatographic profiles in reverse-phase high-performance liquid chromatography (RP-HPLC) analysis. Twenty-nine structurally related furanocoumarin compounds with known effect on cytochrome P450 3A4 (CYP3A4), which is important for phase-I drug metabolism, were selected as a model system, and analyzed using an RP-HPLC system developed for this study. Log values of the partition coefficients (log P) of these furanocoumarin derivatives calculated using Molsuite 2000 molecular modeling pro plus software (ChemSW®) were used to interpolate the capacity factors from a validated correlation curve constructed using five standard references that covered the elution time range in the RP-HPLC analysis system developed in the lab. The obtained correlations were then used to estimate the capacity factor for all of the furanocoumarin derivatives collected from the literatures with reported herb-drug interaction activity in CYP3A4. The capacity factors for most of the furanocoumarins were between 1.65 and 10.57 (with retention times of 10~40 min), a range approximately equivalent to fractions 3 to 8 (Fr3~8) in the RP-HPLC fraction analysis. Each fraction was examined for its inhibition of microsomal nifedipine oxidation represented as the CYP3A4 inhibitory potency. Ru was designated the total response unit and expressed as Ru = R / 7.79 ?e 105; this was calculated for each single peak or each fraction in terms of the sum of the peak area (R) for all chromatographic peaks appearing in the chromatographic analysis. A sigmoidal relationship was established between the CYP3A4 inhibitory potency (y) and the RP-HPLC peak response unit (Ru，x) as y = 85.36 x (14.86 + x)-1 with a correlation coefficient of 0.63. The sigmoidal curve could be divided into three ranges designated low, medium, and high risk that were used to indicate the relative inhibitory potency of the metabolic interactions of herbs or traditional Chinese herb medicines with CYP3A4. These predictive classifications provide information and might be useful for “risk category” decisions concerning herb-drug interactions.

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"Mechanistic study of herb-drug interactions between oseltamivir and TCM formulae." 2010. http://library.cuhk.edu.hk/record=b5894452.

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Wang, Xiaoan. Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. Includes bibliographical references (leaves 145-166). Abstracts in English and Chinese. Table of Contents --- p.I Acknowledgements --- p.VI Publications --- p.VII Abstract (in English) --- p.VIII Abstract (in Chinese) --- p.X List of Figures --- p.XII List of Tables --- p.XVI List of Abbreviations --- p.XVII Chapter Chapter One. --- Introduction --- p.1 Chapter 1.1 --- Overview of oseltamivir --- p.1 Chapter 1.1.1 --- General description of oseltamivir --- p.1 Chapter 1.1.2 --- Pharmacological activities of oseltamivir --- p.3 Chapter 1.1.3 --- Pharmacokinetics of oseltamivir --- p.3 Chapter 1.1.3.1 --- Absorption of oseltamivir --- p.4 Chapter 1.1.3.2 --- Distribution of oseltamivir --- p.5 Chapter 1.1.3.3 --- Metabolism of oseltamivir --- p.6 Chapter 1.1.3.4 --- Elimination of oseltamivir --- p.8 Chapter 1.1.4 --- Side effects and toxicities of oseltamivir --- p.9 Chapter 1.2 --- Overview of Chinese medicine formulae CMF1 (Yinqiaosan and Sangjuyin) --- p.9 Chapter 1.2.1 --- Background and clinical use of CMF1 --- p.9 Chapter 1.2.2 --- Quality control of CMF1 by manufacturer --- p.11 Chapter 1.2.3 --- Major active components of CMF1 --- p.12 Chapter 1.3 --- Previous studies on herb-drug interactions between O and CMF1 --- p.18 Chapter 1.4 --- Rationale of the current study --- p.19 Chapter 1.5 --- objectives --- p.19 Chapter Chapter Two. --- Identification and quantification of major marker compounds in Yinqiaosan and Sangiuyin products --- p.20 Chapter 2.1 --- Introduction --- p.20 Chapter 2.2 --- Materials and methods --- p.23 Chapter 2.2.1 --- Chemicals --- p.23 Chapter 2.2.2 --- Instruments --- p.24 Chapter 2.2.3 --- Chromatographic conditions --- p.24 Chapter 2.2.4 --- Preparation of standard solutions --- p.25 Chapter 2.2.5 --- Calibration curves --- p.26 Chapter 2.2.6 --- Validation of the assay method --- p.26 Chapter 2.2.7 --- Sample preparations for Yinqiaosan and Sangjuyin products --- p.27 Chapter 2.2.7.1 --- Sample extraction from Yinqiaosan or Sangjuyin granules --- p.27 Chapter 2.2.7.2 --- Sample extraction from Yinqiaosan or Sangjuyin tablets --- p.27 Chapter 2.2.7.3 --- Sample extraction recoveries --- p.27 Chapter 2.3 --- Results and discussions --- p.28 Chapter 2.3.1 --- Chromatography --- p.28 Chapter 2.3.2 --- Linearity and sensitivity --- p.33 Chapter 2.3.3 --- Accuracy and precision --- p.33 Chapter 2.3.4 --- Stability --- p.36 Chapter 2.3.5 --- Contents of identified active components in commercial available Yinqiaosan or Sangjuyin products and CMF1 --- p.36 Chapter 2.3.6 --- Sample extraction recovery --- p.40 Chapter 2.4 --- Conclusion --- p.43 Chapter Chapter Three. --- Effect of CMF1/CMF1 components on the metabolism of oseltamivir and related mechanistic studies --- p.44 Chapter 3.1 --- Introduction --- p.44 Chapter 3.2 --- Materials and methods --- p.47 Chapter 3.2.1 --- Materials --- p.47 Chapter 3.2.2 --- "Verification of metabolism of O in rat GI tract, plasma and liver microsome" --- p.48 Chapter 3.2.3 --- Inhibition of metabolism of O by CMFl/CMFl components --- p.49 Chapter 3.2.3.1 --- In vitro inhibition of metabolism of O in rat plasma --- p.49 Chapter 3.2.3.2 --- In vitro inhibition of metabolism of O in rat liver microsome (RLM) --- p.49 Chapter 3.2.4 --- Mechanistic study of enzyme inhibition of O in recombinant human Carboxylesterase 1 (hCE 1) --- p.50 Chapter 3.2.5 --- Sample preparation and LC/MS/MS analysis --- p.50 Chapter 3.2.6 --- Data analyses --- p.52 Chapter 3.3 --- Results --- p.53 Chapter 3.3.1 --- "Verification of metabolism of O in rat GI tract, plasma and liver microsome" --- p.53 Chapter 3.3.2 --- Inhibition of metabolism of O by CMF1/CMF1 components --- p.53 Chapter 3.3.2.1 --- Enzyme inhibition of metabolism of O by CMFl/CMF1 components in rat plasma --- p.53 Chapter 3.3.2.2 --- Enzyme inhibition of metabolism of O by CMF1/CMF1 components in rat liver microsome (RLM) --- p.58 Chapter 3.3.2.3 --- Selection of potent enzyme inhibitor from CMF1 --- p.60 Chapter 3.3.4. --- Mechanistic study of enzyme inhibition of O in recombinant human Carboxylesterase 1 (hCE 1) --- p.61 Chapter 3.4 --- Discussions --- p.63 Chapter 3.5 --- Conclusion --- p.74 Chapter Chapter Four. --- Effect of CMFl/CMFl components on the absorption of oseltamivir and related mechanistic studies --- p.75 Chapter 4.1 --- Introduction --- p.75 Chapter 4.2 --- Materials and methods --- p.79 Chapter 4.2.1 --- Materials --- p.79 Chapter 4.2.2 --- PAMPA permeation model --- p.80 Chapter 4.2.2.1 --- Permeation of O and OC in PAMPA --- p.80 Chapter 4.2.2.2 --- Sample preparation and LC/MS/MS analysis --- p.81 Chapter 4.2.2.3 --- Data analysis --- p.81 Chapter 4.2.3 --- Absorption of O in presence of CMF/CMFl components in Caco-2 and MDCK cell monolayer models --- p.82 Chapter 4.2.3.1 --- Cell culture --- p.82 Chapter 4.2.3.2 --- Preparation of loading solutions to the cell models --- p.83 Chapter 4.2.3.3 --- Stability of O in transport buffer --- p.84 Chapter 4.2.3.4 --- Cytotoxicity tests of O and CMFl/CMFl components --- p.84 Chapter 4.2.3.5 --- Transport study in Caco-2 and MDCK monolayer model --- p.85 Chapter 4.2.3.6 --- Sample preparation and LC/MS/MS analysis --- p.86 Chapter 4.2.3.7 --- Data analysis --- p.87 Chapter 4.2.4 --- Absorption of O in presence of CMF 1 in rat in situ single pass intestinal perfusion model --- p.88 Chapter 4.2.4.1 --- Preparation of perfusion solutions --- p.88 Chapter 4.2.4.2 --- Stabilities of O and arctigenin in perfusate --- p.88 Chapter 4.2.4.3 --- Rat in situ single pass intestinal perfusion of O in presence and absence of CMFl and relevant inhibitors --- p.89 Chapter 4.2.4.4 --- Sample preparation and LC/MS/MS analysis --- p.90 Chapter 4.2.4.5 --- Data analysis --- p.90 Chapter 4.3 --- Resul ts --- p.91 Chapter 4.3.1 --- Permeation of O and OC in PAMPA --- p.91 Chapter 4.3.2 --- Absorption of O in presence of CMF/CMF1 components in Caco-2 and MDCK cell monolayer models --- p.92 Chapter 4.3.2.1 --- Stabilities of O in transport buffer --- p.92 Chapter 4.3.2.2 --- Cytotoxicity tests of O and CMF1/CMF1 components in transport buffer --- p.93 Chapter 4.3.2.3 --- Proof of O as a substrate of P-gp by Caco-2 cell model --- p.95 Chapter 4.3.2.4 --- Effect of CMF 1 on the absorption transport of o in Caco-2 cell mode --- p.98 Chapter 4.3.2.5 --- Effect of CMF1 components on the absorption transport of o in Caco-2 cell model --- p.102 Chapter 4.3.2.6 --- Effect of arctigenin on bi-directional transport of o in Caco- 2 cell model --- p.106 Chapter 4.3.2.7 --- Proof of O as a substrate of P-gp by MDCK transfected cell lines --- p.108 Chapter 4.3.2.8 --- Bi-directional transport of O in MDCK-MDR1 cell model --- p.111 Chapter 4.3.2.9 --- Effect of CMF 1 on the absorption transport of O in MDCK-MDR1 cell model --- p.112 Chapter 4.3.3 --- Absorption of O in presence of CMF1 in rat in situ single pass intestinal perfusion model --- p.113 Chapter 4.3.3.1 --- Stabilities of O and arctigenin in the perfusion buffer --- p.113 Chapter 4.3.3.2 --- Intestinal absorption of O in presence and absence of CMF1 in rat in situ intestinal perfusion model --- p.114 Chapter 4.4 --- Discussions --- p.116 Chapter 4.5 --- Conclusion --- p.124 Chapter Chapter Five. --- Preliminary evaluation of antiviral activity of CMFl/CMFl components --- p.125 Chapter 5.1 --- Introduction --- p.125 Chapter 5.2 --- Materials and methods --- p.128 Chapter 5.2.1 --- Materials and animals --- p.128 Chapter 5.2.2 --- Animal treatment --- p.129 Chapter 5.2.3 --- Plasma sample collection and preparation --- p.130 Chapter 5.2.4 --- Evaluation of antiviral activities of CMFl/ CMFl components --- p.130 Chapter 5.2.4.1 --- Plaque reduction assay --- p.131 Chapter 5.2.4.2 --- Optimization of plasma sample dilution ratio --- p.131 Chapter 5.2.5 --- Data analyses --- p.133 Chapter 5.3 --- Results and discussions --- p.135 Chapter 5.3.1 --- Ex vivo evaluation of antiviral activity of CMF1 --- p.135 Chapter 5.3.2 --- In vitro evaluation of antiviral activity of CMF1 major marker compounds --- p.139 Chapter 5.4 --- Conclusion --- p.141 Chapter Chapter Six. --- Overall conclusion --- p.142 References --- p.145

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Cordier, Werner. "In vitro hepatotoxicity and herb-drug interactions of selected African plant extracts." Thesis, 2016. http://hdl.handle.net/2263/56955.

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Herbal remedies are an important and often-used commodity in developing countries, such as those in Africa. There is a long-standing belief that these medicinal preparations are more effective and safe than allopathic medications due to their natural origins. However, very little information is available to describe the toxicological nature of African herbal remedies, especially with regards to their hepatotoxic effects, or ability to alter the pharmacokinetic profiles of other compunds. The aim of this in vitro study was to assess the hepatotoxic potential of a panel of selected African herbal remedies, as well as their potential to induce drug-herb interactions. Crude hot water and methanol extracts were prepared from seventeen African plants using brewing and ultrasonic maceration techniques, respectively. Phytochemical screening was done to determine the broad constituency of the extracts using thin layer chromatography, biochemical reactions and free radical scavenging. Cytotoxicity against the HepG2 hepatocarcinoma and Caco-2 colon carcinoma cell lines were determined using the sulforhodamine B staining assay. Acokanthera oppositifolia, Boophane disticha, Moringa oleifera, Solanum aculeastrum, Tabernaemontana elegans, Terminalia sericea and Ziziphus mucronata were selected for further hepatotoxic assessment using a mixture of spectrophotometric, fluorometric, chemiluminescent and flow cytometric assays. Oxidative stress (reactive oxygen species, glutathione and lipid peroxidation levels), mitochondrial membrane potential, fatty acid accumulation and caspase-3/7 activation was assessed using fluorometric assays, while adenosine triphosphate levels were assessed using a chemiluminescent assay. The effect of the extracts on cellular kinetics and mode of cell death was determined using flow cytometric techniques. Drug-herb interactions of the crude extracts were assessed by measuring their effect on P-glycoprotein activity, nevirapine permeability and cytochrome P450 (CYP2B6, CYP2D6 and CYP3A4) enzyme activity. Phytochemical analyses successfully identified the broad constituency and antioxidant profiles of the crude extracts, which correlated well with that already described in literature. Phytochemical classes that were most prominent in the majority of extracts were the alkaloids, flavonoids, glycosides, phenolic acids and saponins. These results were used to determine potential contributing factors during the hepatotoxicity and drug-herb interactions assays. Thirteen extracts displayed activity against the HepG2 cell line, while twelve were active against the Caco-2 cell line. Cytotoxicity was in generally more potent against the Caco-2 cell line, indicating a potential susceptibility of the intestinal tract towards these herbal remedies. A high risk of cytotoxicity was identified for extracts such as A. oppositifolia, S. aculeastrum and T. elegans. Further hepatotoxic assessment indicated that the majority of extracts depolarised the mitochondrial membrane, however oxidative stress was rarely induced. Steatotic changes were evident as shown by the increased retention of fatty acids. Cytotoxicity was mostly a mixture of antiproliferative effects, and worryingly, the induction of necrotic cell death. Although the methanol extracts tended to be more potent than the hot water extracts, the latter induced detrimental effects as well, albeit at a higher relative concentration. The most prominent hepatotoxic effects were observed after exposure to T. elegans, with a halfmaximal inhibitory concentration of 3.07 ?g/mL. Only the methanol extract of S. aculeastrum displayed prominent P-glycoprotein inhibitory activity (HepG2 = 2.92-fold, Caco-2 = 1.29-fold). Five extracts (hot water extracts of Burkea africana and Senecio latifolius, and the methanol extracts of Mundulea sericea, Rauvolfia caffra and Solanum aculeastrum) were selected for assessment of their ability to modulate nevirapine transport across the Caco-2 cell line. All five extracts decreased nevirapine efflux, indicating a propensity for increasing its bioavailability. Due to the lack of P-glycoprotein inhibitory activity from the majority, it appears that this reduced efflux is not necessarily P-glycoprotein-dependent. Altered membrane fluidics and inhibition of other membrane transporters are suggested as potential contributing factors. The majority of extracts displayed prominent CYP450 inhibitory activity (CYP3A4>CYP2B6>CYP2D6). Most extracts displayed a higher selectively towards CYP3A4, which highlights the caution required. More than 50% of drugs currently used on the market are metabolised by the CYP3A4 isoform, and thus the risk is high when comparing it to the low concentrations required to elicit an effect. Both extracts of B. africana, the hot water extract of T. sericea and the methanol extract of Z. mucronata displayed non-selective inhibition across all three isoforms, indicating a possible affinity for a structurally-conserved site across CYP450 enzymes. Due to the genetic makeup of the African populace, which has a significant proportion of CYP450 alleles displaying reduced or inactived enzyme activity, risk is thus high for attenuating their metabolic functions. The methanol extract displayed the highest inhibitory activity against CYP3A4, with a half-maximal inhibitory concentration <1.2 ?g/mL. It is evident throughout the study that there is a high risk of hepatotoxicity or drug-herb interactions. This is specifically observed when taking into account the low amount of extract required to reach the inhibitory concentrations determined in vitro. Inhibition of intestinal P-glycoprotein transporters and CYP450 enzymes appear to be more at risk than that of the liver. This is one of the few studies delving into the toxicological natures of African herbal remedies, specifically in light of hepatotoxicity and herb-drug interactions, and thus serves as a foundation for further assessment. Thesis (PhD)--University of Pretoria, 2016. tm2016 Pharmacology PhD Unrestricted

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22

"Mechanistic study of the pharmacokinetic herb-drug interactions between danshen-gegen formula and warfarin." 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1291818.

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Zhang, Zhen. Thesis Ph.D. Chinese University of Hong Kong 2014. Includes bibliographical references (leaves 215-249). Abstracts also in Chinese. Title from PDF title page (viewed on 15, November, 2016).

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Hou, Mei-Ling, and 侯媄菱. "Pharmacokinetics of rhein in Chinese herbal preparation and the herb-drug interactions with clozapine." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/11934182750158473701.

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博士 國立陽明大學 傳統醫藥研究所 103 Rhein is a pharmacological active component found in Rheum palmatum that is the major herb of the San-Huang-Xie-Xin-Tang (SHXXT), a medicinal herbal product for constipation remedy. Here we have investigated the comparative pharmacokinetics of rhein in normal and constipated rats. Microarray analysis was used to explore whether drug-metabolizing genes will be altered after herbal medicine treatment. Herb-drug interaction of rhein on pharmacokinetics of clozapine and changes in extracellular neurotransmitter levels in the medial prefrontal cortex (mPFC) produced by administration of clozapine were studied. A sensitive and specific method combining ultra-performance liquid chromatography with electrospray ionization tandem mass spectrometry has been developed and validated to simultaneously quantify six active compounds in the pharmaceutical herbal product SHXXT. The pharmacokinetic data of rhein demonstrate that the herbal formulae or the single herbal crude extract significantly increase the higher absorption rate than the pure compound. This phenomenon suggests that the other herbal ingredients of SHXXT and rhubarb extract significantly enhance the absorption of rhein in rats. However, loperamide-induced constipation reduced the absorption of rhein. Gene expression profiling in drug-metabolizing genes after oral dosage with SHXXT for 7 days was investigated by microarray analysis. Gene expression indicates that five drug-metabolizing genes, including Cyp7a1, Cyp2c6, Ces2e, Atp1b1, and Slc7a2 were significantly regulated after the SHXXT treatments. The pharmacokinetic results demonstrate that clozapine produced a nonlinear pharmacokinetics within the doses of 10, 30, and 100 mg/kg orally. The results of the herb-drug interaction of rhein on pharmacokinetics of clozapine and norclozapine in the rat mPFC demonstrate that pretreatment with rhein for 7 days significantly attenuated the absorption of clozapine and affected the distribution of clozapine and norclozapine in the mPFC. Furthermore, pretreatment with rhein for 7 days influenced the DA and it metabolites (DOPAC and HVA) efflux in the mPFC.

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Lo, Pei-Tzu, and 羅珮慈. "Surveys and Improving Satisfaction on Website of Herb-Drug Interactions Information and Database Usability." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/28syqd.

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"Herb-drug interactions between scutellariae radix and non-steroidal anti-inflammatory drugs: pharmacokinetic and pharmacodynamic impact." 2014. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1291715.

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Fong, Yui Kau. Thesis Ph.D. Chinese University of Hong Kong 2014. Includes bibliographical references (leaves 325-358). Abstracts also in Chinese. Title from PDF title page (viewed on 07, November, 2016).

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Chang, Jen-Chih, and 張仁治. "Herb-drug Interactions of Silymarin and Silibinin on the Pharmacokinetics of Protein-unbound Trazodone in Rats." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/hr77ge.

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碩士 國立陽明大學 傳統醫藥學研究所 97 Silymarin, one of the most popular herbal medicines, has been widely used for its hepatoprotective effects. The aim of this study is to investigate the effects of silymarin and its major ingredient silibinin on the pharmacokinetics of the antidepressant trazodone. Male Sprague-Dawley rats were randomly divided into six groups in a parallel design as follows: one group treated single-dose silymarin (1.0 g/kg) 4 h prior to the administration of trazodone, the control group treated with vehicle, two groups pretreated with 0.175 and 0.35 g/kg/day silibinin and another two groups treated with 0.5 and 1.0 g/kg/day silymarin for 7 consecutive days. A microdialysis coupled with high performance liquid chromatography system (HPLC) was used to simultaneously monitor blood and bile concentrations of trazodone in rats. The results indicate that pretreatment with 1.0 g/kg/day silymarin significantly decreases trazodone’s area under the concentration curve (AUC) by 43%, distribution half-life (t1/2,α) by 52%, elimination half-life (t1/2,ß) by 31%, and mean residence time (MRT) by 44%. In contrast, the clearance (Cl) is markedly increased by 61%. In addition, single-dose silymarin (1.0 g/kg) significantly decreased the AUC of trazodone in bile by 49% when compared with the control group. The results revealed that 7-day silymarin treatments might result in enhanced cytochrome P450 expression, which facilitated the metabolism of trazodone. Single-dose silymarin treatments might lead to the inhibition of transporter, which suppressed the bile excretion of trazodone. In conclusion, the present study points out a potential herb-drug interaction between long-term silymarin ingestion and trazodone.

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Ventura, Sandra Cristina do Espírito Santo. "Nonclinical assessment of the potential for herb-drug interactions between herbal extracts present in weight loss supplements and lamotrigine." Doctoral thesis, 2019. http://hdl.handle.net/10400.6/6973.

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Plants have been and still continue to be one of the most important sources of active ingredients. Actually, plants are still the backbone of modern pharmacopoeias and remain as a source of new drug candidates. The use of medicinal plants or plant-based medicinal products is also increasing in many developed countries as an alternative and complementary form for the treatment of diseases. Thus, the concomitant use of plants and conventional medications is emerging as a common practice in patients with hypertension, diabetes, epilepsy, depression, and oncological diseases, as well as in people with obesity and being overweight. Recently, obesity and epilepsy have been related as comorbid conditions with a high prevalence, particularly in patients with refractory epilepsy and under polytherapy. Treatment of patients with epilepsy should, therefore, take into account that the presence of comorbid conditions may compromise the efficacy and safety of antiepileptic drugs, which constitute the main therapeutic approach in epilepsy. Lamotrigine (LTG) is a well-tolerated antiepileptic drug widely used in epilepsy; however, it has a narrow therapeutic range and a considerable interindividual variability in its pharmacokinetics. Therefore, the focus of research addressed in this thesis was the nonclinical assessment of the potential for herb-drug interactions between herbal extracts present in weight loss supplements and LTG, using the rat as whole animal model. After optimization and validation of selective, precise and accurate bioanalytical methods for the quantification of LTG in human samples (plasma and saliva) and in rat samples (plasma and brain), the conditions for proceeding with nonclinical studies were met. Therefore, then a number of nonclinical studies were performed in adult male Wistar rats with the main objective of evaluating the effects of standardized extracts of Paullinia cupana (guarana), Garcinia cambogia (malabar tamarind), Citrus aurantium (bitter orange) and Fucus vesiculosus (bladderwrack) on the kinetics of LTG. To this end, at least two independent pharmacokinetic studies were carried out to evaluate the effects of each herbal extract on the pharmacokinetics of LTG; the first study aimed to evaluate the effects after the co-administration of the extract and LTG, and the second one aimed to evaluate the effects of a 14-day pre-treatment period with the extract on the pharmacokinetics of LTG subsequently administered on the 15th day. Globally, the results of the pharmacokinetic studies involving the four herbal extracts pointed out that P. cupana extract is the one that has higher potential to interact with LTG, while G. cambogia, C. aurantium and F. vesiculosus extracts had minor or no effects on LTG pharmacokinetics. The co-administration of P. cupana extract and LTG caused, in particular, a significant decrease in the peak plasma drug concentration (Cmax) and in the extent of systemic exposure to LTG over the first 24 h (AUC0-24). Based on the findings achieved in these nonclinical studies, an important pharmacokinetic interaction between P. cupana extract and LTG was herein described for the first time, which potentially may have clinical impact in patients treated with LTG. Moreover, the repeated administration of the tested herbal extracts during a 14-day period did not have relevant effects on the body weight gain of rats, which raises doubts about their effectiveness in reducing body weight. So, in conclusion, the nonclinical assessment of herb-drug interactions is of utmost importance to anticipate the potential effects of herbal preparations in the pharmacokinetics of narrow therapeutic index drugs like LTG, constituting these data the starting point for further confirmation and investigation of the relevance of these interactions at a clinical level. As plantas têm sido, e continuarão ainda a ser, uma das fontes mais importantes de princípios ativos. Na realidade, as plantas constituem ainda a “espinha dorsal” das farmacopeias modernas e continuam a ser uma fonte de novos candidatos a fármacos. A utilização de plantas medicinais ou de preparações medicinais à base de plantas está também a aumentar em muitos países desenvolvidos como uma forma alternativa e complementar para o tratamento de doenças. Por conseguinte, o uso concomitante de plantas e medicamentos convencionais é uma prática comum em doentes com hipertensão, diabetes, epilepsia, depressão e doenças oncológicas, assim como em pessoas com obesidade e excesso de peso. Recentemente, a obesidade e a epilepsia têm sido consideradas comorbilidades com uma elevada prevalência, particularmente em doentes com epilepsia refratária e polimedicados. O tratamento de doentes com epilepsia deve, portanto, ter em consideração que a presença de comorbilidades pode comprometer a eficácia e a segurança dos fármacos antiepiléticos, os quais constituem a principal estratégia terapêutica na epilepsia. A lamotrigina (LTG) é um fármaco antiepilético bem tolerado e amplamente utilizado na epilepsia, mas que apresenta uma margem terapêutica estreita e uma variabilidade interindividual considerável na sua farmacocinética. Por isso, o foco de investigação considerado nesta tese foi a avaliação não-clínica do potencial de interação entre extratos de plantas presentes em suplementos à base de plantas para emagrecimento e a LTG, usando o rato como modelo animal. Após a otimização e a validação de métodos bioanalíticos seletivos, precisos e exatos para a quantificação da LTG em amostras humanas (plasma e saliva) e em amostras de rato (plasma e cérebro), as condições para prosseguir com os estudos não-clínicos estavam reunidas. Portanto, de seguida, um conjunto de estudos não-clínicos foi realizado em ratos Wistar machos adultos com o objetivo principal de avaliar os efeitos de extratos padronizados de Paullinia cupana (guaraná), de Garcinia cambogia (tamarindo de Malabar), de Citrus aurantium (laranja-amarga) e de Fucus vesiculosus (bodelha) na cinética da LTG. Para tal, pelo menos dois estudos farmacocinéticos independentes foram realizados para avaliar os efeitos de cada extrato na farmacocinética da LTG; o primeiro estudo teve como objetivo avaliar os efeitos após a coadministração do extrato e da LTG, e o segundo estudo foi realizado para avaliar os efeitos de um período de pré-tratamento de 14 dias com cada extrato na farmacocinética da LTG administrada subsequentemente ao 15º dia. Globalmente, os resultados dos estudos farmacocinéticos envolvendo os quatro extratos de plantas revelaram que o extrato de P. cupana é aquele que tem maior potencial para interagir com a LTG, enquanto que os extratos de G. cambogia, C. aurantium e F. vesiculosus tiveram poucos ou nenhuns efeitos na farmacocinética da LTG. A coadministração do extrato de P. cupana e LTG causou, em particular, um decréscimo significativo da concentração plasmática máxima (Cmax) e da extensão de exposição sistémica à LTG nas primeiras 24 h (AUC0-24). Com base nos resultados obtidos nestes estudos não-clínicos, uma interação farmacocinética importante entre o extrato de P. cupana e a LTG foi aqui descrita pela primeira vez, a qual potencialmente pode ter impacto clínico em doentes tratados com a LTG. Além disso, a administração repetida dos extratos testados durante um período de 14 dias não teve efeitos relevantes sobre o ganho de peso corporal dos ratos, o que levanta dúvidas sobre a eficácia deles na redução do peso corporal. Assim, em conclusão, a avaliação não-clínica de interações planta-fármaco é de extrema importância para antecipar os efeitos potenciais de preparações à base de plantas na farmacocinética de fármacos de índice terapêutico estreito como a LTG, constituindo esses dados o ponto de partida para confirmação posterior e investigação da relevância dessas interações a nível clínico. UID/Multi/00709/2013

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Kuo, Yung Te, and 郭永德. "Monitoring and Evaluation of Herb-Drug Interactions in Outpatient Service - A Pilot Study of taking Warfarin with Traditional Chinese Medicine." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/55746703169456947357.

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碩士 長庚大學 管理學院碩士學位學程在職專班資訊管理組 100 Concomitant administration of Western and Traditional Chinese Medicines (TCM) that may result in decreased efficacy or adverse reactions has long been of great clinical concern. Yet with few relevant literature available, systemic analyses of these concomitant uses is due and necessary. Owing to this, a well-organized, systematic study collecting cases of herb-drug interactions in Taiwan is urgently needed to analyze and assess the incidence of adverse drug reactions in combined Chinese and western medication uses. In the pilot study, patients concurrently were taking warfarin with Traditional Chinese medicines simultaneously in our outpatient services. On the one hand retrospective review our patients’ data from 2008 to 2010 and the other hand to intensive monitoring the patients’ interaction from January to October in 2011. In the retrospective review from 2008 to 2010, 305 outpatients were found to have combined warfarin and Chinese medicine. The longest term was 673 days since use formula. The dosage of warfarin was 2.77 ±1.56mg/day and the International Normalized Ratio (INR) was 1.911 ±0.7042. Of the 54 people that combined Radix Salviae Miltiorrhizae. Neither paired t-Test analysis warfarin with traditional Chinese medicine or Wilcoxon signed rank test analysis of warfarin with Radix Salviae Miltiorrhizae, the INR expressed no remarkable. In this study and reference review, there was no consistence between warfarin with Radix Salviae Miltiorrhizae and literature review. In intensive monitoring study from January to October in 2011, 128 outpatients were found to have combined warfarin and Chinese medicine. The longest term was 231 days since use formulas. There were only 3 possibly-related adverse drug reaction cases in this study. Of the 31 people that combined warfarin and Radix Salviae Miltiorrhizae. Only one case was possibly-related adverse drug reaction in herb-drug interaction. During duration of taking warfarin with Traditional Chinese Medicine, there were 13 outpatients showed the INR over 3.5. Only 1 cases show possibly-related adverse drug reaction. According to the concept of Pharmacovigilance, we should exploit information technology to set up an Intensive Monitoring System for herb-drug interactions. Monitor and assess the reciprocation of the drug interaction in medical clinic for a long term program. Try to find, warn and predict the adverse drug reactions of the Chinese and Western medicine interaction in early days. All these were for improving the patients’ drug safety.

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Yang, Ling, and 楊淩. "Chemical analysis of ginsenosides in ginseng and herb-drug pharmacokinetic interactions of ginseng on selegiline and its potential neuroprotective effects." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/v588ys.

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30

Shaw, Lee-Hsin, and 邵荔昕. "Herb-drug interactions of bu-yang-huan-wu-tang on the pharmacokinetics of aspirin using microdialysis coupled with LC-MS/MS." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/21978744013783615327.

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碩士 國立陽明大學 傳統醫藥研究所 100 The usage of Chinese herbal medicine combined with Western medicine has raised an important clinical issue of herb-drug interaction. Pharmacokinetic research is the most convincing evidence for herb-drug interaction study. The western medicine of aspirin has been a commonly prescribed pharmaceutical for ischemic stroke prevention. Bu-yang-huan-wu-tang (BYHWT) is the most popular formulated traditional Chinese medicine (TCM) prescriptions widely used in the prevention of ischemic cardio-cerebral vascular diseases and stroke-induced disability. There is concern about the potential hemorrhagic complications if aspirin is used as an adjunctive treatment with BYHWT. Therefore the herb-drug interaction of BYHWT and aspirin can be investigated using a well established pharmacokinetic animal model. This study develops an in vivo microdialysis technique coupled with a validated high-performance liquid chromatography (HPLC) system to monitor protein-unbound aspirin and its major metabolite, salicylic acid, in rat blood and brain for additional evaluation of herb-drug interaction. The results of pharmacokinetic and bleeding time indicate that the herbal formula of bu-yang-huan-wu-tang did not statistically affect aspirin in blood and brain. Our study provides extremely constructive information for the clinical practice when combination treatment of bu-yang-huan-wu-tang and aspirin may not induce significant interaction. 　　The second part of the experiment, the purpose of the investigation was to develop a comprehensive analytical method by using liquid chromatography with tandem mass spectrometry (LC-MS/MS) for simultaneous quantiﬁcation of nine main bioactive components, i.e., astragaloside I, astragaloside II, astragaloside IV, formononetin, ononin, calycosin, calycosin-7-o-β-D-glucoside, ligustilide and paeoniflorin in rat plasma after oral administration of bu-yang-huan-wu-tang extract. This method was applied to investigate the pharmacokinetics in a conscious and freely moving rat by an automated blood sampling device. These pharmacokinetic results provide a constructive contribution to better understand the absorption mechanism of BYHWT and to support additional clinical evaluation. Furthermore, the established analytical method has now been extended to quantitate and compare in different brands of commercially available BYHWT successfully.

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Lu, Chia-Ming, and 呂家銘. "Herb-drug interactions of Long-Dan-Xie-Gan-Tang on the pharmacokinetics of lamivudine using microdialysis coupled with LC-MS/MS." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/20658652005416707312.

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碩士 國立陽明大學 傳統醫藥研究所 102 The interaction between herbal medicines and western medicines is increasingly being recognized as an important issue and antiretroviral drugs have frequently been implicated in herb–drug interactions. Pharmacokinetic research is the most convincing evidence for herb-drug interaction study. The western medicine of lamivudine has been a commonly prescribed pharmaceutical for HBV treatment. According to a survey from the Database of National Health Insurance Research in Taiwan, the herbal formulation of Long-Dan-Xie-Gan-Tang (LDXGT) is the most frequently used in the treatment of chronic hepatitis. There is concern about the potential herb–drug interactions if LDXGT is used as an adjunctive treatment with lamivudine. Therefore the herb-drug interaction of LDXGT and lamivudine can be investigated using a well- established pharmacokinetic animal model. The aim of study is to develop a novel multiple microdialysis technique coupled to a validated chromatographic system for the measurement of protein-unbound form lamivudine and investigation of its herb-drug interaction in rat blood and liver. The analyte was separated by a reverse-phase C18 column using the mobile phase comprising methanol and 10 mM KH2PO4 (15:85, v/v, adjusted to pH 6.0 with NaOH) with the flow rate of 0.8 mL/min, and the UV wavelength was set at 270 nm. The processes of method validation followed Food and Drug Administration (FDA) guidelines. The pharmacokinetic data demonstrated that the area under the concentration time curve (AUC) of the lamivudine alone and the LDXGT pretreated group were 532 ± 37.6 and 550 ± 44.2 min μg/mL in rat blood after lamivudine administration (10 mg/kg, i.v.) and 682 ± 196 and 642 ± 153 min μg/mL in rat liver, respectively. The herb-drug pharmacokinetic interaction showed that with either lamivudine alone or in combination with pretreated with LDXGT, the pharmacokinetic parameters were not significantly changed except for the apparent volume of distribution (Vd) at a high dose of lamivudine (30 mg/kg). The second part of the experiment, the purpose of the investigation is to develop a sensitive and efficient LC-MS/MS method for the simultaneous determination of gentiopicroside, geniposide, baicalin and swertiamarin in rat plasma. Analytes were separated by a Waters BEH C18 column with a gradient mobile phase system of methanol–water containing 1 mM ammonium acetate (0.1% formic acid added). The analysis was performed on a positive ionization electrospray mass spectrometer via multiple reaction monitoring (MRM). Sample preparation was carried out by one-step protein precipitation with methanol. The validated LC-MS/MS method was successfully applied to a pharmacokinetic study in freely moving rats after the administration of a Chinese herbal formula of Long-Dan-Xie-Gan-Tang (10 g/kg, p.o.). The pharmacokinetic data demonstrated that the area under concentration-time curve (AUC) values of gentiopicroside, geniposide, baicalin and swertiamarin were 1417 ± 83.8, 302 ± 25.8, 753 ± 86.2 and 2.5 ± 0.1 min µg/mL, respectively. In conclusion, this study may provide a useful model of pharmaceutical research for future application and contribute to the understanding of the herb–drug interactions between Chinese herbal formulations and common Western drugs.

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Liao, Hui-Ling, and 廖慧伶. "Analysis of Drug-Herb Interactions Induced by Co-Administration of NHI-Covered Traditional Chinese Medicines and Western Medicines Prescribed in Outpatient Clinics of Taiwan." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/23669110143741161101.

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博士 中國醫藥大學 中國藥學研究所博士班 97 In 1995, Taiwan launched its national health insurance (NHI). Traditional Chinese medicine (TCM) was not covered by NHI until 1996. The inclusion of both TCM and western medicine in NHI coverage has substantially increased the convenience and accessibility of medical services. However, multiple accesses to different TCM and western medicine clinics also increased, resulting in the elevation of drug-drug interactions (DDIs) or drug-herb interactions. Some patients, especially the elderly with multiple diseases, often visit different hospitals or specialists and receive many different medications. Therefore, elderly patients have higher chances of DDIs when they are taking many medications at the same time. Taiwan has become an aging society. Drug safety for the elderly needs special attention. This research was to explore the extent of DDIs in the elderly associated with the concurrent use of medications prescribed from NHI contracted clinics. Furthermore, based on the National Health Insurance Research Database (NHIRD) of potential drug-herb interactions, a number of aspects were analyzed. For example, the prevalence, duration of prescription, associated diseases and relative risks for the co-administration of warfarin with herbs (dong quai, danshen and/or ginseng) or the co-administration of systemic corticosteroids with liquorice and liquorice-containing herbal medicine were investigated. In Taiwan, it is very common for people to purchase and use over-the-counter TCM which is not covered by NHI. A questionnaire survey was conducted to identify the behavioral pattern of outpatients in purchasing TCM not covered by NHI, and factors that might influence their behavioral patterns. The result will provide reference for the formulation of drug safety related policies and strategies. Three major research methods were used: (1) A cross-sectional study was conducted to analyse the potential DDIs existing in the medications prescribed to nursing home residents. The medicines prescribed to nursing home residents were compared with the “DDIs Database System” constructed by the Department of Health, Executive Yuan. Next, SPSS 10.0 was used to run statistic analysis. (2) The retrospective research method was used to analyze potential drug-herb interactions induced by TCM and western medicines covered by NHI. Data were randomly selected from the complete datasets of western and TCM outpatient reimbursement claims from 1997 to 2003 contained in Taiwan’s National Health Insurance Research Database. The outpatients concurrently using both warfarin and TCM (dong quai, danshen and/or ginseng) or both systemic corticosteroids and liquorice were screened, and then the prevalence and relative risk with respect to different demographic characteristics of outpatients, types of hospital ownership, levels of hospital accreditation and types of diseases were analyzed. (3) A structured questionnaire was used to survey the behavioral patterns of outpatients who purchased TCM not covered by NHI. The questionnaire was administered randomly to outpatients waiting for Chinese medicine at pharmacies in selected academic hospitals. SPSS 10.0 was used to run descriptive analysis and one-way ANOVA. In addition, LISREL 8.30 was used to modify and analyze the relationship between the variables of the hypothetical path way model in order to identify the fitness between the model and the actual data. The findings of this study showed that mean number of medications per resident was 5.74±2.4. Of the 323 samples, 81 (25.08%) had experienced DDIs, 63(64.95%) were of moderate and 7(7.22%) of major severity in the nursing home residents. The resident with 9 or more medications tended to have drug interactions in comparison with those with one or two medications. The odds ratio was 11.389. By analyzing potential drug interaction induced by the co-administration of NHI TCM and western medicines prescribed to the outpatients, it was found that the prevalence rate for the co-administration of warfarin with herbs (dong quai, danshen or ginseng) was 2.75%, and 1.495% for the co-administration of systemic corticosteroids with liquorice. The age group “71~80 years old” had the highest prevalence rate (3.63%) for the co-administration of warfarin with herbs (dong quai, danshen and/or ginseng). The relative risk for the age group “71~80 years old” was 7.9 times higher than the age group “≦30 years old”. The age group “61~70 years old” had the highest prevalence rate (2.08%) for the co-administration of systemic corticosteroids with liquorice. The relative risk for the age group “61~70 years old” was 2.5 times higher than the age group “≦20 years old”. With respect to the major disease category, “diseases of the circulatory system” coded 390-459 in ICD-9-CM had the highest frequency in the co-administration of warfarin with herbs (dong quai, danshen and/or ginseng). “Diseases of the respiratory system” coded 460-519 in ICD-9-CM had the highest frequency in the co-administration of systemic corticosteroids with liquorice. The research on the behavioral pattern of outpatients purchasing TCM not covered by NHI showed that outpatients’ behavioral intention and purchasing behavior were influenced by factors like “diseases suffering”, “people’s influence” and “usable resource”. Especially the more diseases the outpatients had, the more prominet the TCM purchasing behavior would be. According to the analysis on the complete datasets of Taiwan’s National Health Insurance Research Database, it was found that the potential risk of drug interaction did exist in the current NHI system when patients received prescriptions from different physicians at various clinics. Drug safety is a crucial issue that should not be overlooked. The more types of medicines used concurrently, the higher the chance of drug interaction. Patients with chronic diseases or elderly patients tend to purchase over-the-counter TCM and co-administrate them with prescribed NHI medicine, which in turn result in the increased risk of drug interaction. It is suggested that NHI coverage should be extended to the health education of alerting public awareness on the risk of drug interaction and the correct usage of medicines that not only ensures the therapeutic effect but also avoids adverse drug reactions.

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Chang, Hsing-Yi, and 張杏怡. "Chemical analysis of active compounds from Suan-Zao-Ren decoction and herb-drug interactions on the pharmacokinetics and pharmacodynamics of zolpidem in Sprague-Dawley rat." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/09235555155066478390.

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碩士 國立陽明大學 傳統醫藥研究所 102 Suan-Zao-Ren decoction (SZRD) is one of the most popular traditional Chinese medicine prescriptions for the treatment of restlessness, anxiety and insomnia. Nowadays, TCMs faced on some difficulties, such as quality control of herbs, multi- component analysis, less evidence base for clinical use, and the potential impact of Chinese and Western medicine combined interactions. In this thesis, the main research about SZRD study into two parts, the first part is to develop a comprehensive analytical method by using liquid chromatography with tandem mass spectrometry(LC-MS/MS)for simultaneous quantification of seven main bioactive components, ie., jujuboside A, jujuboside B, spinosin, mangiferin, ferulic acid, pachymic acid and glycyrrhizic acid. The established analytical method has been extended to quantitate and compare in different brands of commercially available SZRD successfully. Furthermore, this method was applied to investigate the pharmacokinetics of bioactive components of SZRD in conscious and freely moving rat by collecting blood sample. These pharmacokinetic results provide a constructive contribution to better understand the absorption mechanism of SZRD and to support additional clinical evaluation. Besides, mangiferin is one of the main active flavonoid components of Anemarrhenae Rhizoma and SZRD and was worth further pharmacokinstic study. This validated method was also applied to a comparative study on the pharmacokinetics and bioavailability of mangiferin following administration of mangiferin (a single compound), Anemarrhenae Rhizoma extracts (single herbal extract), and Suan-Zao-Ren decoction (SZRD; a multiple herbal extract). Prescription compatibility and other components of Anemarrhenae Rhizoma were significantly altered by the pharmacokinetics of mangiferin. The phenomenon may due to herbal ingredient-ingredient or herb-herb interaction. The second part of the experiment, according to National Health Insurance in Taiwan research, the western medicine of zolpidem has been a commonly prescribed pharmaceutical for insomnia treatment. SZRD is one of the most popular traditional Chinese medicine prescriptions for the treatment of insomnia. Since there is concern about the potential clinical treatment efficacy, the herb-drug interaction between SZRD and zolpidem is investigated using the well established pharmacokinetic animal model and pentobarbital-induced loss of righting reflex model. This study develops a validated high-performance liquid chromatography (HPLC) with fluorescence detection system to monitor zolpidem in rat plasma for additional evaluation of herb-drug interaction. After oral administration of SZRD for five days, the zolpidem was given intragastrically. Then, blood samples were collected for four hours and the plasma samples were pretreated by liquid-liquid extraction with ethyl acetate and then injection into high performance liquid chromatography systems for analysis. The results showed no significant difference between the pharmacokinetics of normal dose oral administration of high-dose and control. Pentobarbital-induced loss of righting reflex pharmacological experiments show that the combination of normal dose SZRD and zolpidem a can shorten sleep latency, this result can be used as a reference for clinical use.

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Calitz, Carlemi. "Impact of selected herbal products on intestinal epithelial permeation and metabolism of indinavir / Carlemi Calitz." Thesis, 2014. http://hdl.handle.net/10394/14481.

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Patients on anti-retroviral (ARV) drug treatment are sometimes simultaneously taking other prescribed drugs and/or over-the-counter drugs and/or herbal remedies. Pharmacokinetic drug-drug or herb-drug interactions can occur in these patients, which might be synergistic or antagonistic in nature leading to increased or decreased bioavailability of the ARV. Consequences of bioavailability changes may either be adverse effects due to increased plasma levels, or lack of pharmacological responses due to decreased plasma levels. The aim of this study is to determine if pharmacokinetic interactions exist between selected commercially available herbal products, namely Linctagon Forte®, Viral Choice® and Canova® and the ARV, indinavir, in terms of transport and metabolism in cell culture models. Bi-directional transport of indinavir was evaluated across Caco-2 cell monolayers in four experimental groups, namely indinavir alone (200 μM, negative control group), indinavir in combination with Linctagon Forte®, indinavir in combination with Viral Choice® and indinavir in combination with Canova® at three different concentrations. Verapamil (100 μM), a known P-gp inhibitor, was combined with indinavir in the positive control group. Samples obtained from the transport studies were analysed by means of a validated high performance liquid chromatography (HPLC) method. The apparent permeability coefficient (Papp) values were calculated from the transport results in both directions and the efflux ratio (ER) values were calculated from these Papp values. The metabolism of indinavir was determined in LS180 cells in the same groups as mentioned for the transport study but with ketoconazole (40 μM), a known CYP3A4 inhibitor, as the positive control group. Indinavir and its predominant metabolite (M6) were analysed in the metabolism samples by means of liquid chromatography linked to mass spectroscopy (LC/MS/MS) to determine the effect of the herbal products on the biotransformation of indinavir. The BL-AP transport of indinavir increased in a concentration dependent way in the presence of Linctagon Forte® and Viral Choice® when compared to that of indinavir alone (control group). Canova® only slightly affected the efflux of indinavir compared to that of the control group. Noticeable increases in the efflux ratio values of indinavir were found for Linctagon Forte® and Viral Choice®, whilst the effect of Canova® on the efflux ratio value was negligible. There was a pronounced inhibition of the metabolism of indinavir in LS180 cells over the entire concentration range for all the herbal products investigated in this study. These in vitro pharmacokinetic interactions indicate the selected herbal products may affect indinavir’s bioavailability, but the clinical significance needs to be confirmed with in vivo studies before final conclusions can be made. MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2015

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Rodrigues, Márcio José de Abreu Marques. "Evaluation of the effect of herbal extracts used in slimming regimens in the kinetic profile of narrow therapeutic range drugs used for cardiovascular pathologies: the amiodarone." Doctoral thesis, 2013. http://hdl.handle.net/10316/24327.

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Tese de doutoramento em Ciências Farmacêuticas, na especialidade de Farmacologia e Farmacoterapia, apresentada à Faculdade de Farmácia da Universidade de Coimbra The use of plants for the prevention and treatment of various health diseases has been a practice that comes from the ancient civilizations. However, in recent years has been observed an increase in the use of herbal products. In developed countries is particularly worrying the increasing consumption of herbal weight loss medicines/dietary supplements as alternative or complement to the traditional programs of body weight reduction. In addition, this issue is even more serious because among the general population prevails the notion that herbal preparations are devoid of health risks due to the natural origin of the constituents. Indeed, only a minority recognizes that herbal medicinal products are complex mixtures of phytochemicals, which may be substrates, inhibitors or inducers of the same biological systems that are involved in the biodisposition of conventional drugs, existing, therefore, a high potential for clinically significant pharmacokinetic interactions. Accordingly, considering the close relationship between obesity and cardiovascular diseases, as well as the scarcity of scientific information available about the safety of herbal slimming medicinal products, it is absolutely justified to assess the potential for pharmacokinetic interactions between the most relevant herbal weight loss extracts and high-risk drugs required in multiple cardiovascular diseases such as the case of amiodarone (AM). Thus, from the perspective of protecting public health, it is warranted to characterize the interference of standardized herbal extracts commonly used in weight loss programs (e.g. Fucus vesiculosus, Paullinia cupana, Citrus aurantium and Carica papaya) in the pharmacokinetic profile of AM. This thesis emerged in this context and aimed to carry out the in vivo nonclinical systematic assessment of the potential for occurrence of significant herb-drug interactions between commonly used standardized herbal weight loss extracts and AM, a drug of narrow safety range widely used in clinical practice for the management of cardiovascular diseases. One technique of high performance liquid chromatography (HPLC) with diode-array detection (DAD) was developed and fully validated for adequate quantification of AM and its main metabolite (mono-N-desethylamiodarone) in human plasma in order to provide a useful analytical tool for clinical purposes. A second technique was developed and validated in plasma and heart, liver, kidney, and lung tissue homogenates of rats – species used for in vivo investigations. The herbal extracts that have more pronounced effects on the pharmacokinetics of AM were F. vesiculosus, P. cupana and C. papaya extracts. F. vesiculous extract and P. cupana extract following the co-administration with AM showed a significant reduction of the peak concentration of AM as well as a reduction in the extend of systemic exposure to AM. For the first time were reported herb-drug interactions between F. vesiculosus extract and P. cupana extract with AM, which determined a considerable decrease on AM bioavailability in rats. Therefore, the therapeutic efficacy of AM may be compromised by the concurrent administration of herbal slimming medicines/dietary supplements containing F. vesiculosus or P. cupana. On the other hand, it should be highlighted that the pre-treatment with C. aurantium extract significantly increased the peak concentration of AM, while the extension of systemic exposure was comparable between both groups. At last, in the rats pre-treated with C. papaya extract was observed a significant increase in the systemic exposure of AM. In conclusion, the findings reported along this thesis showed the relevance of screening herb-drug pharmacokinetic interactions. The knowledge of relevant herb-drug interactions is certainly useful to help in the preparation of appropriate herbal monographs such those in course by the Herbal Medicinal Products Committee (HMPC) of the European Medicines Agency (EMA). The availability of this kind of information gathered together in a single and easily accessible document (monograph) may be of great value to promote a more rational and safer use of herbal products, having high importance in terms of protecting the public health. O uso de plantas para a prevenção e tratamento de várias doenças tem sido uma prática desde as civilizações antigas. No entanto, nos últimos anos tem-se observado um aumento da utilização de produtos à base de plantas. Nos países desenvolvidos tem sido particularmente preocupante o aumento do consumo de produtos de emagrecimento/suplementos alimentares como alternativa ou complemento aos programas tradicionais de perda de peso corporal. Além disso, esta questão é ainda mais grave porque entre a população prevalece, em geral, a noção de que as preparações à base de plantas são desprovidas de riscos para a saúde devido à origem natural dos constituintes. De facto, apenas uma minoria reconhece que os produtos medicinais à base de plantas são misturas complexas de fitoquímicos, que podem ser substratos, inibidores ou indutores dos mesmos sistemas biológicos que estão envolvidos na biodisposição de fármacos convencionais, existindo, por isso, um elevado potential para interações farmacocinéticas significativas. Por conseguinte, considerando a relação estreita entre a obesidade e as doenças cardiovasculares, bem como a escassez de informação científica disponível sobre a segurança de produtos medicinais de emagrecimento à base de plantas, é absolutamente justificado avaliar-se o potencial de interação de base farmacocinética entre os extratos de emagrecimento de origem vegetal mais relevantes e fármacos de maior risco usados em várias doenças cardiovasculares, como é o caso da amiodarona (AM). Assim, tendo em perspetiva a proteção da saúde pública, justifca-se a caraterização da interferência de extratos padronizados de plantas medicinais comummente utilizadas em programas de perda de peso (por exemplo, Fucus vesiculosus, Paullinia cupana, Citrus aurantium e Carica papaya) no perfil farmacocinético da AM. Esta tese surgiu neste contexto e visou conduzir estudos não-clínicos in vivo para a avaliação do potencial de ocorrência de interações significativas extrato-fármaco entre os extratos padronizados para perda de peso e a AM, um fármaco de margem terapêutica estreita amplamente utilizada na prática clínica para o tratamento de doenças cardiovasculares. Para tornar estes estudos exequíveis, foi desenvolvida e validada uma técnica de cromatografia líquida (HPLC) com um detetor de fotodíodos (DAD) para a quantificação adequada da AM e do seu principal metabolito (mono-N-desetilamiodarona) em plasma humano, a fim de disponibilizar uma ferramenta analítica para aplicação clínica. A segunda técnica foi desenvolvida e validada em plasma e em homogeneizados de tecido do coração, fígado, rim e pulmões de ratos – espécie utilizada nos ensaios in vivo. Os extratos vegetais testados que mostraram efeitos mais pronunciados na farmacocinética da AM foram o F. vesiculosus, a P. cupana e a C. papaya. Os extratos de F. vesiculosus e P. cupana após a coadministração com a AM mostraram uma redução significativa da concentração máxima de AM bem como uma redução na extensão de exposição sistémica à AM. Pela primeira vez foram descritas interações extrato-fármaco entre o extrato de F. vesiculosus e de P. cupana com a AM, que determinaram uma diminuição considerável na biodisponibilidade da AM em ratos. Portanto, a eficácia terapêutica da AM pode ser comprometida pela administração concomitante de extratos medicinais de emagrecimento/suplementos dietéticos que contêm F. vesiculosus ou P. cupana. Por outro lado, deve ser realçado que o pré-tratamento com extrato de C. aurantium aumentou significativamente o pico de concentração plasmática (Cmax) da AM, enquanto que a extensão de exposição sistémica foi comparável entre ambos os grupos. Por último, nos ratos pré-tratados com o extrato de C. papaya foi observado um aumento significativo da exposição sistémica à AM. Em conclusão, os resultados descritos ao longo desta tese mostram a relevância da investigação de interações farmacocinéticas extrato-fármaco. O conhecimento das interações relevantes extrato-fármaco é certamente útil para ajudar na elaboração de monografias apropriadas, tais como aquelas em curso pelo Comité dos Produtos Medicinais à Base de Plantas (HMPC) da Agência Europeia do medicamento (EMA). A disponibilidade deste tipo de informação reunida num documento único e de fácil acesso (monografia) pode ser de grande valia para promover uma utilização mais racional e segura dos produtos à base de plantas, tendo grande importância em termos de proteção da saúde pública. FCT - (SFRH/BD/61901/2009)

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Couto, Catia Sofia Silva. "A Utilização da Canábis para Fins Medicinais em Oncologia no Contexto Português." Master's thesis, 2020. http://hdl.handle.net/10316/92949.

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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia O cancro apresenta-se como a segunda maior causa de morte no Mundo, tendo provocado a morte de aproximadamente 29000 portugueses em 2018. Embora haja várias abordagens terapêuticas ao seu tratamento, uma grande percentagem de doentes faz ou irá fazer quimioterapia. Tal como todos os medicamentos também estes podem induzir efeitos secundários. Por vezes há possibilidade de mitigar estes sintomas, mas nem sempre a abordagem é eficaz, o que se pode traduzir numa diminuição de adesão à terapêutica antineoplásica. Dado que a taxa de sobreviventes ao cancro está a aumentar, torna-se fulcral aumentar a qualidade de vida destes indivíduos, de modo a que eles possam voltar ao seu normal quotidiano com o mínimo de sequelas possível. Nos últimos anos, tem existido um grande interesse em torno destas questões e uma das mais recentes propostas inclui a planta medicinal Cannabis sativa L., (flores). O facto de algumas correntes associadas a esta proposta a caracterizarem para consumo livre enquanto medicinal, isso tem gerado uma discussão a nível mundial num enorme conjunto de países. Em Portugal, assim como na Europa, já havia legislação para os medicamentos à base de plantas, mas neste caso específico a Lei n.º 33/2018 veio regular a utilização de medicamentos, preparações e substâncias à base da planta da canábis, para fins medicinais. No presente trabalho, aqui desenvolvido, o objetivo principal é apresentar as indicações terapêuticas aprovadas para a canábis para fins medicinais autorizadas em Portugal relacionadas com a Oncologia, bem como analisar as soluções autorizadas para estas situações. Uma breve abordagem ao mercado nutracêutico neste contexto completa a informação geral disponível, de modo a contribuir para tecer algumas conclusões mais integradas no panorama nacional. Cancer is the second most common cause of death. In 2018, approximately 29,000 Portuguese died. Despite the several therapeutic approaches to treat cancer, there are a large percentage of patients that will undergo into chemotherapy. All medicines include side effects, and chemotherapy is not an exception. Sometimes it is possible to mitigate these symptoms, but the approach is not always effective. This can translate into a decrease in adherence to antineoplasic therapy. Considering that the rate of cancer survivors is increasing, it’s crucial to improve the life quality of these individuals. It’s important that they return to their quotidian life. Recently, there has been a great deal of interest in these issues and the most recent proposals include the medical plant Cannabis sativa L. (flowers). There is a growing current of support that characterizes it for free consumption as medicinal. But this has generated a worldwide discussion in a huge set of countries. In Portugal, as well as in Europe, there was already legislation for herbal medicines. In this specific case, Law No.33/2018 regulates the use of medicines, preparations and substances based on the cannabis plant, for medicinal purposes. In the present work, the main objective is to present the therapeutic indications approved for cannabis for medicinal purposes authorized in Portugal related to Oncology, as well to analyze the authorized solutions for these situations. In order to contribute to drawing some conclusions more integrated in the national panorama,a brief approach to the nutraceutical market completes the general information available.

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Lin, Shun-Yong, and 林舜雍. "Constructing Drug-Herb Interaction Inquiry Website." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/h97w4c.

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碩士 國立虎尾科技大學 資訊管理研究所 98 Although the Western drug is widely developed in Taiwan, there are still 1/3 of people taking traditional Chinese medicine. After year 2000, Chinese and Western medicine cooperation rise one after another. Integrated Chinese and Western medical treatment is performed more often. Moreover, many people are taking Chinese and Western medicine on their own. So it is more important and urgent to study the interaction of Chinese and Western medicine. Chinese and Western medicine interaction may come with adverse drug reaction, as well as side-effects reduction. At year 2000, Pew Internet & American Life Project show, 55% of Americans have tried to search for health care information via internet. When abnormal drug reaction is observed, information related to drug use can be located in a single website, and provided for physicians, pharmacists, and the general public to use. Website is developed through Prototyping model. PubMed and Electronic Theses and Dissertations System are the main data source for website database. Questionnaire is adopted to perform website system test and evaluation. According to analysis results, system quality and information quality have a significant positive influence on user satisfaction. As for user characteristics – education level and job title have a significant difference on user satisfaction. This website will continue to update medicine database, and provide statistical data of website inquiry logs for future research. Hopefully this website will reduce adverse drug interaction and promote overall medication safety. It is the main purpose of this research.

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Lin, Sheng-Shing, and 林聖興. "Constructing a Web Site for Drug-Herb Interaction." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/w3m6s4.

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碩士 中國醫藥大學 中西醫結合研究所 94 In order to provide the convenience for the clinical knowledge about combination use of Chinese herbs and modern medication, this study is aimed to construct a web site offering comprehensive information on drug-herb interaction. We searched journals from the PubMed websites as well as the dissertations and theses published in Taiwan with the topic of drug-herb interactions, and finally 147 articles totally been reviewed. Among these articles, there were 219 different kinds of drug-herb combinations in 481 records about drug-herb interaction. The most commonly described herbs were Ginkgo, Ginseng, Ma Huang, St. John’s wort, Licorice, and Dan Shen. We constructed a database which classified these data with the columns of the names of the drugs (both in Chinese and English), interaction and so forth. Subsequently, we designed a web page to present this database. Nevertheless, the usages of herbs in western countries is quite different from those in Taiwan. Herb is made in single form in the United States, while the traditional Chinese doctors prescribe composition of multiple herbs in Taiwan. The web site constructed in this study does not offer the validation of the drug-herb interactions because it needs further check in detail. The adverse reactions of drug-herb interactions mentioned in the international journals are worthy to beware. Further study is necessary to discuss the advantage and disadvantage of the integration of Chinese and western medicine.

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Hsueh, Tun-Pin, and 薛敦品. "Pharmacokinetic Study and Herb-Drug interaction of Yin-Chen-Hao-Tang." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/w3he39.

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博士 國立陽明大學 傳統醫藥研究所 107 Introduction: Hepatitis and chronic liver disease have been a sequelae healthcare problem worldwide including Taiwan. Patients having chronic hepatitis may be treated with diuretics spironolactone while compensative cirrhosis develops. Artemisia capillaris Thunb (Yin-Cen-Hao), Gardenia jasminoides Ellis (Zhi-Zi), and Rheum officinale Baill (Da-Huang) were a combined formulation intended to deal with hepatitis and jaundice. Researches have proved it with anti-hepatic fibrosis, anti-hepatic apoptosis, and alleviation of hepatic oxidative stress effects in bile duct ligation rats. However, herb-drug interactions of this common available herbal formula products could be a priority safety issue for the patient with the chronic liver disease under conventional diuretic treatment. The purpose of the study was aimed to discover the herb-drug interactions between the herbal formula Yin-Chen-Hao-Tang (YCHT) and diuretic drugs spironolactone, to guarantee the quality, safety, and efficacy of commonly used natural products. Material and methods: Selective high-performance liquid chromatography (HPLC) and HPLC tandem mass spectrometry (HPLC-MS/MS) methods were developed and validated for simultaneous determination of the bioactive compounds, scoparone, geniposide and rhein in YCHT and for diuretic spironolactone and metabolite canrenone, respectively. The interaction study was collecting urine sample after oral administrated with spironolactone (20 mg/kg, p.o.) with or without the pretreatment of pharmaceutical products YCHT (1 g/kg/day or 3 g/kg/day p.o.) for 5 days. The interaction experiments were performed in both normal and common bile duct ligation (CBDL) rats. Pharmacokinetic parameters of urine including cumulative amounts, excretion rate, the area under the rate curve (AURC), and terminal elimination half-life (t1/2) of spironolactone, as well as pharmacodynamics data of urine weight and volume, urinary sodium and potassium concentration, and sodium to potassium (Na+ / K+) ratio were acquired. Results: The interaction experiment combined the pharmacokinetic and pharmacodynamic results showed a significant raising in the cumulative amount and AURC of the metabolite canrenone under pretreatment of high dose YCHT. Meanwhile, the decrease of Na+ / K+ ratio in YCHT 3 g/kg group was noted accompanying with the increased potassium elimination. Besides, the significant decrease of the cumulative amount of canrenone, mean excretion rate, and area of rate curve in urine was discovered in the pretreatment of high dose YCHT in common bile duct ligation (CBDL) rats. The urine weight and volume were decreased significantly but not in urinary Na+ / K+ ratio under the high dose of YCHT.

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CAI, MING-CHANG, and 蔡明昌. "Development of cloud service and mobile application for drug-herb interaction query system." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/48s363.

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碩士 大仁科技大學 製藥科技研究所 106 Although today’s treatment is mainly based on the western medicine which had undergone more empirical researches, the well-developed traditional Chinese medicine has become a popular alternative for people in searching for cure of their diseases. Western medicines are usually composed of pure chemicals with known active pharmaceutical ingredients and possible adverse reactions. On the other hand, Chinese medicines usually consist of a whole tissue of plants or animals. Oftentimes, even if we identify the main active ingredients, there might be some subsidiary components which have not yet been analyzed. Making the matter more complicated, traditional Chinese medicines are often prescribed as a compound prescription. This is why when the patient is taking both western and Chinese medicines might pick up unexpected side effects due to the lack of understanding of the drug interactions might have taken place. Therefore, it is important to establish a database for searching drug interactions between traditional Chinese medicines and western medicines. In this study, we have established a cloud database providing the recent studies of drug-herb interaction, and drug-health food interaction and their searching attached systems. We also released a downloadable mobile application (APP) of this database, which can provide correct information for patients conveniently. From the database, if patients have any worries regarding to questions such as drug interactions, they can consult and discuss with the medical professionals in no time. Since both Chinese and western medicines are involved with intricate pharmacological science, it is hard to train qualified people to meet the needs. Accordingly, the ability of drug evaluation very much depends on the kind of hospital and its allocation of medical professionals the patient chooses. This database will continue to update when new studies are being released. By providing the latest reference for both patients and medical staffs, this database can help to develop combination treatment of Chinese medicine and western medicine.

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"Investigation of herb-drug interaction between statins and danshen-gegen decoction on cardiovascular disease." 2015. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1291778.

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Yau, Ka Chun. Thesis M.Phil. Chinese University of Hong Kong 2015. Includes bibliographical references (leaves 129-136). Abstracts also in Chinese. Title from PDF title page (viewed on 11, November, 2016).

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"Study on Herb-Drug Interaction and Anti-Cancer Effect of Polyoxypregnane Compounds from Marsdenia Tenacissima." 2016. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1292185.

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抗腫瘤中藥在臨床中的作用已經引起廣泛關注。通關藤Marsdenia tenacissima (Roxb.) Wight et Arn. 作爲一種傳統中藥，其提取物（MTE）現今被廣泛應用于腫瘤臨床，幷在非小細胞肺癌及結腸癌中療效明顯。本研究旨在通過對通關藤提取物的物質基礎和藥效基礎的研究，特別是在成分分析，藥物相互作用及抗腫瘤機制方面，爲其臨床應用和二次開發提供科學依據。 首先，雖然以前的研究證明多氧孕甾烷類化合物（POPs）是通關藤提取物的主要抗腫瘤藥效成分，但是目前對于這類化合物的系統定性和定量分析方法仍然欠缺。因此本研究首先建立了基于超高壓液相色譜聯用三重四級杆質譜的POPs定性和定量方法。在定性中，我們采用母離子掃描與全掃描相互結合以提高母離子確認的置信度，隨後針對鈉和銨加合離子進行子離子掃描以獲得豐富的特徵離子碎片。比較于其他文獻建立的方法，該方法靈敏度和特异性更好，幷能提供足够的特徵離子碎片進行POPs的結構解析。采用這種方法，我們從通關藤提取物中快速鑒定了110種POPs，而之前的報道采用離子阱質譜只鑒定了18或31種POPs。此外，我們建立了同時測定25種POPs的定量方法。我們采用甲酸作爲流動相添加劑以避免鈉和銨加合離子的競爭，幷采用鈉加合離子建立綫性方程，以進行定量分析。結果表明POP68, POP69以及POP70這三種POPs在提取物中含量最高，分別占有18%，12%以及14%。 其次，通關藤提取物在臨床上經常與其他化療藥物如紫杉醇聯用。我們前期結果表明，通關藤提取物中含量最高的三種化合物POP68, POP69以及POP70聯合運用（Mix-POPs）時，作爲前藥可以通過抑制P-gp以逆轉P-gp介導的紫杉醇多藥耐藥。由于P-gp是引起藥物相互作用的重要因素，我們針對通關藤提取物及其主要化合物Mix-POPs 進行了與紫杉醇的藥物相互作用研究。在SD大鼠中，單劑量口服通關藤提取物或Mix-POPs能顯著提高紫杉醇的體內暴露水平。這是由于通關藤提取物或Mix-POPs抑制了P-gp介導的紫杉醇膽汁消除。但是聯用幷沒有影響紫杉醇的消除半衰期。此外，我們發現Mix-POPs不會影響紫杉醇的體外和體內代謝以及組織分布。連續七天給予大鼠Mix-POPs幷不影響P-gp和藥物代謝酶CYP450s在肝臟和小腸中的表達，在大鼠中也沒有引起毒性。在 Mix-POPs與紫杉醇在連續給藥（每天一次，連續六天）後，我們發現，與紫杉醇單用組比較，在最後一次劑量下，紫杉醇的消除半衰期及其在24 h後的組織分布沒有顯著改變，這證明Mix-POPs與紫杉醇間的相互作用是可預測的；雖然大鼠體內紫杉醇的暴露增加了，但是其毒性幷無明顯增加。基于以上結果，Mix-POPs與紫杉醇之間存在一定的藥物相互作用，也爲它們的聯合用藥提供了可靠的有利依據。另外，我們首次報道了通關藤提取物及其主要化合物POPs由P-gp介導的草藥-藥物相互作用。 再者，雖然通關藤提取物已被廣泛證實具有直接抗腫瘤作用，但是目前爲止只有個別POPs被發現有細胞毒作用。而且，這些POPs的作用機制尚不清楚。因此，本研究篩選了一系列POPs的細胞毒活性，以期研究它們的作用機制。我們發現POP14在非小細胞肺癌細胞和結腸癌細胞上具有顯著的細胞毒作用，其IC50值（48 h）在7.70 ± 0.98到18.50 ± 1.1 µM 之間，幷且不影響正常結腸細胞CCD 841 CoN 的生長。POP14能誘導DNA損傷，從而增加p53在p53野生型以及突變型腫瘤細胞中的蛋白表達，進一步通過p53介導阻滯腫瘤細胞周期在G0/G1期，誘導細胞雕亡。有趣的是，我們發現POP14作爲前藥可以通過抑制P-gp作用逆轉P-gp介導的紫杉醇多藥耐藥。POP14可以在體內和體外經過腸道菌介導的脫葡萄糖轉化爲其活性代謝産物POP14M。而POP14M是有效的P-gp抑制劑，能特异性地通過氫鍵與P-gp的藥物結合位點結合，進而抑制P-gp的ATP酶活性。因此，我們的研究結果首次證實，POP14不但具有直接細胞毒作用，而且可以作爲前藥抑制P-gp作用以逆轉P-gp介導的多藥耐藥。因此，POP14是有潜力的抗腫瘤活性成分，幷有可能與通關藤提取物有相似的用途，既可單用又可與其他藥物聯用，既可口服亦可通過靜脉注射。 綜上所述，本研究從不同的角度（包括成分分析，質量控制，藥物相互作用以及作用機制）對通關藤提取物及其活性成分POPs進行了系統研究，爲其合理的臨床運用提供了科學依據，幷且有助于從通關藤提取物及其活性成分POPs進行新的抗癌藥物研發。 There have been growing interests in the anti-cancer effect of traditional Chinese medicine (TCM). This study focused on a TCM herb, Marsdenia tenacissima (Roxb.) Wight et Arn.. Clinically, M. tenacissima extract (MTE) have long been used for treatment of various cancers such as non-small cell lung cancer (NSCLC) and colon cancer. The aims of present study were to investigate the chemical and pharmacological basis of MTE, and to provide scientific evidences for its anti-cancer use. In particular, the main issues addressed in this study included chemical analysis, herb-drug interaction and anti-cancer mechanisms. Firstly, although existing evidences have suggested that polyoxypregnanes (POPs) are the main active ingredients responsible for the anti-cancer effect of MTE, till now, the method for systematically qualitative and quantitative analysis of POPs in MTE is still lacking. Therefore, the present study firstly developed a method based on UHPLC-QqQ mass spectrometry (MS) for rapid profiling and robust quantification of POPs in MTE. POPs profiling was achieved by using a precursor ion scan together with full scan followed by information-rich adduct ion targeted product ion scans. This new approach showed advantage over previous studies because it obtained sufficient MS/MS fragmentation information for the structural elucidation of most POPs. Using this newly developed method, 110 POPs were identified from MTE, while previous studies using ion trap-MS detected only 18 or 31 POPs from MTE. Subsequently, robust quantification of 25 POPs in MTE was performed by monitoring [M+Na]+ ions. The great advantage of using formic acid rather than ammonium acetate as additive in the mobile phases was the avoidance of the simultaneous presence of [M+NH4]+ and [M+Na]+ ions during ionization which led to low reproducibility of MS response. The results showed that POP68, POP69 and POP70 were the three most abundant POPs representing 18%, 12% and 14% (g/g), respectively, of the total extract. Secondly, combinational use of MTE and its main constituents, POPs, with other anticancer drugs like paclitaxel may lead to herb-drug interactions, since our previous study demonstrated that a mixture of three most abundant POPs (Mix-POPs, containing POP68, POP69 and POP70) from MTE as pro-drugs could be used in combinational therapy to circumvent paclitaxel multi-drug resistance (MDR) via modulating P-gp function. Therefore, in the present study, the potential pharmacokinetic interactions between MTE or its major constituents (Mix-POPs) and paclitaxel were investigated. In male SD rats, a single oral dose of MTE (110 mg/kg, containing 50 mg/kg Mix-POPs) or Mix-POPs (50 mg/kg) significantly increased systemic exposure of paclitaxel by inhibiting P-gp-mediated biliary excretion, but not altering its elimination half-life (t1/2). Notably, oral Mix-POPs did not change the metabolism and the tissue distribution profile of paclitaxel. Moreover, multiple-dose treatment of Mix-POPs did not change the gene and protein expression of P-gp and major CYP450s in both liver and intestine, and did not show any toxicity in rats. Subsequently, it was demonstrated that, after repeated doses (once daily for 6 days), the combinational use of Mix-POPs with paclitaxel did not significantly change the paclitaxel elimination t1/2 and tissue distribution profile, comparing with the paclitaxel alone group. More importantly, no obvious enhancement of adverse effects of paclitaxel was observed in rats, despite the systemic exposure of paclitaxel was significantly enhanced by Mix-POPs. The results demonstrated that the pharmacokinetic interaction via inhibiting P-gp-mediated paclitaxel excretion by Mix-POPs provided a potential benefit for their combinational use for the reversal of paclitaxel MDR. Moreover, to the best of our knowledge, this is the first report on the herb-drug interactions between MTE (and its major constituents) and paclitaxel. Thirdly, although it has been repeatedly demonstrated that MTE had direct cytotoxicity, cytotoxic POPs were only reported in scattered studies, and the underlying mechanisms remain unclear. In the present study, it was found that POP14 exhibited cytotoxicity in human NSCLC and colon cancer cells with IC50 (48 h) ranged from 7.70 ± 0.98 to 18.50 ± 1.1 µM, but did not affect the viability of normal colon cells. Further study delineated that POP14 induced p53-dependent G0/G1 phase arrest and apoptosis via causing DNA damage in both p53 wide type and mutant cells. More interestingly, POP14 was found to be underwent gut microbiota-mediated biotransformation both in vitro and in vivo and acted as a pro-drug to exert P-gp modulating effect and to reverse paclitaxel MDR in P-gp-overexpressing cancer cells. It was demonstrated that POP14M, the active metabolite of POP14, was a potent P-gp modulator, and could bind to P-gp drug binding pocket to inhibit P-gp ATPase activity. The finding revealed that POP14 showed direct cytotoxicity and also acted as a pro-drug to reverse P-gp mediated MDR. The dual action of POP14 has made it a promising anti-cancer drug candidate that could be used in a similar way as MTE, singly or jointly, orally or intravenously. Taken together, the present study from different aspects, including chemical profile, quality control, pharmacokinetic interaction and mechanisms of pharmacological action, provided scientific basis for the rational use of MTE and its constituents in the clinical setting, and also facilitated novel drug development from MTE and its main constituents POPs. Wu, Xu. Thesis Ph.D. Chinese University of Hong Kong 2016. Includes bibliographical references (leaves ). Abstracts also in Chinese. Title from PDF title page (viewed on …). Detailed summary in vernacular field only. Detailed summary in vernacular field only. Detailed summary in vernacular field only. Detailed summary in vernacular field only. Detailed summary in vernacular field only.

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Wang, Er-Ying, and 王爾瑩. "Implementation and outcome of herb-drug interaction alert system at one teaching hospital in Taiwan." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/75738725885906173470.

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碩士 臺北醫學大學 藥學研究所 98 Background: The widely use of herbal products among the public has raised some concerns regarding issues of herb-drug interactions. In Taiwan, traditional medicine (TM) continues to be widely used. However, current information about herb-drug interactions, including the incidence of herb-drug interactions and the risk of related adverse drug events (ADEs) in Taiwan are still limited. Objectives: The purpose of this study is to (1) establish a herb-drug interaction alert system; (2) estimate the incidence of herb-drug interactions and the risk of ADEs related to herb-drug interaction; (3) evaluate the outcomes of implementation of the herb-drug interaction alert system. Method: (1) The potential herb-drug interactions in the alert system were established based on case reports, clinical trials, or theoretical interactions. (2) Outpatients who had also visited traditional medicine clinics and had potential herb-drug interaction(s) in 2009 and 3 months after implementation of alert system were enrolled. Patient’s demographic information, the information on the prescriptions and laboratory data were collected from health information system to evaluate the incidence and the patterns of herb-drug interactions, and the risk of ADEs. (3) Information from alert system was collected to evaluate the doctors’ reply after receiving the alerts. Results: There were 1,891 potential herb-drug interactions documented in the herb-drug interaction alert system, 61 (3.2%) interactions were based on case reports. In 2009, the incidence of herb-drug interactions was 13.7%. There were 563 patients had potential herb-drug interactions, 72.3% were female, the most common western medicines were antihypertensive agents (25.5%), hypoglycemics (22.3%), antacids (17.4%) and anticoagulants (17.3%). Among these patients, 4 (0.7%) patients experienced an adverse drug event related to herb-drug interaction(s). The incidence of herb-drug interactions after implementation of alert system was decreased from 15.1% to 11.2% (p = 0.014), and approximately 36.2% of doctors changed prescription medicine after receiving the alarm information and and 27.7% monitored available parameters. Conclusion: The incidence of herb-drug interactions among outpatients was 13.7%, and the risk of ADEs was 0.7%. The incidence of herb-drug interactions significantly decreased to 11.2% (p = 0.014) after implementation of the herb-drug interaction alert system. The information of evidence-based herb-drug interactions is still limited, more studies are needed in the future.

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Arnold, Christof Karric, and 安珂. "Herb-drug interaction of Radix Scutellariae herbal extract powder and indinavir in Sprague-Dawley rats." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/21429358066086009397.

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碩士 國立陽明大學 傳統醫藥研究所 98 The integration of traditional Chinese medicine into a modern context poses certain difficulties. Pharmacological mechanisms developed in the field of science can be used as a tool to examine the properties of medicinal herbs. Identifiable small molecules help to provide some outline of a medicinal herb’s characteristics. The root, known as Radix Scutellariae (黃芩) which is an herb appearing in the oldest known Han records on medicinal substances, is chosen for this investigation due to its properties of CYP450 3A enzyme inhibition. The human immunodeficiency virus (HIV) protease inhibitor, indinavir (IDV), is metabolized by CYP450 3A enzymes making it a prime candidate for an herb-drug interaction. HIV positive patients on highly active anti-retroviral therapy (HAART) medications are exposed to the inherent risks of this pharmaceutical intervention, and it is important for clinicians to be aware of herb-drug interactions for the safety of the patient. This leads to the hypothesis that concurrent treatment with Radix Scutellariae herbal extract powder would enhance the absorption of IDV due to less of the drug being metabolized in the intestine and liver during first pass metabolism. A free moving Sprague Dawley (S-D) rat model combined with a cross-over study protocol is used to test this hypothesis. A validated liquid chromatography-mass spectrometry (LC-MS/MS) method analyzes the drug’s plasma concentration. The Mann-Whitney-Wilcoxon rank-sum test is performed to determine statistical relevance. The results show that the area under the plasma concentration versus time curve (AUC) of IDV undergoes a dose dependent increase with the concomitant treatment of Radix Scutellariae. In patients currently using Radix Scutellariae, the kidney toxicity of IDV can be taken into consideration, and patients should choose an alternative HAART drug or start on the lowest dose of IDV.

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Lai, Jian-Long, and 賴建龍. "Construct a Knowledge Management Information System of Chinese Herb and Drug Interaction-Utilizing Data Mining Technique." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/50214514030909563015.

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碩士 亞洲大學 生物資訊學系碩士班 97 The domestic and international periodical research to the Chinese and Western medicine reciprocation has already been popular, it was shown that the traditional Chinese medicine popularizes the phenomenon and already treats and reaches model influence to the people's Western medicine in domestic use, combine with computer progress, information of science and technology, a lot of experts and scholars medical institutes set up Chinese and Western medicine reciprocation database website support people to require safely to use. However, it is limited to expert's knowledge result, and make the Chinese and Western medicine reciprocation information benefit reduce. Our study can utilize materials prospect technology utility to make medicine information from a large number of periodical thesis of international research reports, and that immediately quantization convey to computer database materials, offer a clinician to do the Chinese and Western medicine through the information system, even reach the goal of the prescription modification.

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Hsueh, Thomas Y., and 薛又仁. "Herb Drug Interaction between Epimedium sagittatum Extract on the Pharmacokinetics of Sildenafil and Dapoxetine in Rats." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/03177491635402574879.

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博士 國立陽明大學 傳統醫藥研究所 104 Epimedium sagittatum (Sieb. et Zucc.) Maxim is one of the herbs used to treat erectile dysfunction and premature ejaculation in Traditional Chinese Medicine. Sildenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction in Western Medicine. Dapoxetine is a selective serotonin reuptake inhibitor used for the management of premature ejaculation in Western medicine. This study was divided into two subsets, aiming to evaluate the herbal-drug interaction of Epimedium sagittatum extract on the pharmacokinetics of sildenafil in rats by ultra-performance liquid chromatography and the herb–drug interaction of Epimedium sagittatum extract on the pharmacokinetics of dapoxetine in rats by using high-performance liquid chromatography-tandem mass spectrometry. In the first part, the rat plasma was sampled from each anesthetized rat after pretreatment with 3-days Epimedium sagittatum extract (1/2 g/kg/day) and intravenous injection with sildenafil (10/30 mg/kg). The pharmacokinetic data demonstrate that the area under the concentration-time curve (AUC) of sildenafil (10 mg/kg) was significantly decreased in groups that received a high dose of Epimedium sagittatum extract. In the second part, the rat plasma was pretreated for 3 days with Epimedium sagittatum extract (2g/kg/day) and dapoxetine on the fourth day (10 mg/kg) by oral or intravenous administration. The AUC of oral dapoxetine was 81 ± 13 minμg/mL compared with 114 ± 13 minμg/mL in those pretreated with Epimedium sagittatum extract for 3 consecutive days. The herb drug pharmacokinetic interaction was not significant between Epimedium sagittatum extract and dapoxetine. In conclusion, the study demonstrates the v diverse pharmacokinetic activity of Epimedium sagittatum while used with different medications. The use of Epimedium sagittatum extract should be advised so as to prevent possible herb drug interaction in clinical practice.

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Lo, Pei-Chia, and 羅珮嘉. "The Herb-Drug Interaction among Children with Asthma in Taiwan: A Population-Based Nationwide Cohort Study." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/69936258600599010645.

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碩士 國立陽明大學 傳統醫藥研究所 104 Introduction The prevalence of childhood asthma under 18 years old is 12% worldwide, and the prevalence rate of childhood asthma in Taiwan increased year by year from 13.0% in 2002 to 16.9% in 2008. According to the past research, a proportion of medication induced asthma exacerbation, such as aspirin or NSAIDs. On the other hand, some parents seek traditional Chinese medicine (TCM) to help their children to relieve asthma symptoms. The safety and efficacy of TCM in treating childhood asthma has not been established, therefore, the aim of the study is to (1) investigate the relationship between NSAIDs and asthma exacerbation in children (2) investigate the relationship between integration of Western medicine and TCM and asthma-related hospitalization in children with asthma. Methods The study population included one million randomized people enrolled in the year 2005 from the National Health Insurance Research Database (NHIRD) in Taiwan. The research contains two parts. Both the study designs were conducted retrospective cohort study, and population aged less than 18 years old and having at least three times confirmed diagnosis by physicians were enrolled. In the research Part 1, all the medical records from 1997 to 2012 were researched, and the study populations were divided into groups of concurrently using NSAIDs with anti-asthmatic drugs (index group), and only using anti-asthmatic drugs (reference group). The start of the observation date was the first diagnosis date of asthma and the endpoint was either the date that patients were hospitalized with asthma initially or the date of last medical visit before December 31, 2012. The Relative Risk was used to estimate the risk of asthma-related hospitalization in the two groups, and logistic regression model was used to ananlyze the most frequently prescribed NSAIDs in 1-2 days prior to asthma-related hospitalization. In the research Part 2, we conducted a retrospective cohort study with the population who was diagnosed with asthma at the age less than 18 years old, indeed, at least three times confirmed diagnosis by physicians were enrolled. The medical records from 2000 to 2012 were researched, and we divided the study population into group of using TCM more than 30 days (traditional Chinese medicine, TCM users), and group of using TCM less than 30 days or without using TCM (Non TCM users). After adjustment for gender, age, comorbidities and types of asthma medication, the risk of asthma-related hospitalization in the two groups were estimated by using Cox proportional hazards model. Results In research Part1, among total 29,484 patients, 19,622 (66.6%) patients used anti-asthmatic agents alone (reference group), while 9,862 (33.4%) patients used anti-asthmatic agents concurrently with NSAIDs (index group). Index group had more asthma-related hospitalization (RR: 1.35, 95% CI: 1.30–1.41). After adjusting for NSAIDs, we found that aspirin, ibuprofen, and diclofenac posed certain risks with regard to asthma-related hospitalization, and exposure to ibuprofen in 7 to 365 days had positive correlation to asthma-related hospitalization (aOR: 1.53-1.54, 95% CI:1.01-2.33). In research Part2, among the total 33,685 patients, 14,783 (43.6%) were TCM users, and 19,082 (56.4%) patients were non-TCM users. The TCM users were mostly girls in gender, and the age distribution were older than non-TCM users, and higher percentage was found living in central Taiwan, Kaohsiung city, and southern Taiwan. In the aspect of cormobidity, patients combined with allergic rhinitis, acute bronchitis, sinusitis, gastroesophageal reflux disease, or urticaria are prone to use TCM combination therapy. After adjustment for gender, age, cormobidities and types of asthma medication, TCM therapy had a lower risk of asthma-related hospitalization in comparison with non-TCM therapy (aHR:0.90,95% CI: 0.83-0.95). Moreover, children older than 6 years of age using TCM therapy more than 180 days had a 29% reduction in the asthma-related hospitlaization consequently (aHR:0.71,95% CI:0.51-0.98). Conclusion NSAIDs have positive correlation with asthma-related hospitalization in children, especially ibuprofen, diclofenac, and aspirin. Furthermore, long-term exposure to ibuprofen of 7 to 365 days increased the risk for asthma-related hospitalization. On the other hand, integration of Western medicine and TCM in treating children with asthma was safe and did not increase the risk of asthma-related hospitalizaion. Moreover, using TCM combination therapy in children older than 6 years of age decreased the risk of subsequent asthma-related hospitalization.

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Chen, Jiun-Liang, and 陳俊良. "In Vivo and In Vitro Studies of Herb-Drug Interaction in Human Breast Cancer Cells Treated with Tamoxifen or Trastuzumab." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/15399455985723996186.

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博士 國立陽明大學 傳統醫藥研究所 101 There is recent trend whereby patients with breast cancer seek integrative medical treatment when receiving either hormonal (tamoxifen) or target (trastuzumab) therapies. Our previous in vitro studies demonstrated that the Chinese medicine Si-Wu-Tang (SWT) stimulates MCF-7 cell growth via activation of ER-α and HER-2 signaling. Traditional Chinese medicine (TCM), one of the most commonly used complementary and alternative medicine (CAM) in Taiwan, has been increasingly used to treat breast cancer when receiving hormonal (tamoxifen) therapies recently. Jia-Wei-Xiao-Yao-San (JWXYS) was the most common Traditional Chinese medicine used in all prescriptions from the National Health Insurance Research Database of Taiwan. The present study was aimed to investigate herb-drug interaction of cell proliferation in tumor-bearing mice (in vivo) treated with SWT and tamoxifen and such interaction of proliferation capacity in breast cancer cells treated with SWT and trastuzumab in vitro and in vitro and in vitro evidence of interaction between JWXYS and tamoxifen. To assess in vivo SWT-Tamoxifen interaction, female MCF-7 implanted athymic nude mice were randomly separated into five groups, namely, vehicle, estradiol, SWT, tamoxifen and SWT + Tamoxifen groups. All mice were sacrificed after 21 days of treatment. Body weight, uterine weight, tumor volume and tumor weight were measured. To assess in vitro SWT-trastuzumab interaction, BT-474 and SK-BR-3 breast cancer cells were co-treated with SWT and trastuzumab. This was followed by MTT assays and cell cycle analysis to measure cell proliferation and Western blotting to analyze the protein expression in growth-related signal pathways. To assess JWXYS + Tamoxifen interaction, MCF-7 breast cancer cells were co-treated with JWXYS and Tamoxifen. This was followed by MTT assays and cell cycle analysis to measure cell proliferation and Western blotting to analyze the protein expression in growth-related signal pathways. Immunohistochemistry was performed to detecting autophage in cancer cells.To assess JWXYS-Tamoxifen interaction, female MCF-7 implanted athymic nude mice were randomly separated into six groups, namely, vehicle, estrodial, Tamoxifen , JWXYS(1.3 g /kg) + Tamoxifen, JWXYS(2.6 g /kg) + Tamoxifen, JWXYS(3.9 g/kg) + Tamoxifen groups. All mice were sacrificed after 21 days of treatment. Body weight, tumor volume and tumor weight were measured. SWT reversed tamoxifen-induced anti-proliferative effects such as tumor weight, tumor volume and increased ER-α and N-cadherin expression among the SWT + Tamoxifen-treated group, compared to Tamoxifen-treated group. Furthermore, SWT reversed trastuzumab-induced anti-proliferative activity in HER2 (+) cell lines (SK-BR-3 and BT-474) through increased phosphorylation of the cell cycle regulatory protein p27(Kip1) and possibly the anti-apoptosis protein P38. The results showed that JWXYS had no cytotoxicity on MCF-7 cells. There were no statistical changes, in terms of cell number, cell cycles, proliferation signals such as AKT, ERK, P38, p27(Kip1), and LC3II expression between JWXYS + Tamoxifen groups and Tamoxifen alone group. Besides, in MCF-7 xenograft mice, there was no significant changes, in terms of tumor weight, the protein expression of AKT, ERK, P38 and p27(Kip1), between JWXYS (1.3 ~ 3.9 g/kg) + Tamoxifen groups and Tamoxifen alone group. However, there was a significantly decreased LC3II protein expression in low dose (1.3 g/kg), but not middle dose (2.6 g/kg) or high dose (3.9 g/kg), of JWXYS + Tamoxifen groups, compared to Tamoxifen alone group. Based on the in vivo and in vitro demonstration of herb-drug interference in breast cancer cells, we conclude that physicians should pay more attention to such interference when treating patients with receptors (+) [ ER (+) or PR(+) or HER2 (+) ] breast cancers.

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Camelo, Sandra Marisa Alves. "Riscos e/ou benefícios da fitoterapia no tratamento da obesidade de pacientes com co-morbilidades associadas." Master's thesis, 2017. http://hdl.handle.net/10284/5938.

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Atualmente a obesidade é considerada a desordem nutricional mais comum em todo o mundo. É considerada não apenas um problema de estética, mas principalmente um problema de saúde, responsável pelo aparecimento de doenças graves e pelo aumento da mortalidade e da morbilidade. A obesidade é reconhecida como um distúrbio inflamatório crónico de baixo grau e vários estudos sugerem que este estado inflamatório favorece o aumento do risco de várias doenças, incluindo doenças cardiovasculares, diabetes, osteoartrite, dispneia, apneia do sono, doença pulmonar obstrutiva crónica, entre outras. De entre estas complicações, a diabetes é a que se relaciona mais fortemente com a obesidade. Segundo alguns estudos, em países ocidentais, cerca de 58% dos casos de diabetes tipo 2 estão relacionados com o excesso de peso. Existem igualmente evidências que a obesidade e a diabetes do tipo 2 predispõem para a doença de Alzheimer. A obesidade e o excesso de peso podem ser combatidos utilizando diversas terapias. Uma destas é a fitoterapia, terapia que se tem vindo a assumir cada vez mais como um tratamento de escolha pelo doente que pretende reverter a sua patologia, principalmente pela facilidade de acesso a este tipo de compostos. A fitoterapia é uma forma de tratamento baseada nas propriedades naturais curativas de plantas medicinais e os efeitos destas plantas dependem da sua composição. A fitoterapia tem sido reconhecida como benéfica e eficaz em vários tipos de patologias, entre as quais a obesidade e excesso de peso. O recurso à fitoterapia no tratamento da obesidade é uma prática comum, destacando-se como exemplos de fitoterápicos que foram alvo de um estudo mais aprofundado nesta tese: a laranjeira amarga (Citrus aurantium), o tamarindo do malabar (Garcinia cambogia) e a planta de chá verde (Camellia sinensis). Estes extratos de plantas contendo moléculas bioativas podem contribuir para a ocorrência de interações medicamentosas, quando administrados a pacientes sob tratamento farmacológico convencional. De acordo com estudos publicados, os compostos farmacologicamente ativos das plantas podem interferir significativamente na farmacocinética e/ou farmacodinâmica de diversos fármacos, podendo provocar consequências graves aos pacientes. O objetivo principal desta dissertação é a apresentação de uma revisão bibliográfica sobre o uso da fitoterapia como uma opção viável e acessível, para o tratamento da obesidade, realçando quer os seus benefícios, quer os potenciais riscos e/ou limitações. Pretende-se identificar os fitoterápicos com ação anti obesidade, e ainda outros usados na perda de peso corporal, discutindo o seu mecanismo de ação e debatendo outros efeitos que possam resultar da sua utilização, nomeadamente no que respeita a aspetos relacionados com a toxicidade e/ou a possível ocorrência de interações com outros fármacos em pacientes polimedicados. Currently obesity is considered the most common nutritional disorder in the world. It is considered not only an aesthetic problem, but mainly a health problem, responsible for the appearance of serious diseases and increased mortality and morbidity. The obesity is recognized as a chronic inflammatory disorder of low grade and several studies suggest that this inflammatory condition favors increased risk of various diseases including cardiovascular disease, diabetes, osteoarthritis, dyspnea, sleep apnea, chronic obstructive pulmonary disease, among others. Diabetes is the complication that present a higher correlation with obesity. According to some studies, in western countries, about 58% of type 2 diabetes cases are related to the excess of weight. There is also evidence that obesity and type 2 diabetes predisposes for Alzheimer's disease. Obesity and overweight can be treated using several therapies. One of these is the phytotherapy that has been assuming more and more as a key treatment for the patient to revert to its pathology, especially due to the facility of access to this type of compounds. The phytotherapy is a form of treatment based on natural healing properties of medicinal plants, and the effects of these plants depend on the composition they have. Phytotherapy has been recognized as beneficial and effective in some pathologies, including obesity and overweight. The use of herbal medicine in the treatment of obesity is a common practice. Bitter orange (Citrus aurantium), tamarind of malabar (Garcinia cambogia) and green tea plant (Camellia sinensis) are some examples of medicinal plants which have anti-obesity properties and that were studied in more detail as part of this thesis. These plant extracts containing various bioactive molecules may contribute to the occurrence of interactions with several drugs when administered to patients under conventional pharmacological treatment. According to published studies, the pharmacologically active compounds of the plants can significantly interfere with the pharmacokinetics and/or pharmacodynamics of various drugs, which can lead to serious consequences for patients. The main objective of this work is to present a literature review on the use of herbal medicine as a viable and affordable option for the treatment of obesity, highlighting either their benefits or potential risks and / or limitations. The aim is to identify herbal medicine with an anti-obesity action, as well as others used in body weight loss, discussing its mechanism of action and debating other effects that may result from its use, particularly with regard to aspects related to toxicity and /or the possible occurrence of interactions with other drugs in polymedicated patients.

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Ting, Chin-Tsung, and 丁金聰. "Prescription frequency and patterns of Chinese herbal medicine for liver cancer patients in Taiwan and herb-drug interaction between LongDan XeiGan Tang and sorafenib in rats." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/wz94p3.

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博士 國立陽明大學 傳統醫藥研究所 106 English abstract Background: Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). Patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines (CHM) to reduce the side effects of sorafenib. The aim of this study is to investigate the prescription frequency and patterns of CHM use in treating HCC in Taiwan, and to understand the herb-drug interactions between Longdan Xiegan Tang (LDXGT) and sorafenib as well as the hepatoprotective effect of LDXGT on sorafenib induced hepatotoxicity and histopathological change. Materials and methods: The claims data of the National Health Insurance and the Registry for Catastrophic Illness during 2002 to 2009 in Taiwan were analyzed. The data was adjusted with cumulative survival, person-year and ratio of standardized incidence rate to identify the potentially effective CHM in clinical practice in Taiwan. A validated HPLC system was developed to investigate the herb-drug interactions, metabolism between Longdan Xiegan Tang formulation (LDXGT) and sorafenib. Liver enzyme levels and histopathology of liver slices were used to evaluate the potential hepatoprotective effects of LDXGT on sorafenib-induced hepatotoxicity. Results: 73918 newly diagnosed HCC subjects were identified. Of them, Oldenlandia diffusa (Bai-Hua-She-She-Cao), Radix et Rhizoma Rhei (Da Huang), Xiao-Chai-Hu-Tang, Jia-Wei-Xia-Yao-San, Longdan-Xiegan-Tang and Gan-Lu-Yin were the most obviously increased CHMs been used for HCC patients. The pharmacokinetic studies showed no significant herbal drug interaction between LDXGT and sorafenib. Grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Pretreatment with variable doses of the LDXGT did not suppress the sorafenib-induced hepatotoxicity and histopathological alterations. Conclusion: In this study, we established an accurate and validated method for the frequency and patterns of CHM use in treating HCC in Taiwan and a validated HPLC system the herb-drug interaction between LDXGT and sorafenib in rats. Our study can be provided as physician reference of CHM selection, modernization of CHM, clinical research and treatment of liver cancer.

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