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1
Reimche, Leanne D. "Potential drug-drug interactions in a Canadian tertiary-care hospital." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27724.
Full textAbstract:
Drug-Drug interactions (DDIs) are an important focus of patient safety because they account for a substantial number of adverse drug events and are preventable.
Objective. To study DDIs in a Canadian hospital, a retrospective observational study was completed using the Ottawa Hospital Data Warehouse.
Study cohort. Admissions to the Ottawa hospital between January 1, 1999 and September 30, 2005.
Methods. Potential drug-drug interactions were identified by examining all co-administered medications for combinations of drugs previously reported to have potential interactions. Poisson regression was used to examine potential patient and hospital factors associated with drug-drug interactions.
Results. Between 1999 and 2005, we found at least one DDI in 19.3% of all hospitalizations and 18.8% of hospitalization time. Category 1 (drug combinations to be avoided) and Category 2 (drug combinations usually avoided) interactions were rare, accounting for only 0.022% and 1.4% of hospitalization time, respectively. Category 3 interactions (drug combinations requiring alteration) occurred with 5.7% of all drug orders and were present for 17.4% of hospitalization time. Poisson regression analysis found that DDIs were significantly more likely to occur in patients who were: older; admitted to a surgical service; had a greater number of comorbidities; and were prescribed a greater number of drugs.
Conclusion. Drug-Drug interactions occurred frequently during hospitalization. Future study is required to determine if the interactions identified are associated with important clinical outcomes.
2
Sánchez, Pascua Teresa. "Carboxylesterase 1 genetic variability, expression and potential for drug-drug interactions." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2006752/.
Full textAbstract:
Carboxylesterase 1 (CES1) is the main human liver esterase and is involved in the metabolism and disposition of numerous endogenous and pharmacological compounds. Some of the substrates of this enzyme are widely prescribed agents such as clopidogrel (Plavix®), methylphenidate (Ritalin®) and oseltamivir (Tamiflu®). However, there is much uncertainty regarding the genetic variability within CES1, and its regulation and involvement in drug-drug interactions (DDI). Polypharmacy is frequent in elderly, HIV and tuberculosis infected populations, and the risk of harmful DDIs is high, especially when these populations overlap. The role played by CES1 on the treatment of all these three pathologies and vice versa needs to be better characterized. In this thesis the role of CES1 genetic variability and its potential role in DDIs are explored both in isolation and in conjunction with other genetic, demographic, physio-pathological and iatrogenic factors. The impact of CES1 genetic variability was assessed on the anti-platelet effect of clopidogrel as well as on isoniazid pharmacokinetics in acute coronary syndrome (ACS) and HIV/Tuberculosis co-infected populations respectively. DDIs mediated by CES1 were explored in a HIV positive cohort treated with clopidogrel and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Also, in vitro experiments with primary hepatocytes were used to investigate CES1 intracellular expression in the presence of prototypical PXR inducers used in tuberculosis treatment. The results of this thesis show that the CES1 rs2244613 SNP does affect clopidogrel anti-aggregant activity and may contribute to treatment non-response. Another CES1 variant, rs3815583, was found to be associated with changes in isoniazid pharmacokinetics. The studies did not indicate that NNRTI coadministration with clopidogrel would impair the anti-platelet activity since no relevant changes in exposure of the antiplatelet agent were identified. In the same way, the results do not anticipate DDIs between CES1 substrates and rifamycins, since no induction of expression was identified after incubating primary human hepatocytes in vitro with rifampicin, rifabutin and rifapentine. In conclusion, the results shown in this thesis support the idea that CES1 genetic variability may play a bigger role than previously suspected in treatment response but may not be a mediator of clinically relevant DDIs.
3
Scott, Rebecca Jane. "An in vivo cytochrome P450 probe cocktail approach to identify potential drug-drug interactions." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407189.
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Ventura, Ventanachs Verònica. "In vitro metabolism and drug-drug interaction potential of irosustat, a steroidal sulfatase inhibitor." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/124483.
Full textAbstract:
Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. Its structure is a tricyclic coumarin-based sulfamate that undergoes desulfamoylation in aqueous solution, yielding the sulfamoyl-free derivative, 667-coumarin.
The first aim of the present work was to study the in vitro metabolism of irosustat, including its metabolic profile in liver microsomes and hepatocytes, the potential species differences, and the identification of the main metabolites. And the second aim of the present work was to predict potential drug-drug interactions between irosustat and possible concomitantly administered medications through the investigation in vitro of the enzymes participating in the metabolism of irosustat and its inhibition/induction potential with the main drug-metabolizing enzymes. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied.
Irosustat was extensively metabolized in vitro, showing similar metabolite profiles among rat, dog, monkey, and humans (both sexes). In liver microsomes, the dog was the species that metabolized irosustat most similarly to metabolism in humans. Marked differences were found between liver microsomes and hepatocytes, meaning that phase I and phase II enzymes contribute to irosustat metabolism. Various monohydroxylated metabolites of irosustat and of 667-coumarin were found in liver microsomes, which mostly involved hydroxylations at the C8, C10, and C12 positions in the cycloheptane ring moiety. 667-Coumarin was formed by degradation but also by non-NADPH-dependent enzymatic hydrolysis, probably catalyzed by microsomal steroid sulfatase. The main metabolites formed by hepatocytes were glucuronide and sulfate conjugates of 667-coumarin and of some of its monohydroxylated metabolites.
The major cytochrome P450 enzymes involved in the transformation of irosustat were CYP2C8, CYP2C9, CYP3A4/5, and CYP2E1. Moreover, various phase II enzymes (UDP-glucuronosyltransferases and sulfotransferases) were capable of conjugating many of the metabolites of irosustat and 667-coumarin; however, the clinically relevant isoforms could not be elucidated.
Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 μM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 μM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.<br>Irosustat és un inhibidor irreversible de la sulfatasa esteroidal, de primera generació, actualment en desenvolupament per al tractament del càncer dependent d'hormones.
Els objectius d'aquest treball van ser estudiar el metabolisme in vitro d'irosustat, incloent el seu perfil metabòlic en microsomes hepàtics i hepatòcits, les diferències entre espècies, així com la identificació dels principals metabòlits. I també predir les possibles interaccions fàrmac-fàrmac entre irosustat i possibles medicaments administrats de forma concomitant, a través de la investigació in vitro dels enzims que participen en el metabolisme de irosustat i el seu potencial d'inhibició / inducció dels principals enzims metabolitzants de fàrmacs. La interacció dels inhibidors de l'aromatasa en el metabolisme in vitro del irosustat també es va estudiar.
Irosustat és extensament metabolitzat in vitro, mostrant perfils metabòlics similars entre rates, gossos, micos i humans (ambdós sexes). En microsomes de fetge, el gos va ser l'espècie que metabolitza irosustat de forma més similar al metabolisme en humans. 667-coumarin es va formar per degradació, però també per hidròlisi enzimàtica no dependent de NADPH, probablement catalitzada per la sulfatasa esteroidal microsomal. Es van trobar grans diferències entre els perfils metabòlics de microsomes hepàtics i de hepatòcits, significant que tant enzims de fase I com de fase II contribueixen al metabolisme del irosustat. Els principals metabòlits formats pels microsomes de fetge van ser monohidroxilats del irosustat i de la 667-coumarin, mentres que en hepatòcits van ser conjugats glucurònids i sulfats de 667-coumarin i d'alguns dels seus metabòlits monohidroxilats.
Els principals enzims del citocrom P450 involucrats en la transformació del irosustat van ser CYP2C8, CYP2C9, CYP3A4/5, i CYP2E1. D'altra banda, diversos enzims de fase II (UDP-glucuronosiltransferasas i sulfotransferasas) eren capaços de conjugar molts dels metabòlits de irosustat i 667-coumarin, però, les isoformes clínicament rellevants no es van poden dilucidar.
Irosustat inhibeix les activitats dels CYP1A2 i CYP2C19 en microsomes de fetge humà a través de la formació de 667-coumarin. Es recomanen estudis clínics addicionals d'interacció entre irosustat i substrats del CYP1A2. Pel CYP2C19, aquesta inhibició va augmentar amb l'avaluació en hepatòcits humans, tot i que no va ser causada per la repressió de l'expressió del gen CYP2C19. Per tant, es recomanen experiments mecanistics addicionals o estudis de seguiment amb avaluació clínica.
Irosustat no inhibeix CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, UGT1A1, UGT1A4 ni UGT2B7. Tampoc indueix CYP1A2, CYP2C9, CYP2C19 o CYP3A4/5, a concentracions clínicament rellevants. Els resultats dels microsomes hepàtics humans van indicar que no s'espera canvis en la farmacocinètica del irosustat com a resultat de la inhibició del seu metabolisme en els casos d'administració concomitant d’inhibidors de l’aromatase: letrozole, anastrozole, o exemestane.
5
Song, Mi Chi, and Austin Gessay. "Medical, Nursing, and Pharmacy Students’ Ability to Recognize Potential Drug-Drug Interactions: A Comparison of Healthcare Professional Students." The University of Arizona, 2009. http://hdl.handle.net/10150/623967.
Full textAbstract:
Class of 2009 Abstract<br>OBJECTIVES: The purpose of this study is to evaluate and compare the DDI knowledge of pharmacy, medical, and nurse practitioner students who are beginning clinical clerkships.
METHODS: This study utilized a prospective evaluation of DDI knowledge among healthcare professional students who were currently enrolled in their final didactic year at the University of Arizona College of Medicine, College of Pharmacy, or College of Nursing’s nurse practitioner course. Students were provided with 15 possible DDI pairs, and asked to select an appropriate management strategy for each pair. Management options included: “Avoid Combination,” “Usually Avoid Combination,” “Take Precaution,” “No Special Precaution,” and “Not Sure.” The primary outcome measure was the ability to correctly categorize each DDI pair into one of the five management responses. The secondary outcome measure was the number of clinically significant DDIs recognized. Analysis of variance was used to evaluate differences between groups. An alpha of 0.05 was set a-priori.
RESULTS: Response rates were 61% for medical students (72 of 119), 82% for pharmacy students (64 of 78) and 100% for nurse practitioner students (29 of 29). The mean number correct for management strategies was comparable in the medical students (2.5, SD= 1.9) and nurse practitioner students (3.0, SD= 1.9), while the pharmacy students had a mean score of 6.1 (SD= 2.2) correct answers. There was a significant difference between the groups in correct responses (p< 0.001). In regards to student ability to identify interactions, the mean number correct was 10.1 (SD= 2.6), 5.0 (SD= 3.3), and 4.4 (SD= 3.0) for pharmacy, medicine, and nursing respectively (F= 60.6; p< 0.001). Post hoc analysis demonstrated that pharmacy students performed significantly better than medical and nurse practitioner students in regards to their ability to: 1) select management strategies for DDI pairs; and 2) identify a DDI interaction. No significant differences were found between the medical and nurse practitioner students.
CONCLUSIONS: Pharmacy students demonstrated better knowledge than medical and nurse practitioner students with respect to identifying and selecting management strategies for possible DDIs. However, there is much room for improvement for all groups.
6
Sepcic, Kelly Hall. "Sythesis of mazindol derivatives as potential irreversible antagonists of cocaine and other stimulants." Thesis, Georgia Institute of Technology, 1992. http://hdl.handle.net/1853/26819.
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7
au, low@wehi edu, and CK Andrew Low. "Characterisation and Evaluation of Novel Potential Target (Tubulin) for Antimalarial Chemotherapy." Murdoch University, 2004. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20050930.125714.
Full textAbstract:
Malaria has long affected the world both socially and economically. Annually, there
are 1.5-2.7 million deaths and 300-500 million clinical infections (WHO, 1998).
Several antimalarial agents (such as chloroquine, quinine, pyrimethamine,
cycloguanil, sulphadoxine and others) have lost their effectiveness against this
disease through drug resistance being developed by the malarial parasites (The-
Wellcome-Trust, 1999). Although there is no hard-core evidence of drug resistance
shown on the new antimalarial compounds (artemisinin and artesunate), induced
resistant studies in animal models have demonstrated that the malarial parasites have
capabilities to develop resistance to these compounds (Ittarat et al., 2003; Meshnick,
1998; Meshnick, 2002; Walker et al., 2000). Furthermore, a useful vaccine has yet
to be developed due to the complicated life cycle of the malarial parasites (The-
Wellcome-Trust, 1999). As such, the re-emergence of this deadly infectious disease
has caused an urgent awareness to constantly look for novel targets and compounds.
In this present study, Plasmodium falciparum (clone 3D7) was cultured in vitro in
human red blood cells for extraction of total RNA which was later reverse
transcribed into cDNA. The áI-, áII- and â-tubulin genes of the parasite were then
successfully amplified and cloned into a bacterial protein expression vector, pGEX-
6P-1. The tubulin genes were then sequenced and analysed by comparison with
previously published homologues. It was found that the sequenced gene of áItubulin
was different at twelve bases, of which only six of these had resulted in
changes in amino acid residues. áII- and â-tubulin genes demonstrated 100%
sequence similarity with the published sequences of clone 3D7, but differences were
observed between this clone and other strains (strains NF54 & 7G8) of â-tubulin.
Nevertheless, the differences were minor in áI- and â-tubulins and there was greater
than 99% homology. Subsequently, all three Plasmodium recombinant tubulin
proteins were separately expressed and purified. Insoluble aggregates (inclusion
bodies) of these recombinant tubulins were also refolded and have been tested
positive for their structural characteristics in Western blot analysis.
Both soluble and refolded recombinant tubulins of malaria were examined in a drugtubulin
interaction study using sulfhydryl reactivity and fluorescence quenching
techniques. Known tubulin inhibitors (colchicine, tubulozole-c and vinblastine) and
novel synthetic compounds (CCWA-110, 239 and 443) were used as the drug
compounds to determine the dynamics and kinetics of the interactions. In addition,
mammalian tubulin was also used to determine the potential toxicity effects of these
compounds. Similarities were observed with other published reports in the binding
of colchicine with the recombinant tubulins, hence confirming proposed binding sites
of this compound on the Plasmodium recombinant tubulins. Two synthetic
compounds (CCWA-239 and 443) that have previously tested positive against P.
falciparum in vitro were found to bind effectively with all three tubulin monomers,
while displaying low binding interactions with the mammalian tubulin, thus
indicating that these compounds have potential antimalarial activity. Therefore, this
study has satisfied and fulfilled all the aims and hypotheses that have previously
been stated.
8
SHROFF, PURVI B. "AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF BEXAROTENE." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123813553.
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Martínez-Jiménez, Francisco 1988. "Structural study of the therapeutic potential of protein-ligand interactions." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/565402.
Full textAbstract:
Most of the cellular functions are driven by small-molecules that selectively
bind to their protein targets. Is such their importance, that the pharmacological
intervention of proteins by small molecule drugs is frequently used
to treat multiple conditions. Herein I present a thesis that leverages a threedimensional
study of small molecule protein interactions to improve their therapeutic
relevance. More specifically, it introduces nAnnolyze, a method for
predicting structurally detailed protein-ligand interactions at proteome scale.
The method exemplified its applicability by predicting the human targets of
all small molecule FDA-approved drugs. A second application of nAnnolyze
in Mycobacterium tuberculosis identified the bacterial targets for two sets of
compounds with known antitubercular activity. Finally, the thesis describes a
computational model that predicts cancer associated mutations with the highest
chances to confer resistance to a targeted cancer therapy. Additionally, for those
mutations identified as responsible of resistance, the model also suggested alternative
non-resistant treatments.<br>La mayor´ıa de las funciones celulares est´an dirigidas por peque˜nas mol´eculas
que selectivamente se unen a sus prote´ınas diana. Es tal su importancia que la
intervenci´on farmacol´ogica de prote´ınas mediante peque˜nas mol´eculas es frecuentemente
usada para tratar m´ultiples enfermedades. A continuaci´on presento
a una tesis que utiliza un estudio tridimensional de las interacciones
entre peque˜nas mol´eculas y prote´ınas para mejorar su relevancia terap´eutica.
Espec´ıficamente, presento nAnnolyze, un m´etodo que predice interacciones
prote´ına-ligando estructuralmente detalladas y a nivel de proteoma. El m´etodo
ejemplifica su aplicabilidad a trav´es de la predicci´on de dianas terap´euticas humanas
para todas las peque˜nas mol´eculas usadas como f´armacos aprobados por
la FDA. Una segunda aplicaci´on de nAnnolyze en Mycobacterium tuberculosis
identific´o las prote´ınas diana para dos conjuntos de compuestos con actividad
contra dicha bacteria. Finalmente, la tesis describe un modelo computacional
que predice mutaciones asociadas a c´ancer con alta probabilidad de conferir
resistencia a una terapia dirigida. Adem´as, para aquellas mutaciones identificadas
como responsables de producir resistencia, el modelo tambi´en sugiere
terapias alternativas predichas como no resistentes.
III
10
Bossaer, John B. "Addressing Potential Interactions Between Antineoplastics and Dietary Supplements." Digital Commons @ East Tennessee State University, 2015. https://doi.org/10.2146/ajhp140295.
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Wang, Li. "ASSESSMENT OF THE DRUG-DRUG INTERACTION POTENTIAL OF ANIONIC COMPONENTS IN THE DIET AND HERBAL MEDICINES ON ORGANIC ANION TRANSPORTERS (SLC22 FAMILY)." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3181.
Full textAbstract:
Numerous natural products are widely used as first-line/alternative therapeutics and dietary supplements in both western and eastern society. However, the safety and efficacy profiles for herbal products are still limited. Organic anion transporters (OATs; SLC22 family) are expressed in many barrier organs and mediate in vivo body disposition of a broad array of endogenous substances and clinically important drugs. As some dietary flavonoids and phenolic acids were previously demonstrated to interact with OATs, it is necessary to explore the potential interaction of such components found in natural products in order to avoid potential OAT-mediated drug-drug interactions (DDIs). The inhibitory effects of 23 natural products were assessed on the function of human (h) OATs, hOAT1 (SLC22A6), hOAT3 (SLC22A7), and hOAT4 (SLC22A11) and/or the murine (m) orthologs mOat1 and mOat3. For compounds exhibiting marked inhibition at initial screening, dose-response curves (IC50 values) and DDI indices were determined. At the initial screening concentrations, 14, 19, and 2 test compounds exhibited significant inhibition on hOAT1, hOAT3, and hOAT4, respectively. Additionally, all test Danshen (a Chinese herbal medicine) hydrophilic components significantly reduced mOat1- and mOat3-mediated substrate uptake at 1 mM. For selected compounds, the IC50 and Ki values were estimated to be in the micromolar or even nanomolar range. Considering the clinical plasma concentration and unbound fraction in plasma, DDI indices for gallic acid, gentisic acid, lithospermic acid, protocatechuic acid, rosmarinic acid, salvianolic acid B, and tanshinol indicated DDIs may occur in vivo in situations of co-administration of these compounds and clinical therapeutics known to be OAT substrates. Finally, a new, rapid, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify gallic acid and gentisic acid in cell lysates in order to measure cellular uptake of these compounds in mOat1- or mOat3-expressing cells. Significant cellular uptake of gallic acid was observed in mOat1-expressing cells, compared with background control cells. The absorptive uptake was completely blocked by probenecid (known OAT inhibitor) at 1 mM. These results indicate that gallic acid is a substrate for mOat1 and suggest that human OAT1 might be involved in the active renal secretion of gallic acid.
12
Arora, Priyanka. "Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1552398989110981.
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Lamberty, Nina Sibylle [Verfasser], Irenäus A. [Akademischer Betreuer] Adamietz, and Oliver [Akademischer Betreuer] Lindner. "Potential drug interactions and potentially inappropriate medications in daily radiooncology practice / Nina Sibylle Lamberty. Gutachter: Irenäus A. Adamietz ; Oliver Lindner." Bochum : Ruhr-Universität Bochum, 2015. http://d-nb.info/1079842888/34.
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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.
Full textAbstract:
Thesis (PhD)--Stellenbosch University, 2013.<br>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.<br>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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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.
Full textAbstract:
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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Zhou, Shu. "Riboswitch Drug Discovery: Identification and Characterization of T Box Antiterminator RNA Ligands as Potential Antibacterial Agents." Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1311780947.
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Nadal, Bufi Ferran. "Peptide-based drugs to inhibit LDH5, a potential target for cancer therapy." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/232526/1/Ferran_Nadal%20Bufi_Thesis.pdf.
Full textAbstract:
This thesis investigates novel strategies to target lactate dehydrogenase 5 (LDH5), a protein involved in cancer. After decades of research without success, this thesis reports the development of the first molecules able to inhibit the activity of LDH5 with an alternative mechanism of action: disrupting its structure. To do that, an emerging class of drugs called peptides are explored. The lead peptide of this work successfully kills breast cancer cells via LDH5 inhibition. The validation of this strategy is relevant because it can be applied to many other cancer targets that have been traditionally considered “undruggable”.
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Naisbett, B. "The interaction of tomato lectin with adult rat small intestine : potential for oral drug delivery." Thesis, Keele University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293534.
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Sibanda, Thulani. "Assessment of antibacterial potentials of Garcinia Kola seed extracts and their interactions with antibiotics." Thesis, University of Fort Hare, 2007. http://hdl.handle.net/10353/71.
Full textAbstract:
The antibacterial potency of the extracts of the seed of Garcinia kola (bitter kola) was investigated in this study against a panel of referenced, environmental and clinical bacterial strains. The killing rates of the active extract as well as their potential for combination antibacterial therapy with standard antibiotics were also elucidated using standard procedures. The aqueous and acetone extracts of the seed were screened for activity against 27 bacterial isolates. The aqueous extract exhibited activity mainly against Gram positive organisms with Minimum inhibitory concentration (MIC) values ranging from 5 mgml-1 – 20 mgml-1, while the acetone extract showed activity against both Gram negative and Gram positive organisms with MIC values ranging from 10 mgml-1 - 0.156 mgml-1. The acetone extract also showed rapid bactericidal activity against Staphylococcus aureus ATCC 6538 with a 3.097 Log10 reduction in counts within 4 hours at 0.3125 mgml-1 and a 1.582 Log10 reduction against Proteus vulgaris CSIR 0030 at 5 mgml-1 after 1 hour. In addition, the aqueous, methanol and acetone extracts of the seeds also exhibited activity against four clinical strains of Staphylococcus isolated from wound sepsis specimens. The MIC values for the aqueous extract were 10 mgml-1 for all the isolates while the acetone and methanol extracts had lower values ranging from 0.3125 - 0.625 mgml-1. The acetone extract was strongly bactericidal against Staphylococcus aureus OKOH3 resulting in a 2.70 Log10 reduction in counts at 1.25 mgml-1 within 4 hours of exposure and a complete elimination of the organism after 8 hours. The bactericidal vi activity of the same extract against Staphylococcus aureus OKOH1 was weak, achieving only a 2.92 Log10 reduction in counts at 1.25 mgml-1 (4× MIC) in 24 hours. In the test for interactions between the acetone extract of the seeds and antibiotics, synergistic interactions were observed largely against Gram positive organisms using the FIC indices, (indices of 0.52 - 0.875) with combinations against Gram negatives yielding largely antagonistic interactions (indices of 2.0 to 5.0). Synergy (≥ 1000 times or ≥ 3 Log10 potentiation of the bactericidal activity) against both Gram negative and Gram positive organisms was detected by time kill assays mainly involving the antibiotics tetracycline, chloramphenicol, amoxycillin and penicillin G. Combinations involving erythromycin and ciprofloxacin consistently gave antagonistic or indifferent interactions. We conclude that the acetone extract of Garcinia kola seeds possess strong bactericidal activities against both Gram positive and Gram negative organisms and can be therapeutically useful in the treatment of bacterial infections including the problematic staphylococcal wound infections. In addition, the acetone extract can be a potential source of broad spectrum resistance modifying compounds that can potentially improve the performance of antibiotics in the treatment of drug resistant infections.
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AIROLDI, CRISTINA. "Development of new potential antitumor drugs based on Ras protein inhibition." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2007. http://hdl.handle.net/10281/116562.
Full textAbstract:
Because of their role in oncogenesis, inhibition of Ras proteins, particularly of their tumorigenic variants, represents today one of the principal strategies finalized to the obtainment of new antitumoral therapies. Among the different possible approaches, one of the most innovative and less explored is represented by the inhibition of this protein activation, key event for the explication of their biological activity, but also for the Ras-induced tumoral cell transformation.
Objective of this thesis has been the development of new small molecules able to inhibit, at least partially (total inhibition in fact would result lethal for cell), Ras protein activation, in particular the GEFs-promoted GDP/GTP
nucleotide exchange.
Inhibitors able of inactivating Ras have been previously described by Schering-Plough. All these molecules contain a phenylhydroxylamino group that binds Ras in a region close to the nucleotide binding site and one aromatic group. Nevertheless, they present some negative characteristics that prevent their employment as potential drugs: (1) they are chemically unstable and (2) they are insoluble in water and in the most commonly used organic solvents.
In order to obtain new more efficient inhibitors, we adopted the rational drug design strategy.
Firstly, we studied the structure-activity relationship (SAR) of Schering-Plough compounds and of new molecules containing variants of their functional groups that we designed and synthesized. The data collected
demonstrated that the phenylhydroxylamino group is an essential pharmacophore, while other positions are not so critical for the biological activity.Keeping in mind this, we prepared new compounds in which the phenylhydroxylamino moiety is supported on glycidic templates, in an attempt to try to take advantage of carbohydrate capability of orienting substituents in space, in this case in a suitable manner for the interaction with Ras proteins. In addition, the sugar portion can improve compound pharmacokinetic properties and decrease their toxicity.
In this way, a new class of Ras inhibitors was obtained, their biological activity and the nature of their interaction with the molecular target were characterized.
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Farhood, Sara. "„Arzneimittelinteraktionen und potentiell inadäquate Medikation (PIM) auf einer onkologischen Station“." Master's thesis, Dresden International University, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-229724.
Full textAbstract:
Drug Interactions and potentially inappropriate medications at an oncology ward
Objectives: this study aimed to quantify the prevalence of clinically significant interactions and potentially inappropriate medication (PIM) use through involving a pharmacist among the cancer patients at an oncology ward and an oncology day- unit.
Materials and Methods: Prospective study in patients taking more than 5 drugs who had been admitted to Harzklinikum, Wernigerode, Germany between August 2016 and February 2017. The pharmacist conducts a complete comprehensive medication review including over-the-counter drugs and herbal medications. Besides, she took into consideration the intake of grapefruit juice. This information together with the information in the patient's medical history permits identifying critical drug-drug interactions using the mediQ interaction analysis program as well as PIMs using the Beers, Forta, Priscus and STOPP lists.
Results: One hundred and eighty-five cancer patients (mean age ± SD = 70 ± 11 years) were included in the study. The interaction analysis program identified 177 potentially interactions. These interactions were evaluated by the pharmacist and 34 interactions for 31 patients (17 %) were considered clinically significant or critical. After the pharmacist interventions, these interactions were resolved in 51 percent. 123 patients aged over 65 years old were enrolled in the study for PIM. By using the four lists (Beers, Forta, Priscus, STOPP) 52 PIMs at 41 elderly persons (33%) were identifies. 11 recommendations in 10 elderly patients (8 %) were made by the pharmacist and result in 55 % of the cases in a prescription change.
Conclusion: the use of an interaction analysis program and the lists of inappropriate medications allowed the pharmacist to identify clinically relevant interactions and PIMs and result in prescription change in agreement with the oncologist.
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Mannheimer, Buster. "Drug-related problems with special emphasis on drug-drug interactions." Stockholm : Department of Clinical Science and Education, Karolinska Institutet, 2009. http://diss.kib.ki.se/2009/978-91-7409-602-6/.
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Pandie, Mishal. "Drug-drug interactions between antiretrovirals and bedaquiline." Master's thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/27401.
Full textAbstract:
Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. People living with HIV are particularly susceptible to TB infection, and treatment of HIV-TB co-infection is challenging for multiple reasons, including potential drug-interactions. Drug-resistant TB is difficult to treat and is associated with high treatment failure rates, mainly because the antimycobacterial drugs currently available are ineffective against drug-resistant TB. Bedaquiline is a new antimycobacterial drug which has shown great promise through its excellent efficacy for treating drug-resistant TB. Being a new drug, however, potential drug interactions with antiretrovirals are a major concern. Bedaquiline is metabolized in the liver by an enzyme called cytochrome P450 3A (CYP3A). The antiretrovirals nevirapine, efavirenz, and lopinavir/ritonavir (LPV/r) can affect the activity of this enzyme, and consequently affect the concentration of bedaquiline in the patient's blood. Nevirapine and efavirenz increase the activity of CYP3A, which may result in increased metabolism of bedaquiline, thus decreasing the concentration of bedaquiline, with consequent risk of treatment failure or the further development of drug-resistance. LPV/r inhibits the CYP3A enzyme, which may result in decreased bedaquiline metabolism, thus causing high concentration of bedaquiline in the blood, with consequent risk of toxicity. We conducted a pharmacokinetic study in 43 adult patients with drug-resistant TB to evaluate the drug-interactions between bedaquiline and the antiretrovirals nevirapine and LPV/r. We did serial measurements of the bedaquiline concentration in their plasma over 48 hours, and compared these concentrations in patients who were on antiretroviral and those who were not on antiretrovirals. Our results showed that nevirapine had no significant effect on bedaquiline concentrations, while patients on LPV/r had bedaquiline concentrations 2 fold higher than patients not on antiretrovirals. We could not determine the clinical significance of this, but recommend that patients receiving LPV/r and bedaquiline in combination must be closely monitored for side-effects.
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Rooney, E. K. "Drug-membrane interactions." Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375371.
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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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Raedisch, Steffen. "Drug transport and drug-drug interactions at the blood-brain barrier." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2005162/.
Full textAbstract:
Membrane transporters are increasingly recognised as being important in determining drug pharmacokinetics at whole body, organ, and cellular levels. At the blood-‐brain barrier (BBB), membrane transporters determine the passage of drugs into and out of the brain. About 30 % of all patients are classed as non-‐responders for both epilepsy and schizophrenia. Drug transporters from the adenosine 5'-‐ triphosphate (ATP)-‐binding cassette (ABC) transporter family or from the solute carrier (SLC) superfamily may contribute to these drug resistant phenotypes but most have received limited attention. Treatment response to carbamazepine (CBZ) has been associated with genetic polymorphisms in ABCC2, particularly -‐24C>T, c.1249G>A, and c.3972C>T. However, the results have been conflicting and inconclusive amongst the different studies. A functional and clinical analysis was undertaken to investigate the impact of ABCC2 on CBZ treatment response. In vitro, no ABCC2-‐mediated CBZ transport could be observed in efflux assays with an ABCC2-‐transfected human fibrosarcoma cell line (Rht14-‐10) and a dog kidney cell line (MDCKII). In addition, uptake into inside-‐out vesicles derived from the Rht14-‐10 cell line was negative. Clinical analysis of patients from the SANAD (Standard and New Antiepileptic Drugs) trial (assessing the clinical end-‐points time to first seizure (n = 229) and time to 12-‐month remission (n = 134)) did not show any significant associations between the three ABCC2 gene polymorphisms, -‐24C>T, c.1249G>A, c.3972C>T, and clinical outcomes. In an attempt to identify currently unrecognised human drug transporters with potential relevance to epilepsy and schizophrenia, screening of transport of CBZ, lamotrigine (LTG), topiramate (TPM), levetiracetam, valproate, phenytoin, and clozapine (CLP) was undertaken using an immortalised human brain endothelial cell line (hCMEC/D3) as an in vitro model of the BBB. Accumulation of TPM was significantly enhanced by 44-‐53 % in the presence of the typical ABCC efflux transporter inhibitors MK571 and montelukast. Furthermore, CLP uptake was significantly reduced by 94 % and 83 % in the presence of the typical organic cation transporter inhibitors prazosin and verapamil, respectively. CLP uptake into the hCMEC/D3 cell line followed classical Michaelis-‐Menten kinetics with Vmax of 3288 (pmol/million cells)/min and Km of 35.93 μM. To identify the exact underlying transporters involved in TPM efflux and CLP uptake, both functional siRNA screening was undertaken and transport was investigated in transfected cell lines. None of the known functional ABCC transporters were shown to transport TPM. In addition, none of the expressed and functionally characterised organic cation transporters from the SLC22A family, as well as transporters from the SLC6A, SLC28A, and SLC29A families, had an effect on CLP accumulation. LTG has recently been identified as a substrate for SLC22A1 (OCT1). Interaction with the human immunodeficiency virus protease inhibitors lopinavir/ritonavir and the antipsychotic CLP was therefore investigated. At clinically relevant concentrations, lopinavir was found to significantly reduce SLC22A1-‐mediated uptake of LTG by 39 %. In addition, CLP was a potent inhibitor of SLC22A1-‐mediated LTG uptake yielding an IC50 of 1.8 μM. Similarly low IC50 values were obtained with primary human hepatocytes from two patients (IC50 = 7.9 μM and IC50 = 3.9 μM, respectively) and the hCMEC/D3 cell line (IC50 = 2.0 μM). The clinical consequences of these observations will require further in vivo pharmacokinetic and epidemiological research. In conclusion, the results presented in this thesis demonstrate that membrane transporters can be involved in the passage of AEDs and antipsychotics across the BBB and other membrane barriers. However, currently available in vitro methods proved to be insufficient to identify and characterise the underlying transporters involved and to further evaluate the impact on treatment efficacy. The development of large-‐scale functional screening methodologies will be crucial for a more systematic and comprehensive understanding of drug transport processes involved in determining access of drugs to the central nervous system. This will help in improving drug efficacy and drug safety, allow prediction of drug-‐drug interactions, and eventually allowed a more personalised approach to prescribing in diseases such as epilepsy and schizophrenia.
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Clark, Justin. "An evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/623593.
Full textAbstract:
Class of 2012 Abstract<br>Objectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin.
Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four.
Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction.
Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters.
Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case- reports and are of low quality and quantity.
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Clark, Justin, and Daniel Malone. "An Evaluation of Warfarin and Statin Drug-Drug Interactions." The University of Arizona, 2012. http://hdl.handle.net/10150/614476.
Full textAbstract:
Class of 2012 Abstract<br>Objectives: To evaluate the literature with respect to drug-drug interactions of the hydroxymethylglutaryl CoA reductase inhibitors atorvastatin, fluvastatin, lovastatin, pitavastitin, pravastatin, simvastatin, and rosuvastatin with warfarin.
Methods: This descriptive retrospective study identified articles reporting on each drug-drug interaction from the online databases PubMed (1970 – February 2012) and the drug compendia Micromedex and Facts & Comparisons. The studies included in this investigation were primary literature reports, written in English with human subjects. All studies included were evaluated using the van Roon 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions. This scale rates the study type from lowest to highest quality, from zero to four. Case-reports were evaluated using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction.
Results: Twenty studies met the inclusion criteria. One study involved atorvastatin, four for fluvastatin, three for lovastatin, 2 for pitavastatin, 1 for pravastatin, 5 for rosuvastatin, and 6 for simvastatin. The mean van Roon quality of evidence score was 2.1+/- 0.74, the mean score for atorvastatin, pitavastatin, and pravastatin was 3, with the mean score of fluvastatin, lovastatin, rosuvastatin, and simvastatin was 2. 70% of the literature reviewed were case-reports or letters.
Conclusions: The studies and reports supporting HMG-CoA reductase inhibitors and warfarin drug-drug interactions are most commonly case-reports and are of low quality and quantity.
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Rahman, Samina. "Predicting drug-polymer interactions." Thesis, University of Strathclyde, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488511.
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Todorova, Niya Ancheva. "Energetics of drug interactions." College Park, Md.: University of Maryland, 2008. http://hdl.handle.net/1903/8800.
Full textAbstract:
Thesis (Ph. D.) -- University of Maryland, College Park, 2008.<br>Thesis research directed by: Dept. of Cell Biology and Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Claborn, Jordan, Moses Holleyman, and John B. Bossaer. "Consistency of Drug Information Resources in Identifying Drug-drug interactions with Oral Antineoplastic Agents." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etsu-works/2346.
Full textAbstract:
Targeted oral antineoplastic agents (OAs) have become a staple and rapidly growing field in the realm of cancer treatment. As with any chemotherapeutic/narrow spectrum agent, clinicians have to be aware of potential drug interactions that could interfere with therapy. Drug information databases are a common resource utilized to check for interactions between agents and patient's home medications. A major concern with OAs is that they are usually taken at home as well as picked up at a pharmacy by the patient themselves. With this kind of therapy adherence and patient side effect reporting becomes a concern. We wanted to determine the reliability of these databases for picking up potential interactions with patients on OAs. We accessed hospital records to find patients with various malignancies on OAs between the calendar year of 2013-2014, of which we found 876 that were screened for potential use of OAs. The goal was to find patients on OAs specifically and determine the number of drug interactions flagged by either drugs.com and/or Lexicomp®. In addition, the significance of the interaction as well as disagreements between databases were analyzed. A major interaction by Lexicomp® is defined as either a ‘D’ or an ‘X’ level interaction and on drugs.com is labeled ‘major.' Of the 876 screened we found 16 patients (one patient had tried 3 different agents, and another patient had tried two) on OAs. Lexicomp® flagged overall 42 interactions amongst all subjects, of which 17 were major interactions. Drugs.com flagged overall 44 interactions amongst all subjects, of which 11 were major interactions, being the more conservative of the two. Between the 2 databases there were 10 out of 18 major interactions that both were in agreement upon. These discrepancies are of concern in that clinicians hope that resources they utilize are incongruent with one another and allow them to practice in the safest manner in terms of avoided potential serious drug interactions whether it be harm to a patient or decreased effectiveness of the OA. Now that all patients have been screened, future research would be to determine the clinical significance of these interactions and whether or not they had an effect on patient outcomes.
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Clayborn, Jordan, Moses Holleyman, and John B. Bossaer. "Reliability of Drug Information Databases in Identifying Drug-drug Interactions with Oral Antineoplastic Agents." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/2349.
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Yella, Jaswanth. "Machine Learning-based Prediction and Characterization of Drug-drug Interactions." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin154399419112613.
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Beresford, Alan Peter. "Drug interactions with cytochromes P4501A." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301011.
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Patel, Rajesh. "Studies of drug-surfactant interactions." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313319.
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Macey, Rosa. "Studies of drug-lipid interactions." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/24961.
Full textAbstract:
Positron emission tomography (PET) is increasingly being used by the pharmaceutical industry in drug development. Drugs are designed to bind to a specific target, which is usually a membrane embedded receptor or an enzyme. PET is used to establish the utility of radiolabelled drugs and other radioligands in vivo before embarking on expensive clinical trials. In developing new PET radioligands, a common reason for candidate rejection is that the non-specific binding signal obscures the specific binding signal and, thus reduces the quality of the PET scan data. A high non-specific/specific binding ratio is a major reason for radiotracer failure and there is no completely satisfactory predictor of its magnitude. Non-specific binding is a poorly understood phenomenon but is believed to be related to the binding of labelled molecules to tissue membranes. A series of Spiperone analogues have been synthesised and tested in a variety of biophysical assays to increase the understanding of the molecular basis of drug-lipid interactions. Rapid cyclic voltammetry experiments were also performed to examine the interaction of drugs with a DOPC monolayer on a Pt/Hg electrode. The Spiperone analogues were tested in this system and the larger molecules were shown to have a larger interaction with the DOPC monolayer. A set of well characterised central nervous system drugs were also tested in this system and it was found that the strength of their interaction has a strong correlation with the measured in vivo non-specific binding. This technique could therefore be used to screen candidate drugs and radioligands to predict their non-specific binding. An assay that can select compounds that display the greatest likelihood of success would be extremely valuable due to the high cost and low-throughput nature of PET imaging.
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Adedoyin, A. P. "Pharmacokinetic drug-drug interactions : inhibition and induction studies in the rat." Thesis, University of Manchester, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376236.
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Fouche, Desire. "Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/20079.
Full textAbstract:
Thesis (MScMedSc)--Stellenbosch University, 2012.<br>ENGLISH ABSTRACT: Background: HIV-positive patients have a significantly weakened immune system which
makes them highly susceptible for opportunistic infections, requiring additional treatment.
Cryptococcal meningitis and oropharyngeal candidiasis are treated with oral fluconazole. A
great potential for drug-drug interactions (DDIs) between fluconazole and antiretrovirals
(ARVs), efavirenz, nevirapine, and lopinavir/ritonavir, exists due to interference in common
metabolic pathways. The outcome may result in the development of adverse drug reactions
or drug resistance and treatment failure.
Aim: The primary aim of this thesis was to evaluate the effect of fluconazole on the
pharmacokinetics of efavirenz, nevirapine and lopinavir/ritonavir in HIV-infected patients
diagnosed with cryptococcal meningitis or oropharyngeal candidiasis.
Methods: A prospective study was conducted in 80 HIV-positive, treatment experienced
adults (≥18 years old) treated in three different outpatient clinics in the Western Cape region.
Patients were subdivided according to ARV regimen and the use of fluconazole. A sparse
sampling design was used and corresponding ARV serum concentrations were determined by
established HPLC and GC methods. Fluconazole serum concentrations were determined by a
newly developed HPLC method. Patient characteristics, concomitant medications, clinical
test data and ARV serum concentrations were included in a NONMEM generated, onecompartment,
open pharmacometric model with first order elimination to detect any drugdrug
interactions between fluconazole and the studied ARVs. The secondary outcome was to
establish which patient characteristics influence ARV pharmacokinetics.
Results: From 80 outpatients, a total of 276 ARV serum samples (137 efavirenz, 67
nevirapine and 72 lopinavir) were collected for pharmacokinetic evaluation. Efavirenz
clearance was correlated with race and concomitant use of rifampicin. No significant
covariates were established in the nevirapine model. In the lopinavir model, concomitant use
of clotrimazole and the antituberculosis combination isoniazid, pyrazinamide and rifampicin
were identified as significant covariates.
Discussion: No significant effects of fluconazole on the pharmacokinetics of any of the
studied ARVs were observed. Varying efavirenz plasma concentrations in different ethnic
populations may be due to differences in gene expression particularly CYP2B6. Coloured patients had significantly lower efavirenz serum concentrations (56.8% decrease in
clearance), which has not been previously described in the South African context. Although
gender was not a significant covariate in the nevirapine model, female patients tended to have
higher nevirapine serum concentrations. TB treatment in all patients receiving lopinavir
consisted of a combination of isoniazid, pyrazinamide and rifampicin, each with different
effects on CYP isoenzymes. The exact contributing factor of each drug in the ultimate
decrease in lopinavir clearance (46.4%) can therefore not be established.
Conclusions: Given the limitations of the sample size in the present study, no statistical
significant effect of fluconazole on the pharmacokinetics of the investigated ARVs could be
demonstrated. A retrospective analysis of the data showed various co-factors that influence
the pharmacokinetics of the investigated ARVs. This data needs to be confirmed in a
prospective study as the identified covariates are appropriate in the management of HIVinfected
patients in the South African context.<br>AFRIKAANSE OPSOMMING: Agtergrond: HIV-positief pasiënte het ‘n aansienlike verswakte immuunstelsel, wat hul
hoogs vatbaar tot opportunistiese infeksies maak, en dus, addisionele behandeling benodig.
Cryptococcal meningitis en orofaringeale kandidiase word met orale flukonasool behandel.
As gevolg van middeling in algemene metaboliese paaie is daar ‘n groot moontlikheid van
middel-middel interaksies tussen flukonasool en die antiretrovirale (ARV) middels,
efavirenz, nevirapine, en lopinavir/ritonavir. Die uitkomste hiervan mag tot die ontwikkeling
van nadelige middel-middel interaksies of middelweerstandigheid en mislukte behandeling
lei.
Doel: Die primêre doel van hierdie tesis was om die effek van flukonasool op die
farmakokinetika van efavirenz, nevirapine en lopinavir/ritonavir in HIV geïnfekteerde
pasiënte met gediagnoseerde cryptococcal meningitis en orofaringeale kandidiase te evalueer.
Metodes: Die studie was met 80 HIV-positief, behandeling-ervare volwassenes (≥18 jaar)
onderneem. Voorafgenoemde was in drie verskillende buitepasiëntklinieke in die Wes-Kaap
behandel. Pasiënte was volgens ARV regimen en die gebruik van flukonasool, of dan nie,
verder verdeel. ‘n Beperkte steekproef ontwerp was gebruik, en ooreenstemmende ARV
serum konsentrasies is deurgevestigde HPLC en GC metodes vasgestel. Flukonasool serum
konsentrasies was deur ‘n nuutontwikkelde HPLC metode vasgestel. Pasiëntkenmerke,
gepaardgaande medikasie, kliniesetoets data en ARV serum konsentrasies was by ‘n
NONMEM genereerde, een-kompartement, oop farmakometriese model met eerste orde
eliminasie ingesluit om enige middel interaksies tussen flukonasool en die bestudeerde ARVs
op te tel. Die sekondêre uitkomste was om vas te stel watter pasiënt kenmerke ARV
farmakokinetika beïnvloed.
Resultate:Uit 80 buitepasïente was ‘n totaal van 276 ARV serum monsters (137 efavirenz,
67 nevirapine en 72 lopinavir) vir farmakokinetiese evaluasie gekollekteer. Efavirenz
opruiming was met ras gekorreleer asook gepaardgaande gebruik van rifampisien. Geen
betekenisvolle ko-variante was in die nevirapine model vasgestel nie. In die lopinavir model
het die gepaardgaande gebruik van clotrimazole en die anti-tuberkulose kombinasie
isoniazied, pyrazinamied en rifampisien, lopinavir opruiming verminder.
Bespreking: In hierdie studie is geen betekenisvolle effekte van flukanosool op die
farmakokinetika van enige van die bestudeerde ARVs waargeneem nie. Afwisselende
efavirenz plasma konsentrasies in verskillende etniese populasies mag aan verskille in
geenuitdrukking, veral CYP2B6, toegeskryf word. Kleurling pasïente het betekenisvolle
verlaagde efavirenz serum konsentrasies getoon (56.8% verlaging in opruiming). Hierdie
bevinding is nog nooit voorheen in die Suid-Afrikaanse konteks beskryf nie. Alhoewel geslag
nie ‘n beduidende ko-variant in die nevirapine model was nie, het vroulike pasïente geneig
om hoer nevirapine serum konsentrasies te hê. TB behandeling, in alle pasïente wat lopinavir
ontvang het, het uit die volgende kombinasie bestaan: isoniazied, pyrazinamied en
rifampisien, elk met hul eie effekte op CYP isoensieme. Die presiese bydra van elke middel
in die uiteindelike verlaging (46.4%) in lopinavir opruiming kan dus nie vasgestel word nie.
Gevolgtrekking: Gegewe die beperkings van die steekproef in die huidige studie, kon geen
statistiese beduidende effek van flukonazool op die farmakokinetika van die betrokke ARVs
gedemonstreer word nie. ‘n Retrospektiewe analise van die data het gewys dat verskeidene
ko-faktore die farmakokinetika van die betrokke ARVs beïnvloed. Hierdie data moet in ‘n
prospektiewe studie bevestig word omdat die geidentifiseerde covariates die bestuur van
MIV-positiewe pasiente in die Suid-Afrikaanse konteks te verbeter.
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Alavi, Hajar Karimi. "Development of mechanistic mathematical models for gene-mediated drug-drug interactions." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/development-of-mechanistic-mathematical-models-for-genemediated-drugdrug-interactions(b38da88a-bb2a-4667-9809-21a09c8feeeb).html.
Full textAbstract:
The glucocorticoid receptor (GR) is a member of the nuclear hormone receptors family and has been shown to exert significant effects on the induction of cytochrome P450 (CYP) enzymes responsible for the metabolism of many xenobiotics. CYP3A4/5 and CYP2C9 are important CYP enzymes which metabolise more that 60% of drugs. Induction or inhibition of the enzymatic activity and the levels of these enzymes can have significant effects on drug metabolism. Understanding the role of GR and other nuclear receptors, pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), in the mechanisms effecting CYP3A4/5 and CYP2C9 levels and activity can aid in the development of in vitro and in vivo models which have become a target for scientists in the clinic and the industry. The commonly prescribed synthetic glucocorticoid (GC) drug, dexamethasone (Dex), can induce GR, PXR and CAR and was used in this study to analyse its effects on the CYP enzymes studied. The hypothesis of this project was that changes in CYP3A4/5 and CYP2C9 gene expression affect drug metabolism and changes in gene expression of these CYP enzymes was under GR, PXR and CAR control, thus affecting the concentration and therapeutic activity of drugs metabolized by these enzymes during chronic use of GCs in conditions such as rheumatoid arthritis and asthma. This study aimed to measure mRNA, protein, ROS and enzymatic activity levels in human HepG2 hepatocytes treated with Dex for 120 h and analyze the results for various time points to produce a mathematical model. Our study has shown that changes in mRNA, protein and enzymatic activity levels of CYP3A4/5 and CYP2C9 in HepG2 cells were induced by Dex at sub-micromolar (0.1 µM) and supra-micromolar (1.5 mM) concentrations. The induction of CYP3A4/5 and CYP2C9 enzymes during 120 h treatment with Dex may be affected by the NRs studied; GR, phosphorylated GR, PXR and CAR protein levels were also shown to be induced by Dex. The efflux transporter, P-gp’s protein levels were also induced by 0.1 µM Dex, highlighting the importance of considering bioavailability of other drugs co-administered with Dex. The results of some of these laboratory experiments have been used to produce mechanistic mathematical models by MATLAB software with reference to previous studies in rats concentrating on the effects of steroids on GR. The models developed were not effective at the lower Dex concentration of 0.1 µM but were better modelled at the higher Dex concentration of 1.5 mM. The basic mechanistic models developed using HepG2 cells in this study can be utilised to design and conduct drug-drug interaction (DDI) analyses of the induction of CYP3A4/5 and CYP2C9 in other human liver cells and starting pre-clinical studies in animals to aid in drug development.
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Guest, Eleanor. "Assessment of algorithms for the prediction of metabolic drug-drug interactions." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/assessment-of-algorithms-for-the-prediction-of-metabolic-drugdrug-interactions(591ca23c-c75d-445e-a786-9b67689f9cd4).html.
Full textAbstract:
The aim of this work was to assess the ability of the static and dynamic (incorporating the time-course of the inhibitor) prediction models to predict drug-drug interactions (DDIs) using a population-based ADME simulator (Simcyp). This analysis focused on fluconazole, ketoconazole, itraconazole, fluoxetine and fluvoxamine, as CYP inhibitors. The rationale for their selection was an abundance of reported DDI studies, involving a wide range of victim drugs. Preliminary analysis focused on the individual victim drug and inhibitor parameters that are utilised in the DDI prediction models. The victim drug properties included in the DDI prediction models are calculated intrinsically in the Simcyp simulator from in vitro data; these values were compared to estimates obtained by different in vivo methods. Estimations of the fraction metabolised by CYP enzymes were generally consistent with <20% difference between all methods for 15/23 victim drugs. No relationship was observed per CYP enzyme or per inhibitor utilised for phenocopying methods. Estimates of fraction of drug escaping metabolism in the gut were variable across methods with up to 60% coefficient of variation in the case of saquinavir. In vitro assessment of potential liver uptake of the inhibitors was identified for further investigation due to inconsistency in available literature data and sensitivity of the model to this parameter. Extent of liver uptake of selected inhibitors was assessed via comparison of clearance obtained in hepatocytes and microsomes (conventional depletion assay) and values obtained by the conventional depletion and media loss assays in hepatocytes. Clearance was determined at a low concentration (0.1μM) and both rat and human hepatocytes and microsomes were used. The clearance ratios ranged from no difference to >1500 (fluvoxamine from the media loss assay in human hepatocytes). No consistency was observed between methods and human or rat source for any of the inhibitors investigated; therefore, the inclusion of liver uptake into the prediction of DDIs for the current inhibitors was not supported. A database was collated from literature reports of DDIs involving the above named CYP inhibitors (n=97) and used to assess the inclusion of the time-course of inhibition into DDI prediction using the Simcyp simulator. In addition, the impact of active metabolites, dosing time and the ability to predict inter-individual variability in DDI magnitude were investigated using the dynamic prediction model. Simulations comprised of 10 trials with matching population demographics and dosage regimen to the in vivo studies. The predictive utility of the static and dynamic models was assessed relative to the inhibitor or victim drug investigated; both models were employed within Simcyp for consistency in parameters. Use of the dynamic and static models resulted in comparable prediction success, with 67 and 70% of DDIs predicted within two-fold, respectively. Over 60% of strong DDIs (>five-fold AUC increase) were under-predicted by both models, particularly for fluoxetine and fluvoxamine. Incorporation of the itraconazole metabolite into the dynamic model resulted in increased prediction accuracy of strong DDIs (80% within two-fold); no difference was observed for the inclusion of the fluoxetine metabolite. Predicted inter-individual variability in the DDI magnitude was also assessed in healthy, patient and genotyped subjects using a subset of clinical interactions (n=24). Mixed prediction success was observed and the importance of reliable clinical data was highlighted. The differences observed with the dose staggering and the incorporation of active metabolite highlight the importance of these variables in DDI prediction. Finally, the traditional 'two-fold limits' as a measure of the prediction success were reassessed, in particular at AUC ratios approaching one. New limits proposed are applicable for both inhibition and induction DDIs and allow incorporation of the variability in pharmacokinetics of the victim drug when required. DDI predictions were refined using in vitro clearance data for the inhibitors, and assessed using the new predictive measure.
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Galli, C. "NONCOVALENT FLUOROUS INTERACTIONS: NEW APPROACHES FOR DRUG DISCOVERY AND DRUG DELIVERY." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/540156.
Full textAbstract:
The unique chemical properties of fluorine atom (high electronegativity, high ionization potential, low polarizability and low van der Waals interactions) modify the chemical properties of organic compounds as well as their reactivity when hydrogen atoms are replaced by fluorines. Actually, fluorocarbons show low polarity, which is responsible for the high hydrophobicity of these molecules. Additionally, the low polarizability of fluorines leads to weaker van der Waals interactions, which makes fluorocarbons lipophobic. Therefore, fluorinated compounds show an amphiphilic character that leads to the formation of the fluorous phase, which is separated to both aqueous and organic layers.
The aim of my project was applying the strong and noncovalent fluorous interactions to drug discovery and drug delivery.
The first part of my thesis is focused on the development of a new strategy for target identification able to overcome the several limitations associated to classic chemical proteomics techniques. Indeed, traditional chemical proteomics methodology uses agarose beads covalently bound to streptavidin as stationary phase for affinity purification. This resin is able to retain biotin-tagged proteins as well as sticky components abundant in the lysate. These contaminants might be aspecifically eluted with the biological targets, complicating the mass analysis and therefore the target identification. In order to increase the selectivity of the proteomics approach, we designed an innovative fluorous proteomics methodology using the strong fluorous-fluorous interactions as recognition system for affinity purification. Indeed, perfluorinated stationary phase can anchor only fluorinated species, avoiding aspecific binding. To test the fluorous proteomics approach, papain was considered as biological target. Fluorinated inhibitors of papain with different fluorinated-chain length were synthesized. The number of fluorine atom of the inhibitor is crucial for the interaction with the fluorinated stationary phase in the purification step. Actually, only papain inhibitors with a long fluorous alkyl chain are able to bind the fluorinated resin and therefore immobilize papain. In contrast, inhibitors with a short fluorous alkyl chain cannot bind the fluorinated stationary phase by means of fluorous-fluorous interactions. Consequently, papain cannot be anchored to the resin.
The second part of my thesis is focused on the application of fluorous interactions for drug delivery. This project was carried out in the School of Pharmacy, University of Wisconsin-Madison (Madison, WI, U.S.A.) under the supervision of Professor Sandro Mecozzi. The aim was designing and synthesizing semifluorinated dibranched polymers. The synthesis of fluorinated molecules is a challenge, due to their poor reactivity and low solubility in commonly-used organic solvents. To increase the final yield, each step of the synthesis of the semifluorinated dibranched polymers was optimized. The dibranched fluorinated polymers will be used to prepare oil-in-water nanoemulsions for controlled drug release of paclitaxel. We reasoned that semifluorinated polymers with different chemical structures might lead to nanoemulsions with different stability and drug release profile. Small diameter of the nanoemulsion droplets and long half-lives are desired to maximize the tumoritropic accumulation of these nanosystems by EPR effect before drug release. This allows the release of the drug within the tumor instead of in the bloodstream, avoiding side effects due to the interaction of the drug with off targets and consequently reducing the systemic toxicity.
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Parker, S. M., and John B. Bossaer. "Comparison of Drug Information Resources in Identifying Drug-drug Interactions in Newly Approved Oral Antienplastic Agents." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etsu-works/2343.
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Armstrong, Edward, Sharon Wang, Lisa Hines, Sara Gao, Bimal Patel, and Daniel Malone. "Evaluation of a drug-drug interaction: fax alert intervention program." BioMed Central, 2013. http://hdl.handle.net/10150/610041.
Full textAbstract:
BACKGROUND:Clinicians often encounter information about drug-drug interactions (DDIs) during clinical practice. This information is found within product information (hardcopy and electronic) and various electronic systems. Prescribers may receive medication-related communications in practice that are distributed by facsimile (fax), mail, or telephone from pharmacies and pharmacy benefit managers (PBMs). The purpose of this study was to determine if near-real time fax alerts for potential drug-drug interactions (PDDIs) would influence prescribing.METHODS:A prospective study, in cooperation with a pharmacy benefit manager (PBM), was conducted targeting 18 clinically important PDDIs. Fax alerts included an individualized letter to the prescriber with a list of the interacting drugs, PDDI evidence summaries with citations, and recommended clinical management strategies. Among the 18 PDDIs, 13 PDDIs could be assessed for prescription therapy changes using pharmacy claims data. A prospective cohort design was used to evaluate changes in prescription dispensing 90-days following a PDDI fax alert.RESULTS:A total of 8,075 fax alerts were sent to prescribers and there were 4,712 alerts for the 13 PDDIs that could be assessed for change using pharmacy claims data. There were 2,019 patients (interventions) for which fax alerts were sent to their prescribers who were matched with a control group consisting of patients with the same PDDIs but for whom no fax alert was sent. Overall, this study found 154 (7.6%) of patients in the fax alert group compared to 132 (6.5%) in the control group had changes in therapy (p=0.177).CONCLUSIONS:This fax alert intervention program observed no statistically significant differences in prescribing with a fax alert compared to the control group. If PBMs chose to send individualized, evidence-based information to clinicians regarding drug-drug interactions, this study suggests it may not be an effective intervention to mitigate harm.
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Pan, Xiaolei. "THE SLC22 TRANSPORTER FAMILY: NOVEL INSIGHTS TO ROLES IN DRUG EFFICACY, DRUG-DRUG INTERACTIONS AND MOOD DISORDERS." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3983.
Full textAbstract:
Numerous studies have demonstrated the impact of organic cation (OCTs; SLC22 family) and anion transporters (OATs; SLC22 family) on the efficacy and safety of clinically important therapeutics. To be specific, OCTs and OATs have been identified as determinants for uptake into and secretion from enterocytes, hepatocytes and renal proximal tubular cells, and are frequent sites of drug-drug interaction (DDI). In addition, OCTs expressed in brain are components of the low-affinity, high capacity clearance pathway (uptake-2) for biogenic monoamine neurotransmitters. As a result, OCTs may represent novel targets for mood disorders.
The inhibitory effects of several therapeutic agents, designed drugs and novel compounds were assessed on the function of OCTs/Octs and OATs/Oats. Among these compounds, the anthraquinone rhein showed significant inhibition on hOATs. While the antituberculosis drug ethambutol, the herbal products matrine and oxymatrine, synthetic cathinones, and all quinazoline and guanidine compounds produced significant inhibition on hOCT activity with most IC50 values in the micro- and even nanomolar ranges.
Considering the clinically relevant unbound concentrations in biofluids, significant DDI potentials were found for rhein, ethambutol, matrine, oxymatrine and several synthetic cathinones affecting enterocytes, hepatocytes and/or proximal tubules. As hOCT2 and hOCT3 may participate in modulating neurotransmitter homeostasis in the CNS, these findings also suggested that the CNS pharmacological effects of synthetic cathinones, quinazoline and guanidine compounds might be due to their inhibitory effects on OCTs; although their impact may be limited solely to clearance of these compounds. Based upon their in vitro OCT/Oct inhibition profiles, three lead quinazoline and guanidine compounds were chosen for in vivo studies. Potent antidepressant-like effects of one lead hOCT-interacting compound (KEO-099) were re-confirmed in the tail suspension test. While in vivo results of the two newly identified hOCT-interacting lead compounds were somewhat less clear.
Finally, homology modeling and docking studies for hOCT3 identified key amino acid residues that might be involved in interaction between hOCT3 and small molecules. Subsequent experiments confirmed a competitive mode of interaction between MPP+ and lead compounds on hOCT3. Thus, preliminary analysis indicates our hOCT3 homology model can be used to support rational drug design and high-throughput screening of novel hOCT substrates/inhibitors.
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Diaz, Saez Laura. "Assessment of potential antibacterial drug targets." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/4c3fe03b-5ddc-40c9-962c-8c38f811f6ea.
Full textAbstract:
The alarming increase in antibacterial drug resistance indicates an urgent need to develop new drugs. This project aimed to assess and select potential antibacterial targets and carry out initial biochemical characterisation concentrating on enzymes from biowarfare agents <i>Bacillus anthracis</i>, <i>Burkholderia pseudomallei</i>, <i>Francisella tularensis</i> and <i>Yersinia pestis</i>. The overall objective is to combine genetic and chemical studies to validate, or not, targets for early stage drug discovery. In collaboration with the Dstl (Defence Science and Technology Laboratory), a series of potential targets were selected. This was carried out using essentiality prediction data from the Dstl labs, information at AEROPATH and ChEMBL databases, and the literature. Once ten different targets were selected, recombinant protein production was carried out to support structural and biochemical characterisation. Seven proteins were successfully purified and four of them prioritised for further studies. These are kynurenine formamidase (KynB), D-alanine—D-alanine ligase (Ddl), caseinolytic protease subunit P (ClpP), and the dihydrofolate synthase:folyl-poly-glutamate synthase (bifunctional protein FolC). X-ray crystallography was used to determine protein structures of KynB, Ddl and ClpP from various bacteria. Additionally, different enzymatic and binding assays were applied to assess kinetic parameters of KynB, Ddl and FolC, and compound library screenings were carried out for Ddl. In parallel, the genetic validation of these targets was being carried out by the Dstl. KynB is an important enzyme in tryptophan metabolism and predicted to be essential in Pseudomonas aeruginosa. The <i>B. anthracis</i>, <i>B. cenocepacia</i> and <i>P. aeruginosa</i> KynB structures showed an amidase fold not previously described, with a distinctive binuclear Zn<sup>2+</sup> catalytic site that indicated a distinct reaction mechanism. Whilst the characterisation of the enzyme was ongoing, the Dstl lab reported the gene as non-essential and so no additional chemical validation was pursued. Ddl generates a precursor for the peptidoglycan layer and appears to be an essential protein in several Gram-negative bacteria. The structure of <i>B. pseudomallei</i> Ddl (<i>Bp</i>Ddl) in the presence of the co-factor and the reaction product D-alanyl-D-alanine (1.5 Å resolution) gives information about the substrate-binding site. Biolayer interferometry (BLI) and high-throughput (HTP) assay protocols were developed and applied. Despite testing around 22,000 compounds no inhibitors or suitable hits were found. This suggests <i>Bp</i>Ddl is a challenging target and a different approach for drug discovery might have to be considered. Fourteen ClpP subunits form a proteolytic complex which presents two different conformations; open and compressed. Structures of <i>F. turalensis</i> ClpP (<i>Ft</i>ClpP) with open and compressed conformations have been determined indicating this major conformational change is caused by a loop rearrangement at the proteasome inner canal that leads to the protease active site. FolC is an essential protein for the synthesis of folyl-poly-glutamates, a reference pathway for drug development. A new enzymatic assay, using malachite green, has been identified and used to confirm <i>Y. pestis</i> FolC activity. Such an assay could be used to determine kinetic parameters and to develop a HTP assay. The studies carried out informed about potential antibacterial target structures and biochemical properties. Protocols have been developed for protein recombinant expression, purification, crystallisation and structure determination as well as enzymatic assay development and compound library screens.
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Li, Xiaoxiao. "Ranolazine: a Potential Anti-diabetic Drug." Thesis, Virginia Tech, 2012. http://hdl.handle.net/10919/19202.
Full textAbstract:
Diabetes is a life-long chronic disease that affects more than 24 million Americans. Loss of pancreatic beta-cell mass and function is central to the development of both type 1 (T1D) and type 2 diabetes (T2D). Therefore, preservation or regeneration of functional beta-cell mass is one of the essential strategies to treat diabetes [1]. In my study, I tested if ranolazine, a synthetic compound, has potential to prevent or treat diabetes. Diabetes were induced in mice by giving multiple low-doses of streptozotocin (STZ). Ranolazine was given twice daily via an oral gavage (20 mg/kg) for 5 weeks. blood levels of glucose, insulin, and glycosylated hemoglobin (HbA1c) were measured. Glucose tolerance test was performed in control and treated mice. pancreatic tissues were stained with hematoxylin and eosin or stained with insulin antibody for islet mass evaluation. INS1-832/13 cells and human islets were further used to evaluate the effect of ranalozine on beta-cell survival and related signaling pathway. Fasting blood glucose levels after the fourth week of STZ injections were lower in ranolazine treated group (199.1 mg/dl) compared to the vehicle group (252.1 mg/dl) (p<0.01). HbA1c levels were reduced by ranolozine treatment (5.33%) as compared to the control group (7.23%) (p<0.05%). Glucose tolerance was improved in ranolazine treated mice (p<0.05). Mice treated with ranolazine had higher beta-cell mass (0.25%) than the vehicle group (0.07%)(p<0.01). In addition, ranolazine improved survival of human islets exposed to high levels of glucose and palmitate, whereas cell proliferation was not altered. In addition, ranolazine slightly increased the cAMP in MIN-6 cell and human islets. In conclusion, ranolazine may have therapeutic potential for diabetes by preserving beta-cell mass.<br>Master of Science
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Elsherbiny, Doaa. "Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8426.
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Burt, Howard James. "In Vitro Assessment and Prediction of Time-Dependent CYP3A4 Drug-Drug Interactions." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503677.
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Yang, Jiansong. "Quantitative prediction of metabolic drug-drug interactions : in vitro - in vivo extrapolation." Thesis, University of Sheffield, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422638.
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Babits, Lauren, and Courtney Clark. "Evaluation of Pharmacy Software Programs to Detect Clinically Important Drug-Drug Interactions." The University of Arizona, 2009. http://hdl.handle.net/10150/623915.
Full textAbstract:
Class of 2009 Abstract<br>OBJECTIVES: To assess the performance of drug-drug interaction (DDI) software programs utilized in community and hospital pharmacies located in urban and rural settings.
METHODS: A fictitious patient profile with 18 drugs and a penicillin allergy was entered into pharmacy computer systems throughout Arizona. Researchers recorded the software systems’ responses to 20 targeted combinations, 14 of which should have produced an alert and 6 that were not true interactions. The number of true positive, true negative, false positive and false negative responses was determined for each system. These data were subsequently used to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) overall and at each site.
RESULTS: There were 35 participating pharmacies that used a total of 18 different software programs. The overall sensitivity was 0.8, and ranged from 0.21 to 1 between sites. Computer software failed to detect important interactions 20% of the time. The specificity ranged from 0.83 to 1; PPV ranged from 0.89 to 1; and NPV ranged from to 0.35 to 1. Nine sites, using five different software programs returned perfect results. However, some of those programs produced different results at other sites. CONCLUSIONS: This study shows that improvements are needed in software programs to help pharmacists accurately identify DDIs which could prevent potential adverse drug events. Many clinically important interactions remain undetected by software programs, and users should be mindful of current limitations in technology.