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Monkhouse, Donald C. "Dosage Forms for Clinical Trials." Drug Development and Industrial Pharmacy 11, no. 9-10 (January 1985): 1729–55. http://dx.doi.org/10.3109/03639048509057696.
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Smoliga, James M., and Otis L. Blanchard. "Allometric scaling models: history, use, and misuse in translating resveratrol from basic science to human clinical applications." Functional Foods in Health and Disease 7, no. 5 (May 30, 2017): 338. http://dx.doi.org/10.31989/ffhd.v7i5.345.
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Background: Determination of the first-in-human and pharmacologically active dosage for drugs and nutraceutical compounds is a critical step in study design and product development. Allometric scaling is a form of mathematic modeling commonly used to convert dosages between species. While allometric scaling allows for quick and straightforward conversions between species, it is often misunderstood and misused in translational clinical applications. This is readily demonstrated in the case of resveratrol – a polyphenol which is found in red wine. In the past decade, a considerable amount of research has emerged regarding the health benefits of the resveratrol supplementation. Although data from rodent models suggests that resveratrol can have major effects on cardiometabolic and neurologic health, human clinical trials have had mixed results. While some human clinical trials have yielded encouraging results, a few noteworthy trials have reported that seemingly appropriate allometry-derived dosages of resveratrol did not provide the expected health benefits reported in animal models.Here, we discuss the history of various models within allometry, including their advantages, disadvantages, and nuances from a clinical perspective. This historical information will provide some insight into why dosages recommended from allometric scaling are appropriate in some circumstances and inappropriate in others. We will then demonstrate how allometric models have been utilized to translate dosages of resveratrol from rodent models into the dosages recommended for human clinical trials. Pharmacokinetic data from various human clinical trials will be summarized and compared to data predicted from allometric models. Data from selected human clinical trials will then synthesized to demonstrate the dosage-dependent effects of resveratrol, and provide further insight into the appropriate use of allometric models for selecting resveratrol dosage. Together, this information will promote a greater understanding of the role of allometric scaling in dose selection and provide an explanation for some of the apparent inconsistencies in translational research regarding resveratrol.Keywords: allometric scaling, dose conversion, bioavailability, pharmacokinetics, resveratrol
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Gildeeva, G. N., E. A. Ezhova, D. V. Butuzova, N. L. Mishchenko, V. Y. Yurkov, A. V. Teteneva, and T. S. Ageeva. "FEATURES OF THE ORGANIZATION OF CLINICAL TRIALS OF NARCOTIC DRUGS IN RUSSIA." Siberian Medical Journal 34, no. 2 (July 11, 2019): 152–58. http://dx.doi.org/10.29001/2073-8552-2019-34-2-152-158.
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The problem of ensuring the necessary level of availability of narcotic drugs (NLP) in the Russian Federation, especially in the framework of palliative medical care for oncological patients is the area of special and constant attention of the Government and civil society. Recently, a number of necessary changes of the legislation aimed at simplifying the procedures for prescribing and issuing NLP have been introduced, and the possibility of optimizing the rules for their storage and accounting as well as improving the methods for calculating the needs for such drugs are being actively discussed.As part of the import substitution program in Russia, the new dosage forms for NLP are under development. Such process is accompanied by clinical studies with a number of features that take into account the specific chemical composition of finished products.
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Lemaitre, Florian, Clara Locher, Marie-Clémence Verdier, and Florian Naudet. "Clinical trials during pandemics and beyond: time for a more efficient pharmacological strategy." Journal of Antimicrobial Chemotherapy 76, no. 9 (June 2, 2021): 2234–36. http://dx.doi.org/10.1093/jac/dkab190.
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Abstract During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, clinical trials on antiviral or symptomatic drugs have been conducted very rapidly even for drugs with a poor pharmacological rationale for efficacy on SARS-CoV-2. Despite lacking basic pharmacological information, most of these clinical trials were also extremely redundant. Applying simple rules, (such as identifying a mechanistic rationale, confirming the ability to reach exposure targets at therapeutic dosage and ensuring tests show drug efficacy in appropriate in vitro and animal models before entering clinical trials) might have saved considerable amounts of time and money, and might have avoided useless research. Moreover, combining these simple rules with the implementation of a relevant policy at both an international and a national level, by limiting studies with a poor methodological/scientific approach and aggregating studies with similar design into single clinical trials, is potentially a far more-efficient strategy.
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Durán, Josefina, Margarita Bockorny, Deepan Dalal, Michael LaValley, and David T. Felson. "Methotrexate dosage as a source of bias in biological trials in rheumatoid arthritis: a systematic review." Annals of the Rheumatic Diseases 75, no. 9 (April 18, 2016): 1595–98. http://dx.doi.org/10.1136/annrheumdis-2016-209383.
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ObjectivesTo evaluate if optimal dose of either oral or injectable regimens of methotrexate (MTX) of 25 mg/week was used in the comparator arms of studies comparing biologic drugs with MTX in rheumatoid arthritis (RA).MethodsA systematic literature search was carried out in MEDLINE, EMBASE and the Cochrane Library databases for randomised controlled trials comparing biologics with MTX in RA. A systematic review was performed among studies that met predefined criteria focusing on assessment of dose of MTX used in the comparator arm. Study authors were contacted when necessary. Study quality was assessed.ResultsA total of 3276 references were identified and 13 trials were included. We obtained maximal dose and regimen for all. The maximal dose of MTX used in the comparator arm of the trials was no more than 20 mg/week in any trial and for all but one trial, MTX was given orally and not by injection. The trial that used an injectable form reached a maximum of 15 mg/week.ConclusionsA suboptimal dose of MTX was used in biological clinical trials performed in RA, particularly regarding route of administration. This may have biased findings in favour of biological agents.
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Mikhailova, Olga A., Vladimir N. Drozdov, Natalia В. Lazareva, and Evgeniya V. Shikh. "Dosage Problems in Children: Well-Known Facts and Unresolved Issues." Current pediatrics 17, no. 4 (October 5, 2018): 350–55. http://dx.doi.org/10.15690/vsp.v17i4.1931.
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The problem of dosing drugs at an early age is conditioned by specific metabolism of medicinal products (MP) in the child's body. Currently, there are a few clinical trials on the study of physiological characteristics in different periods of childhood and systematised data. It is still relevant to understand the characteristic differences that affect the bioavailability, distribution and excretion of MP, especially in children over one month of life. The results of such studies are necessary in order to formulate the recommendations for use of MP in children taking into account their age and compensate for the lack of data from direct clinical trials in pediatrics. The possibility of using a dose calculation method regarding the fat content of the body in different periods of childhood and the chemical properties of the substance has been discussed.
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Verma, Priyanka, Pooja Mittal, Archana Singh, and Indrakant K. Singh. "New Entrants into Clinical Trials for Targeted Therapy of Breast Cancer: An Insight." Anti-Cancer Agents in Medicinal Chemistry 19, no. 18 (February 7, 2020): 2156–76. http://dx.doi.org/10.2174/1871520619666191018172926.
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Breast cancer is too complex with various different molecular alterations involved in its pathogenesis and progression. Over the decade, we have seen a surge in the development of drugs for bimolecular targets and for the signal transduction pathways involved in the treatment line of breast cancer. These drugs, either alone or in combination with conventional treatments like chemotherapy, hormone therapy and radiotherapy, will help oncologists to get a better insight and do the needful treatment. These novel therapies bring various challenges along with them, which include the dosage selection, patient selection, schedule of treatment and weighing of clinical benefits over side effects. In this review, we highlight the recently studied target molecules that have received indications in breast carcinoma, both in the localized and in an advanced state and about their inhibitors which are in clinical development which can give the immense potential to clinical care in the near future.
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Recker, Mark W., and Karen L. Kier. "Potential Interaction between Clarithromycin and Warfarin." Annals of Pharmacotherapy 31, no. 9 (September 1997): 996–98. http://dx.doi.org/10.1177/106002809703100907.
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Objective To report a possible drug interaction between clarithromycin and warfarin in a patient with chronic atrial fibrillation. Case Summary A patient with chronic atrial fibrillation was placed on warfarin therapy. International normalized ratios (INRs) ranged from 1.61 to 3.99 while the dosage was being adjusted during the first 5 months of warfarin therapy. The dosage was titrated to 20 mg/wk; laboratory tests obtained 2 weeks after this dosage was started indicated an INR of 2.1. The same dosage was continued. Clarithromycin 500 mg bid was started for an acute exacerbation of bronchitis 10 days after the last INR was obtained and was continued for 14 days of therapy. An INR obtained 3 days after completion of the clarithromycin therapy was 16.8. The warfarin was withheld and vitamin K 20 mg im was administered. The INR obtained the next day was 1.52. The warfarin was restarted and the dosage was titrated to between 22.5 and 25 mg/wk, with INRs ranging from 0.85 to 3.14. Discussion Many factors influence the metabolism of warfarin, including disease states, medications, age, and diet. Data collected in this case suggested clarithromycin may have contributed to the increase in the effect of warfarin. Inhibition of the cytochrome P450 oxidizing system appears to be the reason for the increase. Numerous drugs and disease states affect the rate at which this system metabolizes drugs. Conclusions The potential interaction between clarithromycin and warfarin warrants prudent monitoring of the INR during concurrent administration of these drugs. Warfarin dosages may need to be reduced during concurrent clarithromycin therapy to prevent bleeding complications. Further controlled clinical trials are needed to substantiate the interaction between clarithromycin and warfarin.
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Luijn, Johan CF van, Arie C. van Loenen, Frank WJ Gribnau, and Hubert GM Leufkens. "Choice of Comparator in Active Control Trials of New Drugs." Annals of Pharmacotherapy 42, no. 11 (October 28, 2008): 1605–15. http://dx.doi.org/10.1345/aph.1l115.
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Background: When choosing the active control group in a randomized that, it is important to maintain standard treatment for the therapeutic indication for which a medicine is studied. This choice is relevant not only for demonstrating the efficacy and safety of a new drug, but also for assessing Its place in therapy in comparison with existing medicines. Comparative information is important for decisions on prescribing and reimbursement. However, choosing the most suitable comparator is difficult when recommendations on drugs of first choice vary depending on clinical settings and times. Objective: To evaluate the choice of comparator in premarketing randomized active control trials (RaCTs) in comparison with recommendations lor standard treatment. Methods: We evaluated drugs that were authorized for use in the European Union market between 1999 and 2005. Information on active comparators in RaCTs was extracted from the European Public Assessment Reports and information on recommendations regarding standard treatment was retrieved from the annual editions of the Dutch reference book on pharmacotherapy. Data on prescribing and indications at the time of authorization and 3 years before authorization were included. The comparator was considered to be in line with standard treatment if there was a similarity in both active substance or therapeutic class and the dosage. Results: For 58 new medications identified, treatment in the active control group was in line with the recommended standard treatment in 108 of 153 (71%) RaCTs at the time of the drug's authorization; 47 (81%) of the new drugs had been compared with the recommended standard treatment in at least one trial. When dissimilarities occurred, none of the comparators had been recommended as standard treatment 3 years earlier (the supposed time of defining the trials' protocol). Conclusions: Most comparators in the premarketing RaCTs of new medicines were in line with the recommended standard treatment at the moment of marketing authorization. In view of this similarity, most of these trials are also fit for postmarketing decision-making on prescribing and on inclusion in clinical guidelines and reimbursement systems.
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Leleka, M. V., and O. M. Zalis′ka. "Rationale of method of analysis of evidence-based data on the pharmacological activity of succinic acid and its combinations drugs." Farmatsevtychnyi zhurnal, no. 6 (September 4, 2018): 97–102. http://dx.doi.org/10.32352/0367-3057.6.15.06.
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Succinic acid as endogenous metabolite has a wide range of applications in medical practice in Ukraine and abroad. We research a new medicines, based on succinic acid, ascorbic acid and rutin for the prevention and treatment of influenza. Analysis of the data evidence-based medicine necessary for the implementation of quality assessment study feasibility of adding succinic acid in the various dosage forms and determine their pharmacological activity.
It was studied international databases and registers of clinical trials MEDLINE®, EMBASE®, Scopus, Cochrane Library for the period from 1966 to June 2015. In the search for key phrases search engine electronic library «The Cochrane Library» found 872 913 publications, including 71 in the section «Trials». Of these, only 23 were devoted to review the results of clinical trials of medications that contain in their composition succinic acid.
In the analysis of papers revealed that all 12 Trials of the search engine PubMed are present in search results «The Cochrane Library». Therefore, for further analysis we selected directory search results Trials «The Cochrane Library» and 3 Review of retrieval system PubMed.
We analyzed Trials in terms of pharmacological activity and dynamics of publications. For pharmacological properties and relevance RCTs grouped as follows: antihypoxic action confirm 7 RCT (2003–2013 years), improve of iron absorption in the gastrointestinal tract – 6 RCT (1966–1974 years), hepatoprotective – 4 RCT (2013–2014 years). One RCT has effectiveness succinic acid for use in gastroenterology (in combination with omeprazole, 2012), depression (2013), the transplant (1993) during menopause (2008), renal failure (2013) for fever during surgery (2007). We can call such medicines containing succinic acid and have proven clinical efficacy: Remaksol, Tsytoflavin, Vecam (Omeprazole + succinic acid). We analyzed the Review of reviews of retrieval system PubMed. Analysis reviews MedLine (Review) opens new prospects for the use of succinic acid in the treatment of hypoxia and viral hepatitis. The results of clinical trials confirm the feasibility of developing new drugs with succinic acid.
We conducted a review of evidence data about the inclusion of succinic acid in the various dosage forms. Succinic acid is the part of the drugs with different pharmacological effect. The results of clinical trials confirm the feasibility of developing of new drugs with succinic acid.
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Dodson, W. Edwin, Marc Kamin, Lesley Kraut, William H. Olson, and Shu-Chen Wu. "Topiramate Titration to Response: Analysis of Individualized Therapy Study (TRAITS)." Annals of Pharmacotherapy 37, no. 5 (May 2003): 615–20. http://dx.doi.org/10.1345/aph.1c133.
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OBJECTIVE: To evaluate the relationship between baseline seizure frequency and stabilized topiramate dosage and the effect of individualized treatment on tolerability in adults with partial-onset seizures receiving other antiepileptic drugs (AEDs). METHODS: In this 20-week, open-label trial, dosages of medications were adjusted according to clinical response. Dosage and seizure response data were analyzed for 2 groups defined by baseline seizure frequency: <4 and ≥4 seizures per month. RESULTS: In the outcome evaluable population (n = 471), the mean ± SEM stable topiramate dosage was 303 ± 139 mg/d when baseline seizure frequency was <4 seizures/month and 341 ± 153 mg/d when baseline seizure frequency was ≥4 seizures/month (p = 0.005). The most common adverse events were somnolence (8.5%), fatigue (7.3%), nausea (5.3%), and dizziness (5.0%). Cognitive complaints were reported by <3% of patients. When concomitant AED dosages were reduced, 14% of patients discontinued topiramate due to adverse events compared with 23% if the concomitant AED dosage was unchanged or increased. CONCLUSIONS: When clinicians individualize topiramate dosage according to clinical response, the stabilized topiramate dosage as add-on therapy is influenced by baseline seizure frequency. Topiramate tolerability is improved when dosages of concomitant AEDs are reduced.
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De Caterina, Raffaele, and Giulia Renda. "Anticoagulant Therapy in Atrial Fibrillation – Time for a Change?" European Cardiology Review 5, no. 2 (2009): 57. http://dx.doi.org/10.15420/ecr.2009.5.2.57.
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Although to date warfarin and other vitamin K antagonists have clearly had the greatest efficacy among commonly available treatments in preventing stroke in atrial fibrillation, their use is associated with a substantial risk of major bleeding and is impractical because of their narrow therapeutic window, their interaction with drugs and foods and the need for frequent coagulation monitoring. Several new anticoagulants are undergoing phase III clinical trials in atrial fibrillation with the aim of demonstrating non-inferiority compared with vitamin K antagonists or superiority compared with aspirin in patients in whom vitamin K antagonists are contraindicated or not tolerated. In the recently released Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, the first such drug, dabigatran etexilate, was proved substantially equivalent to 2–3 international normalised ratio (INR)-adjusted warfarin at the dosage of 110mg twice a day (BID), with superior efficacy at a dosage of 150mg BID. With these new drugs, cardiologists and internists are witnessing a real revolution in the thromboprophylaxis in atrial fibrillation.
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Arkhipov, V. V., E. A. Sokova, G. I. Gorodetskaya, O. A. Demidova, and T. V. Aleksandrova. "New Anticonvulsants: Interchangeability Issues and the Use of Generic Anticonvulsants in Clinical Practice." Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products 9, no. 2 (June 5, 2019): 101–7. http://dx.doi.org/10.30895/1991-2919-2019-9-2-101-107.
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This article looks into interchangeability and therapeutic equivalence of innovator and generic anticonvulsants — the first-generation and new antiepileptic drugs (AEDs). The results of a number of clinical trials assessing therapeutic equivalence of generic AEDs support the opinion that these medicines could only be substituted provided an ultra-cautious approach is used, even if the case involves only one International Nonproprietary Name, including, but not limited to different dosage forms of one and the same product. The aim of the study was to analyse factors leading to incorrect assessment of therapeutic equivalence of new and generic anticonvulsant drugs, and to improve methodological approaches to conducting clinical trials of these products. The paper cites data from Russian and foreign sources which state that the substitution of AEDs in some patients in full remission may result in adverse reactions or relapse of seizures. The analysis of the experience of scientific, expert, and regulatory institutions made it possible to develop a course of actions to be used when substituting AEDs and conducting clinical trials that assess therapeutic equivalence of new and generic anticonvulsants. The proposed methodology will help minimise potential health risks brought about by various factors that result in incorrect assessment of AEDs therapeutic equivalence and interchangeability.
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Mandpe, Pankaj, Bala Prabhakar, and Pravin Shende. "Potential of Mirabegron and its Extended-release Formulations for the Treatment of Overactive Bladder Syndrome." Current Drug Metabolism 21, no. 2 (June 11, 2020): 79–88. http://dx.doi.org/10.2174/1389200221666200425211139.
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Background: Overactive bladder syndrome is a broadly occurring urological disorder with a distressing impact on the quality of life. The commonly used antimuscarinic drugs show poor patient compliance because of unsatisfactory potency, tolerability and high occurrence of adverse effects such as dry mouth, blurred vision, constipation, dizziness etc. Mirabegron is the first approved β3-adrenoreceptor agonist, used as mono or in combination therapies for overactive bladder syndrome. Objective: The present review provides an insight into the mechanism, pharmacokinetics, toxicokinetics, clinical trials and the development of various conventional and modified-release dosage forms of mirabegron for the treatment of overactive bladder syndrome. Results: The clinical trials of phase II and phase III of mirabegron demonstrated symptomatic relief from the overactive bladder without disturbing the micturition cycle. To date, mirabegron showed promising results for safety, tolerability and efficacy in patients with overactive bladder syndrome. The modified-release tablet dosage form of mirabegron appear to be a proficient and suitable replacement for antimuscarinics and revealed the tremendous potential to overcome the adverse effects of conventional antimuscarinic drugs like Oxybutyline chloride ER, Detrol LA, VESIcare, etc. Conclusion: Mirabegron shows a distinct mode of action, i.e., targeting β3-adrenoreceptors and improving bladder storage without altering void contractions. The limited side effects, high safety, efficacy and tolerability of mirabegron present an adequate substitute to antimuscarinics. However, long-term analysis and clinical studies are prerequisites for assessing the safety, tolerability and efficacy profile of mirabegron.
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Barst, Robyn J. "Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies." Advances in Pulmonary Hypertension 9, no. 4 (December 1, 2010): 214–19. http://dx.doi.org/10.21693/1933-088x-9.4.214.
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Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?
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Chen, Jacqueline, Kaitlyn Park, Sun Young Uhm, Amelia Spinrad, Apurva Uniya, Nancy Pire-Smerkanich, and Eunjoo Pacifici. "3567 An Analysis of Current Trends in Inclusion of Historically Underrepresented Populations in Clinical Trials: Women and Geriatrics." Journal of Clinical and Translational Science 3, s1 (March 2019): 83–84. http://dx.doi.org/10.1017/cts.2019.193.
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OBJECTIVES/SPECIFIC AIMS: Clinical trials (CTs) play an important role in developing new treatments, expanding or refining treatments that are already available, and/or identifying behavioral changes that can prolong or improve the lives of subjects. CTs are also conducted to understand normal human physiology, pathophysiology, and factors associated with health outcomes. Results from CTs are then used to determine the safety and efficacy of medications or treatment. CT participants should reflect the diversity of those receiving the treatments because, exclusion of specific populations in CTs may potentially result in knowledge gaps for clinicians and regulators. Historically, women and geriatrics have been underrepresented as CT participants. For women, this is the result of Food and Drug Administration (FDA) action in 1977 which restricted women with childbearing potential from participating in phase I and early phase II CTs after thousands of birth defects resulted from thalidomide usage during pregnancy. While the U.S. Government Accountability Office’s 1992 and 2001 reports documented an increased female inclusion in later stages of CTs, earlier phases of CTs were still lacking. Likewise, older adults and geriatrics have been excluded in CTs arbitrarily or to avoid adverse events associated with drug-drug interactions and comorbidities. Over the past few decades, the FDA has worked to address this issue and increase diversity and transparency in CTs. In 2015, the FDA’s Action Plan for Food and Drug Administration Safety and Innovation Act (FDASIA) Section 907 called for improved CT inclusion and reporting of demographic subgroups (sex, age, race, and ethnicity), highlighting three priority areas: quality, participation, and transparency. This research examines the current state of female inclusion in phase I and II CTs (2016 to 2017) and geriatric inclusion in phase III CTs (2010 to 2017). METHODS/STUDY POPULATION: To assess female representation in phase I and II CTs, data from 2016 CTs was extracted from clinicaltrials.gov. The average percentage of male and female participation in trials recruiting for males and females was determined; CTs conducted in only males or females (due to sex specific disease states) were excluded. The data was further differentiated into investigator-initiated and industry-sponsored trials to determine any differences in sex representation. Data from 2017 CTs on clinicaltrials.gov will be extracted and analyzed as well as 2016 to 2017 data from FDA novel drug approvals. To assess geriatric representation in phase III CTs, geriatric subsections of drug labels from novel drug applications approved between 2010 to 2017 were assessed for geriatric-specific information based on four areas: 1) reporting of CT including geriatrics, 2) reporting of percentage of CT participants ages 75+, 3) providing geriatric dosage recommendations, 4) determining product safety and efficacy for geriatrics. RESULTS/ANTICIPATED RESULTS: It is mandatory that all US CTs are registered on clinicaltrials.gov with the exception of Phase I studies, and results posted within 1 year of CT completion. In 2016, 916 phase I and 713 phase II CTs were registered on clinicaltrials.gov. Of these registered CTs, 4% of phase I and 9% of phase II CTs posted results. Of these, phase I studies included more males than females. Of these, phase I studies showed higher percentage of males (58%) than females (42%). In phase I/II, phase II, and phase II/III CTs, females were represented at a higher levels than males by 8-20% (Table 1). Phase I industry-sponsored and investigator-initiated trials and phase II/III investigator-initiated trials included less females than males (Table 2); all other types of CTs had more female than male subjects (Table 2). Preliminary findings will be expanded to include 2017 CTs and a wider pool of clinical trials will include all those associated with FDA novel drugs approved in 2016 and 2017. Of the 250 labels of novel drugs approved from 2010 to 2017 assessed for geriatric inclusion, 74% reported a CT including geriatrics, and 55% reported including CT participants ages 75+. Further, 31% provided geriatric dosage recommendations and 62% indicated insufficient evidence to determine product safety/efficacy for geriatrics (Figure 1). There was no consistent increase following the 2015 implementation of FDASIA section 907 in any of the four areas examined (Figure 2). Labels providing geriatric dosage recommendations were consistently the least fulfilled area across all years analyzed (Figure 3). DISCUSSION/SIGNIFICANCE OF IMPACT: A lack of inclusion of specific populations in CTs can lead to serious complications. For example, in 2013, the FDA required a lower recommended dose for women for drugs containing the sedative-hypnotic zolpidem (i.e. Ambien) due to persisting next morning drowsiness; the FDA arbitrarily recommended the dosage be halved from 10 mg to 5 mg as it found that women appeared to eliminate zolpidem from their bodies more slowly than men. Additionally, $35.7 million is spent annually on hospitalization from adverse drug reactions in the elderly. And, although government acts and initiatives have called for greater inclusion of certain populations like females and geriatrics in CTs, there is no penalty for exclusion. Problems like these may be avoided if these specific populations are included in CTs so that drugs can be properly studied. It may be preliminary to make conclusions about female representation in phase I clinical trials because it is not mandatory to register all phase I trials on clinicaltrials.gov, but further investigation will be conducted into FDA summary reports. Preliminary findings indicate that efforts to include female subjects may be effective in the subset of studies that reported their results. As of 2017, 51.3% of the U.S. population over 18 years old is female (U.S. Census Bureau). Early clinical trials often help to establish safety and dosing for phase III trials. Thus, it is pertinent that the inclusion rate is reflective of the general population at all clinical trial stages, not just pivotal, phase III trials. It would be prudent to monitor this trend as more studies report their results. Given that the average US life expectancy is now 78 years and that elderly population is expected to double in coming decades (NIH, 2016), there is an urgent need to include this population in current and future clinical research. Geriatrics, particularly those age 75+, use more than a third of total prescription and over-the-counter medications sold in US (Merck Institute, 2014), but is severely underrepresented in CTs. The effects of polypharmacy and changes in drug metabolism with age increase the need for specific drug dosage recommendations for geriatrics. As there was no discernable difference in drug labels fulfilling areas examined before and after 2015, FDASIA implementation may not have impacted geriatric inclusion in CT for drugs approved between 2010 to 2017. As many of these CTs began prior to FDASIA 2012 signing and 2015 implementation, the legislation’s full impact may occur in future years. Nonetheless, inadequate language currently found in geriatric drug labels can create challenges for clinicians when prescribing these medications for geriatric patients, potentially contributing to adverse drug events.
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Aícua‐Rapún, Irene, Pascal André, Andrea O. Rossetti, Philippe Ryvlin, Andreas F. Hottinger, Laurent A. Decosterd, Thierry Buclin, and Jan Novy. "Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment." Annals of Neurology 87, no. 1 (November 26, 2019): 22–29. http://dx.doi.org/10.1002/ana.25641.
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Tolokonnikov, E. G., A. S. Adekenova, and O. V. Maslova. "PHARMACOECONOMICAL ANALYSIS OF ANTI-PERIODONTOSIS DRUGS." REPORTS 5, no. 333 (October 15, 2020): 13–18. http://dx.doi.org/10.32014/2020.2518-1483.113.
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In this work, a retrospective analysis of anti-periodontosis drugs is carried out using the methods of pharmacoeconomic analysis: analysis of the "cost of disease" (direct costs), "cost-effectiveness" for promoting the original drug "Matripin-Dent" on the pharmaceutical market. In the clinic of the Dental Institute of Kazakh National Medical University named after S.D. Asfendiyarov (Almaty), clinical trials of a new domestic phytopreparation “Dental gel Matripin-Dent” were carried out. The gel preparation was used in the complex therapy of periodontal diseases of an inflammatory and inflammatory-destructive nature. As a result of the experimental studies, it was found that "Matripin-Dent", due to the original composition of the gel composition, provides high adhesion to mucous surfaces, ensures reliable fixation of the drug on the gums, contributes to a better distribution of active components due to good absorption of the ointment base composition. It has been proven that the developed dosage form "Matripin-Dent" based on pharmacologically active compounds of Populus balsamifera L. buds and flowers, leaves, buds of Matricaria chamomilla L. has a number of advantages in comparison with the drugs existing on the pharmaceutical market used in dental practice.
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Walenga, Jeanine M., Debra A. Hoppensteadt, Brigitte Kaiser, W. Jeske, and J. Fareed. "Factor Xa Inhibitors in the Control of Thrombogenesis." Hämostaseologie 19, no. 01 (January 1999): 55–62. http://dx.doi.org/10.1055/s-0038-1660378.
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SummaryIt is now well recognized that drugs with sole anti-Xa activity are capable of producing antithrombotic effects. The basic and clinical studies with pentasaccharide have validated this hypothesis. Synthetic heparin pentasaccharide is currently undergoing clinical trials in the prophylaxis of DVT in orthopedic surgery. While the naturally occuring direct anti-Xa agents such as antistatin, TAP and Yagin are potent anti-Xa agents their clinical development is delayed due to several unresolved developmental issues. On the other hand, several peptidomi-metic agents also demonstrate varying degrees of oral and subcutaneous bioavailability. One of these agents namely the DX 9065a is in clinical trials at this time. The factor Xa inhibitors exhibit a higher margin of safety in contrast to the antithrombin agents, however, their anticoagulant effects are somewhat weaker than the antithrombin agents. Thus, these agents may prove to be very useful in the prophylactic management of both the thrombotic and cardiovascular disorders. However, their use as an anticoagulant may not be very practical. These agents can be given as adjunct agents with hirudin and related antithrombin agents. These agents may also be of value in the outpatient management of thrombotic disorders. These agents may also be of value as an adjunct to various other antithrombotic drugs. Additional adjunct uses as with the antithrombin drugs, GP llb/llla inhibitors, thrombolytic agents and TFPI may increase the therapeutic index of many of these agents. It should be emphasized that each of these individual anti-Xa agents represent distinct drugs which require individual specific dosage optimization.
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Shkolnikova, Marina, Olga Chugunova, and Olga Sokolova. "Comparative Characteristics of Dosage Forms of α-Lipoic Acid." E3S Web of Conferences 222 (2020): 06032. http://dx.doi.org/10.1051/e3sconf/202022206032.
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α-Lipoic acid is a fatty acid, which in its physiological effect is on a par with vitamins and minerals, is a vitamin-like substance (vitamin N). A review of clinical trials of the effectiveness of α-lipoic acid in evidence-based diseases is presented. It is proved that the main indication for the use of α-lipoic acid is diabetes mellitus and complications associated with impaired glucose metabolism, including neuropathy, comprising children and adolescents. In addition, α-lipoic acid can be used for medicinal purposes and for a number of other diseases. α-Lipoic acid is an active substance with “critical bioavailability”: when introduced into the interior, its inter- and intra-individual plasma levels can vary significantly. Therefore, the therapeutic effectiveness of lipoic acid preparations largely depends on its form. A comparative characteristic of solid dosage forms of α-lipoic acid according to pharmacokinetic and clinical indicators is given. It was shown that the pharmacokinetic indices of the solid forms of α-lipoic acid practically do not differ, and the bioavailability of all forms is in the range of 30-60%. The advantages (for manufacturers and consumers / patients) and the disadvantages of α-lipoic acid drugs in solid forms - capsules and tablets are shown. Results proving the best therapeutic effect of α-lipoic acid in micellar form are presented.
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Meyer, Olivier C. "Safety and Security of Daflon 500 mg in Venous Insufficiency and in Hemorrhoidal Disease." Angiology 45, no. 6_part_2 (June 1994): 579–84. http://dx.doi.org/10.1177/000331979404500614.
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Daflon 500 mg* is a new flavonoid vasoprotector venotonic agent whose active principle is micronized and contains 90% diosmin and 10% flavonoids expressed as hesperidin. In animal studies, the safety of Daflon 500 mg is shown by an LD50 (lethal dose so) of more than 3 g/kg, ie, 180 times the daily therapeutic dose, as well as by the absence of any toxic effect after repeated oral dosing for thirteen and twenty-six weeks, using a dose representing 35 times the daily dosage, in the rate and primate. Daflon 500 mg has no mutagenic action nor any significant effect on reproductive function. Gastrointestinal tolerance is good when administered orally in the rat. Transplacental passage and passage into breast milk are minimal. In the rat, 0.003% of the administered dose has been found in each fetus and 1% in breast milk. Clinical trials fulfill international scientific requirements and have collected more than 2850 patients treated with Daflon 500 mg at the dosage of two tablets per day for six weeks to one year. The proportion of patients with side effects (10% of those treated), essentially of a gastrointestinal or autonomic nature and leading to a rate of only 1.1% trial dropouts, is less than described in 225 patients given a placebo (13.9%) in controlled trials. Satisfactory clinical acceptability already confirmed in the short term was equally found in long-term treatment. Hemodynamic parameters (systolic and diastolic blood pressure) as well as laboratory parameters (hematology, liver and renal function, metabolic) were uninfluenced even by prolonged treatment for one year at the dosage of two tablets per day. No contraindications have been found during the therapeutic use of Daflon 500 mg, even in the elderly and in pregnant women. No evidence has been found of any interference with combined drugs. Daflon 500 mg is free of any photosensitizing action. Daflon 500 mg combines thoroughly proven therapeutic efficacy with excellent safety of use confirmed in specific and methodologically reliable toxicologic studies as well as in a large number of clinical trials with patients treated daily for six weeks to one year.
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Kuriakose, Robin K., Rakesh C. Kukreja, and Lei Xi. "Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/8139861.
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Despite their recognized cardiotoxic effects, anthracyclines remain an essential component in many anticancer regimens due to their superior antitumor efficacy. Epidemiologic data revealed that about one-third of cancer patients have hypertension, which is the most common comorbidity in cancer registries. The purpose of this review is to assess whether anthracycline chemotherapy exacerbates cardiotoxicity in patients with hypertension. A link between hypertension comorbidity and anthracycline-induced cardiotoxicity (AIC) was first suggested in 1979. Subsequent preclinical and clinical studies have supported the notion that hypertension is a major risk factor for AIC, along with the cumulative anthracycline dosage. There are several common or overlapping pathological mechanisms in AIC and hypertension, such as oxidative stress. Current evidence supports the utility of cardioprotective modalities as adjunct treatment prior to and during anthracycline chemotherapy. Several promising cardioprotective approaches against AIC pathologies include dexrazoxane, early hypertension management, and dietary supplementation of nitrate with beetroot juice or other medicinal botanical derivatives (e.g., visnagin and Danshen), which have both antihypertensive and anti-AIC properties. Future research is warranted to further elucidate the mechanisms of hypertension and AIC comorbidity and to conduct well-controlled clinical trials for identifying effective clinical strategies to improve long-term prognoses in this subgroup of cancer patients.
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Bahal, Neeta, and Milap C. Nahata. "The New Macrolide Antibiotics: Azithromycin, Clarithromycin, Dirithromycin, and Roxithromycin." Annals of Pharmacotherapy 26, no. 1 (January 1992): 46–55. http://dx.doi.org/10.1177/106002809202600112.
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OBJECTIVE: To review the chemistry, antimicrobial spectrum, pharmacokinetics, clinical trials, adverse effects, and drug interactions of four new macrolide antibiotics: Azithromycin, clarithromycin, dirithromycin, and roxithromycin. DATA SOURCES: Information was obtained from comparative clinical trials, abstracts, conference proceedings, and review articles. Indexing terms included azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, and macrolide antibiotics. STUDY SELECTION: Emphasis was placed on comparative clinical trials involving the new macrolide antibiotics. DATA EXTRACTION: Data from human studies published in the English language were evaluated. Trials were assessed by sample size, macrolide dosage regimen, and therapeutic response. DATA SYNTHESIS: The erythromycins have gained widespread use in treating a variety of infections. Although they are effective, limitations include the need to administer four times a day and the intolerable adverse gastrointestinal effects. Four of the more extensively studied agents, azithromycin, clarithromycin, dirithromycin, and roxithromycin, are currently being studied in patients. Based on the studies to date, the newer macrolides may offer several advantages over erythromycin, including: (1) greater antimicrobial activity against certain organisms; (2) longer elimination half-life, thus allowing less frequent administration; and (3) lower incidence of adverse gastrointestinal effects. CONCLUSIONS: The new macrolide antibiotics appear to offer an improvement over erythromycin. Definitive conclusions about the role of these drugs should await completion of ongoing clinical studies.
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Ramadaniati, Hesty Utami, Heni Safarini, and Aishah A. Regine. "Off-Label Prescribing in Pediatric Inpatients With Pneumonia in a Children's Hospitaal." JURNAL ILMU KEFARMASIAN INDONESIA 16, no. 1 (April 27, 2018): 25. http://dx.doi.org/10.35814/jifi.v16i1.433.
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Off-label is a term used in which a drug prescribed outside the official information of the marketing authorization. Off-label prescribing may occur as the result of several factors including lack of clinical trials data involving pediatrics and suitable formulations for medicines commonly prescribed to this fragile population. Objective: This study aimed to estimate the nature and prevalence of off-label prescribing in pediatric inpatients with pneumonia. Material and Methods: a retrospective study was conducted in a study hospital using medical records from pediatric inpatients with pneumonia during the period of January-December 2015. Patient and prescribing data were collected, and drugs were classified as on-label or off-label based on the Indonesia National Drug Information (IONI) and British National Formulary for Children (BNFC). Thereafter, off-label drugs were categorized with a hierarchical system of age, indication, route of administration and dosage. Results: There were 1141 drugs with 77 different types of drug were administered to 207 patient during the study period. The data uncovered that 405 (35,5%) of the drug prescriptions were used off-label based on IONI, and 319 (28%) of the drug were used off-label based on BNFC. Based on IONI and BNFC, most off-label drugs were from anti infection drugs. Conclusion: The prevalence of off-label use in pediatric inpatients with pneumonia is not high. The off-label prescribing may not be necessarily be considered irrational, yet this fact reveals that the use of drugs does not comply with the drug label. Clinical trials for pediatric drugs are essential to provide complete product information for pediatric use.
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Cui, Cheng, Siqi Tu, Valerie Sia Jie En, Xiaobei Li, Xueting Yao, Haiyan Li, and Dongyang Liu. "Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19." Current Drug Metabolism 21, no. 6 (September 25, 2020): 427–35. http://dx.doi.org/10.2174/1389200221666200610172929.
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Background: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. Methods: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. Results: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. Conclusion: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.
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Feng, Ling, Wen-Ke Liu, Lan Deng, Jia-Xing Tian, and Xiao-Lin Tong. "Clinical Efficacy of Aconitum-Containing Traditional Chinese Medicine for Diabetic Peripheral Neuropathic Pain." American Journal of Chinese Medicine 42, no. 01 (January 2014): 109–17. http://dx.doi.org/10.1142/s0192415x14500074.
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Diabetic peripheral neuropathy is a common chronic complication of diabetes. Routine clinical management uses analgesics to relieve pain in combination with drugs for nerve repair. The drugs are often not effective for the severe pain cases, and these western medications also have side effects. We report a more effective treatment of diabetic peripheral neuropathic pain using a high dose of a traditional Chinese medicine, aconitum (including both Radix aconite preparata and Radix aconite kusnezoffii), in combination with Huangqi Guizhi Wuwu Tang (i.e., astragalus, cassia twig, white peony root, and spatholobi). In order to achieve stronger analgesic effects, we increased the clinical dosage of aconitum from 15 to 120 g. The aconitum was boiled for 6–8 hours, and licorice was also used to reduce potential toxicities of aconitum. In the four reported cases, the patients' neuropathic pain was remarkably reduced and the EMG profile was also improved with this treatment regimen. Adverse reactions were not observed during the therapy. Thus, aconitum represents a promising and safe treatment for the well-being of patients and their diabetic peripheral neuropathic pain. Future controlled clinical trials using traditional Chinese medicines containing aconitum in treating the neuropathic pain are warranted.
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Tripodi, Armando. "The Laboratory and the New Oral Anticoagulants." Clinical Chemistry 59, no. 2 (February 1, 2013): 353–62. http://dx.doi.org/10.1373/clinchem.2012.189704.
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BACKGROUND The new oral anticoagulants (NOAs) dabigatran, rivaroxaban, and apixaban have proved effective and safe when used in clinical trials, without a need to adjust the dose in response to laboratory testing. This demonstrated efficacy does not necessarily mean that the laboratory, considered the mainstay for the management of the old anticoagulants, will no longer play a role in treatment with NOAs. CONTENT Laboratories are involved in the management of anticoagulants in 2 ways. The first, monitoring, implies laboratory testing to assess the drug's effect and to adjust the dosage to maintain anticoagulation within the therapeutic interval. This consideration applies to the old drugs. The second way, measurement, implies laboratory evaluations of drug effect to determine whether patients are under- or over-anticoagulated, information that can be useful for decision-making in special circumstances. The latter applies to NOAs. SUMMARY Measurements of the effect of NOAs are indicated in several situations: (a) patients with adverse events (i.e., thrombotic/hemorrhagic), particularly those who present with overdosage owing to excessive drug intake or decreased clearance; (b) patients undergoing surgical procedures for ensuring that no residual drug remains in the circulation; (c) patients requiring anticoagulation reversal because of life-threatening hemorrhage; (d) patients with renal insufficiency, who are likely to accumulate the drug in the circulation; (e) patients with liver failure, because NOAs are metabolized by the liver; (f) patients taking other drugs that might increase/decrease the effects of NOAs via drug–drug interactions. The choice of tests is based on such characteristics as availability, linearity of the dose–response curve, standardization, and responsiveness to increasing drug dosage. Practitioners need to be aware that NOAs can interfere with the measurement of common hemostasis parameters.
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Pecherina, T. B., V. O. Zlydneva, V. V. Kashtalap, and O. L. Barbarash. "Patient with myocardial infarction, atrial fibrillation and high risk for hemorrhage: reasonable choice of anticoagulant for effective prevention of ischemic events." Complex Issues of Cardiovascular Diseases 7, no. 4S (February 3, 2019): 135–45. http://dx.doi.org/10.17802/2306-1278-2018-7-4s-135-145.
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Current clinical practice faces the challenges in selecting optimal drugs and the duration of antithrombotic treatment in patients with acute coronary syndrome with atrial fibrillation. A continuous increase of using non-vitamin K oral anticoagulants (NOAC), dabigatran, rivaroxaban, apixaban, edoxaban, and novel antiplatelet agents, prasugrel and ticagrelor, has complicated the decision-making process in this group of patients. The presented clinical case reports the use of dabigatran as a part of double antithrombotic therapy in an elderly patient with type 2 myocardial infarction, paroxysmal AF and a high risk for hemorrhage. The drug choice and its dosage were chosen using the personalized risk assessment. The presented approach has been early proved by the results of the recent randomized clinical trials and, therefore, may be translated into routine clinical practice.
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Benker, G., D. Reinwein, H. Creutzig, H. Hirche, W. D. Alexander, D. McCruden, G. Galvan, et al. "Effects of high and low doses of methimazole in patients with Graves' thyrotoxicosis." Acta Endocrinologica 116, no. 1_Suppl (August 1987): S312—S317. http://dx.doi.org/10.1530/acta.0.114s312.
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Abstract. In spite of the long-established use of antithyroid drugs, there are many unsettled questions connected with this treatment of Graves' disease. There is a lack of controlled prospective trials studying the results of antithyroid drug therapy while considering the many variables such as disease heterogeneity, regional differences, drug dosage and duration of treatment. Therefore, a multicenter study has been set up in order to compare the effects of two fixed doses of methimazole (10 vs 40 mg) with thyroid hormone supplementation on the clinical, biochemical and immunological course of Graves' disease and on remission rates. Experience accumulated so far suggests that treatment is safe using either 10 or 40 mg of methimazole. While there is a tendency for an advantage of the higher dose within the first weeks (higher effectiveness in controlling hyperthyroidism), this difference is not significant. The impact of dosage on remission rates remains to be shown.
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Clemons Bankston, Page, and Rami A. Al-Horani. "New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations." International Journal of Molecular Sciences 20, no. 12 (June 20, 2019): 3013. http://dx.doi.org/10.3390/ijms20123013.
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This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.
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Engel, Christoph, Markus Scholz, and Markus Loeffler. "A computational model of human granulopoiesis to simulate the hematotoxic effects of multicycle polychemotherapy." Blood 104, no. 8 (October 15, 2004): 2323–31. http://dx.doi.org/10.1182/blood-2004-01-0306.
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Abstract Moderate intensification of conventional multicycle chemotherapy has recently been shown to improve treatment results in malignant lymphomas and might prove to be beneficial also in other malignancies. However, the feasibility of such regimens is mainly limited by their granulopoietic toxicity. To identify and quantify the basic cell kinetic mechanisms of damage and stimulation caused by cytotoxic drugs and recombinant human granulocyte colony-stimulating factor (rhG-CSF), respectively, we developed a mathematical model of human granulopoiesis that allows simulation of leukocyte concentration profiles under 10 different multicycle polychemotherapy regimens with varying drug composition, dosage, and scheduling, including rhG-CSF assistance. Clinical data on leukocyte profiles were obtained from large numbers of patients treated within several multicenter trials. Simulation studies show that the leukocyte profiles of all regimens can be appropriately fitted using one single set of assumptions and parameters for the cell kinetic effects of cytotoxic drugs and rhG-CSF. Furthermore, the model can be used to explain the interindividual heterogeneity of hematotoxicity by a differential chemosensitivity, which might be useful in drug scheduling for specific risk groups. It is demonstrated that the model can be used to design and to select new drug schedules for subsequent clinical trial testing.
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Maddix, Daniel S., Kimberly B. Tallian, and Paul S. Mead. "Rifabutin: A Review with Emphasis on its Role in the Prevention of Disseminated Mycobacterium Avium Complex Infection." Annals of Pharmacotherapy 28, no. 11 (November 1994): 1250–54. http://dx.doi.org/10.1177/106002809402801108.
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OBJECTIVE: To discuss the mechanism of action, in vitro and in vivo activity, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosage guidelines of rifabutin. DATA SOURCES: Pertinent literature published between 1982 and 1993 was identified via a MEDLINE search. Published proceedings of selected conferences were also reviewed. STUDY SELECTION: Selected basic science, microbiologic, and pharmacokinetic articles were evaluated. Because only limited data regarding rifabutin were available in the literature, all clinical trials involving the use of rifabutin in the prevention of Mycobacterium avium complex (MAC) infection in AIDS patients were reviewed. DATA SYNTHESIS: Rifabutin is a rifamycin derivative that was approved recently for the prevention of disseminated MAC disease in patients with advanced HIV infection. The drug has in vitro and in vivo activity against gram-positive bacteria, gram-negative bacteria, and mycobacteria. Two prospective, randomized, double-blind, placebo-controlled, multicenter trials demonstrated that rifabutin decreased the progression to MAC bacteremia in AIDS patients by about 50 percent. Adverse effects that resulted in the discontinuation of rifabutin prophylaxis occurred in 16 percent of patients. Rifabutin induces hepatic enzymes to a lesser extent than does rifampin, but dosage adjustment of drugs that are known to interact with rifampin may be required. CONCLUSIONS: Rifabutin is the only drug shown to be effective in the prevention of MAC bacteremia in AIDS patients; therefore, it should be made available as a formulary agent. It may be reasonable to delay initiation of rifabutin prophylaxis until CD4 lymphocyte counts are less than 75–50/mm3.
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Dyadyk, A. I., T. E. Kugler, Y. V. Suliman, S. R. Zborovskyy, and I. I. Zdykhovskaya. "STATIN ADVERSE EFFECTS: MECHANISMS, DIAGNOSIS, PREVENTION AND MANAGEMENT." Russian Archives of Internal Medicine 8, no. 4 (August 12, 2018): 266–76. http://dx.doi.org/10.20514/2226-6704-2018-8-4-266-276.
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Statins are one of the most common lipid-lowering drugs in clinical practice. The purpose of this review was to systemize the most frequent statin adverse effects, including mechanisms, diagnosis, treatment and prevention. The frequency of statin-associated muscle symptoms is significantly higher in registries and observational studies than in randomized controlled trials. Diagnosis of muscle symptoms is difficult because it is subjective. The serum creatine kinase is often normal or slightly elevated. Association between statin use and the risk of new cases of diabetes mellitus was demonstrated in numerous studies. The drug interaction of statins, high dosage and concomitant diseases can lead to a persistent and clinically significant increase of hepatic enzymes. Basic glycemic tests, hepatic enzymes and serum creatine kinase have been necessary done before statin administration to identify patients with high risk of intolerance. The risk of hemorrhagic strokes after statin therapy is ambiguous due to randomized controlled trials. It is suggested that statins can inhibit cancerogenesis by inducing apoptosis or reducing cell growth, angiogenesis, and invasion. However, the results of preclinical and clinical studies are conflicting. The majority of the studies are observational or of retrospective nature. It is necessary to provide a larger prospective randomized placebo-controlled trials with a long follow-up. Any doctor should know the potential negative consequences of statins taking into account their expansion. Understanding the pharmacokinetics of statins is important for the safety of patients. Dosages, metabolism and risk factors of drug interactions should be considered to minimize statin adverse effects.
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Harzallah, Ines, Josselin Rigaill, Nicolas Williet, Stephane Paul, and Xavier Roblin. "Golimumab pharmacokinetics in ulcerative colitis: a literature review." Therapeutic Advances in Gastroenterology 10, no. 1 (November 15, 2016): 89–100. http://dx.doi.org/10.1177/1756283x16676194.
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Golimumab (GLM) is the latest anti-tumor necrosis factor (TNF) that gained its marketing license. Thanks to the PURSUIT induction and maintenance trials, it was approved for the treatment of ulcerative colitis (UC) in 2013. The other anti-TNF drugs available are infliximab and adalimumab. These two drugs have validated algorithms concerning prescription and therapeutic drug monitoring (TDM) but little is known about GLM. The available data on GLM’s exposure–response relationship in UC are from the PURSUIT trials and are recently published. The data reveal all the factors that may impact the pharmacokinetic (PK) parameters: dosage, body weight (BW), concomitant drugs, the presence of anti-drug antibodies (ADAbs), sex and age. In addition, the GLM trough level at steady-state appears to be correlated with the patient’s improvement which may make it a precious indicator to predict the clinical response. There is, however, no consensus on a possible therapeutic level or cutoff associated with clinical response, remission, or any other outcome measure such as endoscopic healing in UC. This lack of a threshold value, and its validation with different assay techniques, makes it difficult to use GLM TDM in clinical practice. As with other anti-TNF agents, GLM is associated with development of ADAbs, of which the prevalence and effects are still insufficiently described. The objective of this review is to describe current data and understanding of the PK of GLM including serum concentrations of GLM and ADAbs in UC patients. Better understanding of these parameters could lead to improved patient care with GLM.
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Morton, W. Alexander, Susan C. Sonne, and Michael A. Verga. "Venlafaxine: A Structurally Unique and Novel Antidepressant." Annals of Pharmacotherapy 29, no. 4 (April 1995): 387–95. http://dx.doi.org/10.1177/106002809502900410.
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Objective: To introduce the new antidepressant venlafaxine. Basic pharmacokinetic data and clinical trials are reviewed, as well as adverse reactions, drug interactions, dosing guidelines, and therapeutic considerations. The article also discusses several pharmacotherapy issues and how venlafaxine compares with other available antidepressants. Data Sources: A MEDLINE search was used to identify pertinent literature, including reviews. Study Selection: As this is a relatively new agent, all available clinical trials were reviewed. Data Extraction: All clinical trials that were available prior to submission for publication were reviewed. Preliminary trials and unpublished reports were not reviewed. Data Synthesis: Venlafaxine hydrochloride is a structurally novel agent that has recently been approved in the US for the treatment of depression. This unique antidepressant blocks neuronal reuptake of norepinephrine, serotonin, and, to a lesser extent, dopamine. Venlafaxine and its major active metabolite, O—desmethylvenlafaxine, exhibit linear kinetics with an elimination half-life of 5 and 11 hours, respectively. Venlafaxine has been evaluated in 7 clinical trials for the treatment of depression. These have consisted of 2 open trials, 3 double-blind, placebo-controlled trials, and 2 double-blind trials where venlafaxine was compared with trazodone and imipramine. All 7 trials have established efficacy for venlafaxine using standard psychiatric rating scales to measure change of depressive symptoms. The usual daily dosage ranges from 75 to 225 mg/d in 2 to 3 divided doses, with a maximum daily dosage of 375 mg/d. The drug's adverse effect profile differs somewhat from other more specific serotonin reuptake inhibitors in that it appears to cause dry mouth, somnolence, and elevated blood pressure as well as nausea, headache, and dizziness. Conclusions: Although venlafaxine has recently become available for use as an antidepressant in the US, few clinical trials have been conducted to help the practitioner evaluate its place in the treatment of depression. There are no comparative trials of venlafaxine with the serotonin specific reuptake inhibitor antidepressants, which are rapidly becoming the newest comparative standard. The clinical place for venlafaxine in the treatment of depression has yet to be determined.
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Sunoto, Sunoto, S. H. Pudjiadi, Suharjono Suharjono, and Z. Sulaiman. "Tiberal (Ro 7-0207-Roche) in the Treatment of Intestinal Amoebiasis - Part II." Paediatrica Indonesiana 16, no. 9-10 (September 18, 2019): 403–11. http://dx.doi.org/10.14238/pi16.9-10.1976.403-11.
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Twenty-four intestinal amoebiasis patients have been treated with a new amoebicid tiberal (Roche) or metronidazole as a control in a dosage of 15- 30 mg/kg body weight per day for 5 consecutive days. The results show that both drugs achieve a 100% cure rate. No side effects or signs of drug toxicity as evaluated from the results of the safety tests were observed. No signs of clinical or parasitological relapses were seen (after discharge. In comparison with the previous trial with a lower dosage (7~ - 15 mg.) and longer course (7 days) the results were even better, e.g. clinical improvement and parasitological disappearance were achieved in a shorter time.
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Sánchez-Barceló, Emilio J., Maria D. Mediavilla, and Russel J. Reiter. "Clinical Uses of Melatonin in Pediatrics." International Journal of Pediatrics 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/892624.
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This study analyzes the results of clinical trials of treatments with melatonin conducted in children, mostly focused on sleep disorders of different origin. Melatonin is beneficial not only in the treatment of dyssomnias, especially delayed sleep phase syndrome, but also on sleep disorders present in children with attention-deficit hyperactivity, autism spectrum disorders, and, in general, in all sleep disturbances associated with mental, neurologic, or other medical disorders. Sedative properties of melatonin have been used in diagnostic situations requiring sedation or as a premedicant in children undergoing anesthetic procedures. Epilepsy and febrile seizures are also susceptible to treatment with melatonin, alone or associated with conventional antiepileptic drugs. Melatonin has been also used to prevent the progression in some cases of adolescent idiopathic scoliosis. In newborns, and particularly those delivered preterm, melatonin has been used to reduce oxidative stress associated with sepsis, asphyxia, respiratory distress, or surgical stress. Finally, the administration of melatonin, melatonin analogues, or melatonin precursors to the infants through the breast-feeding, or by milk formula adapted for day and night, improves their nocturnal sleep. Side effects of melatonin treatments in children have not been reported. Although the above-described results are promising, specific studies to resolve the problem of dosage, formulations, and length of treatment are necessary.
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Saluja, Ronak, Erica McDonald, Vanessa Sarah Arciero, Sierra Cheng, Matthew C. Cheung, and Kelvin K. Chan. "Examining the relationship between cost of novel oncology drugs and their clinical benefit over time." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6598. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6598.
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6598 Background: The average launch price of oncology drugs has increased by 10% annually from 1995 to 2013. The purpose of this study was to determine if the clinical benefit of novel oncology drugs has increased proportionally over time and is correlated with launch price. Methods: Novel oncology drugs fromrandomized controlled trials (RCTs) cited for clinical efficacy evidence in drug approvals between January 2006 and August 2015 were identified. For each drug, only the first FDA approved indication was included. To determine clinical benefit, all included RCTs were scored using the ASCO Value Framework and the ESMO Magnitude of Clinical Benefit Scale. The launch price for the FDA approval year of each drug was extracted from RedBook. Each drug’s 28-day cost was determined using the dosage schedule outlined in the respective RCT and was adjusted to 2015 USD using the consumer price index. The relationships between 28-day drug cost and FDA approval year, and between incremental drug cost (difference in total drug cost between experimental and control arms accounting for treatment duration) and FDA approval year were examined using generalized linear regression models (gamma distribution and log link). Ordinary least square models were used to evaluate the relationship between ASCO/ESMO scores and FDA approval year. Spearman’s correlation coefficients between 28-day/incremental drug costs and ASCO/ESMO scores were also calculated. Results: Forty RCTs were included in this analysis. The 28-day drug cost was significantly associated with FDA approval year (p = 0.04), with an average increase of 8.5% per year. Incremental drug cost was also significantly associated with FDA approval year (p < 0.001) with an increase of 28.6% per year. The mean ASCO and ESMO scores were 26 and 3, respectively. Both scores were not statistically associated with FDA approval year (p = 0.73 and p = 0.86, respectively) and were also not correlated with 28-day or incremental drug costs (all rho < = 0.2). Conclusions: Novel oncology drugs are not priced according to their clinical benefit. The rising cost of novel oncology drugs over time is not associated with an increase in their clinical benefit, suggesting a decrease in their value over time.
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Kareva, E. N., and Т. Е. Samoylova. "Uterine myoma: new and perspective options for medicinal treatment." Meditsinskiy sovet = Medical Council, no. 3 (April 17, 2020): 49–58. http://dx.doi.org/10.21518/2079-701x-2020-3-49-58.
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The review provides information on the medical treatment of uterine fibroids (MM) in a comparative aspect. MM are one of the most common gynecological diseases requiring surgical intervention in the presence of symptoms. As a drug treatment, gestagens and their combinations with estrogens, which did not demonstrate reliable efficacy, were the first to be proposed. Later, obvious advantages of using GnRH agonists/antagonists that cause the effect of “central” chemical castration were discovered, and therefore their use is limited to 6 months, and they are successfully used to prepare patients for surgery. Recently, non-peptide orally active GnRH receptor antagonists have been proposed that are in the early stages of clinical trials. However, changes in the dosage form and route of administration of drugs that inhibit the activity of GRH do not improve their safety profile. Another breakthrough in MM therapy has been the use of selective progesterone receptor modulators, previously called “antiprogestins.” The drugs of this group have comparable efficacy and better tolerance to AGnRH, which makes the possible long-term treatment of uterine fibroids, especially in premenopausal women, using these drugs.
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Gasser, Beatriz, and Ricardo Andres Ramirez Uscategui. "POTENTIAL THERAPIES FOR TREATMENT OF COVID-19." Revista de Ciência Veterinária e Saúde Pública 7, no. 1 (August 28, 2020): 062–71. http://dx.doi.org/10.4025/revcivet.v7i1.55502.
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Since discovery of the novel coronavirus (SARS-CoV-2) in December of 2019, this viral pneumonia originated in Wuhan, China quickly spread around the world. This new disease, called COVID-19 can cause Acute Respiratory Distress Syndrome (ARDS) due to an uncontrolled inflammatory response like sepsis, that leads to multiple organ failure and even death. Several pharmacotherapeutics alternatives are being tested over the world, looking for most diverse drugs that might be able to fight the infection. The objective of this paper is to review the main pharmacotherapeutics techniques development, as remdesivir, chloroquine/hydroxychloroquine, lopinavir plus ritonavir, interferon-β, ivermectin, anticoagulants, convalescent plasma and vaccine, currently undergoing clinical trials in order to evaluate its effectiveness and safety to combat the COVID-19, presenting their characteristics, possible adverse effects and main scientific findings of its potential action. In conclusion, some therapies presented promising in-vitro results or in the treatment of some patients, nonetheless, multicentric blinded placebo controlled clinical trials are necessary to determine their effectiveness, safety, dosage, and best time point of treatment.
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Zwingenberger, K., J. A. Nogueira Queiroz, U. Poggensee, J. E. Alencar, J. Valdegunas, F. Esmeralda, and H. Feldmeier. "Efficacy of oxamniquine, praziquantel and a combination of both drugs in schistosomiasis mansoni in Brazil." Revista do Instituto de Medicina Tropical de São Paulo 29, no. 5 (October 1987): 305–11. http://dx.doi.org/10.1590/s0036-46651987000500007.
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A randomized clinical trial was carried out to compare the efficacy of a low-dosage combination of oxamniquine (7.5 mg/kg) plus praziquantel (20 mg/kg) against either agent, oxamniquine (15 mg/kg) or praziquantel (40 mg/kg) alone, in the treatment of schistosomiasis mansoni in the Brazilian north-east. The drugs were randomly administered per os to 91 patients. Six and twelve months after treatment 89% of those admitted to the trial were reexamined by Kato-Katz method (ten slides) and MIF technique (one gram of stool) The achieved cure rates, as defined by absence of S. mansoni eggs in the faeces of individual patients at all points during the parasitological follow-up, were 81.8%, 81.2% and 67.6% for praziquantel, oxamniquine and the combination respectively. The reduction of eggs excretion in non cured patients six months after therapy ranged from 93.8-96.8% with praziquantel, 32.5-97% with oxamniquine and 76.9-99.5% with the combination. It is concluded that, at the used dosages, the three therapeutical regimens give similar and satisfactory results in the treatment of uncomplicated S. mansoni infection in Brazil.
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Romodanovsky, D. P., D. V. Goryachev, A. L. Khokhlov, and A. E. Miroshnikov. "INFLUENCE OF SEX DIFFERENCES ON PHARMACOKINETICS OF DRUGS WITHIN THE FRAMEWORK OF BIOEQUIVALENCE STUDIES OF GENERIC MEDICINAL PRODUCTS." Acta Biomedica Scientifica 3, no. 5 (October 29, 2018): 94–105. http://dx.doi.org/10.29413/abs.2018-3.5.15.
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Background. Evidence of the effect of sex on the pharmacokinetics of drugs and, accordingly, on the clinical response is significantly accumulated, because of a growing number of clinical studies of the early development of original drugs, which include female subjects. The number of bioequivalence studies of replicated drugs involving both sexes is also growing. Of particular importance for the bioavailability of oral medications are differences in the anatomy and physiology of the digestive system. Along with this factor, the differences may be due to the dosage form of the reproduced drug, which may differ from that of the reference (original). The aim of the study was to identify the effect of sex differences on the pharmacokinetics of drugs and to propose an algorithm for assessing their detection. Materials and methods. The article presents a general analysis of the works devoted to the pharmacokinetics of medicines in men and women and includes literature data. Results. The main factors influencing the pharmacokinetics of drugs (absorption, distribution, metabolism, excretion) are identified. Examples of medicinal products for which differences in pharmacokinetics in men and women are revealed are given. The article describes the main international requirements for conducting clinical trials and bioequivalence studies with regard to the choice of gender of subjects and their number to be included in the clinical study. It is suggested that there is a need to further study of the effect of sex differences on bioequivalence results in carrying out relevant studies. Conclusion. An algorithm for estimating the detection of sex differences and their effect on the results of bioequivalence studies of generic drugs is proposed.
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Painuly, Utkarsh, and Shaji Kumar. "Efficacy of Bortezomib as First-Line Treatment for Patients with Multiple Myeloma." Clinical Medicine Insights: Oncology 7 (January 2013): CMO.S7764. http://dx.doi.org/10.4137/cmo.s7764.
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Recent years have seen a dramatic change in the approach towards diagnosing and treating Multiple Myeloma. Newer and more target specific approach to treatment has prolonged the survival for patients with multiple myeloma. The proteasome inhibitors make an important class of anti-myeloma drugs that disrupts the proteolytic machinery of the tumor cells preferentially, enhancing their susceptibility to apoptosis. Bortezomib, in particular has shown significant clinical efficacy in myeloma treatment. It is the most commonly used proteasome inhibitor and has been tested to be effective in prolonging the overall survival in several trials. Its combinations with cyclophosphamide and dexamethasone are the treatment of choice for standard risk patients following the mSMART guidelines. The success with its lower dosage in elderly and its proven efficacious subcutaneous usage makes Bortezomib a useful agent for maximizing patient compliance and minimizing therapy related toxicity and costs. This review discusses several trials where Bortezomib has been used as a single/combination agent for front-line treatment of multiple myeloma.
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Podzolkov, V. I., A. E. Bragina, and K. K. Osadchiy. "Resistant Hypertension: Questions and Contemporary Answers." Rational Pharmacotherapy in Cardiology 15, no. 4 (September 2, 2019): 568–77. http://dx.doi.org/10.20996/1819-6446-2019-15-4-568-577.
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The review presents the important problem of resistant hypertension. Its real prevalence is unknown. According to population studies and metaanalyzes of clinical studies, the prevalence of this most severe form of hypertension reaches 12-15% in the general population and 15-18% in clinical cohorts. Over the past decades, an increase in its frequency among patients with hypertension has been noted. Based on the results of large-scale studies, risk factors are detected that allow to assess the risk for the resistance to antihypertensive drugs. Adherence to ongoing antihypertensive therapy is crucial to addressing the issue of hypertension resistance; there are acceptable ways to evaluate it in clinical practice. The review discusses the most common mistakes in the choice of therapy, which can cause resistance to antihypertensive treatment, namely irrational drug combinations, insufficient dosage of the drug, and the use of non-prolonged forms of drugs. The latest recommendations for the diagnosis and treatment of hypertension, including its resistant form, are analyzed. The review contains a rationale based on the results of randomized clinical trials, the choice antihypertensive strategy in this variant of arterial hypertension. The importance of fixed combination antihypertensive drugs, as well as thiazine-like diuretics and amlodipine is stressed. The results of studies demonstrate the rational for the use of antimineralcorticoid drugs, namely spironolactone, for this category of patients. The authors offer an updated algorithm for the diagnosis and treatment of resistant hypertension, based on the sections of the latest clinical recommendations on this problem.
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Herbelet, Sandrine, Arthur Rodenbach, Boel De Paepe, and Jan L. De Bleecker. "Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents." International Journal of Molecular Sciences 21, no. 13 (June 28, 2020): 4596. http://dx.doi.org/10.3390/ijms21134596.
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In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.
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Dan, Gheorghe-Andrei, and Adrian Catalin Buzea. "Stroke Prevention in Atrial Fibrillation — The Use of NOACs in Everyday Clinical Practice." European Cardiology Review 10, no. 2 (2015): 76. http://dx.doi.org/10.15420/ecr.2015.10.2.76.
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Non-antivitamin K oral anticoagulants (NOACs) have recently emerged as a new class of antithrombotic drugs. Four large-scale, randomised controlled trials (RCT) accredited dabigatran, rivaroxaban and edoxaban with evident advantages for stroke prevention in atrial fibrillation (AF) compared with warfarin. The superiority concerns not only the manageability but also the antithrombotic efficacy and safety. Aspects of real-life clinical experience with NOAC for stroke prevention in AF are analysed in an attempt to underline some practical differences. If at present the individualisation of the NOAC class drugs is still a subject of debate it is probable that in the near future we will be able to adapt the drug and dosages to individual patient’s profile.
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Godínez-Chaparro, Beatriz, Fabiola Guzmán-Mejía, and Maria Elisa Drago-Serrano. "Lactoferrin and Its Potential Impact for the Relief of Pain: A Preclinical Approach." Pharmaceuticals 14, no. 9 (August 28, 2021): 868. http://dx.doi.org/10.3390/ph14090868.
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Pain is one of the most disabling symptoms of several clinical conditions. Neurobiologically, it is classified as nociceptive, inflammatory, neuropathic and dysfunctional. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are conventionally prescribed for the treatment of pain. Long-term administration of opioids results in the loss of analgesic efficacy, leading to increased dosage, tolerance, and addiction as the main drawbacks of their use, while the adverse effects of NSAIDs include gastric ulcer formation, intestinal bleeding, acute kidney injury, and hepatotoxicity. Lactoferrin is an iron-binding, anti-inflammatory glycoprotein that displays analgesic activities associated, in part, by interacting with the low-density lipoprotein receptor-related protein (LRP), which may result in the regulation of the DAMP–TRAF6–NFκB, NO–cGMP–ATP K+-sensitive channel and opioid receptor signaling pathways. This review summarizes and discusses for the first time the analgesic effects of lactoferrin and its presumable mechanisms based on pre-clinical trials. Given its anti-nociceptive and anti-inflammatory properties, lactoferrin may be used as an adjunct to enhance the efficacy and to decrease the tolerogenic effects of canonical therapeutic drugs prescribed for pain treatment.
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Baldwin, D. "Recent guidelines for evidence-based pharmacological treatment of social anxiety disorder." European Psychiatry 33, S1 (March 2016): S46—S47. http://dx.doi.org/10.1016/j.eurpsy.2016.01.907.
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Pharmacological and psychological treatmentsThe findings of meta-analyses and randomized placebo-controlled treatment studies indicate that a range of approaches are efficacious in acute treatment. Pharmacological and psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment. However, acute treatment with cognitive therapy (group or individual) may be associated with a reduced risk of symptomatic relapse at follow-up. Cognitive behaviour therapy is efficacious in adults and children: cognitive therapy appears superior to exposure therapy, but the evidence for the efficacy of social skills training is less strong. It is unlikely that the combination of pharmacological with psychological treatments is associated with greater overall efficacy than with either treatment, when given alone, as only 1 of 4 studies of the relative efficacy of combination treatment found evidence for superior efficacy.Efficacy and length of acute pharmacological treatmentAntidepressant drugs with proven efficacy include most SSRIs, the SNRI venlafaxine, the MAOI phenelzine and the RIMA moclobemide: the potential efficacy of tricyclic antidepressants is unknown. Some benzodiazepines and anticonvulsants and the antipsychotic olanzapine also appear efficacious in acute treatment. A number of small single-dose placebo-controlled crossover studies together suggest that beta-blockers can be beneficial in reducing anxiety symptoms in individuals with ‘performance anxiety’ (for example, when speaking in public), which overlaps with mild non-generalized social anxiety disorder. Acute treatment studies indicate that the proportion of responding patients increases steadily over time. A post-hoc analysis of the clinical trial database with paroxetine indicates that many non-responders to treatment at 8 weeks become responders with a further 4 weeks of double-blind treatment: however a post-hoc analysis of the clinical trial database for escitalopram indicates that response is unlikely if there is no onset of clinical effect within the first 4 weeks of treatment.Longer-term treatment and further treatment after non-responseThe findings of randomized placebo-controlled relapse prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (clonazepam, escitalopram, paroxetine, pregabalin, sertraline) for up to six months. Fixed-dose randomized controlled trials do not provide consistent evidence of a dose-response relationship with antidepressant drugs: but a fixed-dose study of pregabalin found that only the higher daily dosage was efficacious. A double-blind randomized controlled dosage escalation trial found no advantage for increasing to a higher daily dosage (of duloxetine), when compared to continuing treatment with a lower dosage. Switching between treatments with proven efficacy may be helpful. An uncontrolled study of augmentation of SSRI treatment with buspirone found some evidence of beneficial effects; but a placebo-controlled crossover-study of the augmentation of paroxetine with pindolol found no evidence of efficacy. A small placebo-controlled study of the augmentation of paroxetine with clonazepam found the combination was marginally short of superiority, when compared to paroxetine alone.Disclosure of interestThe author has not supplied his declaration of competing interest.
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Hernández Vera, Rodrigo, Teresa Padró, Gemma Vilahur, and Lina Badimon. "Antithrombotic therapy in obesity." Thrombosis and Haemostasis 110, no. 10 (2013): 681–88. http://dx.doi.org/10.1160/th12-12-0928.
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summaryClinical management of obese subjects to reduce their risk of suffering cardiovascular events is complex. Obese patients typically require preventive strategies, life-style modifications, and multi-drug therapy to address obesity-induced co-morbidities. Data regarding the effects of excess weight on the pharmacokinetics of most drugs is scarce as these individuals are often excluded from clinical trials. However, the physiological alterations observed in obese patients and their lower response to some antiplatelet agents and anticoagulants have suggested that dosage regimes need to be adjusted for these subjects. In this review we will briefly discuss platelet alterations that can contributeto increased thrombotic risk, analyse existing data regarding the effects of obesity on drug pharmacokinetics focusing on antiplatelet agents and anticoagulants, and we will describe the beneficial effects of weight loss on thrombosis.
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Carreca, I., F. Bellomo, G. Bronte, M. Burgio, A. Carreca, D. Piazza, S. Rizzo, S. Russo, and L. Balducci. "Comparison between gemcitabine-based combination (G) and single-agent chemotherapy (S) for elderly patients (EP) with advanced non-small cell lung cancer (NSCLC): A literature-based meta-analysis." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 19586. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.19586.
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19586 Background: It was estimated that a quarter of all patients who have a diagnosis of NSCLC worldwide are more than 70 years old. This meta-analysis tries to shed light on the controversial results of phase III trials evaluating in NSCLC EP doublets against third generation S. Methods: We performed a literature search using MEDLINE and Cochrane Library. We selected only clinical trials responding to the question of our meta-analysis. Outcomes recorded were 1-year survival rate (1-y SR), overall response rate (ORR) and haematological toxicity (HT). Fixed-effects and random-effects models were used to calculate pooled odds ratios (OR). An OR greater than 1 indicates that doublet is more effective for 1-y SR and ORR and more toxic for HT. Results: Three published randomized controlled phase III trials (SICOG 9909; MILES; AISCAP-SICOG) were selected yielding a total of 1082 patients (G: 426; S: 655) clustered in seven comparisons. Drugs delivered to randomized patients included gemcitabine, vinorelbine and paclitaxel. EP treated with doublets showed respect to control patients a pooled estimate for 1-y SR advantage of 36%, not statistically significant (OR=1.356; 95% CI=0.925–1.990; p>0.05). The pooled estimate for ORR advantage was 57% and statistically significant (OR=1.559; 95% CI=1.220–2.015; p<0.05). However G showed not significant difference for HT (OR=1.168; 95% CI=0.685–1.992; p>0.05). Conclusions: These data confirm in EP superior efficacy and equal tolerability of G in comparison with S previously demonstrated for adult patients. Anyway G seems to not change prognosis of NSCLC EP. It is worthy to note that all the trials analysed showed some biases: early closure of the study, second-line therapy or crossover, lower dosage of drugs in combination regimen, inclusion of unfit or strongly comorbid patients. This meta-analysis doesn’t solve troubles in decision-making of treatment for EP, but suggest to design a better phase III trial including more patients and improving accrual criteria for reducing biases. An indication of a potentially active combination regimen (gemcitabine + paclitaxel) is suggested in SICOG 9909 trial. No significant financial relationships to disclose.