Current Reviews in Clinical and Experimental Pharmacology最新文献

{"title":"Predictability of Elimination and Excretion of Small Molecules in Animals and Humans, and its Impact on Dosimetry for human ADME Studies with Radiolabeled Drugs.","authors":"Ad Roffel,&nbsp;Jan Jaap van Lier,&nbsp;Gerk Rozema,&nbsp;Ewoud-Jan van Hoogdalem","doi":"10.2174/1574884716666210309103625","DOIUrl":"https://doi.org/10.2174/1574884716666210309103625","url":null,"abstract":"<p><strong>Background: </strong>We assessed the extent to which urinary and fecal excretion of <i>14</i>C-labeled drug material in animal ADME studies was predictive of human ADME studies. We compared observed plasma elimination half-lives for total drug-related radioactivity in humans to pre-study predictions, and we estimated the impact of any major differences on human dosimetry calculations.</p><p><strong>Methods: </strong>We included 34 human ADME studies with doses of <i>14</i>C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans <i>versus</i> animals; observed half-life in humans <i>versus</i> predicted pre-study) and output parameters (effective dose post-study <i>versus</i> pre-study) and assessed their relationship.</p><p><strong>Results: </strong>A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of <i>14</i>C excreted in feces and the ratios of dosimetry outcomes in the entire dataset, but a statistically significant correlation was found when assessing the studies that were based on ICRP 60/62 (n=19 studies; P=0.0028). There also appeared to be a correlation between the plasma half-life ratios and the ratios of dosimetry results. A quantitative correlation assessment showed that there was a statistically significant correlation between these ratios (P<0.0001).</p><p><strong>Conclusion: </strong>In all cases where the plasma elimination half-life for <i>14</i>C in humans was found to be longer than the predicted value, the radiation burden was still within ICRP Category IIa. Containment of the actual radiation burden below the limit of 1.00 mSv appeared to be determined partly also by our choice to limit <i>14</i>C doses to 3.7 MBq.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 1","pages":"26-38"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25466873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ventilatory Response to Hypercapnia as Experimental Model to Study Effects of Oxycodone on Respiratory Depression.","authors":"Lynn R Webster,&nbsp;Erik Hansen,&nbsp;Gregory J Stoddard,&nbsp;Austin Rynders,&nbsp;David Ostler,&nbsp;Harley Lennon","doi":"10.2174/1574884716666210225083213","DOIUrl":"https://doi.org/10.2174/1574884716666210225083213","url":null,"abstract":"<p><strong>Background: </strong>Opioid analgesics used to treat pain can cause respiratory depression. However, this effect has not been extensively studied, and life-threatening, opioid-induced respiratory depression remains difficult to predict. We tested the ventilatory response to hypercapnia for evaluating the pharmacodynamic effect of a drug on respiratory depression.</p><p><strong>Methods: </strong>We conducted a randomized, placebo-controlled, double-blind, crossover study on 12 healthy adult males. Subjects received 2 treatments (placebo and immediate-release oxycodone 30 mg) separated by a 24-hour washout period. Subjects inhaled a mixture of 7% carbon dioxide, 21% oxygen, and 72% nitrogen for 5 minutes to assess respiratory depression. Minute ventilation, respiratory rate, tidal volume, flow rate, end-tidal CO2, and oxygen saturation were recorded continuously at pre-dose and 30, 60, 120, and 180 minutes post-dose. The primary endpoint was the effect on the ventilatory response to hypercapnia at 60 minutes post-dose, as assessed by the slope of the linear relationship between minute ventilation and end-tidal CO2.</p><p><strong>Results: </strong>At 60 minutes post-dose, subjects had a mean slope of 2.4 in the oxycodone crossover period, compared to 0.1 in the placebo period (mean difference, 2.3; 95% CI: 0.2 to 4.5; p = 0.035). Statistical significance was likewise achieved at the secondary time points (30, 120, and 180 minutes post-dose, p <0.05).</p><p><strong>Conclusions: </strong>This model for testing ventilatory response to hypercapnia discriminated the effect of 30 mg of oxycodone <i>vs</i>. placebo for up to 3 hours after a single dose. It may serve as a method to predict the relative effect of a drug on respiratory depression.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 1","pages":"72-80"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25405523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-induced Neuropsychiatric Adverse Events Using Post-Marketing Surveillance.","authors":"Tomohito Wakabayashi,&nbsp;Takahiro Nakatsuji,&nbsp;Hiroko Kambara,&nbsp;Iku Niinomi,&nbsp;Saki Oyama,&nbsp;Ayaka Inada,&nbsp;Sayaka Ueno,&nbsp;Mayako Uchida,&nbsp;Kazunori Iwanaga,&nbsp;Tatsuya Iida,&nbsp;Keiko Hosohata","doi":"10.2174/1574884716666210215104540","DOIUrl":"https://doi.org/10.2174/1574884716666210215104540","url":null,"abstract":"<p><strong>Background: </strong>Several studies reported that abnormal behavior was noted in pediatric patients receiving several drugs, including neuraminidase inhibitors (NIs). However, the information on drugs associated with abnormal behavior in a real-world setting remains limited. The purpose of this study was to clarify the drugs associated with abnormal behavior using a spontaneous reporting system database.</p><p><strong>Methods: </strong>We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio at 95% confidence interval were calculated.</p><p><strong>Results: </strong>A total of 1,144 reports of abnormal behavior were identified. The signals were detected through the association of 4 neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) with the abnormal behaviour. These signals were stronger for oseltamivir than other neuraminidase inhibitors. The signals were also detected for acetaminophen and montelukast.</p><p><strong>Conclusion: </strong>Our results should be able to raise physicians' awareness of drugs associated with abnormal behavior, but further investigation of these medications is warranted.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 2","pages":"144-148"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10237175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Framework for the Design of Cannabis-Mediated Phase I Drug-Drug Interaction Studies.","authors":"Diana L Shuster,&nbsp;Gina Pastino,&nbsp;Dirk Cerneus","doi":"10.2174/2772432816666210813123716","DOIUrl":"https://doi.org/10.2174/2772432816666210813123716","url":null,"abstract":"<p><p>Cannabis has become legal in much of the United States similar to many other countries, for either recreational or medical use. The use of cannabis products is rapidly increasing while the body of knowledge of its myriad of effects still lags. <i>In vitro</i> and clinical data show that cannabis' main constituents, delta-9-tetrahydrocannabinol and cannabidiol, can affect pharmacokinetics (PK), safety, and pharmacodynamics (PD) of other drugs. Within the context of clinical drug development, the widespread and frequent use of cannabis products has essentially created another special population: the cannabis user. We propose that all clinical drug development programs include a Phase 1 study to assess the drug-drug interaction potential of cannabis as a precipitant on the PK, safety, and if applicable, the PD of all new molecular entities (NMEs) in a combination of healthy adult subjects as well as frequent and infrequent cannabis users. This data should be required to inform drug labeling and aid health care providers in treating any patient, as cannabis has quickly become another common concomitant medication and cannabis users, a new special population.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 1","pages":"18-25"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39364123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Review and Meta-Analysis of the Safety of Hydroxychloroquine in a Randomized Controlled Trial and Observational Studies.","authors":"Mahanjit Konwar,&nbsp;Miteshkumar Maurya,&nbsp;Urmila M Thatte,&nbsp;Nithya J Gogtay,&nbsp;Debdipta Bose","doi":"10.2174/1574884716666210726104424","DOIUrl":"https://doi.org/10.2174/1574884716666210726104424","url":null,"abstract":"<p><strong>Introduction: </strong>Hydroxychloroquine (HCQ) has recently become the focus of attention in the current COVID-19 pandemic. With an increase in the off-label use of HCQ, concern for the safety of HCQ has been raised. We, therefore, performed this systematic review to analyze the safety data of HCQ against placebo and active treatment in various disease conditions.</p><p><strong>Methods: </strong>We searched PubMed, Embase, and Cochrane for Randomized Controlled Trials (RCTs) and Observational Studies (OSs) that evaluated HCQ for the treatment of any disease other than COVID19 in adult patients up to May 2020. We assessed the quality of the included studies using Risk of Bias 2 (for RCTs) and Newcastle-Ottawa Scale (for OSs). Data were analyzed with randomeffect meta-analysis. Sensitivity and subgroup analyses were performed to identify heterogeneity.</p><p><strong>Results: </strong>A total of 6641 studies were screened, and 49 studies (40 RCTs and 9 OSs) with a total sample size of 35044 patients were included. The use of HCQ was associated with higher risks of TDAEs as compared to placebo/no active treatment [RR 1.47, 95%CI 1.03-2.08]. When HCQ was compared with active treatments, the risks of AEs [RR 0.74, 95% CI 0.63-0.86] and TDAEs were less in the HCQ arm [RR 0.57, 95% CI 0.39-0.81]. The outcomes did not differ in the sensitivity analysis.</p><p><strong>Conclusion: </strong>The results suggest that the use of HCQ was associated with a lower risk of AEs and TDAEs as compared to active treatment, whereas posing higher risk of TDAEs as compared to placebo.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 3","pages":"216-235"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39379597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Abnormal PI3K/AKT/mTOR Signaling in Intracerebral Hemorrhage: A Systematic Review on Potential Drug Targets and Influences of Signaling Modulators on Other Neurological Disorders.","authors":"Kuldeep Singh Jadaun,&nbsp;Aarti Sharma,&nbsp;Ehraz Mehmood Siddiqui,&nbsp;Sidharth Mehan","doi":"10.2174/1574884716666210726110021","DOIUrl":"https://doi.org/10.2174/1574884716666210726110021","url":null,"abstract":"<p><p>PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin) signaling pathway is an important signal transduction pathway mediated by enzyme-linked receptors with many biological functions in mammals. This pathway modulates the epigenetic modification of DNA and target gene histones and plays a significant role in regulating biological activity, disease progression, oncogenesis, and cancer progression. PI3K/AKT/mTOR signaling pathway involves and mediates many cellular processes such as nutrient uptake, proliferation, anabolic reactions, and cell survival. Several studies have shown that PI3K/AKT/mTOR has been a promising therapeutic approach to intracerebral hemorrhage (ICH). ICH is characterized by the progressive development of hematoma, which leads to the structural destabilization of the neurons and glial cells, leading to neuronal deformation, further contributing to mitochondrial dysfunction, membrane depolarization, oligaemia, and neurotransmitter imbalance. Partial suppression of cell metabolism and necrosis can occur, depending on the degree of mitochondrial dysfunction. Therefore in the following review, we discuss whether or not the activation of the PI3K/AKT/mTOR signaling pathway could minimize neuronal dysfunction following ICH. We further elaborate the review by discussing the updated pathophysiology of brain hemorrhage and the role of molecular targets in other neurodegenerative diseases. This review provides current approachable disease treatment in various disease states, single and dual PI3K/AKT/mTOR signaling pathway modulators.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 3","pages":"174-191"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39364127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Patient Motivation Pyramid and Patient-Centricity in Early Clinical Development.","authors":"Thijs van Iersel,&nbsp;Jocelyn Courville,&nbsp;Cathalijne van Doorne,&nbsp;Remco A Koster,&nbsp;Christina Fawcett","doi":"10.2174/1574884716666210427115820","DOIUrl":"https://doi.org/10.2174/1574884716666210427115820","url":null,"abstract":"<p><strong>Background: </strong>It has been recognized that patients should be involved in the design of clinical trials. However, there is a lack of agreement on what patient-centricity means.</p><p><strong>Methods: </strong>In this article, a Patient Motivation Pyramid based on Maslow's theory of human motivation is introduced as a tool to identify patient needs. This pyramid is used to make a comprehensive overview of options to implement a patient-centric trial design. The Pyramid with the described options can help to identify patient-centric activities suitable for given drug development. The current article further describes the potential benefits of patient-centric trial designs with an emphasis on early clinical development. Especially in early clinical development, during which trials have many assessments per patient, and the safety and clinical efficacy are uncertain, patient-centric trial design can improve feasibility. Finally, we present three case examples on patient-centric trial design. The first example is seeking patient input on the trial design for a First-in-Human trial which includes patients with Immune Thrombocytopenic Purpura. The second example is the use of a video-link for home dosing. The final example is the use of digital medicine in a decentralized trial in heart failure patients.</p><p><strong>Results: </strong>A comprehensive overview of patients' needs can be accomplished by building a Patient Motivation Pyramid as a tool. Patient input can lead to improved endpoints, improved feasibility, better recruitment, less dropout, less protocol amendments, and higher patient satisfaction. The use of digital medicine can lead to a trial design with much less visits to the clinical research center in early clinical development and in a later development phase, even to a complete virtual trial.</p><p><strong>Conclusion: </strong>We recommend using the Patient Motivation Pyramid as a structural approach for identifying elements of patient-centricity. Secondly, we recommend starting using patient-centric approaches in an early phase of the medicine's lifecycle.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 1","pages":"8-17"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39379595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Vitamin C Supplements on Respiratory Tract Infections: A Systematic Review and Meta-Analysis.","authors":"Tahmina Afrose Keya,&nbsp;Anthony Leela,&nbsp;Kevin Fernandez,&nbsp;Nasrin Habib,&nbsp;Mumunur Rashid","doi":"10.2174/2772432817666211230100723","DOIUrl":"https://doi.org/10.2174/2772432817666211230100723","url":null,"abstract":"<p><strong>Background: </strong>Respiratory tract infections are a primary cause of illness and mortality over the world.</p><p><strong>Objective: </strong>This study was aimed to investigate the effectiveness of vitamin C supplementation in preventing and treating respiratory tract infections.</p><p><strong>Methods: </strong>We used the Cochrane, PubMed, and MEDLINE Ovid databases to conduct our search. The inclusion criteria were placebo-controlled trials. Random effects meta-analyses were performed to measure the pooled effects of vitamin C supplementation on the incidence, severity, and duration of respiratory illness.</p><p><strong>Results: </strong>We found ten studies that met our inclusion criteria out of a total of 2758. The pooled risk ratio (RR) of developing respiratory illness when taking vitamin C regularly across the study period was 0.94 (with a 95% confidence interval of 0.87 to 1.01) which found that supplementing with vitamin C lowers the occurrence of illness. This effect, however, was statistically insignificant (P= 0.09). This study showed that vitamin C supplementation had no consistent effect on the severity of respiratory illness (SMD 0.14, 95% CI -0.02 to 0.30: I2 = 22%, P=0.09). However, our study revealed that vitamin C group had a considerably shorter duration of respiratory infection (SMD -0.36, 95% CI -0.62 to -0.09, P = 0.01).</p><p><strong>Conclusion: </strong>Benefits of normal vitamin C supplementation for reducing the duration of respiratory tract illness were supported by our meta-analysis findings. Since few trials have examined the effects of therapeutic supplementation, further research is needed in this area.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 3","pages":"205-215"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39649680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Cannabis Users: A New Special Population to Consider for Drug Development.","authors":"Gina Pastino,&nbsp;Diana Shuster","doi":"10.2174/2772432816666210515145638","DOIUrl":"https://doi.org/10.2174/2772432816666210515145638","url":null,"abstract":"<p><p>The use and acceptance of cannabis, either medically or recreationally, has substantially outpaced the collection of data necessary to evaluate it's use in any population. However, the mere widespread availability does not imply the absence of risk or confirmation of efficacy and should not be treated as such. There is enough data to suggest that not only does the potential for pharmacokinetic and metabolic interactions exist, but also that baseline characteristics for a given population could be different in chronic cannabis users. Either or both of these may impact the safety and efficacy profile for any new drug in development. As such, we encourage drug developers to consider that the cannabis user may very well be a special population that warrants its own clinical pharmacology evaluation.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 1","pages":"4-7"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39364120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient.","authors":"Erica Winter,&nbsp;Scott Schliebner","doi":"10.2174/1574884716666210316120615","DOIUrl":"https://doi.org/10.2174/1574884716666210316120615","url":null,"abstract":"<p><p>Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 1","pages":"39-45"},"PeriodicalIF":1.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25494660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}