The concept of 'one size fits all' - one treatment for patients with a particular disease, seems to be outdated. The advent of precision medicine has prompted profound changes in clinical research and it allows researchers to predict more accurately, the prevention and treatment strategies for a specific disease population. Novel study designs are, therefore, essential to establish safe and effective personalized medicine. Basket, umbrella and platform trial designs (collectively referred to as master protocols) are biomarker enrichment designs that allow for testing more than one hypotheses within a protocol, thus accelerating drug development. These trial designs tailor intervention strategies based on patient's risk factor(s) that can help predict whether they will respond to a specific treatment. Basket trials evaluate therapy for various diseases that share a common molecular alteration, while umbrella trials evaluate multiple targeted therapies for a single disease that is stratified into subgroups based on different molecular alterations/ risk factors. These designs are complex and their major limitations stem from the fact that it would be inappropriate to completely replace histological typing with molecular profiling alone. However, in the upcoming decades, these trial designs are likely to gain popularity and improve the efficiency of clinical research. This article briefly overviews the characteristics of master protocol designs with examples of completed and ongoing clinical trials utilizing these study designs.
BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSION:Our results should be able to raise physicians' awareness of drugs associated with abnormal behavior, but further investigation of these medications is warranted.
BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSION: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.
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.
BACKGROUND:We assessed the extent to which urinary and fecal excretion of 14C-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.METHODS:We included 34 human ADME studies with doses of 14C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans versus animals; observed half-life in humans versus predicted pre-study) and output parameters (effective dose post-study versus pre-study) and assessed their relationship.RESULTS:A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of 14C 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).CONCLUSION:In all cases where the plasma elimination half-life for 14C 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 14C doses to 3.7 MBq.
We suggest that enteral formulation of escin could be used instead of enteral formulation if it is not available.
BACKGROUND 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. METHODS We conducted a randomized, placebo-controlled, double-blind, crossover, study in 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 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. RESULTS 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). CONCLUSIONS This model for testing ventilatory response to hypercapnia discriminated the effect of 30 mg of oxycodone vs. 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.
Background: Patent Ductus Arteriosus (PDA) is associated with adverse clinical outcomes in very low birth weight (<1500g) infants. Objective: In our study, it was aimed to investigate the effect of gentamicin treatment, which is frequently used for early-onset sepsis on ductal patency. Methods: We performed a single-center retrospective review of charts of preterm infants <32 weeks gestation with birth weight <1500 grams born between June 1, 2015 and December 31, 2019 at the neonatal intensive care unit. All infants underwent an echocardiogram (ECHO) at 72 hours. To determine the effect of gentamicin treatment on hemodynamically significant PDA (hsPDA), we compared the frequency and duration of gentamicin administration between infants with hsPDA and without hsPDA. Results: During the study period, 792 patients were evaluated. Gentamicin was given to more infants with hsPDA than to those without hsPDA (89.2% vs. 64.6%, p<0.001), and the duration of therapy was longer in those infants with hsPDA (7 days vs. 9 days, p<0.001). The area under the curve for duration of gentamicin was 0.772 (%95 CI: 0.742-0.804, P-0.0001), sensitivity: 59 (%95 CI: 53-65), specificity: 82 (%95 CI: 78-88), with a cut-off day for duration of gentamicin >7 days. Conclusion: In our study, it was found that ductal contraction decreased and hsPDA rate increased as the rate and duration of gentamicin increased.
BACKGROUND:Immunotherapy drugs, known as immune checkpoint inhibitors (ICIs), work by blocking checkpoint proteins from binding with their partner proteins. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA- 4) and programmed cell death protein 1 (PD-1) that showed potent immune-modulatory effects through their function as negative regulators of T cell activation.METHODS:In view of the rapid and extensive development of this research field, we conducted a comprehensive review of the literature and updated on the use of CTLA-4, PD-1, and PD-L1 targeted therapy in the treatment of several types of cancer, including melanoma, non-small-cell lung carcinoma, breast cancer, hepatocellular carcinoma, Hodgkin lymphoma, cervical cancer, and head and neck squamous cell carcinoma.RESULTS:Based on the last updated list released on March 2019, seven ICIs are approved by the FDA, including ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and cemiplimab.CONCLUSION:This review highlighted the most common adverse effects caused by ICIs which affect people in different ways.
BACKGROUND The use of levetiracetam (LEV) has been increasing given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted. However, there are some discrepancies regarding factors affecting its pharmacokinetic variability. Therefore, this systematic review aimed to summarize significant predictors for LEV pharmacokinetics as well as the need for dosage adjustments. METHODS We performed a systematic search for population pharmacokinetic studies of LEV conducted using a nonlinear-mixed effect approach from PubMed, Scopus, CINAHL Complete, and Science Direct databases from their inception to March 2020. Information on study design, model methodologies, significant covariate-parameter relationships, and model evaluation was extracted. The quality of the reported studies was also assessed. RESULTS A total of 16 studies were included in this review. Only two studies were conducted with a two-compartment model, while the rest were performed with a one-compartment structure. Bodyweight and creatinine clearance were the two most frequently identified covariates on LEV clearance (CLLEV). Additionally, postmenstrual age (PMA) or postnatal age (PNA) were significant predictors for CLLEV in neonates. Only three studies externally validated the models. Two studies conducted pharmacodynamic models for LEV with relatively small sample size. CONCLUSION Significant predictors for LEV pharmacokinetics are highlighted in this review. For future research, a population pharmacokinetic-pharmacodynamic model using a larger sample size should be conducted. From a clinical perspective, the published models should be externally evaluated before clinical implementation.
Background/Objective: Tacrolimus HEXAL®/Crilomus® is an approved generic immunosuppressant for the prevention and treatment of rejection following renal transplantation. For safe and socioeconomically efficient conversion of the innovator into a generic formulation, high- -quality data are necessary, in view of the different and country-specific comorbidities and pharmacokinetics in kidney transplant recipients. Patients and Methods: From 2014 to 2017, we enrolled 32 kidney transplant recipients, receiving newly prescribed Tacrolimus HEXAL®/Crilomus® in 5 German centers. Efficacy and safety data were collected over 6-8 months and retrospectively compared to the period prior to conversion. Results: The mean tacrolimus trough level was 4.91 ng/mL Standard Deviation (SD) (SD ±1.7) before and 5.06 ng/mL (SD ±1.97) after conversion. Mean tacrolimus trough concentration-dose-ratio (+/- SD) was 187.1 ng/mL/mg/kg/day (SD 99.2) for the reference and 205.1 ng/mL/mg/kg/day (SD 133) for the generic product, resulting in a non-significant difference of 18.0 ng/mL/mg/kg/day (SD 71.8) (p=0.84, Wilcoxon V=180). Overall, dosing had to be changed in 4 (14.8%) patients. Graft function remained stable and no rejections occurred. Conclusion: In conclusion, conversion to the generic tacrolimus formulation can be considered safe and feasible in long-term kidney transplant recipients in Germany. As suggested by guidelines, vigilant therapeutic drug monitoring is recommended to account for possible tacrolimus concentration variability on the individual patient level.
Background: Coronary artery disease is a major cause of morbidity and mortality worldwide. A major health concern in the developing countries is opioid addiction, which has controversial cardiovascular side effects. We aimed to investigate whether Myocardial Infarction (MI) and its risk factors are associated with morphine dependency in the Iranian population. Methods: Electronic databases, including PubMed, Medline, Scopus, SID, Element, and Magiran were searched to find published articles including the keywords morphine, coronary artery disease, hypertension, hyperlipidemia, and diabetes mellitus. Results: Twelve studies involving 25,800 people were included in this systematic review and metaanalysis. Morphine dependency was significantly associated with MI with an adjusted odds ratio (AOR) of 2.28 (95%CI=1.26-4.11). It neither has significant associations with hypertension (AOR=0.952; 95%CI=0.696-1.301) nor diabetes (AOR=0.895; 95%CI=0.644-1.246). Morphine dependency also had no significant association with hyperlipidemia with a Crude Odds Ratio (COR) of 0.906 (95%CI=0.786-1.045). Conclusion: Morphine dependency was significantly related to MI, but its risk factors were not significantly associated with morphine dependency. The increasing prevalence of opioid abuse in developing countries may be a reason for the growing incidence of MI in younger ages and individuals with no risk factors. Besides, physicians should consider the presence of impurities in morphine-based opioids and their possible effects on health.
Background: Our study aims at assessing the pre-clinical impact of the synergistic mechanism of Daptomycin (DAP) and Ceftaroline (CFT) on patients with Methicillin-Resistant Staphylococcus aureus Bacteremia infections (MRSAB). Methods: A systematic overview was conducted by searching PubMed, Oxford academic, and Cochrane library up to June 2020. Study selection and data extraction: All English- language clinical trials, in vitro studies, and case reports related to the synergistic drug therapy for MRSAB. Results: In the case of MRSAB infections, we examined two different in vitro studies that showed effective synergism with DAP and CFT. The Minimum Inhibitory Concentration (MIC) range observed for each is as follow: DAP 0.125-1 mg/L, CFT 0.38-1 mg/L, DAP + CFT 0.094-0.5 mg/L, vancomycin (VAN) 0.75-2 mg/L, VAN + CFT 0.25-2 mg/L. DAP + CFT combination displayed the most efficacy with the lowest MIC. The statistical analysis performed showed that DAP + CFT obtained significantly lower fractional inhibitory concentration (FIC) values (0.941 +/- 0.328) compared with VAN + CFT. In vitro activities of regimens tested on DAP non-susceptibility and VAN intermediate after 96 hours showed DAP 8.29 +/- 0.03a log 10 CFU/mL, VAN 6.82 +/- 0.04(a) log(10) Colony Forming Unit (CFU)/mL, CFT 4.63 +/- 0.19a log 10 CFU/mL, DAP + CFT 1.15 +/- 0.20(b) log(10) CFU/mL, VAN + CFT 3.18 +/- 0.49(a) log(10) CFU/mL. (a meaning significantly different than DAP plus CFT, P< equal to 0.001(b) meaning therapeutic enhancement combination was defined as >= 2 log 10 CFU/ml reduction over the most active single agent). Based on these results, although DAP was not susceptible, the Colony Forming Unit (CFU) for DAP and CFT had the best therapeutic results. Conclusion: In vitro studies have shown that a combination DAP and CFT is more efficacious than the combination of VAN and CFT in MRSA bacteremia infections. The synergic effects of DAP (bactericidal) and CFT ( bactericidal) is statistically significant, in recent trials, warranting promising evidence for its use in complicated bacteremia infection.
Background: Anti-hypertensive medications may reduce the incidence of cognitive disorders. This may be due to reasons beyond their pure hypotensive effect. This study aimed to systematically review the association between the use of Angiotensin-Receptor Blockers (ARBs) and the incidence of Alzheimer’s disease (AD). Methods: We systematically searched studies reporting the association between ARB use and the incidence of AD. Results: Ten studies (1 RCT, 2 case-control and 7 cohort studies) met the inclusion criteria. When all observational studies (9) were analyzed, ARB use was associated with a reduced risk of incident AD (HR 0.72, 95% CI: 0.58-0.88, p<0.001). In the only RCT, decrease in the incidence of AD was also significant (HR= 0.31, 95% CI: 0.14-0.68). Conclusion: ARB use may reduce the risk of incident AD. This association does not imply causation and further research is required to clarify potential mechanisms.
BACKGROUND Berberine (BBR), an isoquinoline alkaloid, acts as a multipotent active pharmaceutical ingredient to counteract several types of dementia based on its numerous pharmacological actions including antioxidant, antiinflammatory, cholesterol-lowering effect, and inhibition of Aβ production and AChE. However, BBR suffers from poor absorption, bioavailability and brain drug uptake. The present study is directed for the formulation and characterization of Chitosan BBR-nanoparticles (BBR-NPs) as well as the estimation of its neuroprotective effects against scopolamine induced cognitive impairments. METHODS BBR-NPs were formulated using ionic gelation method and tripolyphosphate was chosen as a cross linker. Nanoparticles size, zeta potential, encapsulation efficiency and releasing profile were estimated. To investigate the neuroprotective effects, adult fifty six Wistar male rats were randomly distributed into: three control groups, received saline, polyethylene glycol or chitosan- NPs respectively; induced group, received scopolamine (2 mg/ kg, i.p.) and three treated groups were orally administrated BBR (50 mg/ kg), BBR- NP (7 mg/ kg) and donepezil (2.25 mg/ kg, as positive control) followed by scopolamine injection after 40 min, daily for 4 weeks. Morris water maze test, oxidative stress parameters, cholinergic and amyloid-β processing intermediates as well as neuroplasticity markers and histopathological examination were assessed. RESULTS Our results showed that BBR- NPs were better than BBR and donepezil as BBR- NPs were powerful inhibitory ligands toward AChE and Aβ42 formation and significantly down regulated Tau, iNOS and BACE gene expression in rats' hippocampus. BBR-NPs administration, at 1/6 of BBR therapeutic recommended dose, significantly improved learning and memory function. This could be accredited to the diminution of oxidative stress and amyloid-β toxicity in addition to the improvement of the neuroplasticity markers. CONCLUSIONS The enhancing effect of BBR- NPs could be related to the enhancing of its bioavailability, absorption and brain drug uptake which need more investigation in future work.
BACKGROUND:Anxiety disorders are the most universal psychiatric problems in the general population. Due to their chronic nature, these diseases are managed with a multi-drug regimen lasting for a long period of time. Medication discontinuation leads to 25% and 80% recurrence in the first month and the first year, respectively. Despite several treatment approaches, there is no specific and optimal method for patient management. Therefore, it is necessary to find some new therapeutic approaches with fewer side effects. Withania somnifera is a plant with GABAergic property responsible for its anxiolytic effect. The aim of this study was to investigate the effect of W. somnifera root extract as an alternative therapy to reduce standard Generalized Anxiety Disorder (GAD) symptoms.METHODS:Forty patients who met the inclusion criteria (with a confirmed diagnosis of GAD as stated in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) took part in this randomized double-blind placebo-controlled trial and were randomly selected for participation in the treatment group (W. somnifera extract, 1g/day; n = 22) or the placebo group (n = 18). All patients were under treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and were prescribed one capsule of the extract or placebo per day for six weeks. The Hamilton anxiety rating scale (HAM-A) was used to assess the severity of GAD symptoms at baseline as well as the second and sixth weeks of the trial.RESULTS:Comparison of the HAM-A scores during the course of the trial revealed a significant amelioration ofHAM-A score in the treatment group versus placebo (14 and 8 units reduction, respectively (P < 0.05)). Moreover, there was a significant difference in the reduction of GAD score between the second (P =0.04) and sixth week (P =0.02) in the treatment group. The extract was safe and no adverse effect was observed during the trial.CONCLUSION:W. somnifera extract offers some potential advantages as a safe and effective adjunctive therapy to SSRIs in GAD. The clinical trial protocol has been registered under the Iranian Registry of Clinical Trials (IRCT20180615040105N1).
BACKGROUND:Cancer is not just one disease; it is a group of diseases either genetic or metabolic due to the malfunction of mitochondria. Thus, metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements.METHODS:We undertook a structured search of bibliographic databases for peer-reviewed research literature dealing with these metabolic pathways.RESULTS:It was found that cancer cells prefer fermentation as a source of energy even in the presence of oxygen, this altered metabolism of cancer cells may confer a selective advantage for survival and proliferation according to the Warburg effect. Furthermore, some molecules like HIF, PKM2, NADPH and others are essential to the survival of cancer cells in the hypoxic abnormal environment which has limited glucose sources.CONCLUSION:As cancer cells use glucose for aerobic glycolysis as a preferred substrate for energyyielding metabolism, we discuss in this review the Warburg effect and a strategy of starving cancer cells from glucose to prevent cancer cell survival and induce apoptosis in various types of cancer which could be the key to future treatment.
Background: The cesarean section has shown an increasing trend within the past few years. The use of appropriate and effective anesthesia for the procedure is important, not only to reduce the incidence of maternal and fetal morbidities but also to reduce the incidence of intraoperative consciousness. The aim of this study is to evaluate the intraoperative and postoperative effects of adjuvant ketamine, when used in combination with general anesthesia. Methods: The study was conducted on the patients referred to Asali hospital for the cesarean section. 100 patients were assigned into two groups. Patients in Group A received thiopental (4 mg / kg) as an anesthetic agent for the surgery, whereas those in group B received thiopental along with 0.5 mg/kg of intravenous ketamine. The effects of ketamine, such as depth of anesthesia, intraoperative and postoperative awareness, vomiting and hallucination were recorded in the questionnaire and data were statistically analyzed using SPSS v25. Results: Of 100 patients in group A, 10 of them were not deeply unconscious. 40 patients in group A and 25 in group B had intraoperative awareness. Depth of anesthesia was significantly associated with the use of ketamine (p = 0.0017) 1 patient in group A and 3 in group B had vomiting and 1 patient in group B was presented with the hallucinations. These parameters were not significantly associated with the dose of ketamine (p = 0.5). Conclusion: Overall use of ketamine is associated with better sedation and no significant side effects, with low doses of ketamine, were seen in our study. Comparative studies using other analgesics, with larger sample size, are therefore recommended.
The aim of the review was to comprehensively characterize the antimicrobial efficacy of bacteriophages in eliminating pathogens occurring in companion animals, as an alternative to antibiotics for controlling infections that pose potential threats to the health and life of people and to the environment.The review contains detailed information on the characteristics and classification of bacteriophages and an analysis of their life cycle. The dominant element is a detailed analysis of the experimental use of bacteriophages in combating infections caused by various microorganisms in companion animals with regard to their potential use in therapy.It seems that in the near future, phage therapies will provide an alternative to antibiotics in the treatment of diseases caused by multi-drug resistant bacteria in people and animals.The effectiveness of phage therapies depends on many factors and the properties of the bacteriophages themselves, which requires comprehensive knowledge of them.
