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- Analyses of Basal and Squamous Cell Carcinoma Reported as an Adverse Drug
Reaction and Comparison with Cases from the Cancer Registry from Germany-
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Abstract: Introduction In Germany, incidence rates of basal cell (BCC) and squamous cell carcinoma (SCC) rose significantly from 1998 to 2010. Ultraviolet (UV) light exposure, immunosuppressants and drugs with photosensitising potential are known to increase the risk to develop BCC and SCC. The aim of our study was to analyse the adverse drug reaction (ADR) reports from Germany referring to BCC and SCC and to compare them to BCC and SCC occurring in the general population. Methods We analysed all validated spontaneous ADR reports referring to BCC (n = 191) and SCC (n = 75) from Germany contained in the European ADR database EudraVigilance prior to 6 March 2019. These reports were compared to 1,267,210 BCC and 476,903 SCC cases from the German Centre for Cancer Registry Data recorded from 2006 to 2018. Results The number of BCC and SCC reports as well as the BCC and SCC incidences in the registry increased in the analysed time period. Patients with drug-associated BCC (60 years) and SCC (64 years) were younger than patients with BCC (72 years) and SCC (76 years) in the registry. In 57.1 and 60.0% of BCC and SCC reports immunosuppressants were reported as suspected. The reported suspected drug was assumed to possess a photosensitising potential in 41.9 and 44.0% of BCC and SCC reports. Conclusions In Germany, drug-associated BCC and SCC occurred at a younger age than in the general population. The results underline the necessity for skin cancer screening of patients treated with immunosuppressants or with drugs with photosensitising potential.
PubDate: 2022-11-19
- Acknowledgement to Referees
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PubDate: 2022-11-17
- Pharmacokinetics, Bioequivalence and Safety of Cloperastine in Chinese
Healthy Subjects Under Fasting and Postprandial Conditions-
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Abstract: Background Cloperastine is a pivotal antibechic widely prescribed to treat cough caused by respiratory diseases. The present trial evaluated the pharmacokinetics (PK), bioequivalence (BE) and safety effects of the generic test (T) tablet of cloperastine after single-dose administration of cloperastine, compared with the original reference (R) tablet of cloperastine. Objective The purpose of this trial was to compare the PK, BE and safety of a test 10 mg versus the reference 10 mg formulation of cloperastine under fasting and postprandial conditions in healthy Chinese volunteers. Methods A single-centre, randomised, open, double-cycle, self-crossover, single oral administration Phase I trial was performed in healthy Chinese volunteers. A total of 60 subjects were enrolled in either the fasting (28 subjects) or the postprandial condition (32 subjects). Subjects randomly received a single dose of the T or R preparation (10 mg dose). Plasma concentrations of cloperastine were analysed by a validated LC-MS/MS method. The primary endpoints of the PK parameters were the area under the plasma concentration-time curve from zero to 72 h (AUC0–72h), under the plasma concentration-time curve from zero to infinity (AUC0–∞) and the maximal plasma concentration (Cmax). The equivalence standard range (80.0–125.0%) was used to evaluate the BE of the two preparations. The safety parameter as secondary endpoint was mainly evaluated by the occurrence of adverse events (AEs). Results A total of 25 and 30 subjects in the fasting and postprandial conditions completed this clinical trial, respectively. The geometric mean ratio (GMR) of the T/R for the Cmax, AUC0–72h and AUC0–∞ were 102.1%, 103.8% and 104.0% in the fasting condition, respectively. In the postprandial condition, the GMR of the T/R for the Cmax, AUC0–72h and AUC0–∞ were 94.2%, 98.8% and 99.0%, respectively. All the values fell within the range (80.0–125.0%). The Cmax and AUC0–72h values of the T and R preparations in fasting and postprandial conditions were not statistically significant (P > 0.05). Furthermore, no serious adverse events (SAEs) occurred during the whole trial. Conclusions The T and R preparations were bioequivalent under both conditions. Food has no significant effect on the absorption of cloperastine. Moreover, T and R preparations were well tolerated. The trial registration number (TRN) and date of registrations were CTR20212515, 13 October 2021.
PubDate: 2022-11-11
- Chinese- and French-Manufactured Immediate-Release Glucophage®
Bioequivalence: A Randomized, Open-Label, Crossover Study-
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Abstract: Objective We aimed to assess the bioequivalence, safety, and tolerability of Chinese- and French-manufactured Glucophage® immediate-release (GIR) tablets under fasted and fed conditions in healthy volunteers. A bioequivalence study was proposed to support the manufacturing transfer. Methods This was an open-label, randomized, two-period, two-sequence, crossover study. Subjects were randomly assigned to receive the test product (one 500 mg GIR tablet manufactured in China) or reference product (one 500 mg GIR tablet manufactured in France). The primary study endpoint was the area under the plasma concentration-time curve from time zero to the last sampling time (AUCt) and maximum observed concentration (Cmax). Results In total, 96 subjects were screened and 44 subjects were randomly assigned to treatment (fasted group, 26 subjects; fed group, 18 subjects). All 44 subjects received the study drug, completed the study, and were included in the pharmacokinetic (PK) and safety analysis sets. Under fasted or fed conditions, the mean AUCt and Cmax (primary PK parameters) were comparable between the test and reference products. Point estimates for both parameters were close to 100% and the corresponding 90% confidence intervals were within the specified 80–125% bioequivalence boundary. There were no hypoglycemia-related adverse events (AEs) in either treatment group. All AEs in the present study were mild in severity. Conclusions Bioequivalence between the test and reference GIR tablets was demonstrated under fasted and fed conditions and both were safe and well tolerated. Clinical Trials Registration This study was registered at ClinicalTrials.gov under the identifying number NCT03393208.
PubDate: 2022-10-20
- Clinical Validation of the Covariates Pharmacokinetic Model for Propofol
in an Adult Population-
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Abstract: Background and Objective Pharmacokinetic or pharmacokinetic-pharmacodynamic models have been instrumental in facilitating the clinical use of propofol in target-controlled infusion systems in anaesthetic practice. There has been debate over which model should be recommended for practice. The covariates model is an updated pharmacokinetic model for propofol. The aim of this study was to prospectively validate this model in an adult population. Methods Twenty-nine patients were included, with a range of ages to assess model performance in younger and older individuals. Subjects received propofol through a target-controlled infusion device programmed with the covariates model. Subjects were randomised to one of two increasing/decreasing regimes of propofol plasma target concentrations between 2 and 5 μg.mL−1. After the start of the infusion, arterial and venous blood samples were drawn at pre-specified timepoints between 1.5 and 20 min and between 1.5 and 45 min, respectively. Predictive performance was assessed using established methodology. Results The model achieved a bias of 9 (− 45 to 82) and precision of 24 (9–82) for arterial samples and bias of − 8 (− 64 to 70) and precision of 23 (9–70) for venous samples. Predicted concentrations tended to be higher than the measured concentrations in female individuals but lower in male individuals. There was no clear systematic difference in the bias between younger and older patients. Conclusions The covariates propofol pharmacokinetic model achieved an acceptable level of predictive performance, as assessed by both arterial and venous sampling, for use in target-controlled infusion in clinical practice. Clinical Trial Registration NCT01492712 (15 December, 2011)
PubDate: 2022-10-07
- Quercetin Supplement to Aspirin Attenuates Lipopolysaccharide-Induced
Pre-eclampsia-Like Impairments in Rats Through the NLRP3 Inflammasome-
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Abstract: Background and Objectives Aspirin is a common drug for the treatment of pre-eclampsia. We aimed to explore whether quercetin as a supplement to aspirin could enhance the therapeutic outcome in pre-eclampsia rat models. We further aimed to evaluate the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome as a potential pre-eclampsia-related molecular mechanism, which can be affected by quercetin treatment. Methods Rat pre-eclampsia models were established using an intravenous lipopolysaccharide injection after gestation. Rats were treated with aspirin and quercetin at 6–18 days after pregnancy. On day 20, blood, fetus, and placenta were harvested. Blood pressure and the level of proteinuria were measured every 4 days. Fetal outcomes were analyzed by pup body weight. Serum soluble Fms-like tyrosine kinase-1, PIGF, interleukin-6, and interleukin-10 levels were measured using the enzyme-linked immunosorbent assay. Caspase-1, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and p-caspase-1 levels in the placenta were assessed using western blot or quantitative real-time polymerase chain reaction analyses. Results Pre-eclampsia rat models showed a pronounced increase in systolic blood pressure and proteinuria after 4 days of pregnancy, while aspirin, quercetin, and aspirin/quercetin combinatory treatment significantly attenuated the blood pressure and proteinuria abnormalities. Notably, the aspirin/quercetin combinatory treatment showed the highest efficacy in attenuating pre-eclampsia-like symptoms. Placental caspase-1 and NLRP3 levels also showed the greatest attenuation in pre-eclampsia rats after aspirin/quercetin treatment. Conclusions Our data suggested that quercetin supplementation to aspirin is more effective in attenuating symptoms of pre-eclampsia and improving pregnancy outcomes compared with quercetin or aspirin alone. Quercetin can ameliorate placental NLRP3 inflammasome activation, which might serve as an underlying mechanism for its therapeutic efficacies in pre-eclampsia.
PubDate: 2022-09-22
- Impact of Renal Function on Anti-factor Xa Activity Concentrations with
Edoxaban Use in Patients with Non-valvular Atrial Fibrillation-
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Abstract: Background Chromogenic anti-factor Xa activity (AXA) assay is used to measure the pharmacodynamics of factor Xa inhibitors, including edoxaban. Although AXA concentrations in patients with non-valvular atrial fibrillation using edoxaban have been reported, the impact of renal function on AXA concentrations with edoxaban use in patients with non-valvular atrial fibrillation has not been fully assessed. Methods Trough and peak AXA concentrations were measured in 93 patients with non-valvular atrial fibrillation taking edoxaban (73.6 ± 11.2 years, 48 were male). The patients were divided into three groups: patients with moderate renal dysfunction (creatinine clearance 15–49 mL/min), mild renal dysfunction (creatinine clearance 50–95 mL/min), and normal renal function (creatinine clearance > 95 mL/min). Both trough and peak AXA concentrations were assessed among the groups according to the edoxaban dose (30 or 60 mg). Results At a 30-mg dose, patients with moderate renal dysfunction showed significantly higher trough AXA concentrations than patients with mild renal dysfunction or normal renal function. At a 60-mg dose, patients with mild renal dysfunction showed significantly higher trough AXA concentrations than patients with normal renal function. Peak AXA concentrations were not significantly different between the groups. Creatinine clearance was significantly and negatively correlated with trough AXA concentrations at a 60-mg dose, whereas the correlation of creatinine clearance with AXA concentrations was borderline significant at a 30-mg dose. No correlation was found between creatinine clearance and peak AXA concentrations at either dose. Conclusions Creatinine clearance tends to be negatively correlated with trough AXA concentrations in patients with non-valvular atrial fibrillation taking edoxaban, while renal function is not correlated with peak AXA concentrations.
PubDate: 2022-09-14
- Roxadustat for SARS-CoV-2 Infection: Old Signaling Raised New Hopes
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PubDate: 2022-08-25
- Novel Strategies for the Treatment of COVID-19
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Abstract: Abstract On 4 September, 2020, the US National Institutes of Health launched a new clinical trial, “A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults with COVID-19.” This open-label, placebo-controlled, multicenter, adaptive platform study was designed to evaluate therapeutic options for patients hospitalized with mild, moderate, or severe COVID-19. A variety of drugs and drug classes were selected, including heparin, the monoclonal antibody crizanlizumab, sodium-glucose cotransporter-2 inhibitors, and purinergic signaling receptor Y12 inhibitors. These medications have been widely used in the treatment of other conditions, from sick cell disease to type 2 diabetes mellitus and some forms of cardiovascular disease, but their inclusion in a study of COVID-19 was somewhat unexpected. This article examines the rationale behind the use of these disparate agents in the treatment and prevention of adverse outcomes in patients with COVID-19 and explores how these strategies may be utilized in the future to address the severe acute respiratory syndrome coronavirus 2 pandemic.
PubDate: 2022-08-24
- Correction: The Pitfalls of Abnormal Laboratory Value Interpretation in
Vaccine Clinical Trials: The Example of Asymptomatic Transient Neutropenia
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PubDate: 2022-08-22
- Risk Factors for Septic Shock After Irinotecan-Containing Chemotherapy: An
Exploratory Case-Control Study-
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Abstract: Background and Objectives Irinotecan sometimes causes lethal septic shock but the risk factors remain unclear. This retrospective case-control study explored the potential risk factors for septic shock following irinotecan treatment. Methods All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital from October 2014 to September 2020 were investigated. The clinical backgrounds and blood test results of those who developed septic shock after irinotecan-containing chemotherapy were compared with those who did not. Odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs), using univariable logistic regression analysis. Results During the study period, 147 women received irinotecan-containing chemotherapy. Three women developed septic shock due to neutropenic enterocolitis after irinotecan treatment, and 144 did not. The three patients with septic shock had recurrent cervical cancer, heterozygous variants in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene (two patients had *1/*6, one had *1/*28 variants), a history of concurrent chemoradiation therapy, 50–60 Gy of pelvic irradiation, and platinum-combined chemotherapy. A history of pelvic irradiation was identified as a possible risk factor for developing septic shock after irinotecan-containing chemotherapy (OR 63.0, 95% CI 5.71–8635; p < 0.001). The OR of UGT1A1 polymorphism for septic shock was 9.09 (95% CI 0.86–1233; p = 0.070) in the complete case analysis. Conclusion Medical personnel involved in cancer therapy should consider the possible risk of septic shock developing due to neutropenic enterocolitis when administering irinotecan-containing chemotherapy in patients with a history of pelvic irradiation.
PubDate: 2022-08-20
- Correction: Association between Acid-Suppressive Drugs and Clinical
Outcomes in Patients with Nonvalvular Atrial Fibrillation-
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PubDate: 2022-08-18
- Study of the Stability of Sandoz Rituximab Biosimilar Rixathon®/Riximyo®
When Subjected for up to 21 Days to Ambient Storage-
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Abstract: Aim The purpose of this study was to evaluate the extended physicochemical and biological stability of Sandoz Rixathon®/Riximyo® (SDZ-RTX) after exposure to out-of-fridge (OOF) conditions. Materials and Methods The impact of the short-term temperature excursion on stability parameters of SDZ-RTX was simulated by subsequently exposing the three batches of SDZ-RTX (100 and 500 mg) to OOF conditions, (I) 25 ± 2 °C/60 ± 5% relative humidity (RH) and (II) 30 ± 2 °C/65 ± 5% RH, for up to 21 days after more than the claimed 36-month shelf-life storage in long-term conditions (5 ± 3 °C). Analytical methods used included the cation exchange chromatography (CEX), size exclusion chromatography (SEC), and non-reducing capillary electrophoresis-sodium dodecyl sulfate (nrCE-SDS), as well as biological activity by complement-dependent cytotoxicity (CDC)-bioactivity as well as further methods, for example, related to identity and pharmacopoeia test methods. Results No notable changes were observed across all batches with respect to identity (charge and primary structure), pharmaceutical tests (clarity, visible and subvisible particles analytics, container appearance, degree of coloration, pH, osmolality, extractable volume, and container closure integrity testing), protein content by UV and microbiological parameters (sterility and bacterial endotoxins) under both OOF conditions. Only minor changes were observed for parameters evaluated via SEC, CEX, and nrCE-SDS. For potency (CDC-bioactivity) only one of the batches showed a relevant change. Even for these stability-indicating test methods, all analyzed parameters complied with the shelf-life specifications. Conclusion SDZ-RTX is safe for use even under worst-case conditions, for example, after subjecting it for up to 21 days at OOF conditions (25 ± 2 °C/60 ± 5% RH or 30 ± 2 °C/65 ± 5% RH) after the batches had reached an age that was already beyond the claimed shelf-life.
PubDate: 2022-08-07
- Antiplatelets Versus Anticoagulation in Cervical Artery Dissection: A
Systematic Review and Meta-analysis of 2064 Patients-
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Abstract: Background and Objectives In young people aged < 50 years, cervical artery dissection (CeAD) is among the most common causes of stroke. Currently, there is no consensus regarding the safest and most effective antithrombotic treatment for CeAD. We aimed to synthesize concrete evidence from studies that compared the efficacy and safety of antiplatelet (AP) versus anticoagulant (AC) therapies for CeAD. Methods We searched major electronic databases/search engines from inception till September 2021. Cohort studies and randomized controlled trials (RCTs) comparing anticoagulants with antiplatelets for CeAD were included. A meta-analysis was conducted using articles that were obtained and found to be relevant. Mean difference (MD) with 95% confidence interval (CI) was used for continuous data and odds ratio (OR) with 95% CI for dichotomous data. Results Our analysis included 15 studies involving 2064 patients, 909 (44%) of whom received antiplatelets and 1155 (56%) received anticoagulants. Our analysis showed a non-significant difference in terms of the 3-month mortality (OR 0.47, 95% CI 0.03–7.58), > 3-month mortality (OR 1.63, 95% CI 0.40–6.56), recurrent stroke (OR 0.97, 95% CI 0.46–2.02), recurrent transient ischaemic attack (TIA) (OR 0.93, 95% CI 0.44–1.98), symptomatic intracranial haemorrhage (sICH) (OR 0.38, 95% CI 0.12–1.19), and complete recanalization (OR 0.70, 95% CI 0.46–1.06). Regarding primary ischaemic stroke, the results favoured AC over AP among RCTs (OR 6.97, 95% CI 1.25–38.83). Conclusion Our study did not show a considerable difference between the two groups, as all outcomes showed non-significant differences between them, except for primary ischaemic stroke (RCTs) and complete recanalization (observational studies), which showed a significant favour of AC over AP. Even though primary ischaemic stroke is an important outcome, several crucial points that could affect these results should be paid attention to. These include the incomplete adjustment for the confounding effect of AP–AC doses, frequencies, administration compliance, and others. We recommend more well-designed studies to assess if unnecessary anticoagulation can be avoided in CeAD.
PubDate: 2022-08-03
- Effectiveness and Safety of Upadacitinib in the Treatment of
Moderate-Severe Atopic Dermatitis: A Multicentric, Prospective,
Real-World, Cohort Study-
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Abstract: Background The efficacy and safety of upadacitinib in atopic dermatitis (AD) have been defined in clinical trials, but no real-world data are currently available. We aimed to assess the safety and effectiveness of upadacitinib in a real-world AD patient cohort that mostly included patients who failed the available systemic therapies, including dupilumab. Methods Prospective cohort study collecting data on upadacitinib-treated AD adult patients completing at least 16 weeks of therapy. Results Forty-three patients showed rapid and marked response to upadacitinib with significant reduction of all disease severity scores since the first follow-up visit. At week 16, Eczema Area and Severity Index (EASI) 75, EASI 90, and EASI 100 response was observed in 97.5%, 82.1%, and 69.2% of patients, respectively. EASI 90 response reflected the achievement of a clear or almost clear condition (POEM 0-2), self-evaluated by 79.5% of patients. Patients’ quality of life improved as suggested by the achievement of DLQI 0/1 by 38.5% of patients at week 4, and by 76.9% at week 16. Conclusion Elevated effectiveness and favorable safety of upadacitinib were confirmed in patients unresponsive to dupilumab, who were not included in upadacitinib trials.
PubDate: 2022-08-03
- Bioavailability of Oniria®, a Melatonin Prolonged-Release Formulation,
Versus Immediate-Release Melatonin in Healthy Volunteers-
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Abstract: Background Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria® is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro. Objectives The main objective of the present study was to evaluate the relative oral bioavailability of Oniria®, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin. Methods We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria® and the reference melatonin (periods 2 and 3). Results Two phases were clearly differentiated in the PK profile of Oniria®. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a Cmax value close to 4000 pg/mL. However, in the delayed phase, Oniria® showed significantly higher melatonin concentrations than the IRT (three times higher at 4–6 h post-administration). Moreover, Oniria® exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria®, not only in the induction of sleep, but also in the maintenance. Conclusion Oniria® could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.
PubDate: 2022-08-02
- Association between Acid-Suppressive Drugs and Clinical Outcomes in
Patients with Nonvalvular Atrial Fibrillation-
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Abstract: Purpose Acid-suppressive drugs (ASDs) are often prescribed for patients with nonvalvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs). However, the risk-benefit balance of ASDs prescription for patients with NVAF taking OACs is still unclear. This study aimed to assess the association between ASDs and clinical outcomes in patients taking OACs for NVAF. Methods This study is a subanalysis of an historical registry study from 71 centers in Japan. We included patients taking vitamin K antagonists for NVAF and excluded those with mechanical heart valves or a history of pulmonary thrombosis or deep vein thrombosis. We registered consecutive patients in February 2013 and followed them up until February 2017. The primary outcomes were ischemic events, major bleedings, and all-cause mortality. Ischemic stroke, acute myocardial infarction, and hemorrhagic stroke comprised the secondary outcomes. Results We included 7826 patients with a mean age of 73 years, 5274 (67%) of whom were males. The adjusted hazard ratios (95% confidence intervals) for ischemic events, major bleedings, and all-cause mortality in the ASD group compared with the no-ASD group were 0.998 (0.78–1.27), 0.98 (0.81–1.18), and 1.22 (1.02–1.47), respectively, while those for ischemic stroke, acute myocardial infarction, and hemorrhagic stroke were 0.96 (0.74–1.24), 0.82 (0.36–1.88), and 1.17 (0.69–1.99), respectively. Conclusions ASDs were significantly associated with all-cause mortality in patients with NVAF taking OACs.
PubDate: 2022-07-19
- Analysis of the US Safety Data for Edaravone (Radicava®) From the
Third Year After Launch-
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Abstract: Background Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US. Methods Edaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date). Results As of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported. Conclusion In the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.
PubDate: 2022-06-20
- Evaluation of the Effect of Food on the Pharmacokinetics of SHR6390, An
Oral CDK4/6 Inhibitor, in Healthy Volunteers-
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Abstract: Background and Introduction SHR6390 is a new developed highly effective and selective small-molecule oral CDK4/6 inhibitor. We aimed to evaluate the effect of food on the pharmacokinetics of SHR6390 tablets. Methods In an open-label two-way crossover study, 24 healthy Chinese volunteers were randomly divided into Group A and Group B, and 12 volunteers in each group received a single oral dose of a SHR6390 150-mg tablet under fasting and high-fat conditions. Blood samples were collected and determined for pharmacokinetic analyses. A liquid chromatography-tandem mass spectrometry method was developed and validated for determining the SHR6390 concentration. Results The time to maximum plasma concentration was not significantly affected by a high-fat diet. Compared with the fasting group, maximum plasma concentration, i.e., the area under the concentration–time curve (AUC0–t and AUC0–∞) was altered significantly, as evidenced by an increase of 56.9%, 38.6%, and 37.5% respectively. We identified seven metabolites of SHR6390 from the plasma samples, and we found no sex differences in metabolic pathways. All treatment-emergent adverse events were Grade 1 or 2. Conclusions Food intake increased the maximum plasma concentration, AUC0–t, and AUC0–∞ significantly compared with the fasting condition. Meanwhile, single-dose SHR6390 for two treatment cycles is safe. SHR6390 was administered in a fasting status in the pivotal phase III study (NCT03927456) and chosen for the final drug label.
PubDate: 2022-05-30
- A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics,
Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects-
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Abstract: Background and Objective AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects. Methods This was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg. Results Following oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity. Conclusion AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.
PubDate: 2022-03-13
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