A comprehensive analysis of liver safety across zibotentan oncology trials: knowledge of the past offers new perspectives on the present.

BACKGROUND: Endothelin receptor antagonists (ERAs) are associated with liver injury. We used data from previous oncology clinical trials to determine the liver safety profile of zibotentan, which is currently in clinical development (in combination with dapagliflozin) for chronic kidney disease and cirrhosis. RESEARCH DESIGN AND METHODS: Six global, double-blinded, phase 2b and 3 clinical trials from the zibotentan oncology development program were pooled to analyze liver safety. Descriptive statistics, proportion of liver-related adverse events, liver biochemistry parameter elevation, and shifts from baseline were analyzed, with individual case assessment. RESULTS: A total of 1532 patients received zibotentan for 285 days (mean), and 1486 patients received placebo for 320 days (mean). The frequency of any hepatic disorder preferred term was similar across zibotentan monotherapy (22/947 patients, 2.3%) and placebo monotherapy arms (30/881 patients, 3.4%). A total of 4 (0.4%) patients receiving zibotentan monotherapy experienced ALT elevations >5× ULN versus 8 (0.9%) receiving placebo. Of the seven patients receiving zibotentan who met criteria for potential Hy's Law, there were no cases of drug-induced liver injury. CONCLUSIONS: We found no evidence of zibotentan-related liver biochemistry changes among cancer-treated patients, suggesting that hepatotoxicity of ERAs is molecule-dependent, and allowing exploration of zibotentan for new indications.

Usage of vildagliptin among patients with type 2 diabetes mellitus attending a public primary healthcare clinics in Kuala Selangor District, Selangor.

INTRODUCTION: Studies showed that vildagliptin can lower HbA1c levels by 0.8%-1%. However, there is limited data looking at vildagliptin use among suburban populations. The efficacy of vildagliptin use may differ among different populations, especially those with low socio-economic status. Thus, this study aimed to assess the HbA1c reduction after vildagliptin initiation, treatment patterns and the reason for its initiation among patients with type 2 diabetes mellitus attending outpatient clinics in Kuala Selangor District, Selangor. MATERIALS AND METHODS: This is a cross-sectional, retrospective study design. All patients who received vildagliptin in the Pharmacy Integrated Health System (PHIS) registry database from 2016 to 2021 were included as study samples. The exclusion criteria were being less than 18 years old and having type 1 diabetes mellitus. Patients' medical records were retrieved after sampling, and data were collected. One medical record was missing, thus SPSS analysis were performed on 144 vildagliptin users. RESULTS: In total, 84 females (58.3%) and 60 males (41.7%) with a mean age of 62.1 (±10.1) years were analysed in this study. Mean HbA1c pre-therapy was 8.5 ± 2.1%; while posttherapy 6 months demonstrated a mean HbA1c of 7.9 ± 1.8%. Use of vildagliptin alone or as an adjunct was associated with a mean reduction of 0.6% in HbA1c (p = 0.01). Factors influencing this HbA1c reduction were advancing age, specifically individuals aged 62 years and older (p = 0.02), patients who are already receiving insulin therapy (p=0.00) and those who express a willingness to commence insulin treatment during the counselling session prior to initiating the treatment plan (p = 0.00). Reasons for vildagliptin initiation documented by prescribers were non-insulin acceptance (n = 59, 40.97%), frequent hypoglycaemia (n = 6, 4.1%) and non-compliance with medications (n = 23, 15.9%). There was no association between demographic, medical background and reason for starting vildagliptin variables and HbA1c reduction (p < 0.001). CONCLUSION: This study showed that initiating vildagliptin alone or as an adjunct therapy significantly reduced HbA1c and is beneficial for uncontrolled diabetes patients. While advancing age, concurrent administration of insulin and the patients' willingness to accept insulin treatment prior to the commencement of therapy were the factors that influenced HbA1c reduction among patients receiving vildagliptin therapy, we recommend primary care providers prioritise all of the significant variables discovered before initiating vildagliptin for their patients.

Renal impairment as a risk factor for trifluridine/tipiracil-induced adverse events in metastatic colorectal cancer patients from the REGOTAS study.

Renal impairment may be associated with an increased risk of hematologic events (AEs) in patients undergoing treatment with trifluridine/tipiracil (FTD/TPI). This study aimed to investigate the specific types of AEs linked to renal impairment in patients with metastatic colorectal cancer (mCRC) receiving FTD/TPI, using real-world data. Among the patients included in the REGOTAS study (a retrospective study of FTD/TPI versus regorafenib), those treated with FTD/TPI were evaluated. Creatinine clearance values of < 30, 30-60, 60-90, and > 90 mL/min were defined as severe, moderate, mild renal impairment, and normal renal function, respectively. Renal impairment was analyzed as a risk factor for grade 3 or higher AEs using a logistic regression model. Overall survival (OS) and progression-free survival (PFS) based on renal impairment were evaluated. A total of 309 patients were included in the analysis, with 124, 130, and 55 patients divided into the normal, mild, and moderate-to-severe groups, respectively. The risk of grade 3 or higher neutropenia was significantly higher in the moderate-to-severe group (odds ratio 3.47; 95% confidence interval 1.45-8.30; P = 0.005), but there was no significant increase in the risk of non-hematologic AEs in any of the groups. The OS and PFS of patients in the mild and moderate-to-severe groups were comparable to those in the normal group. Patients with mCRC and moderate/severe renal impairment receiving FTD/TPI therapy may develop severe neutropenia; however, FTD/TPI remains a viable treatment option due to its clinical benefit.

Daridorexant as a novel pharmacotherapeutic approach in insomnia: a systematic review and meta-analysis.

BACKGROUND: Insomnia is a multi-factorial disorder with conventional treatment options that are not satisfactory for many patients. This metaanalysis analyzed the safety and efficacy of daridorexant. METHODS: An electronic database search for RCTs was conducted on Medline via PubMed, Cochrane, and Clinicaltrials.gov using the terms 'Daridorexant,' 'RCT,' 'Insomnia' trials evaluating the efficacy and/or safety of daridorexant for insomnia were included. The data were synthesized using Cochrane review manager version 5.4.1. Cochrane risk of bias 2.0 tool and GRADEpro-GDT were used to assess the methodological and evidence quality, respectively. RESULTS: Of 109 searched studies, four trials were included. The risk of treatment-emergent adverse events with 25 mg daridorexant [risk ratio (RR) = 1.12 (0.88, 1.43), p = 0.36; I2 = 0%] and 50 mg daridorexant [RR = 1.25 (0.88, 1.79), p = 0.22; I2 = 28%] and serious adverse events with 25 mg [RR = 0.86 (0.23, 3.19), p = 0.82, I2 = 56%] and 50 mg [RR = 1.32 (0.29, 6.08), p = 0.72, I2 = 52%] was comparable to placebo [Moderate quality evidence]. Risk of nasopharyngitis was also comparable to placebo. The efficacy parameters like wake after sleep onset, latency to persistent sleep, and subjective total sleep time showed significant improvement with daridorexant. The risk of bias is low for three studies and some concern for one. CONCLUSION: Daridorexant is a safer and efficacious agent for induction and maintenance of sleep for chronic insomnia. PROSPERO: The registration number is CRD42022335233. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are NCT03575104, NCT03545191, NCT03679884, and NCT02839200).

Effectiveness, safety and quality of life of trifluridine/tipiracil in pretreated patients with metastatic colorectal cancer: Real-world data from the noninterventional TACTIC study in Germany.

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.

Analysis of neutropenia as a predictive factor of the efficacy of trifluridine-tipiracil treatment.

OBJECTIVES: Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent used in adult patients with refractory metastatic colorectal cancer (mCRC), has been associated with neutropenia (chemotherapy-induced neutropenia) (CIN)). MATERIALS AND METHODS: We evaluated the efficacy and safety of TAS-102 in a group of 45 mCRC patients (median age 66 years) in Huelva province, Spain, in a retrospective, multicenter observational study. RESULTS: We showed that the association between TAS-102 and CIN can be used as a predictor of efficacy. 20% (9/45) of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 had received at least one previous chemotherapy treatment. Overall, 75.5% (34/45) and 28.9% (13/45) had received anti-VEGF and anti-EGFR monoclonal antibodies, respectively. Additionally, 80% (36/45) of patients had received third-line treatment. The mean treatment period, duration of overall survival (OS), and duration of progression-free survival (PFS) were 3.4, 12, and 4 months, respectively. A partial response was seen in 2 patients (4.3%), and disease stabilization was observed in 10 patients (21.3%). Neutropenia was the most frequent grade 3 - 4 toxicity (46.7%; 21/45). Other findings were anemia (77.8%; 35/45), all grades of neutropenia (73.3%; 33/45), and gastrointestinal toxicity (53.3%; 24/45). The dose of TAS-102 needed to be reduced in 68.9% (31/45) of patients, whereas treatment needed to be interrupted in 80% (36/45) of patients. Grade 3 - 4 neutropenia was a positive prognostic factor for OS (p = 0.023). CONCLUSION: A retrospective evaluation shows that grade 3 - 4 neutropenia is an independent predictor of treatment response and survival in patients undergoing routine treatment for mCRC, but this finding needs confirmation in a prospective study.

Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer.

BACKGROUND: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival. METHODS: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability). RESULTS: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67). CONCLUSIONS: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.).

Effectiveness and Safety Profiles of Vernakalant for Cardioversion of Acute-onset Atrial Fibrillation: A Systematic Review and Meta-analysis.

PURPOSE: Pharmacologic cardioversion is an effective clinical strategy for fibrillation. Vernakalant is a novel drug used to treat atrial fibrillation (AF). This study aimed to evaluate the efficacy- and tolerability-related data on vernakalant from clinical trials. METHODS: Literature from PubMed and the Cochrane Library was systematically reviewed, and 139 eligible studies were found after specific key words were identified. Twelve randomized clinical trials discussing vernakalant cardioversion in patients with AF were chosen for the meta-analysis after scrutiny. Ten of the 12 trials used placebo while two reported data on active and established drugs to compare the effects of vernakalant. Three of the 12 trials included relevant clinical states in addition to AF. FINDINGS: In this meta-analysis of data from 12 studies (2365 patients, 887 events), the rate of cardioversion from AF to sinus rhythm (SR) was significantly greater with vernakalant compared with placebo and active comparators (risk ratio = 5.60; 95% CI, 2.83-11.09; I2 test for heterogeneity, 92%). Tolerability-related data revealed that dysgeusia, paresthesia, atrial flutter, and hypotension were major adverse events that occurred with vernakalant use, but the data were not clinically significant compared to placebo and active drug (risk ratio = 1.13; 95% CI, 0.86-1.47). Eleven deaths were reported in 4 trials, with vernakalant directly implicated in two deaths. Vernakalant was well tolerated and effective in patients with rapid-onset AF. IMPLICATIONS: Vernakalant appears to be a good choice when AF is manifested postoperatively or exists with ischemic heart disease and valvular states. Tolerability-related data are promising, but a specific trial may be required to identify the causes of the deaths considered unrelated to vernakalant use.

Daridorexant in Insomnia Disorder: A Profile of Its Use.

Daridorexant (Quviviq™) is a useful option for the treatment of insomnia disorder, which has shown efficacy in younger and older adults. It antagonises the orexin receptors, thereby reducing the wake drive. Daridorexant is the first dual orexin receptor antagonist to be approved for the treatment of chronic insomnia in the EU and has been approved for insomnia in the USA. In phase 3 clinical trials, daridorexant dose-dependently improved objective latency to persistent sleep, objective wake time after sleep onset, subjective total sleep time and, at the 50 mg dose, subjective daytime functioning compared with placebo. Daridorexant was generally well tolerated. Adverse events (AEs) commonly associated with insomnia drugs, such as somnolence, fatigue and dizziness, occurred at a similar or slightly greater frequency with daridorexant than with placebo. Falls occurred at a similar or lower frequency with daridorexant than with placebo. Most AEs were mild in severity and the incidence was not dose-dependent. The efficacy of daridorexant was maintained during a 12-month extension trial, with no new safety or tolerability concerns.

Insomnia disorder is characterized by persistent difficulty falling asleep and/or maintaining sleep and impaired daytime functioning. Dual orexin receptor antagonists suppress wakefulness and are generally considered to have a favourable safety profile compared with older classes of insomnia drugs, including less risk of tolerance, dependence, abuse and withdrawal effects. Daridorexant (Quviviq™) is the first dual orexin receptor antagonist approved for the treatment of chronic insomnia in the EU and has been approved for insomnia in the USA. In clinical trials, daridorexant improved objective sleep onset, objective sleep maintenance and self-reported total sleep time, and self-reported daytime functioning at a 50 mg dose. Daridorexant was generally well tolerated, with a low incidence of adverse events such as sleepiness, fatigue, dizziness and falls, most of which were similar to that with placebo. The efficacy and tolerability of daridorexant were sustained for 12 months. With a favourable safety profile compared to other classes of insomnia drugs, minimal residual next-morning effects and improvements in daytime functioning, daridorexant is a useful option for the treatment of insomnia disorder.

Effects of short-term treatment with vibegron for refractory nocturnal enuresis.

BACKGROUND: Long-term nocturnal enuresis treatment leads to stress and lowered self-esteem for children and their parents. This study evaluated the short-term effectiveness and safety of vibegron (50 mg) for children with refractory nocturnal enuresis. METHODS: A retrospective cohort study of children with therapy-resistant enuresis was conducted using data for July to December 2019. Enuresis frequency was recorded during 30 days before and after additional vibegron administration with prior treatment. We assessed the treatment effectiveness based on enuresis frequencies between before and after treatment with vibegron 50 mg. Statistical evaluation was performed using a paired t-test. RESULTS: Among 29 children receiving vibegron, 14 (48.3%) exhibited a partial or complete response to the drug. Enuresis frequencies (mean ± standard deviation [SD]) were, respectively, 15.8 ± 9.2 and 9.5 ± 9.6 before and after treatment with vibegron during the observed 30 days. A statistically significant reduction in enuresis frequency was found (p < 0.001). Moreover, maximum mean±SD morning urine of 200 ± 62.9 mL before treatment with vibegron changed to 232 ± 76.6 mL after treatment. A significant increase in voiding volume in the early morning was found (p < 0.05). No drug-related severe adverse event was found. CONCLUSION: Short-term treatment with vibegron is safe and effective for children with refractory enuresis.

Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder.

BACKGROUND AND OBJECTIVE: Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. In two phase III, 12-week studies in patients with insomnia disorder, daridorexant improved sleep and daytime functioning while maintaining a favorable safety profile. The objective of this 40-week extension study was to assess the long-term safety and tolerability of daridorexant. METHODS: Adults with insomnia disorder who completed the 12-week studies were invited to enroll in this double-blind extension study. Patients originally randomised to daridorexant (10 mg/25 mg/50 mg) remained on their respective treatments; patients randomised to placebo were re-randomised to daridorexant 25 mg or placebo. The 40-week treatment period was followed by a 7-day placebo run-out. The primary objective was to assess safety/tolerability. Exploratory objectives were to evaluate the efficacy of daridorexant on sleep (self-reported total sleep time) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire). RESULTS: In total, 804 patients were enrolled in the study, of whom 801 received at least one dose of the study treatment and 550 patients (68.4%) completed the study. Overall incidence of treatment-emergent adverse events was similar across groups (35-40%). Daridorexant did not induce next-morning sleepiness and no withdrawal-related symptoms or rebound were observed after treatment discontinuation. Improvements in sleep and daytime functioning were maintained through to the end of the study and were most pronounced with daridorexant 50 mg. Daridorexant 50 mg, compared with placebo, increased self-reported total sleep time by a least-squares mean of 20.4 (95% confidence interval [CI] 4.2, 36.5), 15.8 (95% CI - 0.8, 32.5) and 17.8 (95% CI - 0.4, 35.9) minutes and decreased (i.e., improved) Insomnia Daytime Symptoms and Impacts Questionnaire total scores by a least-squares mean of - 9.3 (95% CI - 15.1, - 3.6), - 9.5 (95% CI - 15.4, - 3.5) and - 9.1 (95% CI - 15.6, - 2.7), at weeks 12, 24 and 36 of the extension study, respectively. CONCLUSIONS: Treatment with daridorexant, for up to 12 months, was generally safe and well tolerated. Exploratory efficacy analyses suggest that the sustained improvements in sleep and daytime functioning with daridorexant 50 mg support its use for long-term treatment of insomnia disorder, without concerns of new safety signals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03679884) [first posted: 21 September, 2018], https://clinicaltrials.gov/ct2/show/NCT03679884 .

Insomnia disorder is the long-term inability to fall asleep or stay asleep with a significant impact on daily life. Left inadequately treated, this disorder may increase the risk of other health problems. For patients with insomnia disorder who require a sleep medication, many drugs are not recommended for long-term use and there is an unmet need for one that can be used safely and effectively over the long term. Daridorexant is a new insomnia treatment that was approved for adults following positive results in two 12-week clinical studies. Both studies showed that, in patients with insomnia disorder, daridorexant improved night-time sleep and patients' ability to function during the day, while avoiding major safety concerns. Patients who completed these two studies could continue into a 40-week extension study enabling the safety and tolerability of daridorexant to be investigated for up to 1 year. Treatment remained double blind for the entire 1-year period. The extension study showed that daridorexant, at all doses studied (10 mg, 25 mg, 50 mg), continued to be generally safe and well tolerated. Patients showed no signs of tolerance, physical dependence, rebound nor any excessive daytime sleepiness. Exploratory efficacy analyses suggest that improved night-time and daytime symptoms of insomnia were sustained, in particular with the highest approved dose, 50 mg, and there were no signs that the benefits of the drug were wearing off at the end of the 1 year. These results support the use of daridorexant 50 mg for the long-term treatment of insomnia disorder in adults.

Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1.

PURPOSE: Most patients with Gaucher disease have progressive and often disabling skeletal manifestations. We examined the long-term effect of eliglustat treatment on bone outcomes in clinical trials in adults with Gaucher disease type 1. METHODS: Data from 4 completed phase 2 and 3 trials were evaluated in treatment-naïve patients or patients switching to eliglustat from enzyme replacement therapy (ERT). RESULTS: Overall, 319 of 393 (81%) eliglustat-treated patients remained in their trials until completion or commercial eliglustat became available. Mean eliglustat treatment duration ranged from 3.3 to 6.5 years. In treatment-naïve patients and ERT-switch patients, frequency and severity of bone pain decreased during eliglustat treatment. Mean lumbar spine T-scores shifted from abnormal to normal in treatment-naïve patients and remained in the healthy reference range or improved modestly in ERT-switch patients. Mean total bone marrow burden score shifted from marked-to-severe to moderate in treatment-naïve patients and remained moderate in ERT-switch patients. MIP-1ß (marker of active bone disease) was elevated at baseline and decreased to the healthy reference range in treatment-naïve patients and remained in the healthy reference range among ERT-switch patients. CONCLUSION: These findings confirm the long-term efficacy of eliglustat on skeletal complications of Gaucher disease in treatment-naïve and ERT-switch patients.

Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. PATIENTS AND METHODS: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. RESULTS: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. CONCLUSIONS: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Efficacy and safety of combination therapy with vildagliptin and metformin vs. metformin monotherapy for Type 2 Diabetes Mellitus therapy: a meta-analysis.

OBJECTIVE: The aim is to assess the comparative efficacy and safety of combination therapy with vildagliptin and metformin vs. metformin monotherapy in the treatment of type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We searched on PubMed, Cochrane Library, Web of Science, and Embase databases for randomized controlled trials (RCTs) of combination therapy with vildagliptin and metformin vs. metformin monotherapy in patients with T2DM published up to 30 February 2021. The Cochrane tool and Revman 5.3 software was used to assess the risk of bias and conducted the meta-analysis in the included RCTs. Evidence level was assessed by the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: A total of 11 RCTs and 8533 patients were included. For the efficacy, we found that combination therapy with vildagliptin and metformin (dose of metformin ≥1500mg/d) had a significantly higher reduction in hemoglobin A1c (HbA1c) [mean differences (MD)= -0.59, 95% CI (-0.28, -0.16), p<0.00001] and fasting plasma glucose (FPG) level [MD= -0.82, 95% CI (-1.09, -0.56), p<0.00001] than combination therapy with vildagliptin and metformin (dose of metformin <1500 mg/d). Vildagliptin plus metformin as combination therapy reduced body weight loss ratio [MD=0.22, 95% CI (0.17, 0.27), p<0.00001] when compared with metformin monotherapy. In terms of safety, the vildagliptin plus metformin as combination therapy did not increase risk of total adverse events (AEs) [RR=0.98, 95% CI (0.94,1.02), p=0.29], however there were significant statistical difference and did not increase the risk of diarrhea [RR=0.55, 95% CI (0.40, 0.76), p=0.0003] and Gastrointestinal (GI) disorders [RR=0.72, 95% CI (0.58, 0.91), p=0.006], but significantly increased risk of dizziness [RR=1.41, 95% CI (1.06, 1.88), p=0.02] when compared with metformin monotherapy. CONCLUSIONS: Compared with metformin, vildagliptin combined with metformin could significantly reduce FPG, HbA1c and body weight. When the dose of metformin in the combination group of vildagliptin and metformin is ≥1500mg/d, the results showed significant reduction in HbA1c and FPG. In addition, it had no risk of increase in total AEs, diarrhea, and GI disorders, but had significant risk of increase in dizziness. GRADE showed that the quality of evidence had high certainty in FPG and moderate certainty in HbA1c, body weight and all AEs.

Long-term eliglustat treatment of Gaucher patients over up to 10 years in Vienna.

Gaucher disease has been the first lysosomal storage disorder for which an enzyme replacement therapy has been approved in the 1990s and was the first to receive approval for a first-line substrate reduction therapy in 2015. Eliglustat treatment has been started in Austria in patients recruited to a clinical trial, followed by its long-term extension and prescription treatment overall covering up to 10 years. In this case series the experience of treating Gaucher patients with eliglustat in Vienna is summarized. Patients were either switched from enzyme replacement therapy or were therapy naïve. Significant improvements were shown in hematological (thrombocytes, hemoglobin) and visceral (spleen volume) manifestations as well as in biomarkers (chitotriosidase, glucosylsphingosine [lyso-GL1], angiotensin converting enzyme) in a routine setting in a therapy-naïve patient. Stability was found in switch patients with slight improvement in bone density. Eliglustat was generally very well tolerated. Patient selection and regular monitoring is required to ensure effective and safe use.

At-home compounding preparation of slow desensitization of elexacaftor/tezacaftor/ivacaftor for delayed hypersensitivity rash.

As elexacaftor/tezacaftor/ivacaftor has proven to have robust clinical efficacy for eligible persons with cystic fibrosis, desensitization should be offered to those with maculopapular eruption hypersensitivity reactions to achieve tolerance. As presented in this case, if provided with tools for crushing and mixing the medication, a successful escalation protocol can be completed at home without coordinating the help of a compound pharmacy.

Glecaprevir/Pibrentasvir and Renal Dysfunction in Deceased Donor Renal Transplantation: A Case Report.

BACKGROUND: Glecaprevir/pibrentasvir is a novel anti-hepatitis C virus (HCV) drug, and it is currently the only drug available for patients with severe renal impairment. Here we report a case with renal dysfunction after an administration of glecaprevir/pibrentasvir. CASE REPORT: The case was 66-year-old Japanese man who turned out to be HCV-positive 14 years ago at the time of his second deceased renal transplantation. He had no prior history of HCV treatment. HCV genotype was serogroup 1, and baseline HCV-RNA was 5.3 LOG IU/mL. Since glecaprevir/pibrentasvir became available, he started to take it for treatment of HCV. His immunosuppressants were tacrolimus (trough levels 4.3∼6.5 ng/mL) and 5 mg of prednisolone. His baseline renal function was serum creatinine (Cr) 2.1 mg/dL and urine protein (-). Shortly after starting glecaprevir/pibrentasvir, the serum Cr started to increase. Serum Cr reached up to 2.92 mg/dL and urine protein was (+) at day 36. Right pleural effusion was observed while cardiac function was normal. His liver function had been consistently normal. We concluded glecaprevir/pibrentasvir was the cause of renal dysfunction as no other drugs were added. Immediately after discontinuation of glecaprevir/pibrentasvir at day 36, serum Cr decreased to 1.9 mg/dL and urine protein turned negative at day 64. Although the patient completed a half course of glecaprevir/pibrentasvir, HCV-RNA turned to be negative at day 36. CONCLUSIONS: We experienced a case with renal dysfunction after the initiation of glecaprevir/pibrentasvir in deceased donor renal transplant recipient. Renal dysfunction caused by glecaprevir/pibrentasvir has not been reported so far.

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP ("flakka") Derivatives.

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).