Clinical Drug Investigation

Proton Pump Inhibitor Therapy and Hepatic Encephalopathy Risk in Cirrhotic Patients: A Systematic Review with Meta-analysis Abstract Background and Objectives Use of proton pump inhibitor (PPI) in patients with cirrhosis has been linked to the development of hepatic encephalopathy (HE). Little is known about the incidence rate of HE due to PPI therapy. We conducted a meta-analysis to explore the association between PPI use and the incidence of HE. Methods We searched PubMed, EMBASE databases and The Cochrane Library from inception to March 2019 for studies describing the association between PPI exposure and incidence of HE; we identified studies that provided the adjusted estimates of odds ratio (OR)/relative ratio (RR)/hazard ratio (HR), and the pooled RRs on the incidence of HE were calculated. Summary estimates were calculated using random effects models. Results We analyzed data from 10 eligible studies; PPI users had an increased risk of HE compared with non-PPI user, with a pooled RR of 1.81 (95% CI 1.58–2.06), with notable heterogeneity (I2 = 85.2%, p <0.0001). In subgroup of considering the incidence of HE after yrans-jugular intrahepatic portosystemic shunt (TIPS), the pooled RR was 3.09 (95% CI 2.23–4.27), with no statistical heterogeneity (I2 = 0.0%, p = 0.484); another subgroup analysis was conducted for the complication of the enrolled patients with the status of ascites, the pooled RR was 1.39 (95% CI 1.10–1.77). The result of statistical heterogeneity was low (I2 = 46.2%, p = 0.156). Conclusions We found PPI therapy increased the risk of HE in cirrhotic patients, and higher risk was found in post-operative TIPS. Additional studies are warranted to inform clinical decision making.

Determinants of Antithrombotic Treatment for Atrial Fibrillation in Octogenarians: Results of the OCTOFA Study Abstract Background and Objective Atrial fibrillation, the most frequent form of arrhythmia, affects 5–15% individuals aged > 80 years. Stroke is a major risk for atrial fibrillation patients. The benefits of anticoagulant therapy clearly outweigh the risk of hemorrhage, even in the elderly. Despite the efficacy of warfarin, many eligible patients receive no prophylactic antithrombotic therapy. New generation oral anticoagulants compare favorably with vitamin K antagonists in the prevention of thromboembolic events and hemorrhage. These new agents are likely to influence the prescribing habits of anticoagulants in atrial fibrillation. The aim of this study to investigate both the frequency and the determining factors of anticoagulant prescriptions in AF patients aged ≥ 80 years and followed up by private-practice cardiologists in France. Methods The OCTOFA (Atrial Fibrillation in Octogenarians) Study assessed the anticoagulant prescribing habits of cardiologists in France. The volunteer cardiologists recruited all consecutive patients fulilling the inclusion criteria. Results Between June 2013 and September 2016, 89 cardiologists recruited 738 eligible patients: age ≥ 80 years, non-valvular atrial fibrillation, no other compelling indication for anticoagulation therapy, no recent acute coronary syndrome or stroke. Most (90.7%) patients were on oral anticoagulant therapy: vitamin K antagonist or non-vitamin K antagonist oral anticoagulants, low molecular weight heparin (1.4%), aspirin (5.7%), and no antithrombotic treatment (2.2%). Patients on vitamin K antagonists were older (p < 0.001), had lower renal function (p = 0.033), and had a more frequent history of myocardial infarction (p < 0.001), heart failure (p = 0.001), peripheral artery disease (p = 0.033), major hemorrhage (p = 0.025), and falls (p = 0.045). Four determining factors of anticoagulant prescriptions were statistically significant: high CHA2DS2-VASc score (p < 0.001), high HAS-BLED score (p < 0.001), age > 90 years (p = 0.001), and moderate/severe cognitive impairment (p = 0.002). Conclusions Most private-practice cardiologists prescribe anticoagulant treatment according to current guidelines in elderly atrial fibrillation patients. Non-vitamin K antagonist oral anticoagulants represent a significant proportion of prescriptions.

Rifamycin SV MMX ® : A Review in the Treatment of Traveller's Diarrhoea Abstract Rifamycin SV MMX® (Aemcolo™; Relafalk™) is a novel oral formulation of the antibacterial rifamycin SV that uses MultiMatrix (MMX®) technology to enable colonic delivery. Specifically, the active ingredient (rifamycin SV) is released throughout the colon, where it acts locally in the intestinal lumen; systemic absorption is minimal. Rifamycin SV MMX® exhibits antibacterial activity against a broad spectrum of clinically relevant enteropathogens and is available in the EU and the USA for the treatment of adults with traveller's diarrhoea. In two multinational, phase III studies, rifamycin SV MMX® (400 mg twice daily for 3 days) effectively shortened the duration of non-dysenteric traveller's diarrhoea in adults, being significantly more effective than placebo and noninferior to ciprofloxacin in reducing median time to last unformed stool. As expected (given its poor systemic absorption), rifamycin SV MMX® was well tolerated in this patient population, with the overall incidence of treatment-emergent adverse events generally similar to those of placebo and ciprofloxacin. Current evidence indicates that twice-daily rifamycin SV MMX® is an effective and well tolerated treatment option for shortening the duration of non-dysenteric traveller's diarrhoea in adults.

Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel Na V 1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers Abstract Background and Objective Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that NaV1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel NaV1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects. Methods This phase I, randomized, double-blind, placebo-controlled study assessed GDC–0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2–270 mg (seven cohorts) and 45–540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15–540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined. Results Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred. Conclusion GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.

Inflammatory Bowel Disease Onset During Secukinumab Treatment: Real Concern or Just an Expression of Dysregulated Immune Response? Abstract Background Up to December 2018, eight cases of new-onset inflammatory bowel disease (IBD) were reported in the literature in patients being treated with secukinumab, an interleukin-17A antagonist prescribed for dermatologic or rheumatologic indications. The duration of secukinumab treatment ranged from a single administration to 12 months of treatment. Objective The aim of our investigation was to estimate the cumulative incidence of new-onset IBD in patients treated with secukinumab for either dermatologic or rheumatologic indications. Methods We carried out a survey among the dermatology and rheumatology centres in the Sicilian region (Italy) in order to identify the number of patients treated with secukinumab in the previous 24 months (November 2016–November 2018), and to understand how many of these patients eventually developed IBD after the start of secukinumab therapy. Results Overall, four cases of IBD during secukinumab treatment were identified, with higher variability in time to onset compared with what has been previously reported, i.e. from 1 month to 5 years of secukinumab exposure. Overall, 434 patients were treated with secukinumab in Sicily between November 2016 and November 2018, and approximately 1% of these patients developed new-onset IBD. Conclusions Careful clinical examination of patients with respect to possible susceptibility to IBD prior to secukinumab therapy is advised.

Addendum to: Relative and Absolute Risk of Tendon Rupture with Fluoroquinolone and Concomitant Fluoroquinolone/Corticosteroid Therapy: Population-Based Nested Case–Control Study

Paediatric Integrase Inhibitor Use in a Real-Life Setting: A Single-Centre Cohort Experience 2009–2018 Abstract Background and Objective Integrase strand transfer inhibitors (INSTIs) have become the preferred first-line antiretroviral therapy in adults. There is paucity of published data on their use in children outside of clinical trials, particularly long-term safety and tolerability. This study aimed to describe INSTI use including the number of, and reasons for INSTI discontinuation. Methods We conducted a retrospective cohort analysis by database and electronic record review of children aged under 18 years with perinatally acquired human immunodeficiency virus who started INSTI-based antiretroviral therapy between May 2009 and March 2018, in a single tertiary centre. Results Fifty-six INSTI-based regimens were prescribed in 54 children, 64.9% from 2015 onwards. Twenty-one of 56 (37.5%) regimens commenced with raltegravir, 29 (51.8%) with dolutegravir and six (10.7%) with elvitegravir. The median age at the start of treatment was 15 years (interquartile range 13.5–16.4) with a median duration of INSTI-antiretroviral therapy of 1.65 years (range 0.01–8.8). Twenty-four children had a detectable viral load at the start INSTI therapy; 20 (83%) achieving viral suppression in a median of 26 days (interquartile range 19.5–34.5). There were 26 discontinuations of INSTI-based antiretroviral therapy after a median of 183 days; 9/26 because of adverse events. Four of nine adverse events were attributed to INSTI use, all in patients taking dolutegravir and the adverse events were neuropsychiatric and gastrointestinal in nature. Conclusions INSTI-based regimens were generally efficacious and well tolerated in this paediatric cohort, with 4/26 discontinuations due to INSTI-attributed adverse events. Further post-marketing surveillance of INSTI use in children is warranted.

Pharmacokinetics, Safety and Tolerability of Chiglitazar, A Novel Peroxisome Proliferator-Activated Receptor (PPAR) Pan-Agonist, in Healthy Chinese Volunteers: A Phase I Study Abstract Background and Objectives Chiglitazar is a novel configuration-restricted non-thiazolidinedione peroxisome proliferator-activated receptor pan-agonist currently in the Phase III clinical development stage for type 2 diabetes mellitus patients. The objective of this Phase I study was to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of chiglitazar tablets taken orally and the effect of food on its pharmacokinetics in healthy Chinese subjects. Methods A single-centre, open-label, randomised, two-stage Phase I study was carried out. In the first-stage study, we evaluated a single dose of 8, 16, or 32 mg, and multiple doses of 16 mg, taken once daily for 9 days. The effect of food consumption was also studied in this stage. In the second-stage study, a greater range of single doses (24, 48 or 72 mg) were further evaluated. Pharmacokinetics, safety and tolerability profiles were assessed at each study stage. Results After a single oral dose of chiglitazar, at doses ranging from 8 to 72 mg, the maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were proportionally increased (165–1599 ng/mL for the mean Cmax and 1356–12,584 ng·h/mL for the mean AUC0−t), with low inter-subject variability. There were no significant changes in the mean terminal phase half-life (t1/2), which ranged from 9.0 to 11.9 h, and the clearance and volume of distribution were similar for all evaluated doses. The results from the examination of multiple dose of 16 mg once daily for nine consecutive days showed that a steady-state condition was achieved by Day 6. There was no apparent accumulation of chiglitazar observed at Day 9, as compared with the first administration. While food increased the AUC0−t of chiglitazar by about 13%, there were no effects on other parameters, including Cmax, Tmax and t1/2. There were no serious or severe adverse events observed in the single- or multiple-dose studies. Conclusions Chiglitazar tablets showed a good dose-dependent linear pharmacokinetic profile in the dose range of 8–72 mg. There was no accumulation after multiple daily administration of chiglitazar at a dose of 16 mg.  High-fat/calorie food increased the absorption of the drug, but there were no significant changes in exposure and other pharmacokinetic parameters. Chiglitazar was safe and well tolerated in healthy Chinese subjects at the dose levels and administration regimens evaluated.

Sodium-Glucose Co-Transporter 2 Inhibitors Compared with Sulfonylureas in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A Meta-Analysis of Randomized Controlled Trials Abstract Background and Objective When metformin is insufficient for patients with type 2 diabetes mellitus (T2DM), the optimal adjunctive therapy is unclear. This meta-analysis was to compare the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors with sulfonylureas (SUs) as second-line therapy in patients with T2DM inadequately controlled on metformin. Methods We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials comparing SGLT2 inhibitors with SUs as add-on to metformin. Our primary endpoints were glycemic control, hypoglycemia, and change in weight. We assessed pooled data using a random-effects model. Results Five trials involving 4300 participants were included in our meta-analysis. Compared with SUs, SGLT2 inhibitors led to no significant reduction in changes in HbA1c (mean difference [MD] − 0.06; 95% confidence interval [CI] [− 0.12, 0.08]), but less hypoglycemia as add-on to metformin (odds ratio [OR] 0.12; 95% CI [0.07, 0.21]). SGLT2 inhibitors led to a reduction in weight by about 3.5 kg; however, SUs caused a gain in weight by about 1 kg (MD − 4.39; 95% CI [− 4.64, − 4.14]). SGLT2 inhibitors also showed a reduction in blood pressure, but increased the incidence of genital tract infections compared with SUs. Interestingly, subgroup analysis by duration of interventions showed that reduction of HbA1c from baseline was similar between the two groups at 12–52 weeks, but SGLT2 inhibitors led to a greater reduction in HbA1c at 104–208 weeks. Conclusions Despite similar glycemic efficacy in a relatively short term, SGLT2 inhibitors are more effective in the longer term than SUs as add-on to metformin. In addition, SGLT2 inhibitors produce less hypoglycemic events and lead to greater reductions in weight and blood pressure compared with SUs.

Prediction Model for Significant Bleeding in Patients with Supratherapeutic International Normalized Ratio After Oral Administration of Warfarin Abstract Background and Objective The use and range of indications for anticoagulation therapy are steadily growing. The objective of this study was to develop a scoring model to predict the occurrence of significant bleeding in patients taking warfarin with a supra-therapeutic international normalized ratio. Methods Data were collected from the medical records of patients taking warfarin with an international normalized ratio > 3.5. The characteristics of bleeding episodes and the need for transfusion of blood products were recorded. Regression models were constructed to predict the occurrence of significant bleeding (requiring a transfusion of more than 2 units of packed red blood cells, intrapericardial or intracranial hemorrhage). The predictive values of previously published scores (ATRIA: anemia, hypertension, severe renal disease, age ≥ 75 years, or prior bleeding history; and ORBIT: old, reduced hemoglobin, bleeding history, kidney insufficiency or antiplatelet treatment) were compared with our New Bleeding Score (NBLDSCOR); the areas under the curve for the receiver-operating characteristic plots were compared using a non-parametric DeLong test. Results Significant bleeding was reported in 87 out of 389 admitted patients. With an area under the curve of 0.736 ± 0.032, NBLDSCOR was the best predictor of significant bleeding in this population. Neither ATRIA nor ORBIT was a good predictor of significant bleeding, where the area under the curve for the receiver-operating characteristic plot for ATRIA was 0.654 ± 0.034 and for ORBIT was 0.604 ± 0.033. The predictive power of NBLDSCOR was superior to ATRIA and ORBIT (p < 0.001), while there was no meaningful difference in the predictive powers of ATRIA and ORBIT. Conclusion The NBLDSCOR including age, negative Rhesus factor, low hemoglobin, renal impairment, and concomitant peptic ulcer and disseminated cancer is a good predictor of significant bleeding in this patient population.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com