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Ledipasvir-Sofosbuvir for 8 Weeks in Non-Cirrhotic Patients with Previously Untreated Genotype 1 HCV Infection ± HIV-1 Co-Infection.
Isakov, V, Gankina, N, Morozov, V, Kersey, K, Lu, S, Osinusi, A, Svarovskaia, E, Brainard, DM, Salupere, R, Orlova-Morozova, E, et al
Clinical drug investigation. 2018;(3):239-247
Abstract
UNLABELLED BACKGROUND AND OBJECTIVES The efficacy of < 12 weeks of hepatitis C virus (HCV) treatment in patients co-infected with HCV and human immunodeficiency virus type 1 (HIV-1) has not been established. We assessed the efficacy and safety of ledipasvir-sofosbuvir for 8 weeks in HCV mono-infected and HCV/HIV-1 co-infected patients. METHODS We enrolled patients mono-infected with genotype 1 HCV or co-infected with HCV and HIV-1 who were HCV treatment-naive and did not have cirrhosis. HCV/HIV-1 co-infected patients were either not receiving antiretroviral treatment and had a CD4 T-cell count > 500 cells/mm3 or were receiving a protocol-approved antiretroviral regimen for ≥ 8 weeks (or ≥ 6 months for abacavir-containing regimens) and had HIV-1 RNA < 50 copies/mL and a CD4 T-cell count > 200 cells/mm3. Patients received ledipasvir-sofosbuvir (90/400 mg) once daily for 8 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment discontinuation (SVR12). RESULTS The SVR12 rate was 100% (67/67) for HCV mono-infected patients and 97% (57/59) for HCV/HIV-1 co-infected patients. Two patients relapsed by the week 4 post-treatment visit. Overall, the most common adverse events were headache (52%) and upper abdominal pain (26%). There were no serious adverse events or treatment discontinuations due to adverse events. No HCV/HIV-1 co-infected patients receiving antiretroviral treatment experienced HIV virologic rebound, and no clinically meaningful changes in CD4 T-cell counts were observed in any co-infected patient. CONCLUSIONS Non-cirrhotic, treatment-naive patients with genotype 1 HCV mono-infection and HCV/HIV-1 co-infection achieved high rates of SVR12 with 8 weeks of treatment with ledipasvir/sofosbuvir. ClinicalTrials.gov identifier: NCT02472886.
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Continuous administration of ramosetron with patient-controlled analgesia after laparoscopic distal gastrectomy does not delay postoperative bowel function recovery: A prospective, randomized, double-blinded study.
Jung, HS, Huh, J, Kim, Y, Hong, SH, Lee, J
Medicine. 2018;(31):e11503
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Abstract
BACKGROUND Currently, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are indicated to slow gastrointestinal motility in the diarrhea-predominant subtype of irritable bowel syndrome. They are commonly used to prevent or treat postoperative nausea and vomiting (PONV) and opioid-induced nausea and vomiting (OINV). We conducted a prospective, randomized, double-blinded study to investigate whether the continuous administration of ramosetron, a selective 5-HT3 receptor antagonist, for preventing PONV and/or OINV after laparoscopic distal gastrectomy (LDG) might influence bowel function recovery. METHODS Patients scheduled to undergo LDG were randomly assigned to 1 of 3 treatment regimens: no prophylactic ramosetron (Group C); ramosetron 0.6 mg added to 2-day intravenous patient-controlled analgesia (IV-PCA) (Group R0.6); and ramosetron 1.2 mg added to 2-day IV-PCA (Group R1.2). Postoperative recovery profiles of bowel function, incidence of postoperative nausea/vomiting and pain, and perioperative data that affected bowel function recovery were evaluated. RESULTS Seventy-three patients completed the study protocol. Parameters associated with postoperative recovery of bowel function, such as time to first flatus, time to first bowel movement, time to first defecation, and time to commencement of soft diet, were not significantly different between the 3 groups. The incidence of nausea 2 to 24 hours after surgery was significantly lower in Group R0.6 (20.0%) and Group R1.2 (12.5%) than in Group C (45.8%) (P < .022). The ratio of complete response 2 to 24 hours after surgery was significantly higher in Group R0.6 (80.0%) and Group R1.2 (87.5%) than in Group C (54.2%) (P < .022). The incidence of retching 24 to 48 hours after surgery was significantly lower in Group R0.6 (0.0%) and Group R1.2 (4.2%) than in Group C (16.7%) (P < .043). CONCLUSION Continuous administration of ramosetron with patient-controlled analgesia to prevent PONV and OINV after LDG did not delay postoperative bowel function recovery.
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Pooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical Trials.
Krishnan, P, Pilot-Matias, T, Schnell, G, Tripathi, R, Ng, TI, Reisch, T, Beyer, J, Dekhtyar, T, Irvin, M, Xie, W, et al
Antimicrobial agents and chemotherapy. 2018;(10)
Abstract
Over 2,200 patients infected with hepatitis C virus (HCV) genotypes (GT) 1 to 6, with or without cirrhosis, who were treatment naive or experienced to interferon, ribavirin, and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight registrational phase 2 and 3 clinical studies. High rates of sustained virologic response at 12 weeks postdosing (SVR12) were achieved with a <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BPs) in NS3 at amino acid position 155 or 168 was low (<3%) in patients infected with GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid position 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients infected with GT1 to GT6, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates of ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% of patients and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when the recommended durations are used, allows for a pan-genotypic treatment option without the need for baseline resistance testing.
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Long-term Effects of Statins, Blood Pressure-Lowering, and Both on Erectile Function in Persons at Intermediate Risk for Cardiovascular Disease: A Substudy of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) Randomized Controlled Trial.
Joseph, P, Lonn, E, Bosch, J, Lopez, P, Zhu, J, Keltai, M, Dans, A, Reid, C, Khunti, K, Toff, W, et al
The Canadian journal of cardiology. 2018;(1):38-44
Abstract
BACKGROUND It is unclear whether modifying cholesterol, blood pressure, or both affect erectile dysfunction. Also, there are concerns that erectile dysfunction is worsened by common medications used to treat these risk factors. In this study, we evaluated the effect of: (1) cholesterol-lowering with a statin; (2) pharmacologic blood pressure reduction; and (3) their combination, on erectile function. METHODS A priori, this was a secondary analysis of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) randomized controlled trial. Men were 55 years of age or older with at least 1 cardiovascular risk factor. Erectile function was measured using the erectile function domain of the International Index of Erectile Function (IIEF-EF) score. Men with incomplete scores, or who did not engage in sexual activity, were excluded. Using a 2 × 2 factorial design, participants were randomized to rosuvastatin (10 mg/d) or placebo, and to candesartan with hydrochlorothiazide (HCTZ; 16 mg/12.5 mg/d; Cand+HCTZ) or placebo. Primary outcome was change in IIEF-EF from baseline to end of study follow-up. RESULTS Two thousand one hundred fifty-three men were included; mean age was 61.5 years, and mean follow-up was 5.8 years. Mean IIEF-EF score at baseline was 23.0 (SD 5.6). Least square mean change in the IIEF-EF score did not differ with rosuvastatin compared with placebo (-1.4; standard error [SE], 0.3 vs -1.5; SE, 0.3; P = 0.74), Cand+HCTZ compared with placebo (-1.6; SE, 0.3 vs -1.3; SE, 0.3; P = 0.10), or combination therapy compared with double placebo (P = 0.35). CONCLUSIONS Cholesterol-lowering using a statin, and blood pressure-lowering using Cand+HCTZ, either alone or in combination, do not improve or adversely affect erectile function.
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Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study.
Scheltens, P, Hallikainen, M, Grimmer, T, Duning, T, Gouw, AA, Teunissen, CE, Wink, AM, Maruff, P, Harrison, J, van Baal, CM, et al
Alzheimer's research & therapy. 2018;(1):107
Abstract
BACKGROUND PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. METHODS This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naïve at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses. RESULTS There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestinal and skin/subcutaneous tissue disorders. PQ912 treatment resulted in a significant reduction in glutaminyl cyclase activity, which resulted in an average target occupancy of > 90%. A significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of our Neuropsychological Test Battery was observed. The exploratory biomarker readouts, neurogranin for synaptic toxicity and YKL-40 as a marker of inflammation, appear to be sensitive enough to serve as efficacy markers in the next phase 2b study. CONCLUSIONS The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching > 50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study. TRIAL REGISTRATION Clinicaltrials.gov, NCT 02389413 . Registered on 17 March 2015.
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Effects of Lipid-Lowering and Antihypertensive Treatments in Addition to Healthy Lifestyles in Primary Prevention: An Analysis of the HOPE-3 Trial.
Dagenais, GR, Jung, H, Lonn, E, Bogaty, PM, Dehghan, M, Held, C, Avezum, A, Jansky, P, Keltai, M, Leiter, LA, et al
Journal of the American Heart Association. 2018;(15)
Abstract
BACKGROUND It is not clear whether the effects of lipid-lowering or antihypertensive medications are influenced by adherence to healthy lifestyle factors. We assessed the effects of both drug interventions in subgroups by the number of healthy lifestyle factors in participants in the HOPE-3 (Heart Outcomes Prevention Evaluation) trial. METHODS AND RESULTS In this primary prevention trial, 4 healthy lifestyle factors (nonsmoking status, physical activity, optimal body weight, and healthy diet) were recorded in 12 521 participants who were at intermediate risk of cardiovascular disease (CVD) and were randomized to rosuvastatin, candesartan/hydrochlorothiazide, their combination, or matched placebos. Median follow-up was 5.6 years. The outcome was a composite of CVD events. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. Participants with ≥2 healthy lifestyle factors had a lower rate of CVD compared with those with fewer factors (HR: 0.85; 95% CI, 0.73-1.00). Rosuvastatin reduced CVD events in participants with ≥2 healthy lifestyle factors (HR: 0.74; 95% CI, 0.62-0.90) and in participants with <2 factors (HR: 0.79; 95% CI, 0.61-1.01). Consistent results were observed with combination therapy (≥2 factors: HR: 0.74; 95% CI, 0.57-0.97; <2 factors: HR: 0.61; 95% CI, 0.43-0.88). Candesartan/hydrochlorothiazide tends to reduce CVD only in participants with <2 healthy lifestyle factors (HR: 0.78; 95% CI, 0.61-1.00). CONCLUSIONS Healthy lifestyles are associated with lower CVD. Rosuvastatin alone and combined with candesartan/hydrochlorothiazide is beneficial regardless of healthy lifestyle status; however, the benefit of antihypertensive treatment appears to be limited to patients with less healthy lifestyles. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.
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Efficacy and Safety of Lomitapide in Japanese Patients with Homozygous Familial Hypercholesterolemia.
Harada-Shiba, M, Ikewaki, K, Nohara, A, Otsubo, Y, Yanagi, K, Yoshida, M, Chang, Q, Foulds, P
Journal of atherosclerosis and thrombosis. 2017;(4):402-411
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Abstract
AIM: There is an unmet need in Japan for more optimal lipid-lowering therapy (LLT) for patients with homozygous familial hypercholesterolemia (HoFH) who respond inadequately to available drug therapies and/or apheresis, to achieve goals of low-density lipoprotein cholesterol (LDL-C) reduction by 50% or to <100 mg/dL. METHODS In this study, Japanese patients with HoFH on stable LLT and diet were treated with lomitapide, initiated at 5 mg/day and escalated to maximum tolerated dose (up to 60 mg/day) over 14 weeks. The primary efficacy endpoint was mean percentage change from baseline to Week 26 in LDL-C. Secondary endpoints included changes in other lipid parameters and safety throughout the 56-week study (including follow-up). RESULTS Nine patients entered the efficacy phase of the study and, of these, eight completed 56 weeks. Mean LDL-C was reduced by 42% (p<0.0001) at 26 weeks, from 199 mg/dL (95% CI: 149-250) at baseline to 118 mg/dL (95% CI: 70-166). A 50% reduction in LDL-C and LDL-C <100 mg/dL was achieved by five and six of nine patients, respectively, at 26 weeks. After 56 weeks, LDL-C was reduced by 38% (p=0.0032) from baseline. Significant reductions in non-HDL-C, VLDL-C, triglycerides, and apolipoprotein B were also reported at Week 26. There were no new safety signals and, similar to previous studies, gastrointestinal adverse events were the most common adverse events. CONCLUSION Lomitapide, added to ongoing treatment with other LLTs, was effective in rapidly and significantly reducing the levels of LDL-C and other atherogenic apolipoprotein B-containing lipoproteins in adult Japanese patients with HoFH.
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Comparison of Efficacy and Safety of Azilsartan and Olmesartan in Patients With Essential Hypertension.
Shiga, Y, Miura, SI, Motozato, K, Norimatsu, K, Yano, M, Hitaka, Y, Adachi, S, Kuwano, T, Inoue, K, Inoue, A, et al
International heart journal. 2017;(3):416-421
Abstract
Many patients still have high blood pressure (BP) after treatment with angiotensin II type 1 (AT1) receptor blockers (ARBs). We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective randomized clinical trial. Sixty-four hypertensive patients who were treated with ARBs other than azilsartan and olmesartan were enrolled in this study. We randomly assigned patients to changeover from their prior ARBs to either azilsartan or olmesartan, and followed the patients for 3 months. Systolic BP (SBP) in the azilsartan group was significantly decreased at 3 months, and diastolic BP (DBP) and pulse rate (PR) in the olmesartan group showed significant reductions after 3 months. There were no significant differences in ΔSBP, ΔDBP, or ΔPR (Δ = the value at 3 months minus the value at 0 months) between the groups. Serum levels of creatinine (Cr), uric acid (UA), and potassium (K) in the azilsartan group significantly increased after 3 months. While the changes in Cr, UA, and K were within the respective normal ranges, ΔSBP was positively associated with ΔCr in the azilsartan group. In conclusion, there was no difference in the depressor effects of azilsartan and olmesartan, and there were no serious changes in biochemical parameters with azilsartan and olmesartan.
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Hydrolysis mechanism of carbendazim hydrolase from the strain Microbacterium sp. djl-6F.
Lei, J, Wei, S, Ren, L, Hu, S, Chen, P
Journal of environmental sciences (China). 2017;:171-177
Abstract
The carbendazim (MBC) hydrolyzing enzyme gene was cloned and heterologously expressed in Escherichia coli BL21 (DE3) from a newly isolated MBC-degrading bacterium strain Microbacterium sp. strain djl-6F. High performance liquid chromatography-mass spectrometry (HPLC-MS) analysis revealed that purified MheI-6F protein catalyzes direct hydrolysis of MBC into 2-aminobenzimidazole (2-AB) with a high turnover rate and moderate affinity (Km of 6.69μmol/L and kcat of 160.88/min) without the need for any cofactors. The optimal catalytic condition of MheI-6F was identified as 45°C, pH7.0. The enzymatic activity of MheI-6F was found to be diminished by metal ions, and strongly inhibited by sodium dodecyl sulfate (SDS). Through generating amino acid mutations in MheI-6F, Cys16 and Cys222 were identified as the catalytic groups that are essential for the hydrolysis of MBC. This is the first report on the biodegradation of MBC at the enzymatice level.
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Voltage gated ion channels blockade is the underlying mechanism of BIMU8 induced cardiotoxicity.
Iqbal, SM, Lemmens-Gruber, R
Toxicology letters. 2017;:64-68
Abstract
BIMU8 is a 5-HT4a receptor agonist and used as an experimental drug to counteract opioid induced respiratory depression. In preliminary experiments serious disturbances in ECG were observed in anesthetized rabbits which prompted us to explore the underlying cause of BIMU8 induced abnormal changes in ECG recordings. Electrophysiological experiments were performed on HEK-293 cells expressing hERG, CaV1.2 and NaV1.5 ion channels. In whole-cell recordings BIMU8 effectively blocked these three channels, with IC50 values of 0.06±0.05, 1.46±0.26 and 4.66±0.58μM for hERG, NaV1.5 and CaV1.2, respectively. Additionally it also produced a hyperpolarizing shift of 3.27mV in half maximal activation and 12.87mV in fast inactivation of NaV1.5 channel. These experimental findings indicate that BIMU8 is a potent blocker of hERG, NaV1.5 and CaV1.2 cardiac ion channels thus revealing its proarrhythmic potential.