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1.
Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.
Singh, AD, Maitra, S, Singh, N, Tyagi, P, Ashraf, A, Kumar, R, Shalimar,
Alimentary pharmacology & therapeutics. 2020;(5):490-504
Abstract
BACKGROUND The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear. AIM: To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen. METHODS The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019. The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies. RESULTS After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I2 = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients. CONCLUSION Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients.
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2.
Untargeted metabolomics study and pro-apoptotic properties of B-norcholesteryl benzimidazole compounds in ovarian cancer SKOV3 cells.
Gan, C, Huang, X, Wu, Y, Zhan, J, Zhang, X, Liu, Q, Huang, Y
The Journal of steroid biochemistry and molecular biology. 2020;:105709
Abstract
The current study aims to evaluate the antiproliferative activity of B-norcholesteryl benzimidazole compounds in human ovarian cancer cells (SKOV3). Our experimental data indicates that the tested compounds can induce apoptosis in SKOV3 cells, block S-phase growth, and decrease mitochondrial membrane potential. Western blot results showed that B-norcholesteryl benzimidazole compounds (1 and 2) induced apoptosis in SKOV3 cells via activation of the mitochondrial signaling pathway. Following SKOV3 cells treatment with compounds 1 and 2, the cell metabolism was assessed using the UHPLC-QE-MS (Ultra High Performance Liquid Chromatography-Q Exactive Orbitrap- Mass Spectrometry) non-target metabolomics analysis method. The results showed 10 metabolic pathways that mediated the effects of compound 1, including arginine and proline metabolism; alanine, aspartate, and glutamate metabolism; histidine metabolism; D-glutamine and D-glutamine and D-glutamate metabolism; cysteine and methionine metabolism; aminoacyl-tRNA biosynthesis; purine metabolism; Glutathione metabolism; D-Arginine and D-ornithine metabolism; and Nitrogen metabolism. From the perspective of metabolomics, compound 1 inhibits intracellular metabolism, protein synthesis, and slows down energy metabolism in SKOV3 cells. These changes result in the inhibition of proliferation and signal transduction, abrogate invasive and metastatic properties, and induce apoptosis, thus, exerting anti-tumor effects. Application of compound 2 altered activation of metabolic pathways in SKOV3 cells. The main metabolic pathways involved were glycerophospholipid metabolism; arginine and proline metabolism; purine metabolism; glycine, serine, and threonine metabolism; and ether lipid metabolism. The metabolic pathway with the greatest impact and the deepest enrichment was the glycerophospholipid metabolism. In conclusion, compound 2 inhibits proliferation of SKOV3 cells by interfering with glycerate metabolism, which plays a major role in regulation of cell membrane structure and function. Additionally, compound 2 can inhibit the invasion and metastasis of SKOV3 cells and induce apoptosis via interfering with the metabolism of arginine and proline.
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3.
Therapeutic Options for Homozygous Familial Hypercholesterolemia: The Role of Lomitapide.
Giammanco, A, Cefalù, AB, Noto, D, Averna, MR
Current medicinal chemistry. 2020;(23):3773-3783
Abstract
BACKGROUND Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the Microsomal Triglyceride Transfer Protein (MTP) approved as a novel drug for the management of Homozygous Familial Hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine. AIMS The present review aims at summarizing the recent knowledge on lomitapide in the management of HoFH. RESULTS The efficacy and safety of lomitapide have been evaluated in several trials and it has been shown a reduction of the plasma levels of Low-Density Lipoprotein Cholesterol (LDL-C) by an average of more than 50%. Although the most common side effects are gastrointestinal and liver events, lomitapide presents generally with a good tolerability and satisfactory patients compliance. Recently, in Europe, to evaluate the long-term safety and efficacy of lomitapide, the LOWER registry (ClinicalTrials.gov Identifier: NCT02135705) has been established in order to acquire informations on HoFH lomitapidetreated patients from "real life" clinical practice. Furthermore, the observation that lomitapide decreases triglyceride levels may be considered for patients affected by severe forms of hypertriglyceridemia who undergo recurrent episodes of pancreatitis and are poor responders to conventional treatment. CONCLUSION Lomitapide represents an innovative and efficacious drug for the treatment of HoFH. Longterm safety data, treatment of pediatric and pregnant HoFH patients and management of severe hypertriglyceridemia still require further investigations.
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4.
Successful treatment of chronic hepatitis C virus infection with crushed glecaprevir/pibrentasvir administered via a percutaneous endoscopic gastrostomy tube: case report and review of the literature.
Tanaka, Y, Tateishi, R, Koike, K
Clinical journal of gastroenterology. 2019;(6):588-591
Abstract
Glecaprevir (GLE)/pibrentasvir (PIB) is a direct-acting antiviral regimen approved for patients infected with hepatitis C virus. No data are available on the safety and efficacy of this regimen when crushed and administered through a percutaneous endoscopic gastrostomy (PEG) tube. Here, we report a patient who successfully achieved a sustained viral response after treatment with GLE/PIB administered via a PEG tube. A 41-year-old female with chronic hepatitis C viral infection was referred to our department for treatment. She had a history of spina bifida and hydrocephalus, and she received a PEG tube for nutrition and medication due to an aftereffect of hydrocephalus. She received crushed GLE/PIB treatment through a PEG tube for 8 weeks and achieved a sustained viral response 12, without any treatment-related severe adverse events. This is the first documented case treated with GLE/PIB administered through a PEG tube. Based on this case report and a review of the literature, we discuss the safety and efficacy of direct-acting antiviral treatment via a PEG tube.
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Efficacy and Safety of a Fixed-Dose Combination of Candesartan and Rosuvastatin on Blood Pressure and Cholesterol in Patients With Hypertension and Hypercholesterolemia: A Multicenter, Randomized, Double-Blind, Parallel Phase III Clinical Study.
Cho, KI, Kim, BH, Park, YH, Ahn, JC, Kim, SH, Chung, WJ, Kim, W, Sohn, IS, Shin, JH, Kim, YJ, et al
Clinical therapeutics. 2019;(8):1508-1521
Abstract
PURPOSE The aim of this study was to evaluate the blood pressure-lowering and cholesterol-lowering effects of a fixed-dose combination therapy using candesartan (CND)/rosuvastatin (RSV) compared with CND or RSV monotherapy in patients with hypertension and hypercholesterolemia. METHODS This study was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 394 patients were screened. After a 4-week run-in period, 219 of these patients with hypertension and primary hypercholesterolemia were randomized. Patients received 1 of 3 regimens for 8 weeks: (1) CND 32 mg/RSV 20 mg, (2) RSV 20 mg, or (3) CND 32 mg. The primary outcome variables were changes in the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the percentage changes in LDL-C from baseline to the drug treatment at 8 weeks. The secondary outcome variables were percentage changes of total cholesterol, triglycerides, HDL-C, non-HDL-C, apolipoprotein B, apolipoprotein A-I, high-sensitivity C-reactive protein, and glucose metabolic indices, including percentage changes of the homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and hemoglobin A1c. Tolerability of combination therapy was compared with other monotherapy groups. FINDINGS The percentage changes of LDL-C were -48.6% (from 157.2 to 80.1 mg/dL) in the RSV group and -49.8% (from 160.2 to 78.9 mg/dL) in the CND/RSV group from baseline to the end of 8 weeks of treatment. Mean SBP and DBP were significantly decreased in the CND/RSV and CND groups after 8 weeks (P < 0.001 for all); however, no significant differences were found between the 2 groups. Total cholesterol levels, triglycerides, non-HDL-C, and apolipoprotein B were significantly reduced in the CND/RSV and RSV groups, with no significant differences between the groups compared with the CND group (P < 0.001 for all). The percentage changes of HOMA-IR, adiponectin, and hemoglobin A1c had no significant differences between the combination groups and monotherapy groups. However, in a 2-sample t test, HOMA-IR was significantly decreased in the CND/RSV group compared with the RSV group in nondiabetic patients (mean [SD] percentage change of HOMA-IR, -8.7% [37.6%] vs 17.1% [53.1%]; P = 0.048). There were no significant differences in metabolic indices between the diabetic groups. Adverse events in the CND/RSV group were similar to those in the monotherapy group. IMPLICATIONS Once-daily fixed-dose combination therapy with CND/RSV is an effective, tolerable, convenient treatment option for patients with essential hypertension and hypercholesteremia. ClinicalTrials.gov identifier: NCT02770261.
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6.
Effects of combination of mizolastine and proteoglycan on chronic urticaria: a randomized controlled trial.
Xiong, X, Song, L, Chen, F, Ma, X
Archives of dermatological research. 2019;(10):801-805
Abstract
The present study aimed to observe the therapeutic effect of combined mizolastine and proteoglycan in chronic urticaria. The patients were randomly divided into the treatment group (n = 56) and the control group (n = 44). The treatment group was medicated with calcium gluconate (10 mg/ time, 1 time/day), vitamin D3 (intramuscular 10 mg/time, 1 time/week), mizolastine (10 mg/time, 1 time/day), and proteoglycan (1.2 g/time, 3 times/day), while the control group was administered with the same drugs except proteoglycan for 4 weeks. After treatment with combined mizolastine and proteoglycan, therapeutic effect with symptoms decline index (SDI) more than 60% was significant different (44 vs. 24, p = 0.000973) and the relapse rate after 2 months was significantly lower (17.9% vs. 38.6%, p = 0.0202). Using ELISA, we found that the IFN-γ (37.88 ± 4.27 pg/mL vs. 21.91 ± 4.95 pg/mL, p = 0.028) levels were specifically increased in the experiment group. The combination of mizolastine plus proteoglycan is effective in treating chronic urticaria with better therapeutic effect and lower relapse rate through promoting IFN-γ production.
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7.
Lomitapide and Mipomersen-Inhibiting Microsomal Triglyceride Transfer Protein (MTP) and apoB100 Synthesis.
Blom, DJ, Raal, FJ, Santos, RD, Marais, AD
Current atherosclerosis reports. 2019;(12):48
Abstract
PURPOSE OF REVIEW The goal of this review is to evaluate the role of inhibiting the synthesis of lipoproteins when there is no or little residual LDL-receptor function as in patients with homozygous familial hypercholesterolaemia. Lomitapide is administered orally once a day while mipomersen is given by subcutaneous injection once a week. Lomitapide inhibits microsomal triglyceride transfer protein while mipomersen is an antisense oligonucleotide directed against apoB100. RECENT FINDINGS The pivotal registration trials for lomitapide and mipomersen were published in 2013 and 2010, respectively. More recently published data from extension trials and cohort studies provides additional information on long-term safety and efficacy. The mean LDL cholesterol reduction was 50% with lomitapide in its single-arm open-label registration trial. Mipomersen reduced LDL cholesterol by approximately 25% in its double-blind, placebo-controlled registration study. Both lomitapide and mipomersen therapy are associated with variable increases in hepatic fat content. The long-term safety of increased hepatic fat content in patients receiving these therapies is uncertain and requires further study. Both drugs may cause elevated transaminase in some patients, but no cases of severe liver injury have been reported. Lomitapide may also cause gastrointestinal discomfort and diarrhoea, especially if patients consume high-fat meals and patients are advised to follow a low-fat diet supplemented with essential fatty acids and fat-soluble vitamins. Mipomersen may cause injection-site and influenza-like reactions. The effect of lomitapide and mipomersen on cardiovascular outcomes has not been studied, but circumstantial evidence suggests that the LDL cholesterol lowering achieved with these two agents may reduce cardiovascular event rates.
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8.
Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer.
Palumbo, A, Lau, G, Saraceni, M
The Annals of pharmacotherapy. 2019;(2):178-185
Abstract
OBJECTIVE To review the pharmacology, efficacy, and safety of the cyclin-dependent kinase (CDK) inhibitor, abemaciclib, in the treatment of advanced or metastatic breast cancer (MBC). DATA SOURCES Relevant information was identified through a MEDLINE/PubMed (January 2000 to June 2018) literature search. The new drug application, prescribing information, and abstracts and posters from scientific meetings were also reviewed. STUDY SELECTION/DATA EXTRACTION The literature search was limited to human studies published in the English language. Phase 1, 2, and 3 studies evaluating the pharmacology, efficacy, or safety of abemaciclib for breast cancer were included. DATA SYNTHESIS Abemaciclib is an oral, potent, small molecule inhibitor of CDK4 and CDK6 activity, which blocks retinoblastoma tumor suppressor protein phosphorylation and thereby prevents progression through the cell cycle. Three major clinical trials, MONARCH 1, 2, and 3, established the efficacy and safety of abemaciclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or MBC. In these trials, response rates were promising, ranging from 19.7% to 59%, and median progression-free survival was significantly prolonged over the control arm in 2 of the trials. Common adverse effects included diarrhea, neutropenia, nausea, abdominal pain, infections, and fatigue. Relevance to Patient Care and Clinical Practice: Although no head-to-head studies have been completed between the CDK4/6 inhibitors, abemaciclib may be an attractive option because of its continuous dosing and ability to be used as monotherapy. CONCLUSIONS Abemaciclib is an effective and well-tolerated treatment for HR-positive, HER2-negative advanced or metastatic breast cancer.
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Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study.
Bosch, J, O'Donnell, M, Swaminathan, B, Lonn, EM, Sharma, M, Dagenais, G, Diaz, R, Khunti, K, Lewis, BS, Avezum, A, et al
Neurology. 2019;(13):e1435-e1446
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Abstract
OBJECTIVE To assess whether long-term treatment with candesartan/hydrochlorothiazide, rosuvastatin, or their combination can slow cognitive decline in older people at intermediate cardiovascular risk. METHODS The Heart Outcomes Prevention Evaluation-3 (HOPE-3) study was a double-blind, randomized, placebo-controlled clinical trial using a 2 × 2 factorial design. Participants without known cardiovascular disease or need for treatment were randomized to candesartan (16 mg) plus hydrochlorothiazide (12.5 mg) or placebo and to rosuvastatin (10 mg) or placebo. Participants who were ≥70 years of age completed the Digit Symbol Substitution Test (DSST), the modified Montreal Cognitive Assessment, and the Trail Making Test Part B at baseline and study end. RESULTS Cognitive assessments were completed by 2,361 participants from 228 centers in 21 countries. Compared with placebo, candesartan/hydrochlorothiazide reduced systolic blood pressure by 6.0 mm Hg, and rosuvastatin reduced low-density lipoprotein cholesterol by 24.8 mg/dL. Participants were followed up for 5.7 years (median), and 1,626 completed both baseline and study-end assessments. Mean participant age was 74 years (SD ±3.5 years); 59% were women; 45% had hypertension; and 24% had ≥12 years of education. The mean difference in change in DSST scores was -0.91 (95% confidence interval [CI] -2.25 to 0.42) for candesartan/hydrochlorothiazide compared with placebo, -0.54 (95% CI -1.88 to 0.80) for rosuvastatin compared with placebo, and -1.43 (95% CI -3.37 to 0.50) for combination therapy vs double placebo. No significant differences were found for other measures. CONCLUSIONS Long-term blood pressure lowering with candesartan plus hydrochlorothiazide, rosuvastatin, or their combination did not significantly affect cognitive decline in older people. CLINICALTRIALSGOV IDENTIFIER NCT00468923. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that for older people, candesartan plus hydrochlorothiazide, rosuvastatin, or their combination does not significantly affect cognitive decline.
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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.