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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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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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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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4.
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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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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[Contribution of novel anticoagulants fondaparinux and dabigatran to venous thromboembolism prevention].
Antonijević, N, Kanjuh, V, Živković, I, Jovanović, L, Vukčević, M, Apostolović, M
Srpski arhiv za celokupno lekarstvo. 2015;(3-4):230-6
Abstract
The data that episodes and sequels of venous thromboembolism (VTE) are recorded in a significant percentage of patients receiving standard anticoagulants as VTE prophylaxis (unfractionated, low-molecular-weight heparin and vitamin K inhibitors) as well as the fact that these drugs have significant limitations and that they may cause serious side-effects in some patients indicate the need for the introduction of new anticoagulant drugs. Fondaparinux, a selective inhibitor of Factor Xa, administered following major orthopedic surgeries having a high risk for the development of VTE, is more efficient than enoxaparin sodium used in European and North-American approved doses. The increased incidence of major bleeding (excluding fatal) due to fondaparinux could be perhaps lowered by dosage reduction in patients with a mildly decreased creatinine clearance. Dabigatran, a peroral direct thrombin inhibitor, administered for VIE prophylaxis in elective hip and knee surgery, showed in to date studies the efficacv comparable (if dabiqatran is given in both dosage regimes of 150 mg and 220 mg daily) or superior (if dabigatran is given at a dose of 220 mg daily) to enoxaparin administered in European-approved doses, while North American-approved doses of enoxaparin were superior than dabigatran in VTE reduction. No significant differences in bleeding rates were determined in any of the study groups. We consider that the introduction of new anticoagulants, including fondaparinux and dabigatran, will contribute to the establishment of a better safety profile and efficacy, and will also enable adequate therapy individualization for each patient depending on his/hers clinical characteristics. The introduction of novel peroral anticoagulants will, inter alia, significantly contribute to improvement in the quality of life, release the patient from numerous limitations in nutrition, interreaction, frequent laboratory monitoring, and also significantly improve therapeutic predictability.
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7.
Advantages and limitations of the new anticoagulants.
Schulman, S
Journal of internal medicine. 2014;(1):1-11
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Abstract
During recent years, three new anticoagulants (dabigatran, rivaroxaban and apixaban) have been introduced to the market, probably with one more anticoagulant (edoxaban) in the next 2 years. This review is not intended to compare the efficacy and risks of these new agents, but rather to detail the advantages and limitations. The pharmacokinetic characteristics of these drugs have few drug and food interactions, predictable dose responses, and rapid onset and offset, thus resulting in simplified management of the patient requiring anticoagulant therapy. No routine laboratory monitoring is required. A somewhat unexpected, but exciting observation involving the new anticoagulants, is the uniform reduction in intracranial bleeding by one-half compared with warfarin. The potential limitations of the new anticoagulants include uncertainty regarding assessment of drug levels, safe drug levels for major surgery, management of major bleeding, renal dependence, multiple dose regimens, adherence in the absence of frequent monitoring and unknown, rare side effects that were not captured in the trials. This review should clarify some of these concerns.
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[The use of dabigatran for prevention of ischemic stroke in patiets with atrial fibrillation: special features of treatment in different clinical situations].
Shchendrygina, AA
Kardiologiia. 2014;(9):72-8
Abstract
Atrial fibrillation (AF) is extremely highly prevalent both in Russia and in the world. Ischemic stroke is a severe complication of AF often resulting in disability or death. Therefore important role is given to conduct of primary and secondary prevention of development of thromboembolic complications which is realized by means of administration of antithrombotic therapy. For a long time warfarin has been used for this purpose. However compliance of physicians to its prescription remains unsatisfactory. Recently novel oral anticoagulants (NOAC) have been elaborated. Among them dabigatran has longest period of use and has been recommended as the drug of choice for patients with non-valvular AF. At present time wide use of dabigatran is limited because of lack of clear understanding of some practical questions of the use of this drug. Aim of this review--to analyze available data on efficacy and safety of dabigatran, to study special features of its administration in various clinical situations.
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Meta-analysis of efficacy and safety of rivaroxaban compared with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation.
Aryal, MR, Ukaigwe, A, Pandit, A, Karmacharya, P, Pradhan, R, Mainali, NR, Pathak, R, Jalota, L, Bhandari, Y, Donato, A
The American journal of cardiology. 2014;(4):577-82
Abstract
Several studies have been conducted to study the efficacy and safety of rivaroxaban in the atrial fibrillation periprocedural ablation period with similar rates of thromboembolism and major bleeding risks compared with warfarin or dabigatran. We sought to systematically review this evidence using pooled data from multiple studies. Studies comparing rivaroxaban with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation were identified through electronic literature searches of MEDLINE, EMBASE, clinicaltrials.gov, and the Cochrane library up to March 2014. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 3,575 patients, thromboembolism (composite of stroke, transient ischemic attack, and systemic and pulmonary emboli) occurred in 3 of 789 patients (0.4%) in the rivaroxaban group and 10 of 2,786 patients (0.4%) in the warfarin group (RR 0.71, 95% CI 0.26 to 1.96, I(2) = 0%, p = 0.51). Major hemorrhage occurred in 9 of 749 patients (1.2%) in the rivaroxaban group and 22 of 975 patients (2.3%) in the warfarin group (RR 0.49, 95% CI 0.24 to 1.02, I(2) = 0%, p = 0.06). Furthermore, direct efficacy and safety comparisons between rivaroxaban and dabigatran showed nonsignificant differences in rates of thromboembolism (0.5% vs 0.4%, respectively, RR 1.12, 95% CI 0.25 to 4.99, I(2) = 0%, p = 0.88) and major bleeding (1.0% vs 1.6%, respectively, RR = 0.71, 95% CI 0.16 to 3.15, I(2) = 22%, p = 0.66). In conclusion, our study suggests that patients treated with rivaroxaban during periprocedural catheter ablation have similar rates of thromboembolic events and major hemorrhage. Similar results were seen in direct comparisons between dabigatran and rivaroxaban.
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Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis.
Providência, R, Albenque, JP, Combes, S, Bouzeman, A, Casteigt, B, Combes, N, Narayanan, K, Marijon, E, Boveda, S
Heart (British Cardiac Society). 2014;(4):324-35
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Abstract
BACKGROUND Dabigatran etexilate, a new thrombin inhibitor, has been shown to be comparable to warfarin in patients with atrial fibrillation (AF). However, there is a limited body of evidence on the efficacy and safety of using dabigatran among patients undergoing AF catheter ablation. OBJECTIVE A random effects meta-analysis was performed of controlled trials comparing dabigatran and warfarin in paroxysmal/persistent AF patients undergoing catheter ablation. METHODS Data sources included Medline, Embase, and Cochrane (from inception to April 2013). Three independent reviewers selected studies comparing warfarin to dabigatran. Descriptive and quantitative information was extracted from each selected study, regarding periprocedural all cause mortality, thromboembolic events and major bleeding, as well as modalities of periprocedural anticoagulation bridging. RESULTS After a detailed screening of 228 search results, 14 studies were identified enrolling a total of 4782 patients (1823 treated with dabigatran and 2959 with warfarin). No deaths were reported. No significant differences were found between patients treated with dabigatran and warfarin as regards thromboembolic events (0.55% dabigatran vs 0.17% warfarin; risk ratios (RR)=1.78, 95% CI 0.66 to 4.80; p=0.26) and major bleeding (1.48% dabigatran vs 1.35% warfarin; RR=1.07, 95% CI 0.51 to 2.26; p=0.86). No difference was found between the 110 mg twice daily and 150 mg twice daily dabigatran dosages concerning major bleeding (0% vs 1.62%, respectively; RR=0.19, 95% CI 0.01 to 3.18; p=0.25) and thromboembolism (0% vs 0.40%, respectively; RR=0.72, 95% CI 0.04 to 12.98; p=0.82). CONCLUSIONS In the specific setting of AF catheter ablation, this first pooled analysis suggests that patients treated with dabigatran have a similar incidence of thromboembolic events and major bleeding compared to warfarin, with low event rates overall.