Omega-3 Carboxylic Acids (Epanova®): A Review of Its Use in Patients with Severe Hypertriglyceridemia

Omega-3 carboxylic acids (Epanova^®) [OM3-CA] is the first free fatty acid form of long-chain marine omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid being the most abundant) to be approved by the US FDA as an adjunct to diet to lower triglyceride levels in patients with severe hypertriglyceridemia (≥500 mg/dL). Oral OM3-CA has greater bioavailability than ethyl ester forms of omega-3 and, unlike omega-3 acid ethyl esters, does not require co-ingestion of a high-fat meal, as it does not need pancreatic enzyme activity for absorption. In the 12-week EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial, OM3-CA 2 or 4 g/day significantly reduced serum triglyceride levels relative to placebo. Other lipid parameters, including non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, and very low-density lipoprotein cholesterol (VLDL-C) levels, were also reduced significantly with OM3-CA relative to placebo. Low-density lipoprotein cholesterol levels were increased significantly with OM3-CA relative to placebo; however, these increases were not accompanied by increases in the circulating concentrations of non-HDL-C, VLDL-C, or apolipoprotein B. OM3-CA was generally well tolerated in this study, with most adverse events being of mild or moderate severity. Although additional comparative data are needed to position OM3-CA with respect to other formulations of omega-3 fatty acids, current evidence suggests that OM3-CA is a useful addition to the treatment options available for patients with severe hypertriglyceridemia.     

A Review of: “Statistics: A Guide to the Unknown”

The two-period repeated measurements crossover design is often used in clinical trials. In this article we give a formula for sample size determination for testing treatment effect in two-period repeated measurements crossover design by taking an analysis of variance approach to the repeated measurements analysis. A balanced situation is considered: two treatment sequences that have the same number of patients, and the time points of measurements on each subject within each treatment period equal in number. The formula reveals the relationship between the required number of patients for each treatment sequence the number of repeated measurements within each treatment period the detectable treatment difference with respect to a primary response variable and the power for testing the treatment difference. A clinical trial example is given to illustrate the use of the formula.     

Live attenuated influenza vaccine (Fluenz™): a guide to its use in the prevention of seasonal influenza in children in the EU

Live attenuated influenza vaccine (LAIV).[Fluenz?] has a convenient intranasal route of administration. In the EU, it is indicated for the prevention of influenza disease caused by the influenza virus strains contained in the vaccine in children and adolescents aged 2 years to <18 years. The vaccine elicits a high immunogenic response, is protective against seasonal influenza infection and is associated with the development of herd immunity. LAIV is generally well tolerated, with the safety of the vaccine in the approved pediatric population generally considered to be similar to that of placebo based on clinical trials and extensive experience involving more than 39 million vaccine doses.     

17 α-Hydroxyprogesterone caproate (Makena™): in the prevention of preterm birth

17 α-hydroxyprogesterone caproate is a synthetic progestin of which there is now a US FDA-approved formulation available for intramuscular administration (Makena?) to reduce the risk of preterm birth. Intramuscular 17 α-hydroxyprogesterone caproate (identical in formulation and manufacturing process to Makena?, thus hereafter referred to as Makena?) 250?mg once weekly, initiated at 16-20 weeks' gestation, was effective in reducing the risk of preterm birth in women with a singleton pregnancy at high risk of delivering preterm in a large, well designed, placebo-controlled trial (n?=?463 randomized). Rates of delivery before 37 (primary endpoint), 35, or 32 weeks' gestation were significantly lower with Makena? than with placebo, corresponding to relative risk reductions of 34%, 33%, and 42%, respectively. The benefit of the drug in reducing the risk of preterm birth was observed when deliveries were spontaneous (but not when indicated because of complications) and regardless of maternal race. In addition, there was a significantly lower rate of several adverse fetal/neonatal outcomes among infants of women who received Makena? than among infants of placebo recipients, including necrotizing enterocolitis, need for supplemental oxygen, birth weight of <2500?g, and intraventricular hemorrhage. Makena? was generally well tolerated in pregnant women in this trial. Moreover, fetal exposure to the drug appeared to be safe according to a 2- to 5-year follow-up of the study, with no evidence of a detrimental effect of the drug on child neurodevelopment and a low overall incidence (≈2%) of reproductive or genital abnormalities that was not significantly different from placebo.     

Potential of in vitro reconstituted 3D human airway epithelia (MucilAir™) to assess respiratory sensitizers

Respiratory sensitizers are considered as substances of higher risk, at the same level as carcinogens, mutagens and toxic chemicals for reproduction. Presently, there is no validated assay for identifying the respiratory sensitizers. Based on a fully differentiated and functional in vitro cell model of the human airway epithelium, MucilAir?, we attempt to develop such assay. To this end, we invented a novel method, using Dextran as carrier, for applying the water insoluble chemicals to the apical surface of the airway epithelia. Using the Dextran carrier method, we successfully tested some reference chemical compounds known to cause respiratory sensitisation in human beings, including MDI, TMA and HCPt. Interestingly, these chemical sensitizers differentially up-regulated the releases of certain cytokines and chemokines involved in allergic responses. We believe that based on MucilAir? an in vitro assay could be developed for identification and characterization of the respiratory sensitizers.     

Use of Partial AUC (PAUC) to Evaluate Bioequivalence��A Case Study with Complex Absorption: Methylphenidate

Purpose

Methylphenidate modified-release products produce early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD). Standard bioequivalence (BE) criteria cannot be applied to these products. The performance of partial area under the drug concentration-time curve (PAUC), Cmax and AUCINF to assess BE were independently evaluated for two products.

Methods

A two-stage analysis was performed on plasma data for two methylphenidate modified-release products (Product 1 and 2). Simulations using the fitted parameters determined how changes in fast absorption rate constant (K0Fast) and fraction available (F1) affected curve shape and BE determination using Cmax, AUCINF and PAUC.

Results

The sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in K0Fast(test) are product dependent. Product 1 mean PAUC(test)/PAUC(reference) ratios for PAUC0-4h are more responsive to both decreases and increases in K0Fast(test) than Product 2. Product 2 showed a greater response in the mean PAUC(test)/PAUC(reference) ratio for PAUC0-4h when the K0Fast(test) is decreased and less response as the value is increased.

Conclusions

PAUC estimated curve shape is sensitive to changes in absorption and are product specific, and may require a new PAUC metric for each drug. A non-product specific metric to assess curve shape is warranted.     

A Six-Community Prevention Trial to Reduce Alcohol and Drug Use–Related Problems in Sweden: Planning and Early Findings

The objective of this study was to evaluate a research and development project to reduce alcohol and drug use–related problems, conducted during 2003–2005, in six urban and rural municipalities in Sweden, Umeå, Kramfors, Solna, Kalmar, Laholm, and Lund. The development of alcohol and drug use trends and patterns will be followed through 2008 in the six targeted intervention communities and in the six matched control communities. The evaluation includes archival data, survey data, observational data, as well as process measures. The six communities have gradually reoriented their thinking about prevention from a single focus on youth activities to a broader approach involving the whole population. The project's and the study's limitations are noted and future needed research is suggested.     

Biosimilars Are Here: A Hospital Pharmacist’s Guide to Educating Health Care Professionals on Biosimilars

Background:

Pharmacists are the recognized experts in pharmacotherapy. With the recent introduction of biosimilar agents into the US market, pharmacists are poised to play a pivotal role in evaluating their risks versus benefits within the framework of cost containment.

Purpose:

This article provides hospital pharmacists with the necessary information on the principles surrounding the development, approval process, and use of biosimilars.

Methods:

Information contained in this article enables hospital pharmacists to identify concerns relating to biosimilars, implement educational components, and successfully evaluate biosimilars for the addition to the formulary. Additionally, this article reviews the European experience with biosimilars, the US Food and Drug Administration approval process, and postauthorization safety and pharmacovigilance programs.

Conclusion:

It is important to educate health care providers about the differences between biosimilars and their reference biologics. The adoption of biosimilars is necessary to control long-term costs of biologics, increase patient access to care, and encourage innovation.     

The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP™) predicts in vivo metabolic inhibition

Background Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed that erlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2. Methods A computer-based simulation model, SimCYP™, predicted that CYP3A4 contributed to ∼70% of the metabolic elimination of erlotinib, with CYP1A2 being responsible for the other ∼30%. A drug-drug interaction study was therefore conducted for erlotinib and a potent CYP3A4 inhibitor, ketoconazole, in healthy male volunteers to evaluate the impact of CYP3A4 inhibition on erlotinib exposure. Results Ketoconazole caused an almost two-fold increase in erlotinib plasma area under the concentration curve and in maximum plasma concentration. This is consistent with the SimCYP™ prediction of a two-fold increase in erlotinib AUC, further validating a primary (∼70%) role of CYP3A4 in erlotinib elimination. Conclusion Prediction of clinically important drug-drug interaction with SimCYP™ using in vitro human metabolism data can be a powerful tool during early clinical development to ensure safe administration of anticancer drugs, which are often co-administered at maximum tolerated doses with other drugs as part of a palliative treatment regimen.     

Use of Benzodiazepines in Alzheimer’s Disease: A Systematic Review of Literature

Background:

Benzodiazepines are frequently prescribed in patients with Alzheimer’s disease. Unfortunately, studies evaluating their benefits and risks in these patients are limited.

Methods:

Clinical trials focusing on the effect of benzodiazepines on cognitive functions, disease progression, behavioral symptoms, sleep disturbances, and the general frequency of benzodiazepine use were included in this review. Published articles from January 1983 to January 2015 were identified using specific search terms in MEDLINE and PubMed Library according to the recommendations of The Strengthening the Reporting of Observational Studies in Epidemiology initiative.

Results:

Of the 657 articles found, 18 articles met predefined selection criteria and were included in this review (8 on frequency, 5 on cognitive functions, 5 on behavioral and sleep disturbances). The frequency of benzodiazepine use ranged from 8.5% to 20%. Five studies reported accelerated cognitive deterioration in association with benzodiazepine use. Two studies reported clinical efficacy for lorazepam and alprazolam to reduce agitation in Alzheimer’s disease patients. No evidence was found for an improvement of sleep quality using benzodiazepines.

Conclusion:

This systematic review shows a relatively high prevalence of benzodiazepine use but limited evidence for clinical efficacy in Alzheimer’s disease patients. However, there is a paucity of methodologically high quality controlled clinical trials. Our results underscore a need for randomized controlled trials in this area.     

Green-lipped (greenshell™) mussel (Perna canaliculus) extract supplementation in treatment of osteoarthritis: a systematic review

Objectives

Intervention studies using New Zealand green-lipped or greenshell? mussel (GSM) (Perna canaliculus) extract in osteoarthritis (OA) patients have shown effective pain relief. This systematic review summarises the efficacy of GSM extracts in the treatment of OA.

Methods

A literature search of the three databases EMBASE, MEDLINE, and Scopus was performed to identify relevant articles published up to March 2020. Inclusion criteria were clinical trials published in English measuring the effect of supplementation of whole or a lipid extract from GSM on pain and mobility outcomes in OA patients.

Results

A total of nine clinical trials were included in systematic review, from which five studies were considered appropriate for inclusion in a forest plot. Pooled results showed that GSM extracts (lipid extract or whole powder) provide moderate and clinically significant treatment effects on a visual analogue scale (VAS) pain score (effect size: ? 0.46; 95% CI ? 0.82 to ? 0.10; p?=?0.01). The whole GSM extract improved gastrointestinal symptoms in OA patients taking anti-inflammatory medications. The GSM extract was considered to be generally well tolerated in most of the studies.

Conclusion

The overall analysis showed that GSM provided moderate and clinically meaningful treatment effects on OA pain. However, the current evidence is limited by the number and quality of studies, and further larger and high-quality studies are needed to confirm the effectiveness and to identify the optimal GSM format. Nevertheless, it is worth considering using GSM extracts especially for patients seeking alternative pain relief treatments with fewer side effects compared to conventional treatment.

     

Effects of Semelil (ANGIPARS™) on diabetic peripheral neuropathy: A randomized, double-blind Placebo-controlled clinical trial

Background and the purpose of the study

Diabetic neuropathy is the most common diabetic complication that often is accompanied by significant morbidity, mortality and economic burden. The purpose of this study was evaluation of effect of Semelil (ANGIPARS™), a new herbal drug for treatment of diabetic foot ulcers or diabetic peripheral neuropathy.

Methods

In this double blind clinical trial, 49 type 2 diabetes patients with different degrees of neuropathy were evaluated in two groups (ANGIPARS™ and placebo groups). All patients were assessed at the start and 12 weeks after treatment, with laboratory tests, United Kingdom screening test, Michigan neuropathy screening score, Michigan diabetic neuropathy score, vibration perception thresholds, nerve conduction study, monofilament test and visual analog scale.

Results

Michigan diabetic neuropathy score was decreased notably in ANGIPARS™ group. In the nerve conduction study, appropriate meaningful changes were observed in the distal latency and amplitude in the motor Ulnar nerve in ANGIPARS™ group.

Conclusion

The results showed limited evidence of efficacy of ANGIPARS™ in diabetic neuropathy treatment and more studies with a larger sample size and longer duration are required.     

Use of methimazole and risk of acute pancreatitis: A case–control study in Taiwan

Objective:

Some cases of acute pancreatitis have been reported to be associated with use of methimazole. The aim of this study was to investigate the relationship between use of methimazole and risk of acute pancreatitis on the basis of a systematic analysis.

Methods:

This was a population-based case–control study analyzing the database of the Taiwan National Health Insurance Program. There were 5764 individuals aged 20–84 years with a first attack of acute pancreatitis from 1998 to 2011 as the cases and 23,056 randomly selected sex- and age-matched individuals without acute pancreatitis as the controls. Use of methimazole was categorized as “never use” and “ever use.” We estimated the relative risk of acute pancreatitis associated with the use of methimazole by calculating the odds ratio (OR) with 95% confidence interval (CI) using a multivariable logistic regression model.

Results:

After adjustment for confounding factors, the OR of acute pancreatitis was 0.91 in individuals with ever use of methimazole, when compared with individuals with never use of methimazole (95% CI, 0.60–1.38). Unlike methimazole use, alcohol-related disease, biliary stone, cardiovascular disease, chronic obstructive pulmonary disease, diabetes mellitus, hepatitis B, hepatitis C, and hypertriglyceridemia were factors significantly associated with acute pancreatitis.

Conclusions:

Our study does not detect a substantial association between the use of methimazole and risk of acute pancreatitis on the basis of systematic analysis. There appears to be a discrepancy between case reports and our systematic analysis about the association between the use of methimazole and risk of acute pancreatitis.KEY WORDS: Acute pancreatitis, alcoholism, biliary stone, diabetes mellitus, methimazole     

A phase II clinical trial of ZD1839 (Iressa™) in combination with docetaxel as first-line treatment in patients with advanced breast cancer

Summary This was a phase II multi-institutional trial to determine the efficacy and tolerability of gefitinib (Iressa™) and docetaxel as first-line treatment in patients with metastatic breast cancer. All patients had histologically confirmed breast cancer with metastatic disease. They were permitted to have received adjuvant chemotherapy, but no prior docetaxel or prior chemotherapy for metastatic disease. Patients received gefitinib 250 mg once daily and docetaxel 75 mg/m² every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Thirty-three patients were enrolled and received a median of 5 cycles of treatment. The clinical benefit rate was 51.5% (95% CI: 33.5–69.2%). There were 1 confirmed complete response and 12 confirmed partial responses, and the overall objective response rate was 39.4% (95% CI: 22.9–57.9%). Four patients had stable disease for ≥24 weeks. The median duration of clinical benefit was 10.9 months (95% CI: 6.0–17.6 months). The most common reason for study discontinuation was disease progression (16 patients), followed by toxicity (ten patients). Toxicities were mainly attributable to docetaxel, including ≥grade 3 neutropenia in 43% of patients. The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated metastatic breast cancer, with a clinical benefit rate and toxicity profile in the range of that reported for docetaxel alone. This trial was funded by AstraZeneca Pharmaceuticals, Wilmington, DE. Dr. Swain was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or U.S. Government. The ClinTrials.gov Identifier for this study is: NCT00052169     

Rotavirus vaccine RIX4414 (Rotarix™): a pharmacoeconomic review of its use in the prevention of rotavirus gastroenteritis in developing countries

This article provides an overview of the clinical profile of rotavirus vaccine RIX4414 (Rotarix?) in the prevention of rotavirus gastroenteritis (RVGE) in developing countries, followed by a comprehensive review of pharmacoeconomic analyses with the vaccine in low- and middle-income countries. RVGE is associated with significant morbidity and mortality among children <5 years of age in developing countries. The protective efficacy of a two-dose oral series of rotavirus vaccine RIX4414 has been demonstrated in several well designed clinical trials conducted in developing countries, and the 'real-world' effectiveness of the vaccine has also been shown in naturalistic and case-control trials after the introduction of universal vaccination programmes with RIX4414 in Latin American countries. The WHO recommends universal rotavirus vaccination programmes for all countries. Numerous modelled cost-effectiveness analyses have been conducted with rotavirus vaccine RIX4414 across a wide range of low- and middle-income countries. Although data sources and assumptions varied across studies, results of the analyses consistently showed that the introduction of the vaccine as part of a national vaccination programme would be very (or highly) cost effective compared with no rotavirus vaccination programme, according to widely used cost-effectiveness thresholds for developing countries. Vaccine price was not known at the time the analyses were conducted and had to be estimated. In sensitivity analyses, rotavirus vaccine RIX4414 generally remained cost effective at the highest of a range of possible vaccine prices considered. Despite these favourable results, decisions regarding the implementation of universal vaccination programmes with RIX4414 may also be contingent on budgetary and other factors, underscoring the importance of subsidized vaccination programmes for poor countries through the GAVI Alliance (formerly the Global Alliance for Vaccines and Immunization).