On healthcare by popular appeal: critical assessment of benefit and risk in cannabidiol based dietary supplements

Introduction: In recent decades, federal legislation in the U.S. has recognized a new paradigm of pharmacotherapy in which ideology and popular demand, as opposed to sound clinical evidence, drives the marketing of ostensible herbal therapeutics as ‘dietary supplements’. This vogue of democratizing medicine has more recently manifested in the ongoing legalization of cannabis products at the state level, where an arbitrary variety of definitions, restrictions, and assumed therapeutic uses are applied to a family of phytochemicals with no definitive evidence of efficacy or safety. With the recent publication of clinical trials submitted to the FDA in efforts to gain approval of the cannabidiol based therapeutic Epidiolex, a rare opportunity exists to examine high-quality data for a drug which has in recent years been marketed as a greatly unregulated dietary supplement.

Areas covered: A critical analysis is offered of data regarding efficacy, dosing, exposure, adverse events, drug–drug interactions, and non-specific effects associated with CBD – all of which raise questions regarding the wisdom of assuming the safety and efficacy of cannabinoids in particular and dietary supplements in general.

Expert opinion: Ongoing lack of meaningful regulation of cannabinoid supplements continues to put consumers at undue risk without clear evidence of therapeutic value.     

Tolerability and safety of commonly used dietary supplements and nutraceuticals with lipid-lowering effects

Introduction: Cardiovascular diseases are one of the highest causes of death and disability in industrialized countries, whereas a large portion of patients in primary prevention have cardiovascular disease risk factors that remain uncontrolled. Lifestyle interventions, including dietary supplementation with natural compounds possessing known lipid-lowering effects, are strongly supported by the international guidelines for cardiovascular disease prevention.

Areas covered: This review provides insights on issues concerning the safety of the most commonly used dietary supplements and nutraceuticals with demonstrated lipid-lowering actions. Soluble fibers, phytosterols, soy proteins, omega 3 polyunsaturated fatty acids, monakolines, policosanols, berberine and garlic extracts are all discussed and a specific focus has been placed on their pharmacological interactions.

Expert opinion: A relatively large amount of preclinical, epidemiological and clinical evidence has demonstrated the tolerability and safety of the most commonly used dietary supplements and nutraceuticals with demonstrated lipid-lowering action. However, for most supplements and nutraceuticals, no evidence is currently available from long-term trials on morbidity and mortality. Detailed knowledge of specific health risks and pharmacological interactions for each individual compound is needed for the management of frail patients, such as children, the elderly, patients with liver or renal failure, high-risk patients, and patients consuming numerous drugs.     

Loop diuretics and ultrafiltration in heart failure

Introduction: Despite widespread use of loop diuretics in congestive heart failure (HF) to achieve decongestion and relief of symptoms, as recommended by the current guidelines, there is uncertainty as to their long-term therapeutic efficacy and safety. Their efficacy and safety compared to venous ultrafiltration are currently under investigation in acute decompensated HF patients.

Areas covered: In this article, the authors review current available data related to efficacy and safety of loop diuretics and ultrafiltration in HF.

Expert opinion: The literature review highlights an unmet clinical need for evidence-based algorithms, potentially using not only the classical clinical signs and symptoms of congestion as well as the estimated glomerular filtration rate and serum electrolytes, but also biomarkers of congestion/decongestion, neurohumoural activation or urinary kidney injury molecules, in order to optimize both loop diuretics and renin–angiotensin–aldosterone system blocker use in HF patients.     

DHA derivatives of fish oil as dietary supplements: a nutrition-based drug discovery approach for therapies to prevent metabolic cardiotoxicity

Introduction: During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA-enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease.

Areas covered: This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases.

Expert opinion: The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease.     

Consumers’ attitude towards the use and safety of herbal medicines and herbal dietary supplements in Serbia

Background The use of herbal medicines and herbal dietary supplements in Serbia is very common and many patients consume herbal preparations with conventional drug therapy. Objective The aim of this survey was to evaluate the consumers’ awareness of herbal remedies and the safety of herbal dietary supplements, their attitude towards combining herbals and drugs, and the source of recommendations for their use. Setting The study included all consumers who bought herbal remedies and herbal dietary supplements in 15 pharmacies on the territory of Novi Sad during 2011 and who accepted to be interviewed. Methods Structured interviews using questionnaire, conducted by pharmacists. The questionnaire included 4 parts: socio-demographic characteristics of consumers, source of recommendations for the use of herbal products, attitude towards safety of herbal remedies and herbal dietary supplements use and their combination with regular drugs, as well as the question of purchased herbal products. Main outcome measure Consumers’ attitude towards the safety and use of herbal medicines and herbal dietary supplements measured by 9 items. Results The majority of interviewed participants were highly educated, aged 41–60 and they consumed herbal remedies on their own initiative or on recommendation of nonmedically educated person, without previous consultation with medical doctor or pharmacist. Out of all participants: 88.9 % did not consider it important to inform their physician or pharmacist about use of herbal remedies and herbal dietary supplements; 73.3 % found the use of herbal remedies harmless (where 9.4 % did not have any attitude towards that issue), while 40.3 % of participants regarded the combining of herbal and regular drugs unsafe. Conclusion There is a need for consumers’ education on reliable use of herbal medicines and herbal dietary supplements, in order to improve their awareness of the limits of herbal remedies safety and potential risks of their combination with drugs.     

The discovery and development of prasugrel

Introduction: Prasugrel (CS-747, LY640315) is a third-generation thienopyridine, which gained approval by the FDA in 2009 for its use in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Areas covered: This article focuses on the preclinical profile of prasugrel. Using published preclinical and clinical studies, the authors summarize the pharmacokinetics, pharmacodynamics, and pharmacogenomics of prasugrel and their distinguishing features in efficacy and safety.

Expert opinion: Prasugrel has a more rapid, more potent antiplatelet effect with less interindividual response variability when compared to clopidogrel. Those therapeutic advantages are attributed to features of its chemical structure that favor the metabolic conversion of prasugrel to its active metabolite. However, the increased risk of bleeding has been associated with a greater antiplatelet effect and dosing profile; this is especially the case in those patients who are at a higher risk of bleeding complications. It is therefore important for an optimal dosing strategy of prasugrel to be identified to provide a formulation that has the best balance for efficacy and safety.     

A Safety Evaluation of Empagliflozin for the Treatment of Type 2 Diabetes

ABSTRACT

Introduction: Empagliflozin is a sodium glucose co-transporter 2 inhibitor used to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) by enhancing urinary glucose excretion. Empagliflozin is effective at lowering glycosylated hemoglobin and was recently proven superior to placebo for reduction of cardiovascular disease (CVD) risk. As with any new drug, there are safety considerations that inform its potential use in patients with T2DM.

Areas Covered: Here, we evaluate the safety of empagliflozin and provide an expert opinion as to its current and future role in the treatment of patients with T2DM. A search of the English language literature was performed using PubMed search terms: “empagliflozin”, “sodium glucose cotransporter 2 inhibitors”, and “drug safety”. Articles and bibliographies relevant to the subject were reviewed and additional references known to the authors were included.

Expert Opinion: The evidence for empagliflozin is robust with regard to glycemic efficacy and safety. Low risk of hypoglycemia, absence of weight gain, and demonstrated cardiovascular risk reduction support its consideration as a first line medication in addition to metformin for patients with T2DM and CVD. Ongoing trials will continue to address the safety and efficacy of empagliflozin and expand our clinical knowledge of this medication.     

Bedaquiline as part of combination therapy in adults with pulmonary multi-drug resistant tuberculosis

Introduction: Few innovative anti-microbial products have been brought to market in recent years to combat the global multidrug resistant-tuberculosis (MDR-TB) epidemic. Bedaquiline, a novel oral diarylquinoline, was approved by the US FDA as a part of combination therapy in adults with pulmonary MDR-TB based on phase II trials.

Area covered: Pubmed searches were conducted using search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included World Health Organization, Clinicaltrial.gov, US Food and Drug Administration. Bedaquiline is an ATP synthase inhibitor specific for M. tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4 and it’s drug exposure can be influenced by inducers and inhibitors of this enzyme. Phase II studies showed promising results on efficacy of bedaquiline when being used in combination with a background regimen for MDR-TB. Main safety concerns include QTc prolongation and hepatotoxicity. Phase III trials are ongoing to confirm efficacy findings from phase II studies and provide additional evidence of safety and efficacy.

Expert commentary: Critical data for long-term efficacy and safety are incomplete and scarce, supporting the cautious use of bedaquiline.     

REGULATORY ENVIRONMENT IN THE ADVERTISING OF DIETARY SUPPLEMENTS

ABSTRACT

This paper discusses the advertising of dietary supplements and the changing regulatory environment. The role of the Food and Drug Administration (FDA) and the Federal Trade Commission (FTC) in regulating dietary supplements will be reviewed with emphasis on issues concerning utilizing data to establish advertising claims.     

Assuring Safety of Inherently Unsafe Medications: the FDA Risk Evaluation and Mitigation Strategies

The decision to approve a drug for clinical use is based on an understanding of its benefits versus the risks. Although efficacy is generally understood at the time of submission to the FDA for approval, the risks are more difficult to assess. Both PubMed (from 2000 to 2012) and the FDA website (www.fda.gov) were searched using the search terms “risk evaluation and mitigation strategy” (REMS). Articles for review were selected by relevance to topic, and their references were searched as well for additional relevant resources. Since the search results were not expected to contain research studies, formal quality assessment and inclusion and exclusion criteria were not utilized resulting in a narrative review. Few directly relevant research studies exist, although supporting documents such as government reports were available. For effective drugs with unclear or concerning safety records, the FDA has the option of requiring a risk evaluation and mitigation strategy, which allows a systematic approach to track and assure safe medication use. Over 100 different medications are currently covered by REMS, and each REMS is developed individually based on the needs of the specific drug or class. Although likely associated with improvements in medication safety, the potential benefit, limitations, and consequences of REMS are not yet fully understood.     

Pharmacological treatment of generalized anxiety disorder

Introduction: Generalized anxiety disorder (GAD) is a chronic, relapsing, debilitating disorder, associated with markedly impaired social and occupational functioning. Pharmacological treatment is considered standard care and several drug classes are now FDA approved for the treatment of GAD. While there are clear data for the efficacy of short-term acute treatment, long-term treatment and treatment-resistant GAD remain challenging.

Areas covered: This article describes current pharmacological treatment options for GAD, with focus on benzodiazepines, azapirones, antidepressants and anticonvulsant and antipsychotic drugs. Recent findings from placebo-controlled clinical trials are reviewed and evidence-based clinical implications are discussed. A PubMed search was completed using the terms: ‘generalized anxiety disorder AND treatment’ and ‘generalized anxiety disorder AND therapy’. Additional pivotal trials were included for a historical perspective (older landmark trials that established efficacy and safety for older drug classes in the treatment of GAD).

Expert opinion: Efficacy for treatment of GAD has been established for several different drug classes. At present, based on clear efficacy and good tolerability, first-line treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is indicated. If an initial, at least moderate, clinical response is achieved under antidepressant therapy, treatment should be at least continued for 12 months.     

Dexamethasone for ocular inflammation

Introduction: Corticosteroids, administered systemically and periocularly, have long been used to treat intermediate and posterior segment noninfectious uveitis. In addition to systemic immunosuppressive medications, these therapies are used to reduce inflammation, prevent structural complications and prevent long-term visual loss in patients with uveitis. While systemic immunosuppressive therapies carry their own set of side effects, treatment with local steroids is associated with the risk of development of cataract and glaucoma.

Areas covered: Intravitreal delivery of fluocinolone acetonide via a sustained-release implant (Retisert) was approved by the FDA in 2005 for the treatment of noninfectious intermediate and posterior uveitis. Recently, the FDA also approved the biodegradable dexamethasone implant (Ozurdex) for the treatment of noninfectious uveitis involving the posterior segment.

Expert opinion: The single injection, 26-week data indicate that the implant is well tolerated and produces meaningful improvements in intraocular inflammation and visual acuity that persist through 6 months. The available 6-month data also indicate that this implant confers much less of a risk of ocular hypertension than other forms of intraocular steroid therapy. However, future longer-term trials are needed to evaluate the efficacy and safety data in patients who receive multiple injections. The newly approved dexamethasone implant, Ozurdex, is a useful addition to our local armamentarium in the treatment of noninfectious intermediate and posterior uveitis given its efficacy, safety, and ease of use in the outpatient setting.     

Quality of manufacturer provided information on safety and efficacy claims for dietary supplements for colonic health

PURPOSE: Food and Drug Administration (FDA) approval of dietary supplements is not required. However, manufacturers must ensure that data exist to support safety and efficacy claims of their product. This study was designed to evaluate accessibility and quality of such data from manufacturers of dietary supplements for 'colonic health.' METHODS: Supplements promoting 'colonic health' were identified at area stores. A physician contacted the manufacturers by mail and telephone requesting data to substantiate claims of efficacy and safety. MEDLINE was searched to identify reports of adverse events or medication interactions. RESULTS: Twelve manufacturers of 23 products were surveyed. Eight manufacturers responded, of whom four provided no clinical data to substantiate claims of efficacy or safety. No manufacturer provided data that directly evaluated their product. Our literature review identified a wide range of potential adverse events and drug-supplement interactions, albeit mostly as case reports, animal studies, or in vitro experiments. CONCLUSIONS: There is a need to increase availability of supplement safety data to physicians and the general public. Consideration should be given to various responses, including legislative actions that address this issue.     

Potential side effects to GLP-1 agonists: understanding their safety and tolerability

Introduction: Glucagon-like peptide 1 receptor (GLP-1Rx) agonists might elicit unwelcome side effects and concerns have recently been raised about their safety.

Areas covered: Available evidence about safety, tolerability and potential adverse events relative to GLP-1Rx agonists presently used. We searched the MEDLINE database using the terms: ‘GLP-1 receptor agonists’, ‘Incretin therapy side effects’, ‘exenatide’, ‘ liraglutide’, ‘exenatide long-acting release’, ‘lixisenatide’. Articles were selected on the basis of the study design and importance, in the light of authors’ clinical experience and personal judgment. The main safety concern about GLP-1Rx agonists use is the possible association with increased risk of pancreatitis and/or tumors. This concern stems mainly from limited observations in animal models not confirmed in similar studies. Furthermore, clinical studies reporting association between GLP-1Rx agonist use and pancreatitis/cancer are marred by several biases and both clinical trials and post-marketing analyses failed to demonstrate a significant association.

Expert opinion: As stated by both FDA and EMA, the safety concerns emerged so far about GLP-1RX agonists should not affect present prescribing habits. Thus, although a strict data monitoring must be encouraged, they should not prevent access to the benefits of an innovative treatment, such as GLP-1Rx agonists use, to a large diabetic population still confronted with unmet needs.     

Use of topical corticosteroids and topical calcineurin inhibitors for the treatment of atopic dermatitis in thin and sensitive skin areas

ABSTRACT

Background: Atopic dermatitis (AD) is a common, chronic skin disorder characterized by itch and dry skin, which can develop into pruritic red plaques that ooze when scratched. AD flares often occur in anatomic areas where the skin is naturally thin (the face, neck, and intertriginous zones). Such regions, especially the face, are also areas of sensitive skin and need special consideration when being treated.

Objective: This article will briefly review the concepts of thin and sensitive skin and discuss the treatment of AD in such areas.

Methods: The MEDLINE database was searched for English-language articles published that contained the text terms atopic dermatitis, sensitive skin, treatment, topical corticosteroids, or topical calcineurin inhibitors. Articles that pertained to the safety and efficacy of various treatments were selected for further review.

Results: Topical corticosteroids (TCSs) are effective for the treatment of AD in thin and sensitive skin areas, but their use is limited due to adverse events, such as skin thinning, and the potential for impairing the skin barrier. Topical calcineurin inhibitors (TCIs) also provide effective AD treatment without impairing the skin barrier or inducing skin thinning. Although TCIs may be associated with a higher incidence of application-site reactions such as pruritus and skin burning, these symptoms are typically transient and mild to moderate in nature.

Limitations: This analysis focused primarily on relatively recent key trials evaluating the treatment of AD in sensitive skin; due to the limited number of controlled trials evaluating TCS agents, consensus statements and comprehensive review articles were used for most of the information pertaining to this therapeutic option.

Conclusions: Although both TCSs and TCIs have a place in a long-term, comprehensive treatment strategy for AD, TCIs may have a particular use in thin and sensitive skin areas.     

Pharmaceutical industry perspective on risk evaluation and mitigation strategies: manufacturer take heed

Introduction: Enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require manufacturers to submit Risk Evaluation and Mitigation Strategy (REMS) when it was deemed necessary to ensure that a drug's benefit outweigh its risk. REMS apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs). The objective of this review is to describe the impact of REMS requirements on the pharmaceutical industry.

Areas covered: Articles were identified in MEDLINE searches through October 11, 2011, using the MeSH terms and keywords pharmaceutical industry, risk management, United States Food and Drug Administration, REMS, ETASU, and Medication Guide in various combinations.

Expert opinion: The new powers ascribed to the FDA are notable, as they add enforceability to safety strategies that were not part of FDA's prior risk management tools, risk minimization action plans (RiskMAPs). Failure to comply with REMS can lead to financial penalties up to $10 million, and a drug could be deemed misbranded if the REMS is not followed. The new approach to risk management via FDAAA has elevated the rigor with which manufacturers must fulfill postmarketing safety commitments.     

Anticonvulsant hypersensitivity syndrome: an update

Introduction: Long-acting β-agonists (LABAs) added to inhaled corticosteroids (ICS) reduce symptoms, improve lung function and enhance overall asthma control. However, several studies have indicated an increased risk of asthma mortality and asthma-related serious adverse events and the FDA recently mandated restrictions to the use of LABAs in asthma.

Areas covered: This review highlights the clinical studies on which safety analyses pertaining to salmeterol and formoterol have been based and then focuses on recent meta-analyses of safety outcomes with and without consideration of concomitant ICS.

Expert opinion: The phenomenon of masking of inflammation by LABA if ICS dose is insufficient underscores the potential for confounding in determining real safety risks. Under-treatment with ICS and differential dosing of ICS in many trials are major factors driving the LABA safety concern. The FDA meta-analysis, when stratified for mandatory ICS use, found no significant increase in the composite outcome of asthma mortality, intubations and hospitalizations. Add-on therapy with LABA is effective and safe if the dose of ICS is adequate to treat airway inflammation. LABA and ICS given in a single device will negate the possibility of LABA monotherapy which is contraindicated. The FDA has recommended that LABAs be withdrawn when control is achieved with combination therapy but recent evidence suggests this may result in loss of symptom control.