An update on naltrexone/bupropion extended-release in the treatment of obesity

Introduction: As the prevalence of obesity continues to increase, the need for effective long-term treatment strategies for overweight and obesity is critical. Pharmacology fills a large treatment gap between behavioral therapy, which is insufficient for the majority of patients, and devices and surgery, which are available to only a subset of patients. Naltrexone HCl and bupropion HCl Extended-Release (naltrexone XR/bupropion XR) was approved by the Food and Drug Administration for chronic weight management in 2014.

Areas covered: This review illustrates the efficacy and safety of naltrexone XR/bupropion XR by examining data from clinical trials. It also provides an overview of the market and presents the pharmacodynamics and pharmacokinetics of naltrexone and bupropion.

Expert opinion: The efficacy and safety profile of naltrexone XR/bupropion XR makes it a viable option for many patients who could benefit from its distinctive mechanism. The medication was shown to produce additive weight loss when combined with an intensive behavioral modification program and it may improve food cravings and eating behaviors. Compared to the other three antiobesity medications approved since 2012, naltrexone XR/bupropion XR is neither a controlled substance nor an injectable agent.     

Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release

Introduction: Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval.

Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations.

Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.     

Bupropion/naltrexone fixed-dose combination for the treatment of obesity

The combination of bupropion and naltrexone is one of the most promising new possibilities for the treatment of obesity in an era of increasing prevalence of this disease and decreasing options for its pharmacological management. Although approved by FDA panel members, it was temporally rejected by the FDA afterwards, who demanded more cardiovascular safety data for its commercialization. This monograph will focus on the physiology involved in its mechanisms of action and results of clinical trials.     

Drug safety evaluation of zonisamide for the treatment of epilepsy

INTRODUCTION: Zonisamide is a broad spectrum antiepileptic drug with multiple mechanisms of action which has been recently approved in the US and Europe as an adjunctive therapy for refractory partial seizures in adults. AREAS COVERED: The adverse effect profile of this drug from controlled, randomized studies and open and long-term studies and case reports is described herein. EXPERT OPINION: Zonisamide has several CNS dose-dependent, metabolic and idiosyncratic adverse effects. Knowledge of these effects is essential for the prevention or minimization of several of them. For example, treatment-emergent adverse events may be prevented by slow titration; incidence of kidney stones may be reduced through an increase in fluid intake and avoidance of concomitant treatment with topiramate and/or ketogenic diet; and oligohydrosis may be prevented by hydratation and avoidance of hot temperatures. An accurate selection of patients can be useful for the prevention of some adverse effects. Psychiatric disturbances are mainly observed in predisposed subjects and patients with a previous allergic episode to sulfonamide-containing drugs are at a higher risk for developing a skin rash.     

The safety of indacaterol for the treatment of COPD

Introduction: Bronchodilators, namely long-acting inhaled β2-agonists and long-acting muscarinic antagonists, are the first-line medications for chronic obstructive pulmonary disease (COPD). The safety of these medicines is of great concern since COPD patients usually have other co-morbidities such as cardio- and cerebrovascular diseases.

Areas covered: In this review we present information about the safety and the use of indacaterol in COPD. Indacaterol is the first once-daily, long-acting inhaled β2-agonist approved for COPD. We provide data about its mechanism of action as well as, pharmacodynamics and pharmacokynetics. Moreover, we present the available literature data focused on the the safety of indacaterol. Data from post-marketing studies are presented and also data from comparative reviews and meta-analysis.

Expert opinion: Indacaterol’s safety is very favorable since in controlled trials it was similar to placebo. Nevertheless, physicians must be alerted to use indacaterol only according to its approved indications They must be aware of the possible adverse events since side effects may appear when the medicine is used for a prolonged period of time.     

Drug safety evaluation of maraviroc for the treatment of HIV infection

Introduction: Maraviroc is the only C-chemokine receptor 5 (CCR5) antagonist approved for the treatment of infection with HIV. This article reviews the safety and efficacy of maraviroc in the treatment of HIV infection.

Areas covered: The PubMed database was searched using the keywords ‘maraviroc’ and ‘HIV’. In addition, conference proceedings from CROI, IAS and EACS meetings were searched for maraviroc clinical trials. The PubMed search revealed one Phase IIb – III clinical trial in treatment-naive HIV⁺ patients (MERIT) and three Phase IIb – III randomized clinical trials (RCTs) in treatment-experienced patients (MOTIVATE 1 and 2, A4001029). All RCTs showed an excellent safety profile for maraviroc in the treatment of HIV-1 infection. However, long-term (> 3 years) safety data generated on maraviroc therapy are still scarce. Based on the findings from RCTs so far, no relevant toxicities and co-morbidities such as coronary heart disease or hepatotoxicity have been described. The overall CD4⁺ cell count increase resulting from a maraviroc-containing regimen appears to be higher than those seen with other antiretroviral regimens. However, the significance remains controversial. To date, maraviroc has shown a potent and durable virological efficacy profile for the treatment of HIV-1 infection. The only use of maraviroc depends on pretreatment testing for CCR5 tropism.

Expert opinion: Maraviroc is a generally safe and well-tolerated medication for the treatment of HIV-1 infection with a unique mechanism of action. Long-term (i.e., > 5 years) risks are not known and have to be carefully monitored.     

Drug safety evaluation of maraviroc for the treatment of HIV infection

INTRODUCTION: Maraviroc is the only C-chemokine receptor 5 (CCR5) antagonist approved for the treatment of infection with HIV. This article reviews the safety and efficacy of maraviroc in the treatment of HIV infection. AREAS COVERED: The PubMed database was searched using the keywords 'maraviroc' and 'HIV'. In addition, conference proceedings from CROI, IAS and EACS meetings were searched for maraviroc clinical trials. The PubMed search revealed one Phase IIb - III clinical trial in treatment-naive HIV(+) patients (MERIT) and three Phase IIb - III randomized clinical trials (RCTs) in treatment-experienced patients (MOTIVATE 1 and 2, A4001029). All RCTs showed an excellent safety profile for maraviroc in the treatment of HIV-1 infection. However, long-term (> 3 years) safety data generated on maraviroc therapy are still scarce. Based on the findings from RCTs so far, no relevant toxicities and co-morbidities such as coronary heart disease or hepatotoxicity have been described. The overall CD4(+) cell count increase resulting from a maraviroc-containing regimen appears to be higher than those seen with other antiretroviral regimens. However, the significance remains controversial. To date, maraviroc has shown a potent and durable virological efficacy profile for the treatment of HIV-1 infection. The only use of maraviroc depends on pretreatment testing for CCR5 tropism. EXPERT OPINION: Maraviroc is a generally safe and well-tolerated medication for the treatment of HIV-1 infection with a unique mechanism of action. Long-term (i.e., > 5 years) risks are not known and have to be carefully monitored.     

Drug strategies for the treatment of obesity

There are three major classes of drugs for the treatment of obesity: (i) inhibitors of food intake, which reduce hunger perception and, consequently, food intake; the most representative are centrally acting neurotransmitters and intestinal or neural satiety peptides; (ii) inhibitors of nutrient absorption, which reduce energy disposal through a peripheral gastrointestinal mechanism; and (iii) thermogenic drugs, which increase energy expenditure. At present, there are only two drugs for long-term use: sibutramine, an inhibitor of both serotonin and norepinephrine reuptake, and orlistat, a lipase inhibitor that targets pancreatic lipases and reduces absorption of dietary fat. New treatments and better drugs are expected in the near future because of the rapid expansion of research in body-weight regulation mechanisms.     

Effects of (Des-Tyr1)-gamma-endorphin and alpha-endorphin as compared to haloperidol and amphetamine on nucleus accumbens self-stimulation

The β-endorphin fragment (Des-Tyr¹)-γ-endorphin (DTγE, β-LPH 62–77) attenuated self-stimulation behaviour associated with electrical stimulation of the nucleus accumbens area of rats. This effect was observed after subcutaneous (s.c.) injection of 2.5 and 25 μg of the neuropeptide and appeared to be dose-dependent. It was present only at current intensities in the neighbourhood of the threshold for eliciting the behaviour. Subcutaneous administration of haloperidol (5 μg) exerted a similar effect, but in addition affected the rate of responding at currents associated with maximal performance. Amphtamine (100 μg s.c.) enhanced responding at both low and high current intensities. α-Endorphin (β-LPH 61–76; 2.5 and 25 μg s.c.) did not influence nucleus accumbens self-stimulation behaviour.It is postulated that DTγE affects this behaviour by interfering with mesostriatal dopaminergic neuronal systems projecting to the nucleus accumbens, possibly via an action on synaptic membranes.     

Drug safety evaluation of roflumilast for the treatment of COPD: a meta-analysis

ABSTRACT

Introduction: Roflumilast is the only phosphodiesterase 4 inhibitor approved for the treatment of COPD patients with chronic cough and sputum, and a history of exacerbations, but the compliance to treatment is reduced by poorly tolerated adverse events (AEs).

Areas covered: The synthesis of clinical evidences indicates that roflumilast 500μg once-daily increased the risk of AEs, with no impact on the risk of serious AEs (SAEs), compared with placebo. Gastrointestinal AEs were common in patients treated with roflumilast, that may also induce headache, backpain and insomnia. Roflumilast protects against COPD related AEs. The frequency of very SAEs was rare but greater in patients treated with roflumilast than placebo, although factors other than the study drug were related with these SAEs.

Expert opinion: The safety profile of roflumilast administered in combination with further drugs for the treatment of COPD should be investigated through specifically designed RCTs, and the post-marketing surveillance might help to characterize the real risk of very SAEs. Roflumilast may provide more benefit than harm in patients at high risk of severe exacerbations, and the therapy discontinuation may be reduced by a correct education of patients on the generally transient and mild-to-moderate nature of gastrointestinal AEs induced by this drug.     

An evaluation of liraglutide including its efficacy and safety for the treatment of obesity

ABSTRACT

Introduction: The prevalence of obesity is increasing worldwide and associated conditions, particularly type 2 diabetes mellitus (T2DM), also show increasing prevalence. Lifestyle intervention should be the first line of management for obesity but additional pharmacotherapy is often required and bariatric surgery is appropriate in more severe cases. Drugs acting as glucagon-like peptide-1 receptor agonists (GLP-1RAs) developed for the management of T2DM reduce body weight and liraglutide is the first GLP-1RA to be approved for the treatment of obesity in patients with and without T2DM.

Areas covered: In this review of relevant published material, the authors summarize the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of liraglutide for the treatment of obesity.

Expert opinion: Liraglutide effectively reduces body weight and body fat through mechanisms involving reduced appetite and lowered energy intake, independent of its glucose-lowering effects. Like most of the other medications currently available for obesity, liraglutide has some common adverse effects, although generally not serious ones. Liraglutide has additional benefits in reducing cardiovascular events in patients with T2DM but the cost and the need for daily injections may limit its use in obesity. Newer GLP-1RAs, such as semaglutide, or other drugs in development for obesity may have advantages over liraglutide.     

An evaluation of the efficacy and safety of Tofogliflozin for the treatment of type II diabetes

Introduction: Accumulating data from recent studies has altered the gold standard of care for diabetes treatment. In patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or those at high risk for CVD, subsequently to lifestyle changes and metformin therapy, the administration of an SGLT-2 inhibitor with established benefits for cardiovascular outcome (CVOT) should be considered.

Areas covered: Tofogliflozin is the most selective SGLT-2 inhibitor and has been approved for the treatment of T2D in Japan. This review summarizes the available data on Tofogliflozin as compared to other SGLT-2 inhibitors, and primarily the three SGLT-2 inhibitors with published CVOT: Empagliflozin, Canagliflozin and Dapagliflozin.

Expert opinion: Tofogliflozin’s higher selectivity profile increases the positive effects on cardiovascular (CV) outcomes and death and reduces side effects. However, the clinical data on Tofogliflozin from both clinical and real-world studies remain sparse and much less abundant than the other main 3 SGLT-2 inhibitors, thus calling for caution and underscoring the need for further research.     

Drug evaluation: tagatose in the treatment of type 2 diabetes and obesity

Spherix Inc (formerly Biospherics) is developing tagatose, an orally active lactose derivative for the potential treatment of obesity and type 2 diabetes. The compound is also under investigation for the potential treatment of anemia, hemophilia and medical problems related to infertility, birth weight and excessive maternal food intake. Phase I and II clinical trials have been completed.     

Drug safety evaluation of rosuvastatin

Introduction: Rosuvastatin is a highly efficacious statin approved for use throughout the world. Rosuvastatin has been exhaustively evaluated in the setting of a broad variety of dyslipidemias and cardiovascular disease states in clinical trials encompassed within the GALAXY program.

Areas covered: The efficacy and adverse event profile of rosuvastatin are evaluated based on the results of randomized, controlled clinical trials and observational studies available in the Medline database.

Expert opinion: Rosuvastatin is a safe and efficacious lipid modifying drug in a broad variety of patient populations (men and women, irrespective of race) for treating multiple forms of dyslipidemia. Rosuvastatin reduces atherogenic lipoproteins and triglycerides and increases high-density lipoprotein cholesterol better than other statins. Compared to other statins, it has no excess signal for liver, skeletal muscle or renal toxicity. This is supported by evidence from both an extensive clinical trial program as well as post-marketing surveillance. The incidence of myalgia with this drug is comparable to that observed with other statins. Rosuvastatin does not depend on cytochrome P450 3A4-dependent metabolism and has a favorable drug interaction profile. Care must be taken to reduce the dose of rosuvastatin in patients of Asian ancestry or with stage IV chronic kidney disease (severe renal insufficiency), as well as patients being treated with protease inhibitors or cyclosporine.     

Drug safety evaluation of ziprasidone

Introduction: Ziprasidone is a second-generation antipsychotic approved for the treatment of schizophrenia and bipolar disorder. The purpose of this review is to assess the overall safety profile of ziprasidone, including its risk for prolonging the electrocardiogram (ECG) QT interval.

Areas covered: This paper is a review of product labeling and English language reports located through PubMed and information available on regulatory agency websites, with a focus on the safety and tolerability of ziprasidone.

Expert opinion: Although ziprasidone can prolong the ECG QT interval, this has not resulted in increases in sudden death or cardiac sudden death as noted in a large, simple trial and supported by almost a decade of real-world use in the US. Ziprasidone's principal advantage over some other second-generation antipsychotics has been its overall favorable weight and metabolic profile. Similar to most second-generation antipsychotics, ziprasidone has a lower propensity for extrapyramidal side effects and hyperprolactinemia compared to first-generation antipsychotics.     

Drug safety evaluation of lenvatinib for thyroid cancer

Introduction: Lenvatinib is an oral multitargeted tyrosine kinase inhibitor of VEGFR1,2,3,4, FGFR1,2,3,4, PDGFR-α as well as RET and KIT signaling network. Its activity against radioiodine-resistant differentiated thyroid cancer (DTC) has been recently demonstrated. Patients, who were given lenvatinib, showed significantly longer median progression free survival than placebo group, 18.3 vs 3.6 months, respectively. This review is focused on lenvatinib safety profile in patients treated due to DTC and medullary thyroid carcinoma. Among the most frequent lenvatinib-related adverse events (AEs) were hypertension, proteinuria, diarrhea, appetite decrease, weight loss, nausea and stomatitis. Although a lot of them were manageable, in 35–68% of patients dose reduction was required. Nevertheless, only 15% of subjects withdrew the drug due to its toxicity.Areas covered: published results of clinical trials phase II and III investigating both safety and efficacy of lenvatinib in thyroid cancer.Expert opinion: Lenvatinib shows acceptable safety profile in patients with thyroid carcinoma. Treatment-related side effects are usually manageable by dose modifications or by concomitant non-pharmacological and pharmacological treatment. However, the early recognition of any potential drug toxicity is crucial to avoid serious complications as well as to keep a patient on drug as long as the treatment is beneficial.     

The safety of pharmacologic treatment for pediatric obesity

Introduction: Pediatric obesity is a serious public health concern. Five medications have been approved by the Food and Drug Administration (FDA) for chronic weight management in adults with obesity, when used as an adjunct to lifestyle modification. Orlistat is the only FDA-approved medication for pediatric patients aged 12 years and above.

Areas covered: This paper summarizes safety and efficacy data from clinical trials of weight loss medications conducted among pediatric samples. Relevant studies were identified through searches in PubMed.

Expert opinion: Orlistat, as an adjunct to lifestyle modification, results in modest weight losses and may be beneficial for some pediatric patients with obesity. However, gastrointestinal side effects are common and may limit use. In adults taking orlistat, rare but severe adverse events, including liver and renal events, have been reported. Recent pediatric pharmacokinetic studies of liraglutide have demonstrated similar safety and tolerability profiles as found in adults, with gastrointestinal disorders being the most common adverse events. Clinical trials are needed of liraglutide, as well as other medications for obesity, that systematically evaluate their risks and benefits in pediatric patients.     

Changes in social behaviour of rats following chronic treatment with gamma-endorphin antiserum injected into the nucleus accumbens

Treatment with gamma-endorphin antiserum twice daily for 12 days, by injection into the nucleus accumbens did not change the basal level of social activity or explorative behaviour when pairs of rats were tested in a social interaction test. The decrease in social interactions due to increased light level as observed in placebo-treated rats, was not present in animals treated with gamma-endorphin antiserum. Significantly more freezing and fly-responses were observed in the rats treated with antiserum, as reactions to penetrating sound stimuli. These changed responses to light and sound stimuli persisted for at least 3 days following discontinuation of treatment. It is concluded that treatment with gamma-endorphin antiserum, injected into the nucleus accumbens results in disturbances in the integration of environmental stimuli in social behaviour and in enhanced responsiveness to stressful stimuli. It is suggested that these effects may be related to increased dopaminergic transmission in some dopaminergic systems in the nucleus accumbens, implicating these systems in the environmental control over social behaviour.