Safety and tolerability of extended-release niacin with laropiprant

Introduction: Niacin is one of the oldest drugs used in the treatment of dyslipidemia. Previously its use has been limited because of excessive flushing. Now an agent laropiprant (LRP) has been developed, which blocks the flushing pathway. Therefore, it is time to collate available information to assess the safety and tolerability of combining niacin with LRP.

Areas covered: The authors searched PubMed and MEDLINE for literature published between January 2006 and July 2011, for safety and tolerability reports of extended-release niacin (ERN) with LRP.

Expert opinion: The addition of LRP to ERN, by reducing the side effect ‘flushing’, may enable lipidologists and physicians to use niacin more widely as part of lipid modification therapy, especially since the combination can be safely added to statins. However, it has to be accepted that the addition of LRP does not completely abolish flushing. The favorable safety profile supports the use of LRP to achieve higher therapeutic dosing of niacin.     

Tavaborole for the treatment of onychomycosis

Introduction: Onychomycosis causes approximately one-half of all nail disorders and its prevalence has been steadily increasing. It is difficult to treat, partly due to the subungual location and the inability of both oral and topical antifungals to reach the site of infection. Published cure rates with oral drugs are < 50% and even lower with topical drugs. Pathogenic factors include the diversity of fungal organisms and the difficulty of drugs penetrating the nail plate. Tavaborole is a broad-spectrum oxaborole antifungal agent with low molecular weight, permitting optimal nail plate penetration. In vitro and ex vivo studies have demonstrated the superior nail-penetrating properties of tavaborole compared to existing topical antifungal medications approved for the treatment of onychomycosis.

Areas covered: The clinical characteristics and prevalence of onychomycosis, currently available treatments, and the chemistry, safety and pharmacokinetic properties of tavaborole for the treatment of onychomycosis.

Expert opinion: Tavaborole is a novel, topical antifungal pharmaceutical agent pending FDA approval for the treatment of toenail onychomycosis due to dermatophytes. Efficacy has been demonstrated by a clinical development program including in vitro data and two large Phase III trials that enrolled ～ 1200 patients. When approved, tavaborole topical solution, 5% may become a safe and effective option for the treatment of onychomycosis.     

Macitentan for the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a serious disease characterized by elevation of pulmonary artery pressures and right ventricular failure. It is a progressive disease with a poor 5-year survival despite recent advances in treatment. Endothelin plays an important role in the development and progression of the disease. Endothelin receptor blockers have been used to treat PAH since 2001. More recently, macitentan was approved for treatment of PAH.

Area covered: This review covers the preclinical and clinical data on macitentan.

Expert opinion: Macitentan is a more potent ERA and has been shown to delay progression of the disease. It does not appear to have any significant hepatotoxicity and has a convenient once-a-day dosing. In the large event driven trial, macitentan significantly reduced morbidity in patients with PAH. It was safe and well tolerated and the benefit was seen in treatment-naïve patients and those already receiving PAH therapy.     

Drug safety evaluation of pregabalin

Introduction: Pregabalin is an anticonvulsant with one known mechanism of action which is used most specifically in the management of neuropathic pain.

Areas covered: The adverse effect profile of this medication from controlled, randomized studies as well as open and long-term studies is described with consideration of the evidence-based results for pregabalin's clinical use.

Expert opinion: Pregabalin is a mostly well tolerated medication for the management of neuropathic pain and other conditions. Pregabalin use is associated with benign central nervous system and systemic adverse effects with very limited metabolic, idiosyncratic, or teratogenic adverse effects. Understanding of these adverse effects is essential for the clinician treating the patient and for the patient receiving treatment. Sedation, dizziness, peripheral edema, and dry mouth are the most prevalent adverse events experienced in all clinical populations. Other adverse effects are rare, but are discussed.     

BIBF 1120/nintedanib: a new triple angiokinase inhibitor-directed therapy in patients with non-small cell lung cancer

Introduction: Several new targeted agents with anti-angiogenic properties have been developed recently, including vandetanib, sunitinib, sorafenib, bevacizumab and others. Tumor development, progression, metastasis are strongly linked to angiogenesis. Targeted agents like bevacizumab, a monoclonal antibody which targets VEGF, have been fully developed in several solid tumors. These new agents strongly advocate that targeting angiogenesis is one of the best approaches for cancer therapy.

Areas covered: Those agents that target additional pro-angiogenic intracellular signaling pathways beyond VEGF signaling have also the potential to contribute to anticancer therapies. The authors present here nintedanib (BIBF 1120), a triple angiokinase inhibitor. It targets not only VEGFRs, but also FGFR and PDGFR. All the available clinical information regarding Phase I – II trials and the toxicity and efficacy of BIBF 1120 both as single agent and in combination with cytotoxic agents in non-small cell lung cancer (NSCLC) is reviewed and discussed here.

Expert opinion: Up till now, Phase I and II trials with nintedanib showed an improvement for survival of advanced NSCLC patients. Tolerability profile seems to be acceptable in these clinical trials. However, Phase III trials are mandatory to translate these findings into clinical practice. The research for predictive biomarkers could improve the success of these anti-angiogenic agents.     

Entecavir for the treatment of patients with hepatitis B virus-related decompensated cirrhosis

Introduction: Chronic hepatitis B (CHB) infection is common and carries a significant risk for the development of cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The goal of treatment in patients with CHB-related decompensated cirrhosis is to improve hepatic dysfunction and reduce mortality through the inhibition of viral replication. Several studies have now shown nucleot(s)ide analogs to be safe and effective in decompensated cirrhosis due to CHB.

Areas covered: A review of the evidence for the use of entecavir in the treatment of decompensated hepatitis B cirrhosis is discussed.

Expert opinion: Entecavir is an effective treatment option for most patients with CHB. In treatment naïve patients, it is a potent antiviral agent with a very low resistance rate, making it an excellent option for the treatment of decompensated hepatitis B cirrhosis. The use of entecavir monotherapy in patients with a known rtM204V lamivudine-resistant mutation should be avoided due to increased risk of developing entecavir resistance and failing treatment.     

Umeclidinium for treating COPD: an evaluation of pharmacologic properties,safety and clinical use

Introduction: Umeclidinium (UMEC) is a long-acting inhaled antagonist of muscarinic cholinergic receptors. The FDA approved UMEC for maintenance treatment of chronic obstructive pulmonary disease (COPD) in 2013 and it became available for commercial use as a single agent in 2014. After tiotropium, this is the only other once daily LAMA available for COPD patients.

Areas covered: In this article, we have comprehensively reviewed the pharmacokinetic properties and analyzed the currently available randomized controlled trials on the efficacy and safety profile of UMEC. We have discussed the current clinical application of UMEC and its future implication.

Expert opinion: UMEC is the newer long-acting antimuscarinic agent (LAMA) that has demonstrated significant improvement in lung function and improved the quality of life in moderate-to-severe COPD patients. It is suitable for once daily dosing, has low anticholinergic side effects and is well tolerated. Overall, it is a safe, effective and convenient LAMA for maintenance therapy in COPD patients.     

Dutasteride for the treatment of prostate-related conditions

Introduction: A variety of pharmaceuticals have been developed directed at mitigating the symptoms associated with benign prostatic hypertrophy (BPH) and have also been evaluated for their potential role in prevention and treatment of prostate cancer. One such agent is dutasteride, a non-selective inhibitor of 5α-reductase, an enzyme responsible for conversion of testosterone to a more potent androgen dihydrotestosterone (DHT).

Areas covered: This review will cover the safety profile of dutasteride when it is used in the treatment of prostate-related conditions, specifically looking at the pivotal clinical trials on this drug.

Expert opinion: Dutasteride has proved to be a safe and efficacious treatment for symptoms related to BPH. The primary safety concern relates to the increased incidence of high-grade prostate cancer seen in men treated with dutasteride in the setting of prostate cancer prevention. Dutasteride has a role as an adjunct in the treatment of prostate cancer; however, this is an area still under active investigation. It is not recommended for use in prostate cancer prevention given the increased risk of high-grade cancers.     

Sorafenib in liver cancer

Introduction: With growing knowledge of the molecular pathway of carcinogenesis, targeted therapies have become the ‘blue ocean' of cancer treatment. sorafenib is an oral multikinase inhibitor that targets Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) and several tyrosine kinases (VEGFR-2, VEGFR-3, PDGFR-β) that has shown efficacy in hepatocellular carcinoma (HCC).

Areas covered: An updated summary of the preclinical and clinical experience with sorafenib in HCC is presented in this paper. Data are based on abstracts from international conferences and journal articles found in a PubMed search of literature published up to December 2011.

Expert opinion: Based on favorable data from preclinical and clinical trials, sorafenib has been approved as a standard therapy in advanced HCC. However, further efforts to understand the additional roles of sorafenib in the treatment of HCC are still necessary. Data for sorafenib will guide the development of new drugs for the treatment of HCC.     

Treatment of postmenopausal osteoporosis with odanacatib

Introduction: The market of antiosteoporosis drugs has been declining in recent years, possibly in part due to the publicity around adverse events observed with bisphosphonates. Also, the proportion of patients with clinical fracture who receive adequate treatment remains low. So there are still unmet needs in this field. Odanacatib is a cathepsin K inhibitor currently being developed for the treatment of postmenopausal osteoporosis that could be an advance in this context.

Areas covered: Odanacatib is a bone resorption inhibitor, but it preserves some degree of bone formation, which differentiates this new family of drugs from existing therapies. Odanacatib increases bone mineral density at the spine and hip, improves estimated bone strength using finite element analysis at the spine and hip as well as at the distal tibia and radius. The safety profile has been satisfactory so far. A robust antifracture efficacy has been announced when the Phase III pivotal trial was terminated after interim analysis, but we do not yet have access to the complete results.

Expert opinion: Odanacatib may have an important role in future guidelines if it provides a substantial advantage compared to the effective and inexpensive current generic drugs, in terms of antifracture efficacy or safety.     

Iron sucrose – characteristics,efficacy and regulatory aspects of an established treatment of iron deficiency and iron-deficiency anemia in a broad range of therapeutic areas

Introduction: Iron is a key element in the transport and utilization of oxygen and a variety of metabolic pathways. Iron deficiency is a major cause of anemia and can be associated with fatigue, impaired physical function and reduced quality of life. Administration of oral or intravenous (i.v.) iron is the recommended treatment for iron-deficiency anemia (IDA) in different therapeutic areas.

Areas covered: This article provides an overview of studies that evaluated i.v. iron sucrose for anemia and iron status management, either alone or in combination with erythropoiesis-stimulating agents, across various diseases and conditions.

Expert opinion: Iron sucrose is an established, effective and well-tolerated treatment of IDA in patients with acute or chronic conditions such as chronic kidney disease, inflammatory bowel disease, pregnancy (second and third trimester), postpartum period, heavy menstrual bleeding and cancer who need rapid iron supply and in whom oral iron preparations are ineffective or not tolerated. Available data on patient blood management warrant further studies on preoperative iron treatment. First experience with iron sucrose follow-on products raises questions about their therapeutic equivalence without comparative clinical data in newly diagnosed patients or patients on existing chronic treatment.     

Drug safety evaluation of naltrexone/bupropion for the treatment of obesity

Introduction: Obesity is a known health risk for the development of several preventable diseases. Obesity-related metabolic alterations negatively impact different physiological mechanisms, which supports the rationale for the use of combined drug therapy. Naltrexone is an opioid antagonist for the treatment of opioid and alcohol dependency, whereas bupropion is a norepinephrine/dopamine reuptake inhibitor used to treat depression and smoking cessation. Although not effective as individual monotherapies for obesity, naltrexone and bupropion in combination produce weight loss and a metabolic profile beneficial for the potential treatment of obesity.

Areas covered: This review examines the safety and antiobesity effects of naltrexone and bupropion alone and in combination. It reviews the results of four Phase III clinical trials of a novel fixed dose of sustained-released naltrexone/bupropion.

Expert opinion: Naltrexone/bupropion has a greater weight loss efficacy than two FDA-approved medications, orlistat and lorcaserin. Although the weight loss produced by phentermine/topiramate is superior to naltrexone/bupropion, the safety profile of naltrexone/bupropion has less severe adverse effects. In addition, naltrexone/bupropion is well tolerated, with nausea being the most reported adverse event. Unlike other centrally acting medications, lorcaserin and phentermine/topiramate, naltrexone/bupropion has no abuse potential.     

Clozapine for the treatment of schizophrenia

Introduction: Despite considerable progress in the pharmacological treatment of schizophrenia, about 30% of patients are minimally responsive to antipsychotics and there is still an excessively high rate of mortality in schizophrenia patients. Clozapine, a D₂-5HT₂ antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death.

Areas covered: The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, based on a literature review (PubMed) from 1975 to 2012. Pivotal, as well as supporting, randomized controlled trials are reviewed, along with observational and/or naturalistic safety studies. This review of clozapine will allow the reader to determine the place for clozapine in the schizophrenia treatment landscape. Expert opinion: Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.     

Clinical management of rivaroxaban-treated patients

Introduction: Until recently, only vitamin K antagonists (VKAs) were used for long-term anticoagulation. New oral anticoagulants, with pharmacokinetic and pharmacodynamic characteristics different to VKAs, are now available for some indications. Rivaroxaban (Xarelto®) is an oral Factor Xa inhibitor approved in many countries for long-term treatment of patients with atrial fibrillation or venous thromboembolism. This article is addressed to all professionals involved in the management of treated patients to highlight the characteristics of rivaroxaban and provide practical guidance on management of treated patients.

Areas covered: This article is based on a consensus of specialists involved in the management of anticoagulant treatment, including thrombosis experts, cardiologists, neurologists, emergency medicine specialists, and general practitioners. The authors performed a nonsystematic review of the literature, and expressed guidance statements based on the results of the review as well as personal experience.

Expert opinion: Availability of new anticoagulant drugs, including rivaroxaban, is an important step forward to allow easier, more effective, and safer long-term anticoagulation in patients in whom adequate anticoagulation is currently denied due to the limitations of VKAs. However, given their totally new properties, associated risks, and expected broad clinical use, expert professionals and manufacturers must urgently tackle a series of issues.     

Bazedoxifene + conjugated estrogens in HT for the prevention of osteoporosis and treatment of vasomotor symptoms associated with the menopause

Introduction: The recent concept that estrogen agonist–antagonists, often referred to as selective estrogen receptor modulators, can be combined with an estrogen has led to the development of a novel form of menopausal therapy called Tissue-Selective Estrogen Complex (TSEC). This paper reviews the TSEC bazedoxifene and conjugated equine estrogens (BZA/CE).

Areas covered: This review is based on clinical trials and a PubMed search. The pharmacokinetics and pharmacodynamics of BZA in BZA plus CE are reviewed. This review outlines the effects of this particular TSEC, which maintains or increases bone mineral density in women at high risk for osteoporosis, and has clinical qualities of a promising new menopausal therapy. The potential adverse effects of BZA/CE combinations are summarized.

Expert opinion: A TSEC that contains CE and BZA that has both estrogen agonist and antagonist effects has reached clinical development. Phase III clinical trials show this TSEC relieves hot flashes, improves vulvo-vaginal atrophy and its symptoms, does not stimulate the endometrium, and prevents bone loss. In the trials so far it appears to have a good safety and tolerability profile. The optimum combination of BZA/CE combination is 20 mg BZA with CE 0.45 and 0.625 mg daily.     

Cisplatin: an old drug with a newfound efficacy – from mechanisms of action to cytotoxicity

Introduction: Cisplatin is a highly effective antineoplastic drug with an extremely current mechanism of action. Cisplatin-induced side effects are dose-dependent and limit the administration of increased dosages, thus compromising its therapeutic efficacy.

Areas covered: This review aims to describe the emerging knowledge about the biochemical mechanisms that mediate cisplatin cytotoxicity and side effects. A specific section is devoted to discuss the pathogenesis of cisplatin-related toxicities and the potential measures to counteract them.

Expert opinion: Although cisplatin has been used for a long time, only recently its exact mechanism of action has been better defined. The cytotoxic activity of cisplatin is largely dependent on the glycolytic metabolism of tumor cells: cisplatin redirects cancer cells to oxidative phosphorylation from the ‘Warburg effect', which is considered one of the most important mechanisms of tumor cell survival. The interference of cisplatin with glucose metabolism is also a cause of its relevant toxicities. The emerging knowledge on the complex mechanisms, which mediate cisplatin cytotoxicity and side effect, may lead to a more appropriate and safe use of this drug. Further studies are warranted to define and implement its effectiveness in combination with targeted drugs able to interfere with cellular energy metabolism, such as mTOR inhibitors.     

Efficacy of α-lipoic acid in diabetic neuropathy

Introduction: Neuropathy is a serious complication of diabetes. Its management focuses on glycaemic control, multifactorial cardiovascular risk intervention, pathogenesis-oriented therapy, and analgesics where needed.

Areas covered: The objective of this review is assessment of efficacy and safety of α lipoic acid (ALA, also thioctic acid) in pathogenesis-oriented treatment of diabetic neuropathy. The mechanisms of action of ALA in experimental diabetic neuropathy include reduction of oxidative stress along with improvement in nerve blood flow, nerve conduction velocity, and several other measures of nerve function. There is ample evidence from randomised, double-blind, placebo-controlled clinical trials and meta-analyses, suggesting that ALA is efficacious and safe for the diabetic neuropathy, accomplishing clinically meaningful improvements.

Expert opinion: ALA is a valuable therapeutic option for diabetic neuropathy. When compared with currently licensed analgesic drugs, it is better tolerated, has a more rapid onset of action, and improves paraesthesiae, numbness, sensory deficits, and muscle strength in addition to neuropathic pain. In clinical practice, ALA may be chosen in patients with early neuropathic deficits and symptoms, in whom clinical improvement is more likely. ALA should also be considered when comorbidities render other analgesics less appropriate or in the presence of cardiovascular autonomic neuropathy.     

Bendamustine for treatment of chronic lymphocytic leukemia

Introduction: Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than standard nucleoside analogue-based regimens are needed. Historically, few therapy options are available once CLL has become refractory to nucleoside analogues. Bendamustine has emerged as a feasible therapy for older and less fit CLL patients, with clinical efficacy in previously untreated and refractory CLL.

Areas covered: This paper reviews several of the pivotal clinical trials that established the clinical activity of bendamustine in previously untreated and relapsed/refractory CLL. The toxicity profile of bendamustine, primarily myelosuppression and infections, is reviewed and compared across different CLL populations. A review of the clinical data focuses on potential explanations for differences in response rates and duration of remission reported across studies and how this may impact the development of therapies for CLL.

Expert opinion: Bendamustine is a valuable new agent for the management of CLL. Ongoing clinical trials are comparing bendamustine with standard CLL regimens in untreated disease, and investigating bendamustine combinations with novel targeted therapies and monoclonal antibodies. These studies will help to define the optimal role for bendamustine in CLL management.