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.     

Dimethyl fumarate: a Janus-faced substance?

Introduction: Dimethyl fumarate (DMF) has been used as fungicide, but oral DMF activates anti-inflammatory and anti-oxidative pathways that are beneficial in the treatment of psoriasis. BG-12, a specific formulation of DMF, has been approved very recently for the treatment of relapsing-remitting multiple sclerosis (RRMS), which is characterized by both autoimmune lymphocytes leading to inflammation and mitochondrial alterations associated with oxidative stress.

Areas covered: This review describes the pharmacokinetics and the mode of action of DMF, with a focus on molecular and cellular pathways, and discusses clinical results of DMF in RRMS treatment. To identify relevant publications, the author searched the PubMed database by using appropriate keywords and by searching for references cited within the obtained articles.

Expert opinion: DMF demonstrated efficacy in several RRMS outcome measures related to disease activity and severity, but results on disability progression have been inconsistent. The overall safety profile might qualify DMF for long-term use, the frequency of side effects such as gastrointestinal complaints and flushing might hamper treatment adherence of MS patients. Since DMF covalently binds to intracellular proteins, the fate of this molecule in the body might need thorough long-term observation during clinical use.     

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.     

Tolterodine for the treatment of urge urinary incontinence

Introduction: Overactive bladder (OAB) and its resultant urge urinary incontinence (UUI) are significant problems that medically, psychologically and financially affect people. The constellation of symptoms comprising OAB affects ～ 16% of the adult population and its prevalence increases with aging. The typical class of medications used to treat OAB is antimuscarinics.

Areas covered: OAB medications, with a focus on tolterodine for the treatment of UUI are reviewed. A thorough review of English language literature using EMBASE/Medline and PubMed has been performed.

Expert opinion: Tolterodine provides a reasonable starting point when treating patients with OAB and UUI. Efficacy and tolerability are generally comparable between tolterodine and other newer antimuscarinics. Tolterodine is a good option as part of the algorithm in the treatment of OAB and UUI.     

Asenapine review,part II: clinical efficacy,safety and tolerability

Introduction: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes.

Areas covered: The purpose of this review is to describe the clinical profile of asenapine.

Expert opinion: Asenapine's efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 – 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine's overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine's effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin.     

Lenalidomide as a novel treatment of acute myeloid leukemia

Introduction: Lenalidomide is an oral immunomodulatory drug derived from thalidomide. This drug has been approved by the Food and Drug Administration for transfusion-dependent anemia due to low-risk myelodysplastic syndromes (MDS) associated with deletion 5q abnormality with or without additional cytogenetic abnormalities and multiple myeloma in combination with dexamethasone. Trials have been conducted for its use in higher-risk MDS and acute myeloid leukemia (AML).

Areas covered: The pharmacokinetic and mechanism of action are discussed and clinical studies of lenalidomide in AML are reported herein in detail. An overview of safety and tolerability is also presented.

Expert opinion: Lenalidomide has clinical activity in AML with manageable toxicity. The population that would benefit from lenalidomide and optimal dose needs to be better defined. Recent trials have focused on combining lenalidomide with other agents active in MDS and AML and promising data are emerging.     

Quetiapine for the treatment of acute bipolar mania,mixed episodes and maintenance therapy

Introduction: Bipolar disorder is characterized by mood instability, which can be challenging to manage. First-line pharmacological approaches usually involve lithium, anticonvulsants and antipsychotics. Over the past fifteen years, several second-generation antipsychotics have demonstrated benefits for various phases of this disorder.

Areas covered: This article examines the pharmacodynamics and pharmacokinetics of quetiapine; its evidence base as an acute and maintenance monotherapy or adjunctive therapy for bipolar manic or mixed episodes is also discussed, along with the related issues of its safety and tolerability.

Expert opinion: In the context of bipolar disorder, quetiapine is the only agent approved as a monotherapy or adjunct therapy for acute manic/mixed episodes in adults and adolescents; as a monotherapy for acute depressive episodes in adults; and as an adjunctive maintenance therapy for bipolar I and II disorder in adults. In addition to its antipsychotic properties, this broad mood-stabilizing potential may simplify the management of select patients.     

Vandetanib for the treatment of lung cancer

Introduction: VEGF and EGFR are validated pathways for targeted therapy in non-small cell lung cancer (NSCLC). Once considered to be separate targets, VEGF and EGFR are now shown to have interconnected downstream pathways, potentiating the effectiveness of their dual signaling inhibition in cancer therapy. Molecules such as vandetanib that inhibit VEGFR and EGFR have also been reported to inhibit other receptors, including RET and additional kinases, and may be beneficial in treating patients with solid tumors.

Areas covered: This review covers the significance of targeting VEGF and EGFR in the treatment of NSCLC and the rationale behind their dual inhibition. Clinical trials that evaluate the use of vandetanib in the setting of refractory NSCLC are also explored.

Expert opinion: Vandetanib is currently not approved in the setting of NSCLC. However, its approval for medullary thyroid cancer makes it promising for identifying markers and potentially a NSCLC patient population who will benefit from the treatment.     

Lacosamide in patients with pharmacoresistant epilepsy

Introduction: Lacosamide is a novel antiepileptic drug licensed in the US and Europe as adjunctive therapy for partial-onset seizures in adults. The efficacy, safety, tolerability and favorable pharmacokinetic profile in the adult population suggest that lacosamide could be of benefit for patients with partial-onset seizures.

Areas covered: This paper reviews the available evidence and most recent data concerning the efficacy, safety, tolerability and pharmacokinetics of lacosamide in adults, as well as in the pediatric population.

Expert opinion: Lacosamide is one of the newest drugs of the antiepileptic armamentarium, and it is expected to compete directly with compounds that are currently used for adjunctive therapy in adults with refractory partial epilepsy. The intravenous formulation may be used for replacement therapy in patients temporarily unable to take oral medication. An apparent lack of sedative or cognitive effects might render this drug preferable in patients with mental insufficiency and/or epileptic encephalopathy.     

Safety of topiramate for treating migraines

Introduction: Migraine is a very common medical disorder characterized by attacks of moderate-severe headache, nausea and disability. Topiramate is an effective, popular prophylactic migraine treatment, which is approved for use in adults and adolescents. Due to its multiple mechanisms of action, topiramate has multiple potential safety issues, including systemic and CNS adverse events, which may complicate therapy.

Areas covered: This review evaluates common adverse events as seen in the pivotal trials of topiramate for migraine as well as those observed in postmarketing studies. These include weight loss, metabolic acidosis, renal calculi, acute angle closure glaucoma, visual distortions and cognitive slowing. Topiramate use during pregnancy is associated with an increased risk of cleft lip. This review highlights both common and unusual safety issues associated with topiramate use, including important drug interactions and a comparison with other migraine prophylactic agents.

Expert opinion: Topiramate is highly effective in migraine prophylaxis but clinicians using the drug need to be aware of the potential for bothersome or serious adverse events. When treating with topiramate, use a slow titration to the goal dose of 100 mg or the lowest dose, which helps prevent migraine.     

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.     

Acarbose plus metformin fixed-dose combination in the management of type 2 diabetes

Introduction: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. Concerns in the management of diabetes include drug-induced hypoglycemia, poor control of postprandial blood glucose level and weight gain. A carbohydrate-rich diet can cause more load on the intestinal cells producing α-glucosidase. Many patients need combination treatment based on their level of glycemic control and other associated parameters. In such cases, a therapy that provides effective glycemic control with minimal or no risk of adverse events like hypoglycemia or weight gain is highly desired. The chances of cardiovascular events are high in diabetes patients; hence, medicines providing benefits beyond glycemic control such as reduced cardiovascular risk factors may be ideal in such patients.

Areas covered: Current available data are related to the rationale and clinical trials on the fixed-dose combination of acarbose plus metformin in management of type 2 diabetes.

Expert opinion: Combination therapy is routinely prescribed in the management of T2DM. Drugs with complimentary mechanisms should be used to maximize the efficacy of combination therapy. The combination of metformin and acarbose is a rational therapy because of their different and complimentary mechanisms of action, which provides effective glycemic control with additional cardiovascular benefits and minimizes adverse events.     

Latanoprost/timolol fixed combination for the treatment of glaucoma

Introduction: Glaucoma is a multifactorial optic neuropathy that can lead to progressive and irreversible loss of vision. Today there are > 60 million glaucoma patients worldwide, and this figure is rising due to aging. The aim of glaucoma therapy is to maintain the patient's visual function and quality of life by means of intraocular pressure (IOP) reduction, which currently constitutes the only evidence-based approach.

Areas covered: Briefly discussed are selected, recent evidence on antiglaucoma fixed combinations. Then the efficacy and safety of the latanoprost/timolol fixed combination is comprehensively reviewed.

Expert opinion: The latanoprost/timolol fixed combination can be a helpful stepwise therapeutic option in patients whose IOP is insufficiently controlled with monotherapy options. Future research is needed to better delineate the role and value of this medication in glaucoma therapy.     

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.     

Antiarrhythmic properties of ranolazine – from bench to bedside

Introduction: Pharmacological management of cardiac arrhythmias is limited by the reduced availability of safe and effective antiarrhythmic agents.

Areas covered: Ranolazine is an agent currently used for the treatment of angina, which inhibits transmembrane ionic currents involved in several phases of the action potential in both the atrial and the ventricular cells. Due to its mechanism of action, ranolazine has been shown to exhibit antiarrhythmic properties that have been validated in the experimental models. This article recapitulates the mechanism of antiarrhythmic action of ranolazine, the existing clinical data, and the ongoing relevant clinical trials.

Expert opinion: The combination of the antiischemic properties of ranolazine with its antiarrhythmic potency and minimal proarrhythmia provides a promising background that could expand its therapeutic role in the management of atrial fibrillation and ventricular tachyarrhythmias. Data derived from adequately powered randomized clinical trials will determine whether the door to a new indication will open for ranolazine in the near future.     

Long-term safety of ustekinumab for psoriasis

Introduction: The biologic, Ustekinumab (Stelara®, Centocor, Inc., Malvern, PA, USA), is a fully human monoclonal antibody with a high affinity for the shared p40 subunit of interleukins 12 and 23 (IL-12 and IL-23). Approved for use in treating moderate-to-severe psoriasis in 2009, there has been considerable interest in the long-term safety of ustekinumab.

Areas covered: This review discusses the use of ustekinumab in the treatment of psoriasis and its potential to be an effective and well-tolerated therapy. A literature search was performed for articles published through April 2013 to identify any safety concerns.

Expert opinion: Our results indicate that ustekinumab has demonstrated higher efficacy rates as compared to traditional therapies; and with a favorable dosing schedule and stable safety profile, patients with recalcitrant disease will now have another option for treatment.     

Targeting the Janus kinases in rheumatoid arthritis: focus on tofacitinib

Introduction: Treatment of rheumatoid arthritis (RA) has markedly advanced by the advent of biologic disease-modifying antirheumatic drugs (DMARDs). However, they require special storage and transportation and remission is observed in ～ 30%. Tofacitinib inhibits the nonreceptor tyrosine kinase family Janus kinase (JAK), which is activated immediately after cytokines bind to their receptor within the cytoplasmic membrane.

Areas covered: Tofacitinib is an orally available tablet and treatment efficacy is similar to biologic DMARDs. Pharmacokinetics, and drug–drug interaction is covered in this article. In addition, efficacy and adverse events from the Phase II and Phase III are overviewed. Additionally, the authors have described the novel mechanism of action (MOA) of tofacitinib in relevance to efficacy and adverse events. Because of its MOA, greater caution is necessary for selecting appropriate patients for treatment initiation and further treatment continuation following clinical trials.

Expert opinion: Tofacitinib is a new class of DMARDs orally available with a new mechanism of action and with strong clinical efficacy similar to biologic DMARDs. Multiple cytokines and signaling pathways are partially inhibited at clinical doses that are in contrast to biological DMARDs. Further investigation is necessary to come to a conclusion on risk-benefit ratio and selection of patients.