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.     

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.     

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.     

Desvenlafaxine for the treatment of major depressive disorder

Introduction: Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability.

Areas covered: This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine, one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed.

Expert opinion: Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.     

Azacitidine for myelodysplastic patients aged > 65 years: a review of clinical efficacy

Introduction: Therapeutic strategies for elderly patients affected by myelodysplastic syndromes (MDS) are scarce and only few patients have an advantage in performing allogeneic bone marrow transplant.

Areas covered: Primary endpoints for treatment of elderly MDS patients were not curative, but rather allowing to maintain a good quality of life through prolongation of overall survival. In this context, azacitidine showed to improve responses in this subset of patients compared to conventional established regimens, such as intensive or low-dose chemotherapy and best supportive care. Good safety profile of the drug was reported either when it was used inside or outside clinical trials. Improved quality of response was observed when the drug was administered beyond the first response, and it is now usually recommended to continue it at the same dose and schedule in responding patients.

Expert opinion: Evaluation of baseline prognostic factors and comorbidities may help to identify patients who can benefit from the prolonged administration of the drug. Real life data regarding efficacy and safety of azacitidine in MDS elderly patients are required in order to confirm the results of clinical trials.     

Dapagliflozin: a review on efficacy,clinical effectiveness and safety

Introduction: The prevalence of type 2 diabetes mellitus has reached epidemic proportions. Progressive deterioration in glycaemic control and the current limitations of existing therapies such as weight gain and hypoglycaemia led us to welcome the first of a new class of drugs. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a novel mode of therapy independent of insulin secretion or action. By blocking glucose reabsorption in the kidney they lead to an increase in urinary glucose excretion with reduction in plasma glucose levels.

Areas covered: In this article, we will review inhibition of SGLT2 as a novel strategy for the treatment of type 2 diabetes mellitus with dapagliflozin. PubMed and MEDLINE were searched for literature published up to July 2012, for efficacy, clinical effectiveness and safety reports of dapagliflozin.

Expert opinion: Improvement in glycaemic control with a low risk of hypoglycaemia, concomitant weight loss and the potential of lowering of blood pressure make SGLT2 inhibition an attractive approach using dapagliflozin therapy. Many SGLT2 inhibitors are undergoing Phase III clinical trials and more are in Phase I and II clinical trials.     

Safety and tolerability of pazopanib in the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development.

Areas covered: This review briefly discusses the mechanisms of action and clinical applications of pazopanib. It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC.

Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.     

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.     

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.     

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.     

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.     

A safety evaluation of ranibizumab in the treatment of age-related macular degeneration

Introduction: The use of intravitreal ranibizumab has transformed the outcomes for thousands of patients with wet age related macular degeneration (AMD), which is the leading cause of blindness in developed countries. Prior to its introduction, most patients with wet AMD would rapidly lose central vision. The use of intravitreal ranibizumab has been shown to reduce certifiable visual loss by about a half. Current treatment regimens with ranibizumab in wet AMD require multiple injections over several years and so it is highly relevant to review the safety record of this important drug.

Areas covered: This review considers the important ocular and systemic adverse events (AE) that have been reported in the literature, particularly in the context of the pivotal clinical trials that have been performed. It also reviews the safety of other anti-VEGF drugs that are used in wet AMD, namely bevacizumab and aflibercept, and compares these drugs with ranibizumab.

Expert opinion: Overall, intravitreal ranibizumab can be considered a safe and highly effective drug for patients with wet AMD. However recent concerns about retinal thinning following ranibizumab therapy, possible systemic AE associated with all anti-VEGF drugs and the occurrence of complications relating to drug preparation and delivery must be considered.     

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.     

Nalfurafine hydrochloride for the treatment of pruritus

Introduction: Severe pruritus associated with end-stage renal disease is a particularly troublesome complication, because no effective treatment has been established. However, based on the findings of a recent randomized controlled trial, nalfurafine hydrochloride was officially approved in Japan for the treatment of resistant pruritus in hemodialysis patients.

Areas covered: This review is based upon a PubMed search and personal experience with nalfurafine hydrochloride. The pharmacokinetics and pharmacodynamics of nalfurafine hydrochloride are reviewed and its efficiency and potential adverse effects are discussed, mainly based on the findings of randomized controlled trials.

Expert opinion: A recent long-term open trial showed that the effect of nalfurafine hydrochloride was enhanced by continuous, long-term administration. It will be of future interest to investigate its effect on excoriations, lichen simplex, prurigo nodularis and acquired perforating dermatosis (all caused by uremic pruritus), because it targets both the skin and the central nervous system. In clinical practice, it should be kept in mind that basic skin care with emollients and other topical drugs is essential for stopping the itch–scratch cycle, and the resultant skin barrier dysfunction.     

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.     

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.