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.     

Safety of olanzapine use in adolescents

Introduction: Olanzapine was the second first-line atypical antipsychotic medication approved by the Food and Drug Administration (FDA) for the treatment of adult schizophrenia and later approved for adolescent schizophrenia and bipolar disorder. Initial studies performed on adults demonstrated efficacy compared to placebo and a first-generation antipsychotic medication. Initial assessments in adolescents with schizophrenia demonstrated significant symptom reduction without movement disorder, but with weight gain. Later studies reported efficacy for bipolar disorder in teenagers, but with weight gain. The assessment of olanzapine safety in teenagers has shown substantial weight gain and metabolic measures. Because of equivalent efficacy to other atypical antipsychotic medications and the metabolic side-effects, olanzapine is often recommended as a second-use medication.

Areas covered: Studies of olanzapine use in adolescents with schizophrenia or bipolar disorder demonstrate significant reduction in symptoms while causing no movement disorder side-effects. There has been reduction in use of olanzapine with adolescents as newer atypical antipsychotics have emerged associated with less weight gain.

Expert opinion: Studies of olanzapine have demonstrated effectiveness in adolescents with a psychotic illness. Metabolic side-effects are a strong concern of the field and have led to the recommendation of using the medication in a secondary fashion.     

Drug safety and efficacy evaluation of sertindole for schizophrenia

Introduction: Despite the progress in antipsychotic treatment, modern antipsychotic medication is still associated with side effects, reduced compliance, drug discontinuation and insufficient effects on negative and cognitive symptoms. Sertindole is an antipsychotic compound, with high affinity for dopamine D₂, serotonin 5-HT_2A, 5-HT_2C and α₁-adrenergic receptors, which has been reintroduced in the market after extended re-evaluation of its safety and risk–benefit profile.

Areas covered: Sertindole's pharmacological profile, pharmacokinetics, neuophysiological properties, efficacy on positive, negative and cognitive symptoms and safety issues are covered in this article, based on a literature review from 1990 to 2012.

Expert opinion: Based on five double-blind, randomized, placebo-, haloperidol- or risperidone-controlled studies in patients with schizophrenia, sertindole shows a comparable efficacy with haloperidol and risperidone on positive symptoms, while the effect on negative symptoms seems to be superior. Sertindole is generally well tolerated, but is associated with a dose-related QTc interval prolongation (+22 ms). Risk factors for drug-induced arrhythmia, such as cardiac diseases, congenital long QT syndrome, prolongated QTc at baseline, etc. and drug interactions should be considered before prescribing sertindole. To minimize cardiovascular risk, regular ECG recording is required. Sertindole can be an important second-line option for the treatment of schizophrenia for patients intolerant to at least one other antipsychotic. Further comparison with other SGAs and investigations on subgroups (e.g., children, elderly, first-episode, treatment-refractory patients, etc.) are still needed for a precise understanding of the therapeutic benefits and its role in schizophrenia therapy.     

Drug safety evaluation of olanzapine pamoate

Introduction: Olanzapine pamoate is one of three second-generation antipsychotics available as depot medication. While non-adherence is a major problem in the treatment of schizophrenia, olanzapine pamoate can improve adherence, though its use is limited by its safety profile.

Areas covered: The review covers data on efficacy with a focus on tolerability and safety of olanzapine pamoate using the known databases including PubMed, Psychinfo and Embase using keywords. Relevant websites were also reviewed.

Expert opinion: Olanzapine is an efficacious antipsychotic that can be used in its oral and depot formula (olanzapine pamoate) for the treatment of patients with schizophrenia. It has demonstrated superiority over conventional and some other atypical antipsychotics, with both formulas having comparable low rates of motor side effects. The side effects on body weight and glucose homeostasis are also similar in both formulas and limit its use. The only clear difference regarding side effects is ‘the risk that 0.07% of injections in preclinical trials have led to a post-injection delirium/sedation syndrome event which requires a risk management plan'. Especially in outpatients this could cause inconveniences that should be overcome by offering, for example, psychological therapies or psychoeducation to effectively use the time when patients have to remain in the healthcare facilities.     

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.     

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.     

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.     

Sumatriptan succinate: pharmacokinetics of different formulations in clinical practice

Introduction: Migraine is a common neurovascular disorder characterized by recurrent episodes of disabling headache, autonomic nervous system dysfunction, and in some patients, neurological aura symptoms. Triptans are frequently prescribed drugs for the treatment of the acute migraine attack, considering their capability to provide wide efficacy and tolerability.

Areas covered: This review discusses pharmacodynamics and pharmacokinetics of sumatriptan succinate, considering the clinical impact of new drug formulations in the treatment of acute migraine and cluster headache. The data were obtained by searching the following keywords in MEDLINE: sumatriptan succinate, pharmacokinetics, pharmacodynamics, triptans, migraine, new delivery systems, relative to the period 1989 – 2012.

Expert opinion: Subcutaneous sumatriptan has been considered as the most efficacious treatment in the acute phase of migraine both on pain alone as well as on associated autonomic symptoms. Pharmacologically, pharmacokinetic parameters, in particular bioavailability, T_max and C_max are responsible for the wide efficacy of the compound and the limited adverse effect (AE) profile. The new drug formulations that are the most similar to the pharmacokinetics parameters of the subcutaneous one are promising because they both improve pharmacokinetic bioavailability bypassing the first-pass metabolism and increase patient compliance.     

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.     

Potential use of lurasidone for the treatment of bipolar psychosis

Introduction: Second-generation antipsychotics (SGA) are new treatment options for bipolar disorders (BDs). Lurasidone is one such SGA, which is currently approved as a monotherapy for bipolar I depression (BPID) and as an add-on therapy for acute schizophrenia.

Areas covered: In this drug evaluation, the authors illustrate the pharmacological profile of lurasidone and review its development history. The aim of this review is to evaluate whether this compound could be used in psychotic BDs.

Expert opinion: The pharmacological profile of lurasidone, its action on receptors, its role in neurogenesis and its cognitive performance suggests a potential use in psychotic episodes of BDs and mania. This hypothesis is also supported by the clinical observations from case reports concerning resolutions of BPID with psychotic features, where psychotic episodes were diagnosed as schizophrenia and reclassified as BDs after the patient was able to reconstruct his/her clinical history. The use of lurasidone may have the advantage of a low side-effect profile and a possible efficacy in preventing the impairment of cognitive performance. However, randomized clinical trials assessing the efficacy of lurasidone in the treatment of manic episodes as well as manic episodes with psychotic components are still needed.     

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.     

The mechanism,efficacy, and tolerability profile of agomelatine

Introduction: Agomelatine is a novel antidepressant that acts as a melatonin MT₁ and MT₂ receptor agonist and serotonin 5-HT_2C receptor antagonist, putatively reversing circadian rhythm disruption in major depressive disorder (MDD) and promoting dendritic neurogenesis in animal models of depression. It may be a preferable alternative to antidepressants currently in use due to its improved tolerability profile.

Areas covered: The PubMed database was searched for published randomized controlled trials (RCTs) evaluating the efficacy of agomelatine as well as its tolerability and safety in the treatment of MDD. The key search term used was agomelatine combined with major depressive disorder/depressive disorder/depression and antidepressant. Article selection was based upon sample size and overall methodological quality.

Expert opinion: Agomelatine is a multi-modal agent with novel mechanisms of action, having sound evidence supporting its overall statistical efficacy and adequate tolerability profile for MDD treatment. However, the clinical significance of agomelatine has been contested, calling for additional studies in evaluation of its effect size. Of further concern are reported transient elevations in transaminases and severe but rare liver reactions.     

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.     

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.     

Bepotastine besilate for the treatment of pruritus

Introduction: Bepotastine besilate 1.5% is a newly approved second-generation topical antihistamine indicated for the pruritus associated with allergic conjunctivitis. In Japan, the oral formulation is approved to manage pruritus associated with allergic rhinitis and urticaria.

Areas covered: Bepotastine is a piperidine derivative that antagonizes H1 receptors with high selectivity. It has been labeled a dual-acting or multiple-acting antiallergic medication, because it inhibits histamine at H₁ receptors and stabilizes mast cells to prevent histamine release. Bepotastine may also have other immunoactive properties, such as inhibition of eosinophil migration, interleukin-5 (IL-5), leukotrienes (e.g., LTB₄) and platelet-activating factor (PAF). Human clinical trials demonstrate the efficacy and safety of systemic and ophthalmic bepotastine for pruritus relief, limited penetration across the blood–brain-barrier and kinetics suitable for twice-daily administration.

Expert opinion: Bepotastine besilate 1.5% ophthalmic solution is a safe and effective treatment option for allergic conjunctivitis associated pruritus. Side-effect profile is similar to other ocular antihistamine agents. Additional comparative-effectiveness studies would further advance its clinical use. Oral bepotastine is a safe and effective treatment option approved in Japan for allergic rhinitis, urticaria and pruritus associated with skin diseases.     

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.     

Everolimus for the treatment of pancreatic neuroendocrine tumors

Introduction: Pancreatic neuroendocrine tumors (PNET) represent the second most common primary malignancy of the pancreas. Until recently, therapeutic options for advanced PNET have been limited.

Areas covered: A recently published Phase III clinical trial demonstrated striking therapeutic activity of the mTOR inhibitor everolimus in advanced PNET and led to its approval for this indication by the FDA. This review discusses this landmark discovery in the context of currently available therapeutic options, pathophysiology and molecular genetics of PNET.

Expert opinion: The approval of everolimus for the treatment of PNET marks a major step forward in the clinical management of this disease and represents a notable example of the successful translation of a targeted therapy that was initially developed based on findings at the lab bench, into everyday clinical practice. These results encourage hopes that the overall therapeutic efficacy of such approaches can be further enhanced by the introduction of combinatorial regimens, simultaneously targeting more than one oncogenic signaling pathway, as well as by stratification of patients based on the individual genetic setup of their tumors.