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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Vercirnon for the treatment of Crohn's disease

Introduction: CCR9 antagonism is a promising new therapeutic approach for the treatment of Crohn's disease. CCR9 is expressed on the cell surface of memory/effector CD4⁺ T cells and selectively binds to the small intestinal lymphocyte chemoattractant CCL25 (TECK). Blockade of the CCR9/CCL25 interaction inhibits lymphocyte homing to the intestinal mucosa, thereby limiting inflammation and disease at this site.

Areas covered: This review details the current research on CCR9 antagonism and summarizes available clinical trial data for vercirnon, a selective CCR9 antagonist currently under development.

Expert opinion: If the results of ongoing large-scale clinical trials of vercirnon are in line with preliminary reports, CCR9 antagonism may have comparable efficacy to anti-TNF therapies and a potentially superior safety profile, making it the latest addition to the growing arsenal of immunomodulatory drug therapies available to combat Crohn's disease. Moreover, since vercirnon is an oral drug, its associated costs will likely be much lower than expensive infusion-based anti-TNF therapies, providing further economic benefits.     

Agomelatine in depression

Introduction: Agomelatine is a relatively new antidepressant with a mechanism of action that is different from other antidepressants: it is a melatonergic agonist and a 5-HT2C antagonist. It is an effective treatment for depression, with relatively mild side effects. It may be a valuable pharmacological alternative in the clinical approach on depression.

Areas covered: The literature about agomelatine has been comprehensively reviewed. Agomelatine's efficacy, safety and tolerability are reviewed based on the studies undertaken in patients with major depressive disorder (MDD) and bipolar disorder (BPD).

Expert opinion: Agomelatine has shown an antidepressant effect in preclinical models, and the results of a large-scale clinical trial program, conducted in MDD, indicate both an antidepressant activity and a favorable tolerability profile. Agomelatine has no discontinuation syndrome, sexual discomfort is rare, and it is generally weigh neutral. The drug appears to be relatively safe in case of overdose. However, some cases of elevated hepatic transaminases are reported during treatment. As agomelatine has a mechanism of action that differs from other agents, it may represent a valuable additional treatment option in those patients who do not respond fully or who do not tolerate the side effects of other antidepressants.     

A review of published evidence reporting on the efficacy and pharmacology of lurasidone

Introduction: Lurasidone is a benzisothiazol derivative, approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia. Lurasidone's binding affinities are highest for the 5-HT_2A, 5-HT₇, and D₂ receptors; with lower and similar binding affinities for the norepinephrine α_2C and 5-HT_2C receptor subtypes. It has demonstrated efficacy in fixed-dose studies across a variable dose range (i.e., 40 – 160 mg), with a recommended starting dose of 40 mg and a maximum recommended dose of 80 mg. Lurasidone's preclinical profile is predictive not only of efficacy against psychotic and negative symptoms but also of affective symptomatology and cognitive deficits. Controlled trials are currently underway to evaluate lurasidone's efficacy in bipolar depression as well as its procognitive effects in individuals with schizophrenia. Lurasidone is administered once a day with ≥ 350 calories of food, regardless of fat content. Lurasidone is not known to adversely affect body composition, anthropometrics, metabolic and/or electrocardiographic parameters. Although prolactin elevation might be observed, prolactin-related adverse events are rarely reported.

Areas covered: This paper presents the pharmacodynamics and pharmacokinetics of lurasidone, and discusses its efficacy, safety and tolerability data.

Expert opinion: Lurasidone's simplicity of use and favorable metabolic profile are distinct advantages relative to several other agents (e.g., olanzapine). Outcomes in cognitive data analyses are awaited to determine if there is a key differentiator between lurasidone and other atypical agents with respect to efficacy. Moreover, lurasidone's efficacy in bipolar depression is awaited to determine whether this agent can be considered as a treatment alternative for depressive symptoms in adults with bipolar disorder.     

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.     

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.     

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.     

Evaluating aripiprazole as a potential bipolar disorder therapy for adults

Introduction: Second generation antipsychotics (SGAs) have emerged as new treatment options for bipolar disorders (BDs). Aripiprazole (ARI) is already an SGA approved therapy for the treatment of BD type-I, both as a monotherapy as well as an add-on therapy in acute mania and in long-term maintenance therapy.

Areas covered: The authors provide a systematic review that illustrates ARI’s pharmacological profile including its efficacy on various aspects of BD in adults. It also reviews its role in bipolar treatment algorithms and provides a focus on future research developments and further potential uses of the compound. Additional aspects such as safety and tolerability are also considered.

Expert opinion: Compared with haloperidol, ARI shows fewer extrapyramidal symptoms (EPS), but has a slightly lower efficacy in mania. It has a better metabolic parameter profile and fewer cardiovascular adverse events than other SGAs although the add-on treatment shows a higher risk of EPS. Presently, data doesn’t support its use as a first choice maintenance monotherapy but it may be useful as a combination therapy for BD patients with comorbidities such as drug abuse and obsessive-compulsive disorders. Studies on ARI in bipolar depression are disappointing. However, future studies on the drug, at a low dose combined with a stabilizer or antidepressant may prove interesting.     

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.