Use of duloxetine in patients with an anxiety disorder,or with comorbid anxiety and major depressive disorder: a review of the literature

Importance of the field: Except for generalized anxiety disorder, few reports have been published on the efficacy, safety and tolerability of duloxetine in patients with anxiety disorders individually or in comorbidity with major depressive disorder (MDD).

Areas covered in this review: The literature search in Medline (dating back to 1966) and Embase (dating back to 1988) databases was conducted using the OVID interface on 9 April 2009, restricted to any article or abstract in English, per title, reporting any information on the use of duloxetine in patients with any anxiety disorder with or without concomitant MDD. A systematic review approach was taken.

What the reader will gain: The reader will gain knowledge of the current data available on the use of duloxetine to treat patients with anxiety disorders individually or in comorbidity with MDD.

Take home message: Duloxetine could be considered an effective treatment option in the treatment of anxiety disorders individually or in comorbidity with each other, or with MDD; however, apart from the well-demonstrated efficacy, tolerability and safety of duloxetine in the treatment of MDD with or without anxiety and GAD, data on this subject are preliminary and very limited, and more research is warranted.     

Nervous system adverse responses to topiramate in the treatment of neuropsychiatric disorders

Importance of the field: Nervous system adverse drug reactions (NS-ADRs), such as cognitive complaints and paresthesia, are among the most frequent and clinically important ADRs of topiramate. Studying ADR profiles across disorders is clinically relevant because treatment decision-making in neuropsychiatry is highly guided by ADR profiles.

Areas covered in this review: We used medline searches (until July 2009) to review the NS-ADRs of topiramate across the most investigated topiramate indications: alcohol dependence, essential tremor, binge-eating disorder, bulimia nervosa, migraine and epilepsy. We compared NS-ADRs between these disorders but did not carry out meta-analysis.

What the reader will gain: ADR profiles greatly differed between disorders. Drop-outs due to ADRs highly varied between disorders: from 2% in the bulimia nervosa group to 29% in the migraine group. Paresthesia was the most common NS-ADR for all disorders but frequencies also differed between disorders. Cognitive complaints were frequent and were reported in comparable proportions.

Take home message: When prescribing topiramate in neuropsychiatry, physicians should be aware that NS-ADR profiles have been found to differ between disorders. Differences in drop-out rates due to ADRs and in frequencies of specific NS-ADRs across disorders must be taken into account when evaluating the potential harm of topiramate in clinical practice.     

Prucalopride for constipation

Importance of the field: Chronic constipation has a high prevalence, and current medical and pharmacological therapies do not restore normal bowel function in all patients.

Areas covered in the review: A PubMed search (1965 – 2009) using the following terms alone or in combination: prucalopride, 5-HT₄, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, hERG, arrhythmia, potassium current, elderly.

What the reader will gain: Understanding of the mechanisms of action, safety, efficacy and indications for prucalopride in patients with chronic constipation.

Take home message: Prucalopride is an efficacious and generally safe, new therapeutic option in the management of chronic constipation.     

Supporting Asian patients with metastatic breast cancer during ixabepilone therapy

Importance of the field: Ixabepilone is currently FDA-approved in metastatic breast cancer, and most patients in the registrational trials were Caucasian. Studies in Asian populations receiving other cytotoxic agents have revealed differential pharmacokinetics and clinical outcomes. As such, clinicians should understand the possible contributions of Asian ethnicity and culture to the clinical profile of ixabepilone.

Areas covered in this review: Studies in Asian patients receiving other chemotherapeutics reported altered toxicity profiles for myelosuppression, neurotoxicity and gastrointestinal symptoms. Encouragingly, the limited clinical data in Asian patients receiving ixabepilone suggest that efficacy and toxicity in these women resemble those reported in the ixabepilone registrational trials.

What the reader will gain: The reader will better understand how Asian genetics and culture may influence treatment outcomes and patient attitudes toward therapy and interaction with caregivers. Management of ixabepilone-related adverse events is also discussed with an emphasis on special considerations for Asian patients.

Take home message: Awareness of possible altered drug response in Asian patients will aid clinicians in monitoring for toxicity, recognizing the need for dose modification and educating patients. Sensitivity to cultural aspects that are unique to Asians may improve adherence, reporting of adverse events and trust among Asian patients receiving ixabepilone.     

Pharmacoeconomics of voriconazole

Importance of the field: The recent increase in the use of antineoplastic and immune suppressive agents and the use of broad-spectrum antibiotics, prosthetic interventions, organ transplants and more aggressive surgery have been related to a greater prevalence of invasive fungal infections (IFI). Over the past few years, several new antifungal therapies have become available for these patients. Pharmacoeconomic data can play a useful role in comparing the relative benefits of treatment.

Areas covered in this review: This review summarizes all the available evidence regarding the pharmacoeconomics of voriconazole. A systematic review of pharmacoeconomic analyses through a non-restricted literature search was conducted (until May 2009).

What the reader will gain: The reader will gain a greater understanding of the pharmacoeconomics role of voriconazole.

Take home message: The majority of economic analyses have shown that voriconazole is a more cost-effective alternative in the treatment of invasive fungal infections than the antifungal drugs with which it was compared.     

Quetiapine: novel uses in the treatment of depressive and anxiety disorders

Importance of the field: Quetiapine, an atypical antipsychotic, has been approved for the treatment of schizophrenia, acute mania, bipolar depression and unipolar major depression. However, it is often used (off-label) to treat other depressive disorders and anxiety disorders in children and adults.

Areas covered in this review: This article reviews the evidence for the safety and efficacy of quetiapine in these populations, as both monotherapy and augmentation to other psychotropics.

What the reader will gain: This article provides an in-depth review of the published literature on the topic and also provides recommendations for use.

Take home message: There is strong evidence to support the use of quetiapine in major depressive and generalized anxiety disorders, and preliminary support for treatment-resistant and psychotic depression. There is reasonable evidence of its benefits as an augmenting agent in obsessive-compulsive disorder, while data in other anxiety disorders are limited but promising. While long-term tolerability data are limited, quetiapine appears well tolerated in the short-term. Further randomized controlled trials are needed to confirm the efficacy and tolerability of quetiapine, both short- and long-term, in many of these conditions.     

Indacaterol maleate for the treatment of chronic obstructive pulmonary disease

Importance of the field: Chronic obstructive pulmonary disease (COPD) is a partially reversible, progressive obstructive disorder. Bronchodilators are the mainstay of treatment since they improve lung function and patient-reported outcomes and reduce acute exacerbations. Long-acting inhaled bronchodilators (at present including the once-daily antimuscarinic tiotropium, and the twice-daily β₂-agonists formoterol and salmeterol) are recommended as first-line treatment for patients with persistent symptoms. Indacaterol maleate has been developed as a new once-daily inhaled β₂-selective agonist.

Areas covered in this review: This article reviews the published literature on the pharmacologic properties and the Phase II and III trials that have evaluated the safety and efficacy of this new agent.

What the reader will gain: The reader will obtain an appreciation of the safety and efficacy of indacaterol and the role that it might play in the future management of COPD of varying severity.

Take home message: Indacaterol is a new, once-daily β₂-agonist with an onset of action within 5 min and a duration of bronchodilation of at least 24 h. In doses of 150 and 300 μg, it has sustained benefits over 6 – 12 months with respect to both bronchodilation and patient-reported outcomes and is well-tolerated with an acceptable safety profile.     

The endocannabinoid system as a target for the treatment of neuronal damage

Importance of the field: Cannabinoids have been proposed as clinically promising neuroprotective molecules, based on their capability to normalize glutamate homeostasis, reducing excitotoxicity, to inhibit calcium influx, lowering intracellular levels and the subsequent activation of calcium-dependent destructive pathways, and to reduce the generation of reactive oxygen intermediates or to limit their toxicity, decreasing oxidative injury. Cannabinoids are also able to decrease local inflammatory events by acting on glial processes that regulate neuronal survival, and to restore blood supply by reducing vasocontriction produced by several endothelium-derived factors.

Areas covered in this review: Current literature supporting these neuroprotective effects, particularly evidence generated during the last ten years, concentrating on targets within the cannabinoid signaling system that facilitate these effects. Acute or chronic neurodegenerative disorders where cannabinoids have shown neuroprotective effect.

What the reader will gain: Most of the information reviewed here relates to preclinical studies. However, these molecules may progress from the present preclinical evidence to clinical applications.

Take home message: Treatment of neurodegenerative disorders is a challenge for neuroscientists and neurologists. Unhappily, the efficacy of available medicines is still poor and there is an urgent need for novel neuroprotective agents. Cannabinoids can serve this purpose given their recognized antiexcitotoxic, antioxidant and anti-inflammatory properties.     

Epidemiology,clinical and economic outcomes of admission hyponatremia among hospitalized patients

ABSTRACT

Background: Hyponatremia, the most frequent electrolyte derangement identified among hospitalized patients, is associated with worsened outcomes in patients with pneumonia, heart failure and other disorders.

Research design and methods: We performed a retrospective cohort study of hospitalized patients to quantify the attributable influence of admission hyponatremia on hospital costs and outcomes. Data were derived from a large administrative database with laboratory components, representing 198,281 discharges from 39 US hospitals from January 2004 to December 2005. Hyponatremia was defined as admission serum [Na⁺]?<?135?mEq/L.

Results: The incidence of hyponatremia at admission was 5.5?%?(n?=?10,899). Patients with hyponatremia were older (65.7?±?19.6 vs. 61.5?±?21.8, p?<?0.001) and had a higher Deyo-Charlson Comorbidity Index score (1.8?±?2.1 vs. 1.3?±?1.8, p?<?0.001) than those with normal [Na⁺]. A higher proportion of hyponatremic patients required intensive care unit (ICU) (17.3?%?vs. 10.9?%?, p?<?0.001) and mechanical ventilation (MV) (5.0?%?vs. 2.8?%?, p?<?0.001) within 48?hours of hospitalization. Hospital mortality (5.9?%?vs. 3.0?%?, p?<?0.001), mean length of stay (HLOS, 8.6?±?8.0 vs. 7.2?±?8.2 days, p?<?0.001) and costs ($16,502?±?$28,984 vs. $13,558?±?$24,640, p?<?0.001) were significantly greater among patients with hyponatremia than those without. After adjusting for confounders, hyponatremia was independently associated with an increased need for ICU (OR 1.64, 95?%?CI 1.56–1.73) and MV (OR 1.68, 95?%?CI 1.53–1.84), and higher hospital mortality (OR 1.55, 95?%?CI 1.42–1.69). Hyponatremia also contributed an increase in HLOS of 1.0 day and total hospital costs of $2,289.

Conclusions: Hyponatremia is common at admission among hospitalized patients and is independently associated with a 55?%?increase in the risk of death, substantial hospital resource utilization and costs. Potential for bias inherent in the retrospective cohort design is the main limitation of our study. Studies are warranted to explore how prompt normalization of [Na⁺] may impact these outcomes.     

Emerging drugs for partial onset seizures

Importance of the field: Patients with epilepsy have recurrent unproved seizures. Epilepsy is common, with a prevalence range that centers at around 1%. Patients with epilepsy can have a poor quality of life and suffer significant social stigma. Despite the availability of a large number of antiepileptic drugs (AEDs) including standard and newer ones, a significant percentage of patients with epilepsy remain poorly controlled.

Areas covered in this review: In this review, we briefly summarize data on the available AEDs, then present current information on the emerging AEDs, including their chemical structure, pharmacology, mechanism of action, and efficacy and adverse event profile in clinical trials. The AEDs included are rufinamide, lacosamide, eslicarbazepine, retigabine, brivaracetam, ganaxolone, stiripentol and carisbamate. Most of the literature related to these AEDs was published in the past 5 years.

What the reader will gain: The reader will become familiar with the pharmacology of emerging AEDs and the results of clinical trials with these AEDs. The reader will also be able to assess the advantages of AEDs and their potential respective places in the treatment of epilepsy.

Take home message: The emerging AEDs offer predominantly improved pharmacokinetics and tolerability and occasionally new mechanisms of action. They will probably have a modest impact on drug-resistant epilepsy.     

Paliperidone extended-release: a review of efficacy and tolerability in schizophrenia,schizoaffective disorder and bipolar mania

Importance of the field: Paliperidone extended-release (ER), a once-daily, oral, atypical antipsychotic, has been available in the USA and the EU for the treatment of schizophrenia for more than 2 years and was recently (July 2009) approved in the USA for treatment of schizoaffective disorder. Additional data on its efficacy and safety, including that for additional indications, is emerging.

Areas covered in this review: This review provides a background on the compound and summarizes recent data available on treatment of schizophrenia, including comparative data with other antipsychotics, and efficacy and safety data from clinical trials in schizoaffective and bipolar disorders.

What the reader will gain: The reader will gain knowledge of the compound and the existing clinical data so far for paliperidone ER.

Take home message: Paliperidone ER is effective for the treatment of schizophrenia and is at present the only antipsychotic approved in the USA for treatment of schizoaffective disorder. Its efficacy and tolerability profile in treating patients with schizophrenia or schizoaffective disorder indicates that paliperidone ER offers an important treatment option among atypical antipsychotic therapy for these patients.     

Delivery of celecoxib for treating diseases of the eye: influence of pigment and diabetes

Importance of the field: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two major causes of blindness. In these disorders, growth factors such as vascular endothelial growth factor (VEGF) are upregulated, leading to either enhanced vascular permeability or proliferation of endothelium. While corticosteroid therapies available at present suffer from side effects including cataracts and elevated intraocular pressure, anti-VEGF antibody therapies require frequent intravitreal injections, a procedure that can potentially lead to retinal detachment or endophthalmitis. Thus, there is a need to develop safe, sustained release therapeutic approaches for treating AMD and DR.

Areas covered in this review: This review discusses the pharmacological basis for using celecoxib, an anti-inflammatory drug capable of selectively inhibiting cycloxygenase 2, in treating AMD and DR. In addition, this article discusses the safety, delivery advantage and efficacy of celecoxib by transscleral retinal delivery, a periocular delivery approach that is less invasive to the globe compared with intravitreal injections.

What the reader will gain: The reader will gain insights into the development of a pharmacological agent and a sustained release delivery system for treating DR and AMD. Further, the reader will gain insights into the influence of eye physiology including pigmentation and disease states such as DR on retinal drug delivery.

Take home message: Transscleral sustained delivery of anti-inflammatory agents is a viable option for treating retinal disorders.     

PM101: intravenous amiodarone formulation changes can improve medication safety

Importance of the field: Intravenous amiodarone (A-IV) is used to manage ventricular and atrial arrhythmias. The current formulation uses polysorbate 80 and benzyl alcohol to maintain amiodarone in solution, and these co-solvents are linked with clinically-important adverse events and pharmaceutical incompatibilities. PM101 is a recently FDA-approved intravenous formulation of amiodarone that uses a cyclodextrin to solubilize amiodarone.

Areas covered in this review: This review describes the clinical and pharmaceutical development of formulations of amiodarone for intravenous administration. The medical and pharmaceutical literature was searched for papers discussing A-IV, PM101 and their formulation components. Relevant literature was identified starting from 1948 to the present.

What the reader will gain: The reader will learn about the important medical and pharmaceutical issues complicating A-IV administration, including an understanding of related hypotension and compatibility with commonly used infusion materials and how these issues may impact drug safety. PM101 has been developed to address several of these important issues.

Take home message: PM101 is a new formulation of A-IV that is stable in commonly used infusion materials and avoids co-solvent related toxicities.     

Pharmacological modulation of voltage-gated potassium channels as a therapeutic strategy

Importance of the field: The human genome encodes at least 40 distinct voltage-gated potassium channel subtypes, which vary in regional expression, pharmacological and biophysical properties. Voltage-dependent potassium (Kv) channels help orchestrate many of the physiological and pathophysiological processes that promote and sometimes hinder the healthy functioning of our bodies.

Areas covered in this review: This review summarizes patent and scientific literature reports from the past decade highlighting the opportunities that Kv channels offer for the development of new therapeutic interventions for a wide variety of disorders.

What the reader will gain: The reader will gain an insight from an analysis of the associations of different Kv family members with disease processes, summary and evaluation of the development of therapeutically relevant pharmacological modulators of these channels, particularly focusing on proprietary agents being developed.

Take home message: Development of new drugs that target Kv channels continue to be of great interest but is proving to be challenging. Nevertheless, opportunities for Kv channel modulators to have an impact on a wide range of disorders in the future remain an exciting prospect.     

Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy

Importance of the field: As with all potent therapeutic agents, the use of diuretic compounds has been linked with several adverse effects that may reduce quality of life and patient compliance and, in some cases, may be associated with considerable morbidity and mortality. Among the various types of adverse effects, disturbances of electrolyte and acid–base balance are perhaps the most common, and some of them are the aetiological factors of other side effects (i.e., hypokalaemia causing ventricular arrhythmias or glucose intolerance). The mechanism and site of action and, therefore, the pharmacological effects of each diuretic class largely determine the specific electrolyte or acid–base abnormalities that will accompany the use of each diuretic agent.

Areas covered in the review: This article reviews the major electrolyte disturbances (hypokalaemia, hyperkalaemia, hyponatraemia, disorders of magnesium and calcium balance), as well as the acid–base abnormalities complicating the use of the various diuretic agents.

What the reader will gain: The reader will gain insights into the pathogenesis of the diuretic-induced electrolyte and acid–base disorders together with considerations for their prevention and treatment.

Take home message: Knowledge of the pharmacologic properties of each diuretic class and appropriate monitoring of patients under diuretic treatment represent the most important strategies to prevent the development of diuretic-related adverse events and their consequences.     

Current treatment options for tendinopathy

Importance of the field: Tendon disorders are frequent and are responsible for much morbidity, both in sport and the workplace. Although several therapeutic options are routinely used, very few well-conducted randomised prospective, placebo, controlled trials have been performed to assist in choosing the best evidence-based management.

Areas covered in this review: We performed a comprehensive search of PubMed, Medline, Cochrane, CINAHL, and Embase databases over the years 1966 – 2010 to review the best evidence-based options for the management of patients with tendinopathy.

What the reader will gain: The reader will obtain information on the available medical and surgical therapies used to manage tendinopathy-related symptoms. The effectiveness of therapies, the length of management and the adverse effects are examined.

Take-home message: Management of tendinopathy is often anecdotic and lacking well-researched scientific evidence. Teaching patients to control the symptoms may be more beneficial than leading them to believe that tendinopathy is fully curable.     

Management of idiopathic membranous nephropathy

Importance of the field: Idiopathic membranous nephropathy (IMN) can have a variable natural course. Treatments able to induce remission can improve the long-term prognosis. However, the optimal therapy for IMN remains controversial.

Area covered in this review: We reviewed the historical and current literature from 1979 to 2010 regarding the natural course of IMN and the possible treatments giving special emphasis to randomized controlled trials and to more recent approaches.

What the reader will gain: The reader will gain a comprehensive review of the available treatments of IMN. A personal therapeutic algorithm for nephrotic patients with IMN is also provided.

Take home message: At least five different treatments showed efficacy in many (but not all) patients with IMN.     

Pasireotide for the treatment of Cushing's disease

Importance of the field: It is important to treat patients with Cushing's disease as rapidly as possible to limit both the mortality and morbidity of the disease. Pituitary surgery remains the treatment of choice, but the rate of cure at long-term follow-up is suboptimal and recurrence rates are high. If surgery fails or relapse occurs, no treatment has proven to be fully satisfactory. Currently available medical therapies are considered a transient and palliative treatment. However, recently there has been renewed interest in medical therapy due to new insights in pathogenetic mechanisms of corticotroph pituitary tumors.

Areas covered in this review: We summarize the pharmacodynamics and possible mechanism of action of pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue. Pasireotide has a unique binding profile, with high affinity for four of the five somatostatin receptors, especially SSTR₅, the receptor most prevalent in corticotroph tumors.

What the reader will gain: The reader should gain an understanding of preclinical and clinical data supporting the potential use of pasireotide in patients with Cushing's disease.

Take home message: Preliminary data suggest that pasireotide shows promise as a tumor-targeted medical therapy in patients with Cushing's disease. If the efficacy of pasireotide is confirmed by larger studies, this compound may be a useful treatment option not only in patients with severe Cushing's disease, but also in patients with mild hypercortisolism where its efficacy might be more evident.     

Hyponatremia: an update on current pharmacotherapy

Introduction: Hyponatremia is the most common electrolyte disorder in clinical practice, and it is associated with adverse outcomes. Severe hyponatremia can result in cerebral edema and hypoxia. Moreover, even mild hyponatremia can lead to gait instability and cognitive dysfunction, especially in the elderly. The main cause of hyponatremia is nonosmotic secretion of arginine vasopressin with resultant electrolyte-free water retention. Thus, the available management for chronic hyponatremia must increase solute-free water excretion, such as occurs with blocking vasopressin receptors with selective V2 antagonists.

Areas covered: Several recent trials have assessed the efficacy and safety of hyponatremia treatment using vasopressin receptor antagonists (vaptans). These trials documented the efficacy of vaptans to reverse hyponatremia. Moreover, treatment of hypervolemic hyponatremia, such as in heart failure or liver cirrhosis, with vasopressin receptor antagonist results in increased solute-free excretion without activation of the neurohumoral systems. The current review covers results on management of hyponatremia with different vasopressin receptor antagonists.

Expert opinion: Approaches, such as vasopressin receptor antagonists or urea, have been shown to reverse moderate hyponatremia. However, these agents have not been used to treat severe hyponatremia in clinical trials. Future studies in severe hyponatremic states are required to assess the impact of vaptans on clinically significant end points, such as morbidity and mortality.