Weight gain and antipsychotics: a drug safety review

Introduction: Second-generation antipsychotics (SGAs) are widely used in several psychiatric disease entities and exert to a different extent a risk for antipsychotic-induced weight gain (AIWG). As AIWG is associated with an increase in metabolic syndrome or cardiovascular events, knowledge of these risks is crucial for further monitoring and the initiation of counteractive measures.

Areas covered: We searched PubMed and Web of Sciences for randomized-controlled trials and naturalistic observational studies published between 2010 and 2014 with sample sizes exceeding 100, including all marketed SGAs apart from zotepine, and providing data on weight increase. We also summarized relevant systematic reviews and meta-analyses of head-to-head comparisons.

Expert opinion: Recently published data still support the hierarchical ranking of SGAs already proposed in previous reviews ranking clozapine and olanzapine as having the highest risk, followed by amisulpride, asenapine, iloperidone, paliperidone, quetiapine, risperidone and sertindole in the middle, and aripiprazole, lurasidone and ziprasidone with the lowest risk. Number needed to harm varied considerably in our meta-analysis. Younger patients and patients with a lower baseline body mass index are most vulnerable. The greatest amount of weight gain occurs within the first weeks of treatment. AIWG occurs in all diagnostic groups and is also common in treatment with first-generation antipsychotics; therefore, awareness of this adverse event is essential for anyone prescribing antipsychotics.     

Tyrosine kinase inhibitors with antiangiogenic properties for the treatment of non-small cell lung cancer

Iloperidone is a new-generation atypical antipsychotic agent, acting as a serotonin/dopamine (5-HT_2A/D₂) antagonist, under development by Vanda Pharmaceuticals for the treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Chemically, iloperidone is a benzisoxazole, like risperidone, and shows a multiple receptor binding profile, sharing this feature with the other atypical antipsychotic agents. Administered orally, the drug is highly bound to plasma proteins and extensively metabolised. Several clinical trials have been carried out, to check efficacy, safety and side effects. In order to introduce iloperidone as an agent for the treatment of schizophrenia, a short overview of the disease and of the most important antipsychotic drugs available or under development will be reported. Iloperidone pharmacokinetics and pharmacodynamics are presented herein, together with an evaluation of clinical safety and efficacy results.     

伊潘立酮的合成与表征

目的：为了探索一种合成伊潘立酮的新方法。方法：以4-（2,4-二氟苯甲酰基）哌啶盐酸盐为原料,经肟化、环合反应生成6-氟-3-（哌啶-4-基）-1,2-苯并异嗯唑,然后与4-（3-氯丙氧基）-3-甲氧基苯乙酮在碳酸钾存在下发生N-烷基化反应制得伊潘立酮。结果：探索出一个合成伊潘立酮的新方法,总收率53．29／5,化合物结构经。HNMR和13CNMR表征。结论：合成路线总收率高,操作简便,条件温和。     

Glomerular Nephritis; Recognition and Treatment

For general practitioners, who handle more than 85 per cent of all pediatric care, Postgraduate Medicine here presents authoritative, up-to-date summaries by specialists in pediatric problems.     

Developments in the pharmacological treatment of schizophrenia

Schizophrenia is, at once, a biological disease, a neuropsychological disorder and a dysfunction of social interactions. This presents clinicians with a series of problems with regards to therapy. In the first section of this article, some of the clinical challenges that face those attempting to develop new drugs, are summarised. Several potential pharmacological therapeutic targets that have been, and are continuing to be used, in the development of new antipsychotic drugs, are then considered. This is followed by an outline of the pharmacological and clinical profiles of some of the newer generation antipsychotics, as well as investigational drugs in the pipeline for schizophrenia. Finally, the implications of the introduction of these new drugs for the management of schizophrenia, are discussed.     

Asenapine,iloperidone and lurasidone exposures in young children reported to U.S. poison centers

Context: Asenapine, iloperidone and lurasidone are relatively new atypical antipsychotics. There is limited information on toxicity on pediatric exposures to these drugs. The objective of this study was to compare toxicity associated with asenapine, iloperidone and lurasidone exposures in young children.

Methods: A retrospective study of U.S. National Poison Data System from 2010 to 2015 of single substance exposures to asenapine, iloperidone or lurasidone in children <6 years of age that were followed to known outcome was performed.

Results: There were 95 asenapine, 64 iloperidone and 124 lurasidone cases that met inclusion criteria. Reason was exploratory for 96% of cases. Drowsiness/lethargy occurred most frequently with iloperidone (45%) and least often with lurasidone (8%). Two iloperidone cases had respiratory depression. For asenapine, iloperidone and lurasidone, respectively, management sites were on-site non-health care facility (non-HCF) (32%, 16%, 26%), treated/discharged from emergency department (ED) (46%, 47%, 63%), admitted to noncritical care (9%, 14%, 10%) and admitted to critical care (10%, 22%, 2%). Clinical effect duration was 8?h or less for the majority of non-HCF cases (80%) and for children treated/discharged from the ED (72%). For asenapine, iloperidone and lurasidone, coded outcomes were no effect (50%, 41%, 81%), minor effect (43%, 39%, 17%), moderate (6%, 19%, 2%) and major (0, 2%, 0).

Discussion and conclusions: These findings suggest that in children under 6 years of age, lurasidone exposures were least serious and iloperidone exposures were most serious based on clinical effects, management sites and coded outcomes. Observation of symptomatic children in the ED for 8?h should be sufficient to make triage decisions based on persistence or resolution of clinical effects.     

Safety profile of iloperidone in the treatment of schizophrenia

The use of botulinum toxin to treat cervical dystonia (CD) has dramatically improved the quality of life of patients with this disabling, often painful disease. Two forms of type A toxin (BOTOX® and Dysport®) and one form of type B toxin (MyoBloc®) are available in some parts of the world to treat patients with CD. The literature supports the efficacy of each in reducing the pain and movement of cervical dystonia. The dosing and side effects vary between the toxins. The potential availability of several forms of toxin will allow physicians to offer further treatment options to patients with CD. However, it is incumbent on the treating physicians to have a working knowledge of the different serotypes, different doses used of each formulation of each serotype, the side effect profile of each product and the potential for anti-body formation for each form of toxin.     

伊潘立酮的合成研究

目的：优化抗精神病药伊潘立酮1的合成工艺以适用于工业化生产。方法以4-哌啶甲酸、乙酸、乙酸酐为起始原料,经酰胺化、酰氯化、傅－克酰基化反应、水解得到2,4-二氟苯基-4-哌啶基甲酮盐酸盐4,再经肟化、分子内环合、成盐得6-氟-3-（4-哌啶基）-1,2-苯并异唑盐酸盐2。2和4-（3-氯丙氧基）-3-甲氧基苯乙酮在碱催化下缩合得到伊潘立酮1。结果与结论对反应物配比、催化剂用量、反应温度及时间等因素进行了优化研究,使得该合成方法反应条件温和、易控制,副反应少,后处理简单,总收率可达34．9％（以4-哌啶甲酸计）,其结构经IR、1 H-NMR和MS确证。     

Drugs in development for the treatment of schizophrenia

The overall outcome in schizophrenia is generally poor, despite the undisputed efficacy of antipsychotics in treating the acute symptoms of psychosis. There remains a subset of patients who are refractory to treatment. Also, for most patients treatment is not effective against the full spectrum of symptoms including negative and cognitive symptoms, and severe functional deficits persist. Further, while the newer drugs produce fewer motor side effects, other safety and tolerability concerns have emerged. Since the advent of antipsychotic therapy in the early 1950s, subsequent advances have been modest. While the mechanism of action of the first-generation antipsychotics appears closely linked to D2 antagonism, the second-generation antip-sychotics have broader receptor-binding profiles, particularly 5-HT receptor antagonism. Attempts are now being made to develop antipsychotics with a wider spectrum of efficacy and a more favourable safety and tolerability profile by further exploring the therapeutic potential of D2 and 5-HT2 receptors, as well as investigating other putative mechanisms of action. This article adds to the current literature by providing an up-to-date review of antipsychotic drugs currently in development, focusing on the findings to date for compounds that are presently in Phase III clinical trials. While no exciting breakthroughs appear imminent, several drugs in early development have great potential.