Atypical antipsychotics and polydipsia: a cause or a treatment?

Primary polydipsia (PP) is a frequent complication that affects many chronic schizophrenic inpatients. Due to possible lethal consequences, for example, hyponatremia, coma and death, it's fundamental for the physician achieving early diagnosis and treating this condition. The first step is identifying polydipsia by clinical, biochemical and pharmacological means. Nowadays, the pathophysiology of PP remains unclear, and this limits the possibility of detecting an appropriate drug treatment. Typical antipsychotics have been associated to a worsening of polydipsic behavior, while more recently atypical antipsychotics have been reported as being useful. However results are still mixed and controversial. It appears that risperidone and olanzapine are not clearly effective; clozapine may improve symptoms, although it is difficult to manage from a therapeutic point of view; quetiapine has been poorly studied so far, nonetheless it has given interesting results. Through a case study analysis, this report presents a brief, yet selective, overview of the current state of psychopharmacology in the treatment of PP with atypical antipsychotics in schizophrenia.     

Role of cytokines in non-genotoxic hepatocarcinogenesis: cause or effect?

Chemicals with the potential to cause cancer through damaging DNA can be readily identified in a range of in vitro screens that detect genotoxicity. However, many carcinogens are non-genotoxic yet cause rodent tumours, particularly in the liver. Some non-genotoxic carcinogens such as the peroxisome proliferators (PPs) act directly to cause liver growth and proliferation, whereas others such as carbon tetrachloride cause liver damage, followed by regenerative hyperplasia. Current data support a role for cytokines such as tumour necrosis factor alpha (TNFalpha) and interleukin 1 (IL1) in hepatocarcinogenesis. However, these data give rise to conflicting hypotheses; in some experimental models, TNFalpha appears to mediate damage, whereas in others it is postulated to play a role in tissue repair. Recently, we have shown that TNFalpha acting via TNFalpha receptor 1 and p38 MAP kinase suppresses hepatocyte apoptosis. However, when new protein synthesis is disabled, TNFalpha becomes a death signal. An understanding of the role of cytokines in rodent hepatocarcinogenesis will allow the development of markers that can be used to identify, at an early stage, those chemicals with the potential to induce rodent tumours.     

Anticholinergics in the era of atypical antipsychotics: short-term or long-term treatment?

Anticholinergic agents are usually prescribed to prevent or treat antipsychotic-induced extrapyramidal symptoms. Their long-term benefits are questionable and they carry diverse adverse effects, including cognitive impairment and worsening of tardive dyskinesia. This literature review explores the impact of anticholinergic medication discontinuation on movement disorders, cognition and psychopathology in patients receiving antipsychotics. Medline, Embase and PsycInfo were searched from 1950 to July 2011 using "cessation /withdrawal /discontinuation /stopping" with "anticholinergic*" or "antiparkinson*" and "neuroleptic*" or "antipsychotic*". Additional articles were obtained by searching the bibliographies of relevant references. Earlier studies of anticholinergic agent discontinuation in patients receiving first-generation antipsychotics reported relapse rates of extrapyramidal symptoms between 4% and 80%, reflecting the heterogeneity of the studies. Two recent studies of patients prescribed second-generation antipsychotics obtained relapse rates of 4% and 33%. Some studies suggest improvement in tardive dyskinesia with cessation of anticholinergics. Four studies examined the effects of anticholinergic agent discontinuation on cognition and all observed an improvement post-discontinuation. Changes in symptoms of schizophrenia with anticholinergic discontinuation are conflicting, with more recent studies suggesting an improvement. Given their questionable benefit with continued use, clinicians should consider a gradual withdrawal of anticholinergic agents in stable patients receiving antipsychotics.     

Single-drug or combined antibacterial therapy in the treatment of patients with chronic prostatitis and Chlamydia trachomatis?

The efficacy of antibacterial combinations as compared with single-drug treatment in 57 patients with chronic prostatitis and Chlamydia trachomatis was investigated in this study.     

Metabolic abnormalities associated with second generation antipsychotics: fact or fiction? Development of guidelines for screening and monitoring

Epidemiological studies have demonstrated a relevant increased risk of diabetes in schizophrenic patients who are treated with many atypical antipsychotics, irrespective of concomitant weight gain. Numerous case reports and some large retrospective cohort studies have documented an increased risk of diabetes with some second-generation antipsychotics (SGAs), leading different authors to identify patients on SGA as another high-risk group for diabetes in their review articles. An American consensus conference dealing with this problem has proposed much awaited guidelines for the monitoring of patients on SGA and recommended acquiring additional data, especially from large-scale prospective studies. A more recent Belgian consensus on the screening and management of antipsychotic-related metabolic disturbances has proposed a more stringent approach. Here, we will cover the current diagnosis of metabolic problems, and provide a review of antipsychotic-related metabolic problems (diabetes, lipid abnormalities and the metabolic syndrome), as well as guidelines for the screening and management of metabolic abnormalities in people treated with antipsychotic medication.     

Atenolol: differences in mode of action compared with other antihypertensives. An opportunity to identify features that influence outcome?

The beneficial effect of antihypertensive treatment on the risk of major vascular events is well established. Several trials comparing older and newer drugs in the treatment of primary hypertension suggested that it is the blood pressure achieved, rather than choice of the drug that determines most of the primary outcomes. Beta-blockers have been widely used to treat hypertension and are still recommended as first-line drugs in guidelines. However, recent meta-analyses of trials (either placebo-controlled or using drug comparisons) involving atenolol (a popular beta-blocker), have cast doubt on the suitability of atenolol as a first-line antihypertensive drug. We consider the mechanisms which might be responsible for the inferiority of atenolol in preventing vascular morbidity and mortality in patients with primary hypertension. This knowledge may help design drugs that are not only more effective in achieving blood pressure targets but that also markedly decrease vascular events.     

Use of antipsychotics in elderly patients with dementia: Do atypical and conventional agents have a similar safety profile?

Pharmacological treatment of dementia addresses two main clinical features of the disease: cognitive deterioration with predominantly memory loss and behavioural and psychological symptoms (BPSD). While cholinesterase inhibitors are recommended in an attempt to delay memory loss and disability, what should be considered the most appropriate pharmacological treatment for BPSD has remained questionable. Antipsychotic medications, conventional and atypical agents, have been increasingly utilized in clinical practice but only a small number of clinical studies have investigated their relative cost–benefit ratio. This review focuses on the safety of atypical and conventional antipsychotics when used in patients with BPSD. Overall, atypical and conventional antipsychotics are associated with a similarly increased risk for all-cause mortality and cerebrovascular events. Relative to atypical agents users, patients being treated with conventional antipsychotics have an increased incidence of cardiac arrhythmias and extrapyramidal symptoms. Conversely, users of atypical antipsychotics are exposed to an increased risk of venous thromboembolism and aspiration pneumonia. Also, metabolic effects (i.e. increased risk of diabetes, weight gain) have consistently been documented in clinical studies with atypical antipsychotics, although this effect tends to be attenuated with advancing age and in elderly patients with dementia. Antipsychotics, both conventional and atypical, should be used with caution only when nonpharmacologic approaches have failed to adequately control BPSD. More effective interventions are necessary to improve postmarket drug safety in vulnerable populations.     

Combining temozolomide with other antitumor drugs and target-based agents in the treatment of brain metastases: an unending quest or chasing a chimera?

INTRODUCTION: Medical treatment of brain metastases (BM) is still a controversial issue in cancer therapy being mainly limited by the existence of the BBB. Temozolomide (TMZ) can cross BBB and several clinical trials have been performed attempting to demonstrate the activity of TMZ in combination with whole brain radiotherapy (WBRT) in the treatment of BM. AREAS COVERED: This review summarizes TMZ-WBRT combination trials highlighting the confounding factors that limit the interpretation of the achieved results and describes the main clinical trials using TMZ in combination with other cytotoxic or biological agents. The main limitations of these trials are: i) patient selection for heterogenous primitive neoplasms and for heterogeneous neuro-functional score; ii) poor penetration across BBB of the other drugs; iii) cumulative toxicity and iv) poor control of extracranial tumor sites. EXPERT OPINION: Biotechnological, biological and biochemical advances in the management of BM could allow in short time the definition of new schedules based on the rational use of new anticancer weapons. The latter could be cytotoxic agents encapsulated in nanotechnological tools able to cross BBB, lipophilic small kinase inhibitors (lapatinib, sunitinib), mTOR inhibitors and PARP inhibitors combined with old drugs such as TMZ.     

Targeting cytokines as a treatment for patients with sepsis: A lost cause or a strategy still worthy of pursuit?

Despite often knowing the aetiology of sepsis and its clinical course there has not been the anticipated advances in treatment strategies. Cytokines are influential mediators of immune/inflammatory reactions and in patients with sepsis high circulating levels are implicated in the onset and perpetuation of organ failure. Antagonising the activities of pro-inflammatory cytokines enhances survival in animal models of sepsis but, so far, such a therapeutic strategy has not improved patient outcome. This article addresses the questions of why encouraging laboratory findings have failed to be translated into successful treatments of critically ill patients and whether modifying cytokine activity still remains a promising avenue for therapeutic advance in severe sepsis. In pursuing this task we have selected reports that we believe provide an incisive, critical and balanced view of the topic.     

Ibuprofen and increased morbidity in children with asthma: fact or fiction?

NSAIDs are commonly avoided by patients with aspirin-induced asthma based on the premise that there is a significant cross-reactivity between aspirin and other NSAIDs. However, ibuprofen, a NSAID sold over the counter in most countries, is commonly given to children for relief of fever and mild-to-moderate pain. Consequently, increased risk of acute bronchospasm induced by ibuprofen in children with asthma remains a persistent concern. More recently, the assumption that children with asthma are at a greater risk for exacerbations of their disease if they take ibuprofen has been questioned. There is little evidence to measurably increases morbidity in the great majority of children with asthma. In addition, recent evidence suggest that ibuprofen measurably increases morbidity in the great majority of [corrected] children with asthma. Given the infrequent occurrence of aspirin/NSAID sensitivity in children with asthma, it seems reasonable to allow the use of ibuprofen in this population unless there is a personal or family history of aspirin-induced asthma. In addition, the inflammatory pathogenesis of asthma, anti-inflammatory effect of ibuprofen, and evidence suggesting ibuprofen may reduce morbidity in children with asthma raises the intriguing possibility that ibuprofen might actually have therapeutic benefit for at least some children with asthma.     

Clinical supervision in the alcohol and other drugs field: an imperative or an option?

There is a growing interest in Clinical Supervision (CS) as a central workforce development (WFD) strategy. This paper provides a definition of and rationale for CS, characterises its various forms, identifies selection and training issues, and advises on policy and implementation issues central to redressing shortcomings in supervision practice within the alcohol and other drugs (AOD) field. Relevant selective literature is reviewed. Key conceptual issues were identified, and strategies developed to address implementation barriers and facilitate relevant policy. There is a common conceptual confusion between administrative supervision and CS. Clarification of the role, function and implementation of CS is required. Priority issues for the AOD field include: enhancing belief in CS; ensuring adequate resource allocation; developing evaluation protocols; and addressing specific arrangements under which supervision should occur. CS has been underutilised to date but holds considerable potential as a WFD strategy. It is fundamental to workers' professional development, can contribute to worker satisfaction and retention, and may improve client outcomes. Critical next steps are to establish the generalisability to the AOD field of the benefits observed from CS in other disciplines, and evaluate longer-term gains of CS programs.     

Comparative pharmacogenetic analysis of risk polymorphisms in Caucasian and Vietnamese children with acute lymphoblastic leukemia: prediction of therapeutic outcome?

AimsAcute lymphoblastic leukemia (ALL) is the most common of all paediatric cancers. Aside from predisposing to ALL, polymorphisms could also be associated with poor outcome. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy. The aims of this study were to (a) to determine the prevalence of seven common genetic polymorphisms including those that affect the folate and/or thiopurine metabolic pathways, i.e. cyclin D1 (CCND1-G870A), γ-glutamyl hydrolase (GGH-C452T), methylenetetrahydrofolate reductase (MTHFR-C677T and MTHFR-A1298C), thymidylate synthase promoter (TYMS-TSER), thiopurine methyltransferase (TPMT*3A and TPMT*3C) and inosine triphosphate pyrophosphatase (ITPA-C94A), in Caucasian (n = 94, age < 20) and Vietnamese (n = 141, age < 16 years) childhood ALL and (b) to assess the impact of a multilocus genetic risk score (MGRS) on relapse-free survival (RFS) using a Cox proportional-hazards regression model.ResultsThe prevalence of MTHFR-677TT genotype was significantly higher in Caucasians (P = 0.008), in contrast to the prevalence of TYMS-TSER*3R/3R and ITPA-94AA/AC genotypes which were significantly higher in Vietnamese (P < 0.001 and P = 0.02, respectively). Compared with children with a low MGRS (≤3), those with a high MGRS (≥4) were 2.06 (95% CI = 1.01, 4.22; P = 0.04) times more likely to relapse. Adding MGRS into a multivariate Cox regression model with race/ethnicity and four clinical variables improved the predictive accuracy of the model (AUC from 0.682 to 0.709 at 24 months).ConclusionIncluding MGRS into a clinical model improved the predictive accuracy of short and medium term prognosis, hence confirming the association between well determined pharmacogenotypes and outcome of paediatric ALL. Whether variants on other genes associated with folate metabolism can substantially improve the predictive value of current MGRS is not known but deserves further evaluation.     

Is valproate promising in cardiac fatal arrhythmias? Comparison of P- and Q-wave dispersion in bipolar affective patients on valproate or lithium-valproate maintenance therapy with healthy controls

Autonomic nerve system is considered to be involved in bipolar affective disorder (BAD) or to be influenced by valproate monotherapy or valproate plus lithium combination. We planned to assess the effects of medication on atrial and ventricular conduction. The electrocardiography records were performed with eligible 15 patients with valproate, 20 patients with lithium-valproate combination use in euthymic phases of BAD and 20 healthy participants. The blood valproate and lithium concentrations in groups were in normal range. The difference in P maximum, P minimum, maximum QTc were statistically insignificant. Minimum QTc (F = 6.36; df = 2; P = 0.003) and QT dispersion (QTD) (F = 5.57; df = 2; P = 0.006) were statistically significant among the groups. There were no significant differences between patient groups among ECG parameters. Minimum QTc was significantly longer in combination group than healthy controls, whereas the QTD values in both patient groups were significantly lower than controls'. Valproate might have some preventive effects on ventricular electrical conduction because of lower QTD in both patient groups. Thus, valproate seems to have cardiac conduction stabilizing effect beside its mood stabilizing aspect. However, this finding needs replication and further corroboration in well-designed studies.     

Efficacy of steroid and immunosuppressant combined therapy in Chinese patients with Henoch–Schönlein purpura nephritis: A retrospective study

Suitable and efficient treatments for Henoch-Schönlein purpura nephritis (HSPN) with proteinuria remains unclear. Whether steroids combined with immunosuppressive agents improves prognosis compared to steroid therapy alone also remains controversial. This study explored whether combined therapy reduces proteinuria in HSPN patients with different pathological features. Chinese patients (n = 84) diagnosed with HSPN with proteinuria by renal biopsy between 2010 and 2019 were retrospectively studied. Patients were grouped into the steroid group (control) or the combined steroid and immunosuppressant group. Estimated glomerular filtration rate (eGFR) (mL/min/1.73 m²/y) and proteinuria were measured. The primary outcome progression was analyzed using Kaplan–Meier survival curves. The effect of the combined therapy on renal outcome was analyzed by multivariable Cox regression. Propensity score matching and sensitivity analysis were used to explore whether pathological features impacted prognosis. Patients who received combined steroid and immunosuppressant therapy were more likely to recover from HSPN and had proteinuria <3 g/24 h (P = 0.02) or 1 g/24 h (P = 0.03). Multiple Cox regression analysis confirmed that this decrease was independent of renin–angiotensin system blockers. Further sensitivity analysis showed that combined therapy was effective in patients with crescents (P = 0.02). However, combined steroid and immunosuppressant therapy was not more effective in patients with endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T), or segmental sclerosis (S). Combined steroid and immunosuppressant therapy was significantly associated with HSPN remission, and more effectively decreased proteinuria during the initial disease phase.     

Penetration of nanoparticles and nanomaterials in the skin: Fiction or reality?

The advent of nanotechnological products in the market, while holding great promise, is raising concerns in consumers. Therefore, this contribution will attempt to compare different particulate formulations and to answer whether their passive penetration into, and potential permeation through the skin may be possible or not. To this end, skin structure, composition, and penetration paths will be concisely reviewed. Parameters generally cited to affect skin absorption will be resumed and commented on from the perspective of potentially penetrating nanosized agents. These sections will provide the basis to understand what is fiction and what is reality. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:21–50, 2010