Synthesis, structure-activity relationships, and in vivo properties of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones as corticotropin-releasing factor-1 receptor antagonists

Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.     

Randomized controlled trial of unflued gas heater replacement on respiratory health of asthmatic schoolchildren

BACKGROUND: Previous studies do not provide a clear picture of the relationship between nitrogen dioxide (NO(2)) exposure and asthma. METHODS: Eighteen schools using unflued gas heating in winter were randomly allocated to either retain their heaters (10 control schools) or to have replacement flued gas or electric heaters installed at the beginning of winter (8 intervention schools). Fortnightly telephone interviews were used to record daily individual asthma symptoms that occurred over 12 weeks (including winter). Lung function and histamine challenge tests were performed at baseline and the end of the study. NO(2) was measured in each school classroom on 9 days and in each household on 3 days spread over the study period. RESULTS: From 199 primary school children that met the eligibility criteria, 45 intervention and 73 control children agreed to participate. Baseline characteristics were similar between groups. Difficulty breathing during the day (Relative Risk [RR] = 0.41; 95% CI: 0.07, 0.98) and night (RR = 0.32; 95% CI: 0.14, 0.69), chest tightness during the day (RR = 0.45; 95% CI: 0.25, 0.81), and daytime asthma attacks (RR = 0.39; 95% CI: 0.17, 0.93) were significantly reduced in the intervention group. Percentage predicted forced expiratory volume in one second (FEV(1)), the concentration of histamine inducing a 20% fall in FEV(1) (PD(20)), and the dose-response slope (DRS) were similar between groups at follow-up. Mean (standard deviation) NO(2) levels were 15.5 (6.6) parts per billion (ppb) and 47.0 (26.8) ppb in the intervention and control schools respectively (P < 0.001). CONCLUSIONS: Asthma symptoms were reduced following a replacement intervention that removed high exposure to NO(2). Such replacement should be considered a public health priority for schools using unflued gas heating during winter.     

Psychogenic excoriation. Clinical features, proposed diagnostic criteria, epidemiology and approaches to treatment

Psychogenic excoriation (also called neurotic excoriation, acne excoriée, pathological or compulsive skin picking, and dermatotillomania) is characterised by excessive scratching or picking of normal skin or skin with minor surface irregularities. It is estimated to occur in 2% of dermatology clinic patients and is associated with functional impairment, medical complications (e.g. infection) or substantial distress. Psychogenic excoriation is not yet recognised in the DSM. We propose preliminary operational criteria for its diagnosis that take into account the heterogeneity of behaviour associated with psychogenic excoriation and allow for subtyping along a compulsivity-impulsivity spectrum. Psychiatric comorbidity in patients with psychogenic excoriation, particularly mood and anxiety disorders, is common. Patients with psychogenic excoriation frequently have comorbid disorders in the compulsivity-impulsivity spectrum, including obsessive-compulsive disorder, body dysmorphic disorder, substance use disorders, eating disorders, trichotillomania, kleptomania, compulsive buying, obsessive-compulsive personality disorder, and borderline personality disorder. There are few studies of the pharmacological treatment of patients with psychogenic excoriation. Case studies, open trials and small double-blind studies have demonstrated the efficacy of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors in psychogenic excoriation. Other pharmacological treatments that have been successful in case reports include doxepin, clomipramine, naltrexone, pimozide and olanzapine. There are no controlled trials of behavioural or psychotherapeutic treatment for psychogenic excoriation. Treatments found to be effective in case reports include a behavioural technique called 'habit reversal'; a multicomponent programme consisting of self-monitoring, recording of episodes of scratching, and procedures that produce alternative responses to scratching; and an 'eclectic' psychotherapy programme with insight-oriented and behavioural components.     

Automated attention flags in chronic disease care planning

OBJECTIVES: To assess the value of computerised decision support in the management of chronic respiratory disease by comparing agreement between three respiratory specialists, general practitioners (care coordinators), and decision support software. METHODS: Care guidelines for two chronic obstructive pulmonary disease projects of the SA HealthPlus Coordinated Care Trial were formulated. Decision support software, Care Plan On-Line (CPOL), was created to represent the intent of these guidelines via automated attention flags to appear in patients' electronic medical records. For a random sample of 20 patients with care plans, decisions about the use of nine additional services (eg, smoking cessation, pneumococcal vaccination) were compared between the respiratory specialists, the patients' GPs and the CPOL attention flags. RESULTS: Agreement among the specialists was at the lower end of moderate (intraclass correlation coefficient [ICC], 0.48; 95% CI, 0.39-0.56), with a 20% rate of contradictory decisions. Agreement with recommendations of specialists was moderate to poor for GPs (kappa, 0.49; 95% CI, 0.33-0.66) and moderate to good for CPOL (kappa, 0.72; 95% CI, 0.55-0.90). CPOL agreement with GPs was moderate to poor (kappa, 0.41; 95% CI, 0.24-0.58). GPs were less likely than specialists or CPOL to decide in favour of an additional service (P<0.001). CPOL was 87% accurate as an indicator of specialist decisions. It gave a 16% false-positive rate according to specialist decisions, and flagged 61% of decisions where GPs said No and specialists said Yes. CONCLUSIONS: Automated decision support may provide GPs with improved access to the intent of guidelines; however, further investigation is required.     

A pilot study of rapid lithium administration in the treatment of acute mania

Objectives: The use of rapid lithium dosage administration, a strategy that could lead to rapid improvement in mania, has been largely unexamined. In this open-label, pilot, acute-treatment study, we sought to determine the safety and tolerability of lithium administered at 20 mg/kg/day. A secondary aim was to provide preliminary data regarding the efficacy of this strategy in ameliorating manic, depressive, and psychotic symptoms. Methods: Fifteen patients hospitalized with DSM-IV bipolar disorder, manic or mixed, and who provided written informed consent, received lithium 20 mg/kg/day for up to 10 days. Patients were evaluated for adverse effects daily. Lithium levels were obtained on days 2, 3, 4, 5, 7, and 10 or at study termination. Electrocardiograms (EKGs) were performed at baseline and on days 1–5, 7, and 10 or at study termination. Symptomatic improvement was assessed daily using the Young Mania Rating Scale, 24-item Hamilton Depression Rating Scale, and the Scale for Assessment of Positive Symptoms (SAPS). Results: Five of the 15 patients completed the 10-day study period. Two patients dropped out due to adverse events. Seven patients did not complete the inpatient trial because of improvement sufficient to allow hospital discharge. All patients achieved serum lithium concentrations ≥0.6 mEq/L after 1 day of treatment; the mean±SD concentration on day 5 was 1.1 (±0.1) mEq/L on day 5. There were significant reductions from baseline to endpoint on all rating scales, except the SAPS bizarre behavior subscale. Conclusions: These pilot data suggest that lithium 20 mg/kg/day was well tolerated and that this strategy may produce rapid improvement in affective and psychotic symptoms. These impressions require confirmation in double-blind, randomized trials.     

An outbreak of food poisoning in a military establishment

Background: An outbreak of food poisoning in a military establishment mess was investigated and remedial measures suggested.     

TRACHEOSTOMY COMPLICATIONS AND THEIR MANAGEMENT

The word tracheostomy derived from two greek words meaning ‘I cut the trachea’ has been known for about 3500 yrs. The process has evolved over the years and has undergone revolutionary changes in the methodology, instrumentation and indications. Although tracheostomy is now commonly used the complication rate remains high. In our series it was 48% which is comparable with other series. The purpose of this paper is to discuss the complications of tracheostomy with special attention to their management and prevention.KEY WORDS: Complications, Tracheostomy