Biochemical and behavioural properties of clozapine

The selection and early development of clozapine was based upon its gross behavioural, arousal-inhibiting, sleep-promoting, and caudate spindle-prolonging properties. Compared to classical neuroleptics, clozapine causes only a short-lasting elevation of plasma prolactin levels, elevates both striatal homovanillic acid and dopamine content, is devoid of marked apomorphine-inhibitory or cataleptogenic activity and fails to induce supersensitivity of striatal dopaminergic systems after chronic administration. Clozapine's intrinsic anticholinergic activity, while stronger than that of other neuroleptic agents, does not appear to underlie either its failure to induce tardive dyskinesias or its superior antipsychotic activity. Furthermore, the overlap between clozapine and several classical neuroleptics with regard to alpha-adrenergic-, serotonin- and histamine-blocking activity makes it unlikely that one or more of these properties is the key to its atypical characteristics. More recent findings show that clozapine and classical neuroleptics differ with regard to their indirect effects on nigral GABA-ergic mechanisms implicated in the induction of tardive dyskinesias and, possibly in keeping with this, that clozapine and similar agents exhibit preferential blockade of D-1 dopamine receptors in the whole animal. Such an action of clozapine in man could well explain both its low EPS liability and, in some subjects, its superior antipsychotic activity.     

In vivo whole-body resting energy expenditure and insulin action in human malignant hyperthermia

BACKGROUND: Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics or succinylcholine. The disorder is heterogenetic and caused by abnormal calcium regulation within skeletal muscle cells. No clear metabolic differences have been found in MH-susceptible (MHS) persons in vivo while not having MH episodes, but some reported signs suggest that insulin action and energy turnover might be altered in muscle of MHS persons. METHODS: In fasting and insulin-stimulated conditions, using the glucose clamp technique and indirect calorimetry, we assessed in vivo resting energy expenditure (REE) and nutrient utilization rates in 10 MHS, 5 MH-equivocal (MHE) and 10 MH-negative (MHN) persons from 14 families. With a model using the persons' fat-free mass, fat mass, age, and gender, we calculated their predicted REE and compared it with measured REE in 10 MHS and 10 MHN persons (measured - predicted = residual REE). RESULTS: In vivo measured REE and glucose disposal rates were similar in 10 MHS and 10 MHN persons. Only during insulin stimulation was residual REE greater in MHS persons (6.4%; P = 0. 013). CONCLUSIONS: In vivo insulin action is unimpaired in MHS persons. Although the absolute values of whole-body REE are the same in MHS and MHN persons, the part of REE independent of the determinants fat-free mass, fat mass, age, and gender is moderately greater in MHS than in MHN persons during insulin exposure. This suggests that MH susceptibility might influence insulin-stimulated energy turnover in muscle.     

The performance of rigid scopes for tracheal intubation: a randomised,controlled trial in patients with a simulated difficult airway

We compared the Bonfils^? and SensaScope^? rigid fibreoptic scopes in 200 patients with a simulated difficult airway randomised to one of the two devices. A cervical collar inhibited neck movement and reduced mouth opening to a mean (SD) of 23 (3) mm. The primary outcome parameter was overall success of tracheal intubation; secondary outcomes included first‐attempt success, intubation times, difficulty of intubation, fibreoptic view and side‐effects. The mean (95% CI) overall success rate was 88 (80–94)% for the Bonfils and 89 (81–94)% for the SensaScope (p = 0.83). First‐attempt intubation success rates were 63 (53–72)% for the Bonfils and 72 (62–81)% for the SensaScope (p = 0.17). Median (IQR [range]) intubation time was significantly shorter with the SensaScope (34 (20–84 [5–240]) s vs. 45 (25–134 [12–230]) s), and fibreoptic view was significantly better with the SensaScope (full view of the glottis in 79% with the SensaScope vs. 61% with the Bonfils). This might be explained by its steerable tip and the S‐formed shape, contributing to better manoeuvrability. There were no differences in the difficulty of intubation or side‐effects.     

Neuropeptides are potent modulators of human in vitro immunoglobulin E synthesis

We determined the effect of adrenocorticotropin hormone (ACTH) on the regulation of IgE synthesis. Depending on the concentration, ACTH enhanced or inhibited IgE synthesis in a culture system where IgE synthesis was induced with interleukin-4 (IL-4) and anti-CD40 monoclonal antibody in peripheral blood mononuclear cells. Similar effects on IgE synthesis were observed by adding ACTH-related peptides, e.g. corticotropin-releasing factor (CRF), the inducer of ACTH, or α-melanocyte stimulating hormone (α-MSH), a cleavage product of ACTH. However, ACTH had no effect on IgG or IgM synthesis in this culture system. ACTH did not act directly on either B or T cells as there was no influence on IgE synthesis in a system using purified B cells alone or co-cultured with T cells. The effect of ACTH on IgE synthesis was mediated by accessory cells. This was shown by priming purified CD14-positive monocytes with ACTH and reconstitution experiments. Therefore, these findings suggest that ACTH and the related peptides CRF and α-MSH can influence the microenvironment modulating an IL-4 and anti-CD40 monoclonal antibody driven class switching to IgE via accessory cells.     

Cefetamet pivoxil: a review of its microbiology, toxicology, pharmacokinetics and clinical efficacy

Cefetamet pivoxil is an oral, third-generation cephalosporin whose broad spectrum of antibacterial activity and favorable pharmacokinetic profile make it particularly suitable for the treatment of a wide range of infectious diseases. Cefetamet has high in vitro activity against both gram-positive and gram-negative bacteria that cause a number of respiratory tract and urinary tract infections. These include penicillin-sensitive Streptococcus pneumoniae, Streptococcus spp, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus spp., Klebsiella spp. and Neisseria gonorrhoeae. It is not active against staphylococci, enterococci, Pseudomonas spp. or Bacteroides fragilis but does inhibit most bile-sensitive (oral) Bacteroides spp. Animal toxicology studies indicate that neither cefetamet pivoxil nor the active compound cefetamet have significant teratogenic, mutagenic, photogenic or allergenic potential. Cefetamet is eliminated unchanged in the urine with a half-life of 2.2 h. Volume of distribution approximates the extracellular fluid space (0.3 1/kg), protein binding is minima (22%) and oral bioavailability of cefetamet pivoxil is approximately 50% when taken with food. No significant drug interactions have been noted to date. The efficacy and tolerability of cefetamet pivoxil have been evaluated in the treatment of gram-positive and gram-negative infections in almost 5,000 patients. In comparative studies, cefetamet pivoxil was at least as effective, and in many cases clinically superior, to most currently recommended antibiotics for the treatment of urinary tract infections including gonorrhea and complicated infections in high risk patients. Efficacy has also been demonstrated in acute exacerbations of chronic bronchitis, pneumonia and infections of the ear, nose and throat. Clinical trials have shown that a 7 day treatment period with cefetamet pivoxil is as effective as a 10 day course of phenoxymethylpenicillin in the treatment of pharyngotonsillitis. Cefetamet pivoxil has been well-tolerated in clinical trials with only 1.2% of patients on standard doses discontinuing therapy prematurely. The most common adverse effects are gastrointestinal (diarrhea, nausea, vomiting) which occur in less than 10% of patients. Many current antibiotic treatment regimens involve the administration of three or more daily doses. However, standard doses of cefetamet pivoxil 500 mg twice daily provide unbound plasma concentrations of cefetamet which generally exceed the MIC(90) for susceptible organisms throughout the dosing interval and have been demonstrated to be clinically effective. This should result in good compliance with therapy in out-patients. Dosing regimens for cefetamet pivoxil should be adjusted in patients with impaired renal function while standard doses can be given to elderly patients and those with liver disease. Standard doses in children are 10 mg/kg or alternatively, children may receive a dose reduced in proportion to the ratio of their body surface area to that of an adult.     

Propofol reduces succinylcholine induced increase of masseter muscle tone

Purpose

Succinylcholine is known to increase the tone of the masseter muscles. As excessive jaw tension may complicate rapid sequence induction, we investigated three induction techniques, all including the use of succinylcholine, with respect to masseter muscle tone, neuromuscular blockade, intubation conditions, and time course of intubation.

Methods

Sixty adult patients were allocated to one of three induction groups: Group THIO received 5 mg · kg^?1 thiopentone, Group THIO/ATR received 5 mg · kg^?1 thiopentone plus 0.05 mg · kg^?1 atracurium for precurarization, and Group PROP received 2.5 mg · kg^?1 propofol. All patients received 3 μg · kg^?1 fentanyl and 1.5 mg · kg^?1 succinylcholine. Time for induction of anaesthesia was recorded, and, after inserting a Grass Force Transducer between upper and lower incisors, jaw tone and the time course of jaw tension was recorded before and after the administration of succinylcholine.

Results

No differences in the onset of sleep were observed among the three groups (Group THIO 33 ± 2 sec: THIO/ATR 30 ± 2 sec: PROP 35± 2 sec, mean ± SE). Masseter preloads following induction of anaesthesia were similar in all three groups (THIO 16.4 ± 2.1 N: THIO/ATR 15.1 ± 2.0 N: PROP 12.7 ± 1.6 N). However, after administration of succinylcholine, the increase in masseter tone was less in Groups PROP (5.0 ±1.1 N) and THIO/ATR (6.4 ± 2.1 N) than in Group THIO (12.4 ± 3.0 N;P < 0.05).

Conclusion

Jaw tension after administration of succinylcholine is influenced by the choice of induction agent. The increase of masseter muscle tone is lower following propofol or thiopentone/atracurium induction than with thiopentone alone.     

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia

BackgroundPrimary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: –780, –199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by –943 mL (95% CI: –1473, –413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02770885","term_id":"NCT02770885"}}NCT02770885.FundingSwiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.     

A Review of Multimodal Hallucinations: Categorization,Assessment, Theoretical Perspectives,and Clinical Recommendations

Hallucinations can occur in different sensory modalities, both simultaneously and serially in time. They have typically been studied in clinical populations as phenomena occurring in a single sensory modality. Hallucinatory experiences occurring in multiple sensory systems—multimodal hallucinations (MMHs)—are more prevalent than previously thought and may have greater adverse impact than unimodal ones, but they remain relatively underresearched. Here, we review and discuss: (1) the definition and categorization of both serial and simultaneous MMHs, (2) available assessment tools and how they can be improved, and (3) the explanatory power that current hallucination theories have for MMHs. Overall, we suggest that current models need to be updated or developed to account for MMHs and to inform research into the underlying processes of such hallucinatory phenomena. We make recommendations for future research and for clinical practice, including the need for service user involvement and for better assessment tools that can reliably measure MMHs and distinguish them from other related phenomena.