One-year follow-up on liraglutide treatment for prediabetes and overweight/obesity in clozapine- or olanzapine-treated patients.

OBJECTIVE: Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period. METHOD: One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels. RESULTS: From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide. CONCLUSION: The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.

The significance of sampling time in therapeutic drug monitoring of clozapine.

OBJECTIVE: Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose. METHOD: Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose. RESULTS: Minor changes in median percentage values were observed for both s-clozapine (-8.4%) and s-norclozapine (+1.2%) across the 4-h time span. Maximum individual differences were 42.8% for s-clozapine and 38.4% for s-norclozapine. Compared to 12-h values, maximum median differences were 8.4% for s-clozapine and 7.3% for s-norclozapine at deviations of ±2 h. Maximum individual differences were 52.6% for s-clozapine and 105.0% for s-norclozapine. The magnitude of s-clozapine differences was significantly associated with age, body mass index and the presence of chronic basophilia or monocytosis. CONCLUSION: The impact of deviations in clozapine TDM sampling time, within the time span of 10-14 h postdose, seems of minor importance when looking at median percentage differences. However, substantial individual differences were observed, which implies a need to adhere to a fixed sampling time.

Grass-green urine from propofol infusion.

Green urine from propofol infusion is a benign and rare side effect. The discolouration appears when clearance of propofol exceeds hepatic elimination, and extrahepatic elimination of propofol occurs. This case report presents a 24-year-old male with grass green discolouration of urine based on propofol infusion.

Heart rate limitation and cardiac unloading in sevoflurane post-conditioning.

BACKGROUND: Sevoflurane post-conditioning (SePost) has been found to alleviate ischemic myocardial reperfusion injury through the activation of prosurvival kinases. Lowered myocardial oxygen demand from reduced cardiac work may also contribute to cardioprotection, and is much less well-studied. Our aim was to examine the simultaneous effects of SePost on cardiac work (here, rate-pressure product, RPP) and myocardial infarct size in a porcine model. METHODS: Anesthetized 25 kg pigs were randomly allocated to two groups and underwent 45 min regional coronary artery balloon occlusion and subsequent 2 h reperfusion. SePost (n = 10) was given as sevoflurane 1.5-3% end-tidal concentration during reperfusion while controls (n = 12) were untreated. Aortic blood pressure was measured directly, while mixed-venous oxygen saturation and cardiac output were measured in the pulmonary artery. Cardiac work was determined as RPP. Post-mortem, histologic myocardial infarct size (IS), and area at risk were determined in transverse heart slices after tetrazolium stain. RESULTS: Myocardial infarct size was reduced from (control) 55.0 (mean) ± 13.6% (standard deviation) to 32.5 ± 13.4% in group SePost (P = 0.0009). During reperfusion, SePost resulted in lower heart rate (P = 0.0003), cardiac output (P = 0.0123), mixed-venous oxygen saturation (P = 0.0103), blood pressure, and RPP (P < 0.0001). RPP was highly correlated to IS (P = 0.0055). CONCLUSION: SePost (1.5-3%) reduced infarct size after regional myocardial ischemia in vivo and reduced cardiac work was significantly correlated to myocardial salvage.

d-tubocurarine chloride: effect on insects.

Injection of d-tubocurarine chloride into certain insects produces complete flaccid paralysis. The site of injection is closely related to the region of primary paralysis. The effect depends on concentration, with distinct differences in the optimum concentrations for various species so far tested. A dose-response curve has been prepared for Calliphora erythrocephala.

Hypertrophied hearts: what of sevoflurane cardioprotection?

BACKGROUND: Recent studies have demonstrated that inhalation anaesthetics, like sevoflurane, confer cardioprotection both experimentally and clinically. However, coexisting cardiac disease might diminish anaesthetic cardioprotection and could partly explain why the clinical results of cardioprotection with anaesthetics remain controversial--in contrast to solid experimental evidence. Concomitant left ventricular hypertrophy is found in some cardiac surgery patients and could change cardioprotection efficacy. Hypertrophy could potentially render the heart less susceptible to sevoflurane cardioprotection and more susceptible to ischaemic injury. We investigated whether hypertrophy blocks sevoflurane cardioprotection, and whether tolerance to ischaemia is altered by left ventricular hypertrophy, in an established experimental animal model of ischaemia-reperfusion. METHODS: Anaesthetized juvenile pigs (n=7-12/group) were subjected to 45 min distal coronary artery balloon occlusion, followed by 120 min of reperfusion. Controls were given pentobarbital, while sevoflurane cardioprotection was achieved by 3.2% inhalation throughout the experiment. Chronic banding of the ascending aorta resulted in left ventricular hypertrophy development in two further groups and these animals underwent identical ischaemia-reperfusion protocols, with or without sevoflurane cardioprotection. Myocardial infarct sizes were compared post-mortem. RESULTS: The mean myocardial infarct size (% of area-at-risk) was reduced from mean 55.0 (13.6%) (+/-SD) in controls to 17.5 (13.2%) by sevoflurane (P=0.001). Sevoflurane reduced the infarct size in hypertrophied hearts to 14.6 (10.4%) (P=0.001); however, in hypertrophic controls, infarcts were reduced to 34.2 (10.2%) (P=0.001). CONCLUSION: Sevoflurane abrogated ischaemic injury to similar levels in both normal and left ventricular hypertrophied hearts.

Sevoflurane improves myocardial ischaemic tolerance in a closed-chest porcine model.

AIMS: Volatile anaesthetics prevent experimental myocardial ischaemia-reperfusion injury (I/R) in several species, but this finding is partially inconsistent with clinical evidence. Some experimental models may not accurately represent the complex signal transduction pathways triggered by volatile anaesthetics. We therefore investigated sevoflurane I/R prevention in vivo in a porcine model with greater likeness to human physiology than models previously used and compared it with neutral anaesthetic. METHODS AND RESULTS: Myocardial infarct size [IS/AAR] was compared in three groups of pigs (N=35) randomised to Control anaesthesia (pentobarbital infusion, n=12), sevoflurane inhalation alone (end-tidal concentration 3.2%) (Sevo, n=9), or both Combined (n=14), throughout ischaemia and reperfusion. Anterior/septal myocardial infarcts resulted from distal LAD coronary artery occlusion by balloon catheter for 45 min followed by 120 min of reperfusion. [IS/AAR] was measured in tetrazolium-stained heart slices after standardised image processing with computer-assisted planimetry. Measurements included full invasive monitoring. Control animals developed infarction in 55.0 +/- 3.9% (SEM) of the area at risk, Sevo in 17.5 +/- 4.4% (P=0.0002), and Combined with pentobarbital in 24.3 +/- 3.8% (P=0.0001) of the AAR, sevoflurane reducing infarct size significantly (68% and 60%, respectively). CONCLUSIONS: Sevoflurane markedly decreased myocardial infarct size after prolonged coronary occlusion in a porcine model. In addition to novel sevoflurane cardioprotection in the closed-chest model, which is more comparable to normal human hearts than models previously used, sevoflurane cardioprotection is substantiated in the juvenile intact organism. The perspectives underline recommending volatile anaesthetics in risk patients and in cardiac surgery.

Slow component-a of axonal transport, nerve myo-inositol, and aldose reductase inhibition in streptozocin-diabetic rats.

This study measured sugars and polyols, weight/unit length, and slow component-a of axonal transport (SCa) in dorsal root afferents of the sciatic nerves of control rats and rats with streptozocin (STZ)-induced diabetes of 4-wk duration. The effects of two treatments--aldose reductase inhibition [Statil ("Statil" is a trademark; the property of Imperial Chemical Industries PLC.) ICI 128436 at 25 mg/kg/day, p.o.] and myo-inositol supplementation (650 mg/kg/day, p.o.)--were studied in control and diabetic groups. Inclusion of untreated controls and diabetics gave a total of six groups for the study. The treatments were begun on the day after injection of STZ and were maintained throughout the protocol. The sciatic nerves of the diabetic (untreated) rats showed accumulation of sorbitol and fructose, depletion of myo-inositol, and an 8% increase in weight/unit length. All of these abnormalities were prevented by treatment with Statil. Treatment of diabetic rats with myo-inositol prevented its depletion in the sciatic nerve, but did not affect the accumulation of sorbitol and fructose nor the increase in weight/unit length. Neither treatment exerted any apparent effect on body weight, blood glucose, nerve weight, or nerve sugars and polyols in the control rats. The diabetic rats showed a retardation of the wave of transported-labeled protein (shown as increased leftward skewness of the wave) and a reduction in mean transport velocity (calculated as the mean velocity for all segments contributing to the transport wave: 0.96 +/- 0.09 mm/day in diabetics versus 1.15 +/- 0.07 mm/day in controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal fulminant autoimmune haemolytic anaemia associated with tolmetin use and gastric carcinoma. Case report and literature review.

Presented is a case report of an 80-year-old man with dyspnoea and jaundice who died from autoimmune haemolytic anaemia (AIHA) within 12 hours of arrival at the emergency department. The patient had been taking tolmetin for osteoarthritis. On autopsy he was found to have a superficial gastric adenocarcinoma. A brief presentation on AIHA includes primary (idiopathic) and secondary types. Factors associated with AIHA include nonsteroidal anti-inflammatory drugs (NSAIDs) and gastric carcinoma, although a direct cause cannot be demonstrated. After a discussion of the autoimmune mechanism of drug-associated hemolysis of which methyldopa is the prototype, a review of NSAIDs associated with AIHA is presented. All (18) NSAID cases of immune haemolysis were reviewed to determine which were more likely due to an autoimmune mechanism. These included 3 cases with tolmetin use: one probable and one possibly having an autoimmune basis for haemolysis, while with the third case immune haemolysis was by the drug adsorption mechanism. A review of gastric carcinoma associated with AIHA reveals only 2 previously reported cases. The associations of tolmetin use, as well as gastric carcinoma with AIHA, both rare, are noteworthy but cannot be proven as causative factors with our current level of knowledge and technology.

Clinical performance of a new silver dressing, Contreet Foam, for chronic exuding venous leg ulcers.

OBJECTIVE: This study aimed to evaluate the safety and performance of a new sustained silver-releasing dressing, Contreet Foam (Coloplast A/S), in the treatment of moderately to highly exuding chronic venous leg ulcers in which healing is delayed due to the presence of bacteria. METHOD: The clinical performance of Contreet Foam was studied for four weeks in 25 patients with moderately to highly exuding delayed-healing venous leg ulcers. Healing was assessed on a weekly basis with reference to the wound-bed tissue composition, degree of odour and pain, dressing performance and the dressing's effect on the peri-ulcer area. Blood samples were analysed for silver content. RESULTS: Twenty-three out of 25 patients completed the study. One ulcer healed and no wound infections occurred during the study period. A mean 56% reduction in ulcer area (from 15.6 to 6.9 cm2) was recorded during the four weeks, and there was a mean 25% reduction in granulation tissue from dull to healthy after one week. Wound odour reduced significantly after one week. Mean dressing wear time was 3.1 days, and there were only minimal incidences of leakage. Serum silver levels did not exceed reference values. CONCLUSION: Contreet Foam was found to be safe and performed well when used in the treatment of delayed-healing chronic venous leg ulcers, combining effective antibacterial properties with excellent exudate management. DECLARATION OF INTEREST: This study was supported by Coloplast A/S, Humlebaek, Denmark.