Intramuscular Botulinum toxin A injections induce central changes to axon initial segments and cholinergic boutons on spinal motoneurones in rats.

Intramuscular injections of botulinum toxin block pre-synaptic cholinergic release at neuromuscular junctions producing a temporary paralysis of affected motor units. There is increasing evidence, however, that the effects are not restricted to the periphery and can alter the central excitability of the motoneurones at the spinal level. This includes increases in input resistance, decreases in rheobase currents for action potentials and prolongations of the post-spike after-hyperpolarization. The aim of our experiments was to investigate possible anatomical explanations for these changes. Unilateral injections of Botulinum toxin A mixed with a tracer were made into the gastrocnemius muscle of adult rats and contralateral tracer only injections provided controls. Immunohistochemistry for Ankyrin G and the vesicular acetylcholine transporter labelled axon initial segments and cholinergic C-boutons on traced motoneurones at 2 weeks post-injection. Soma size was not affected by the toxin; however, axon initial segments were 5.1% longer and 13.6% further from the soma which could explain reductions in rheobase. Finally, there was a reduction in surface area (18.6%) and volume (12.8%) but not frequency of C-boutons on treated motoneurones potentially explaining prolongations of the after-hyperpolarization. Botulinum Toxin A therefore affects central anatomical structures controlling or modulating motoneurone excitability explaining previously observed excitability changes.

Systematic review: tranexamic acid for upper gastrointestinal bleeding.

BACKGROUND: Tranexamic acid may reduce upper gastrointestinal bleeding and stabilize patients before endoscopic treatments. AIM: To review randomized trials on tranexamic acid for upper gastrointestinal bleeding. METHODS: Manual and electronic searches of The Cochrane Library, MEDLINE, EMBASE and Science Citation Index were combined. Intention-to-treat random effect meta-analyses were performed and results presented as RRs with 95% confidence intervals. RESULTS: Seven double-blind randomized trials on tranexamic acid vs. placebo were included. Of 1754 patients randomized, 21% were excluded. Only one trial included endoscopic treatments or proton pump inhibitors. Five per cent of patients on tranexamic acid and 8% of controls died (RR: 0.61, 95% CI: 0.42-0.89). No significant differences were found on bleeding, bleeding-related mortality, surgery or transfusion requirements. Adverse events were unclearly reported. Data from three of the included trials suggested that tranexamic acid did not significantly increase the risk of thromboembolic disease. CONCLUSIONS: The present review suggests that tranexamic acid may reduce all-cause mortality. However, because of limitations in the internal and external validity of included trials, additional evidence is needed before treatment recommendations can be made.

D-penicillamine for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a cholestatic disease. D-penicillamine is suggested as a treatment option due to its copper reducing and immunomodulatory potential. OBJECTIVES: To evaluate the beneficial and harmful effects of D-penicillamine for patients with primary sclerosing cholangitis. SEARCH STRATEGY: Eligible trials were identified through searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (August 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 3, 2005), MEDLINE (1950 to August 2005), EMBASE (1980 to August 2005), Science Citation Index EXPANDED (1945 to August 2005), and reference lists of relevant articles. Authors of trials and pharmaceutical companies known to produce D-penicillamine were also contacted. SELECTION CRITERIA: Randomised clinical trials comparing D-penicillamine in any dose, duration, and route of administration versus placebo, no intervention, or other intervention(s). Trials were included irrespective of publication status, year of publication, language, or blinding. DATA COLLECTION AND ANALYSIS: Both authors selected the trials, extracted data, and evaluated the methodological quality of the trials with respect to the generation of allocation sequence, allocation concealment, blinding, and follow-up. The results were reported by intention-to-treat analysis. The outcomes were presented as relative risk (RR) or weighted mean difference (WMD), both with 95% confidence intervals (CI). MAIN RESULTS: One randomised trial was identified and included in the review. It was of low methodological quality. The trial compared D-penicillamine versus placebo in 70 patients with primary sclerosing cholangitis. Compared with placebo, D-penicillamine therapy had no significant effect on mortality (RR 1.14, 95% CI 0.49 to 2.64), liver transplantation (RR 1.11, 95% CI 0.39 to 3.17), hepatic histologic progression (RR 1.17, 95% CI 0.79 to 1.74), or cholangiographic deterioration (RR 0.87, 95% CI 0.43 to 1.79). D-penicillamine led to a significant improvement in the serum aspartate aminotransferase (WMD -23.00 U/L; 95% CI -30.66 to -15.34), but not in serum bilirubin level (WMD 0.40 mg/L; 95% CI -0.19 to 0.99) and serum alkaline phosphatases activity (WMD 44.00 U/L; 95% CI -37.89 to 125.89). There were significantly more adverse events in patients receiving D-penicillamine (P = 0.013). AUTHORS' CONCLUSIONS: There is not sufficient evidence to support or refute the use of D-penicillamine for patients with primary sclerosing cholangitis. We do not recommend the use of D-penicillamine for patients with primary sclerosing cholangitis outside randomised trials.

Systematic review and meta-analysis: D-Penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis--Cochrane Hepato-Biliary Group.

BACKGROUND: D-Penicillamine is used for patients with primary biliary cirrhosis due to its ability to decrease hepatic copper and modulate the immune response. The results on effects of D--penicillamine in randomized-clinical trials of primary biliary cirrhosis patients are inconsistent. AIM: To systematically evaluate the benefits and harms of D-penicillamine for patients with primary biliary cirrhosis. METHODS: We have performed a systematic review with meta-analyses of randomized-clinical trials to evaluate the effects of D-penicillamine for primary biliary cirrhosis. The primary outcomes are mortality and mortality or liver transplantation. We analysed the data by fixed-effect and random-effect models. RESULTS: Seven randomized trials including 706 patients were analysed. d-Penicillamine was without significant effects on mortality (RR 1.08, 95% CI: 0.82-1.43, P = 0.56), mortality or liver transplantation (RR 1.11, 95% CI: 0.74-1.68, P = 0.62), pruritus, liver complications, progression of liver histological stage and liver biochemical variables. D--Penicillamine significantly decreased serum alanine aminotransferase activity (weighted mean difference -45 IU/L, 95% CI: -75 to -15, P < 0.05) and led to significantly more adverse events (RR 4.18, 95% CI: 1.38-12.69, P = 0.01). CONCLUSION: D-Penicillamine did not appear to reduce the risk of mortality or morbidity, and led to more adverse events in patients with primary biliary cirrhosis.