The effect of coniine on presynaptic nicotinic receptors.

Toxicity of coniine, an alkaloid of Conium maculatum (poison hemlock), is manifested by characteristic nicotinic clinical signs including excitement, depression, hypermetria, seizures, opisthotonos via postsynaptic nicotinic receptors. There is limited knowledge about the role of presynaptic nicotinic receptors on the pharmacological and toxicological effects of coniine in the literature. The present study was undertaken to evaluate the possible role of presynaptic nicotinic receptors on the pharmacological and toxicological effects of coniine. For this purpose, the rat anococcygeus muscle and guinea-pig atria were used in vitro. Nicotine (100 µM) elicited a biphasic response composed of a relaxation followed by contraction through the activation of nitrergic and noradrenergic nerve terminals in the phenylephrine-contracted rat anococcygeus muscle. Coniine inhibited both the nitrergic and noradrenergic response in the muscle (-logIC(50) = 3.79 ± 0.11 and -logIC(50) = 4.57 ± 0.12 M, respectively). The effect of coniine on nicotinic receptor-mediated noradrenergic transmission was also evaluated in the guinea-pig atrium (-logIC(50) = 4.47 ± 0.12 M) and did not differ from the -logIC(50) value obtained in the rat anococcygeus muscle. This study demonstrated that coniine exerts inhibitory effects on nicotinic receptor-mediated nitrergic and noradrenergic transmitter response.

Osteoporotic hip fracture costs in the elderly Turkish population.

OBJECTIVE: This study was designed to determine the length of hospital stay and treatment costs of patients with osteoporotic hip fractures in Turkey. METHODS: A total of 1,118 osteoporotic hip fractures taken from patient records in 35 hospitals connected to a Disease Related Group (DRG) network were included in the study. Inclusion criteria were patients over the age of fifty with a diagnosis of a single, low-energy fracture located at the neck, head, or intertrochanteric region of the femur treated with total/hemi-arthroplasty, screw or nail methods. We examined the demographics, location of fracture, treatment type, length of hospital stay (LOS), direct cost and cost extrapolation based on the numbers of hospitals, beds and patient by hospital. RESULTS: Of the 1,118 patients (mean age: 75.3 ± 9.9 years), 62.8% were female. The main fracture type was of the femur neck without precise localization. The average LOS was 11.0 ± 7.9 days. The total weighed cost of all 1,118 hip fractures was $2,249,885 per year, indicating an average direct medical cost of $3,119 per patient in the 35 DRG hospitals. Based on this sample, the estimated total number of patients is 15,602 by number of hospitals; 8,521 by number of hospital beds and 9,365 by number of hospitalization, costing $31,530 million; $14,793 million and $18,948 million, respectively. CONCLUSION: Diverse results in cost estimations of osteoporotic hip fractures reflect the incoherence of data as well as a lack of standardization of health care services. Therefore, ICD and DRG coding needs to be improved and a national database must be created at least for the invoices of importation of prostheses to fully be able to calculate the burden of osteoporosis across Turkey.

Influence of acarbose on blood glucose and breath hydrogen after carbohydrate load with sucrose or starch.

A monocentric, open, randomised, single-dose, six-period crossover trial was carried out in healthy volunteers under fasting conditions to establish the most appropriate study design for a pivotal bioequivalence trial with acarbose (CAS 56180-94-0) regarding a) dosage of the drug, b) type of carbohydrate load, c) type of primary endpoint, and d) sample size. 50 g sucrose or 50 g starch were used as carbohydrate load. Acarbose was administered in doses of 50 and 200 mg. Blood glucose and breath hydrogen were evaluated as endpoints. Both acarbose doses reduced the effect of carbohydrate load. Blood glucose: no statistically significant difference could be noted between the overall effect of 50 mg and that of 200 mg acarbose irrespective of the type of carbohydrate load. Breath hydrogen: an influence could be shown only for sucrose as carbohydrate load. Practically no effect was observed with starch. The overall increase of effect is by more than 200% with sucrose when the dose of acarbose increases from 50 to 200 mg. This difference between the effects of both doses of acarbose on breath hydrogen is statistically significant. For a pivotal trial, sucrose is the most appropriate type of carbohydrate load, baseline adjusted area under the breath hydrogen response is the most appropriate primary endpoint, and a dose of 100 mg acarbose is the most appropriate dosage. A total number of 100 subjects will be needed for proving pharmacodynamic equivalence between two acarbose products in a pivotal trial.

The use of truncated area under the curves in the bioequivalence evaluation of long half-life drugs. Studies with donepezil and memantine.

The bioequivalence of long terminal half-life drugs, donepezil (CAS 120014-06-4) 10 mg and memantine (CAS 19982-08-2) 10 mg, was evaluated by comparing the results obtained for the total areas under the concentration time curves (AUC(0-inf)) with those for partial AUCs: AUC(0-216h), AUC(0-72h) and AUC(0-48h). Pharmacokinetic endpoints were determined by standard formulas from the concentration-time courses of the parent compounds donepezil and memantine. The results of the bioequivalence assessment based on the 90% confidence intervals calculated by means of ANOVA for logarithmically transformed values (ANOVA log) led to exactly the same decision irrespective of the type of AUC used. The 90% confidence intervals for all types of AUCs were practically identical within each product. These results prove that truncated AUCs, e.g. AUC(0-72h) or even AUC(0-48h), can be adequately used in assessing the relative bioavailability of long terminal half-life drugs. The findings suggest that even for drugs with half-lives between 24 and 60 h and thus shorter than those of donepezil and memantine an AUC truncated to 48 h post dose can be successfully used for the assessment of bioequivalence as this sample collection time ensures a proper comparison of the absorption process as recommended in the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence.

Glibenclamide attenuates the antiarrhythmic effect of endotoxin with a mechanism not involving K(ATP) channels.

The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.