Levodopa up-regulates platelet alpha 2-adrenoceptors

Treatment of dogs for 21 days with oral levodopa (100 mg b.i.d.) plus benserazide (25 mg b.i.d.) induced a significant increase in the number of platelet alpha 2-adrenoceptors labelled by [3H] yohimbine with no change in Kd. The rise was maximal at the end of the treatment and remained significant during the month following the cessation of treatment. Plasma catecholamine levels did not vary. Competition experiments showed a low affinity of both dopamine and levodopa for platelet alpha 2-adrenoceptors. These results suggest that levodopa treatment regulates alpha 2-adrenoceptor number in dog platelets.     

Multimodality imaging for focus localization in pediatric pharmacoresistant epilepsy.

Multiple structural and functional imaging modalities are available to localize the epileptogenic focus. In pre-surgical evaluation of children with pharmacoresistant epilepsy, investigations with the maximum yield should be considered in order to reduce the complexity of the workup. OBJECTIVE: To determine the extent to which PET, ictal/interictal SPECT and its co-registration with the patient's MRI contributes to correct localization of the epileptogenic focus, surgical intervention and to the post surgical outcome in paediatric patients. METHODS: The study population included children and adolescents with pharmacoresistant epilepsy (n = 50) who underwent preoperative evaluation, surgery and had postoperative follow-up for at least 12 months. Outcome was measured by postoperative seizure frequency using Engel's classification. RESULTS: Thirty-nine patients (78%) became completely seizure free after surgical intervention. The likelihood to benefit from surgical treatment was significantly higher if localization with more imaging modalities (MRI, PET, SPECT) were concordant with respect to the resected brain area (p < 0.01). Preoperative PET examination provided better localizing information in patients with extratemporal epilepsy and/or dysplastic lesions, whereas SPECT was found to be superior to PET in patients with temporal lobe epilepsy and/or tumors (p < 0.05). No significant difference was noted in the surgical outcome in younger or older age group, in children with or without special education needs. CONCLUSION: In paediatric epilepsy pre-surgical evaluation, the combined use of multiple functional imaging modalities for a precise localisation of the epileptogenic focus is worthwhile for both extratemporal and temporal lobe epilepsy, also when EEG and MRI alone are non-contributive, given the potential benefit of complete postoperative seizure control.     

Propranolol disposition in the rat: variation in hepatic extraction with unbound drug fraction.

The plasma protein binding of propranolol has been described as nonrestrictive for its hepatic extraction to explain the observation that propranolol is efficiently removed by the liver, in spite of extensive protein binding. The present study was designed to examine the relationship between propranolol protein binding, metabolism by isolated hepatocytes, and extraction by the isolated perfused rat liver. In isolated hepatocytes, the intrinsic clearance of free drug increased three- to fourfold as albumin and alpha 1-acid glycoprotein (AAG) concentrations increased, suggesting that albumin and AAG facilitate the elimination of propranolol by hepatocytes. In the isolated perfused liver, propranolol extraction was almost complete (E = 0.996) in the absence of albumin and AAG. With 40 g/L of albumin and 2 g/L of AAG in the perfusate, the free fraction of propranolol decreased to 0.031, but extraction remained high (E = 0.960). With 40 g/L of albumin and 10 g/L of AAG in the perfusate, the free fraction further decreased to 0.014 and extraction dropped sharply (E = 0.820). The observed relationship between propranolol extraction and the free fraction of propranolol was in good agreement with that predicted using estimates of intrinsic clearance measured in isolated hepatocytes suspensions. These data indicate that propranolol extraction is sensitive to changes in binding at very low free fraction values and suggest a facilitation of propranolol clearance by albumin and AAG.     

Short-term dermal toxicity and mutagenicity of coal coprocessing products in the rat.

The present study was conducted to determine the dermal toxicity of coal coprocessing products and to assess their potential health hazards. Groups of 10 male and 10 female Sprague-Dawley rats were administered dermally coal coprocessing products (light gas oil, LGO; heavy gas oil I, HGOI; heavy gas oil II, HGOII) at 1 g/kg body weight/d for 14 d. The control and positive control groups received normal saline and a coal liquefaction product (CLP) at the same dose level, respectively. Treatment with either the three fractions of coprocessing products or CLP caused decreased growth rate and food consumption in animals of both sexes. Liver enlargement occurred in groups treated with HGOI, HGOII, and CLP. Decreased serum glucose was observed in animals of both sexes treated with the three fractions and CLP. Treatment with HGOI and CLP caused an elevation of hepatic microsomal ethoxyresorufin deethylase activity in the rat of both sexes. The three fractions and CLP caused mild anemia. Mild treatment-related histological changes were observed in the liver, spleen, thyroid, bone marrow, and kidney. All three fractions of coprocessing products were tested for their mutagenicity in five strains of Salmonella typhimurium: TA98, TA100, TA1535, TA1537, and TA1538. HGOI, after metabolic activation, was found to be mutagenic in the strains of TA98, TA100, and TA1538. In contrast, HGOII was mutagenic in the five strains with or without metabolic activation. These data indicate that HGOI and HGOII are more toxic than LGO, and should be subjected to further studies to determine their long-term effects.     

Kinetics and dynamics of triamterene at steady-state in patients with cirrhosis

Triamterene is a potassium-sparing diuretic used in patients with cirrhosis for the treatment of ascites. It is extensively metabolized by the liver and is subject to an important first-pass effect after oral dosing. We examined the disposition and diuretic effect of triamterene after repeated oral administration (200 mg daily for 10 days) in 7 healthy controls and 6 patients with cirrhosis and ascites. In the controls the average plasma concentration of triamterene during a dosage interval was 45 +/- 8 ng/ml and that of hydroxy-triamterene sulfate, an active metabolite of triamterene, was 967 +/- 177 ng/ml. In the cirrhotics, the mean concentration of triamterene was 586 +/- 126 ng/ml (a 13-fold increase as compared with the controls) and that of hydroxy-triamterene sulfate was 747 +/- 502 ng/ml. Sodium excretion was correlated with hydroxy-triamterene sulfate levels in the controls (r = 0.81), but in the cirrhotics the diuretic response was correlated with basal sodium excretion (r = 0.86) and was not related to either triamterene or hydroxy-triamterene plasma concentrations. Our results indicate that chronic treatment with triamterene in patients with cirrhosis and ascites results in markedly elevated plasma levels, but these changes do not have a major influence on the magnitude of the diuretic response.     

Patient-centred evaluation and rehabilitative care

The evaluation of health care outcomes is becoming increasingly important in today's health service The wide range of measures used to evaluate these outcomes often makes clinical audit difficult and the comparison of research papers almost impossible In this paper we will discuss some of the issues surrounding outcome measurement in rehabilitative care, examine one of the most commonly used outcome measures from this area (the Barthel Index) and consider Goal Attainment Scaling, a technique which offers both clinicians and researchers the opportunity to evaluate health care outcomes on the basis of patient-centred practice We have identified certain methodological problems that need to be addressed if Goal Attainment Scaling is to become an acceptable measure in the area of physical rehabilitative care     

Tissue distribution metabolism and excretion of 2,2′,4,4′, 5-pentachlorodiphenyl ether in the rat

The tissue distribution, metabolism and excretion of ¹⁴C-2,2,4,4,5-pentachlorodiphenyl ether (PCDE) were studied in the rat. Radioactivity was distributed in all tissues examined, with the highest concentrations being found in the fat followed by the skin, liver, kidney and muscle. Most of the radioactivity found in the tissues was due to unchanged PCDE. Decay of PCDE in the blood was fitted to a four-compartment pharmacokinetic model, and the last compartment had a half-life of 5.8 days. A total of 55% and 1.3% of an orally administered dose was excreted in feces and urine, respectively, in 7 days. More than 64% of the fecal radioactivity was due to unchanged PCDE, while hydroxylated PCDE accounted for 23%.     

Effects of short-duration transients on cardiac rhythm

Cardiac stimulation thresholds of short-duration large-amplitude electrical transients were studied. An isolated rabbit heart model was used and transients were applied directly to the heart through electrodes of 1 mm² and 1 cm² surface area. A variety of oscillatory waveforms and pulse configurations were studied and indicated that, for transients shorter than 100 μs, stimulation thresholds approach a constant charge-transfer density of 3·4 μC cm⁻².