Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal recessive disorder with a frequency of 1 in 50 000 live births. In 97% of patients it is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin. Frataxin is widely expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA levels, aconitase activity and iron content in tissues from FRDA patients. There were significant reductions in the activities of complex I, complex II/III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were normal in FRDA cerebellum and dorsal root ganglia, although there was a mild decrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron deposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respiratory chain and aconitase dysfunction and mitochondrial DNA depletion in FRDA heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation or iron sulphur centre synthesis. However, the severe deficiency in aconitase activity also suggests that oxidant stress may induce a self-amplifying cycle of oxidative damage and mitochondrial dysfunction, which may contribute to cellular toxicity.

Mitochondrial DNA depletion syndrome is expressed in amniotic fluid cell cultures.

Mitochondrial DNA depletion syndrome is an autosomal inherited disease associated with grossly reduced cellular levels of mitochondrial DNA in infancy. Most patients are born after a full and uncomplicated pregnancy, are normal at birth, but develop symptoms in the early neonatal period. These observations have led to the suggestion that the patients have a defect affecting the control of mitochondrial DNA copy number after birth. Using immunocytochemical techniques, we demonstrated that the disease is already expressed in amniotic fluid cells. Detection of mitochondrial DNA depletion in these fetal cells indicates that the defect may already be expressed early in embryological development.

The pharmacokinetics of intravenous ondansetron in patients with hepatic impairment.

The pharmacokinetics of the 5-HT3 receptor antagonist ondansetron were investigated following a single 8 mg intravenous dose given over 5 min in 19 patients with varying degrees of hepatic impairment and in six young healthy subjects. In comparison with the healthy controls, the patients with severe hepatic impairment had a lower mean plasma clearance (96 ml min-1 vs 478 ml min-1) and increased AUC (1383 ng ml-1 h vs 279 ng ml-1 h) and t1/2 (21 h vs 3.6 h). These differences were all statistically significant (P < 0.001). The corresponding values for patients with mild or moderate hepatic impairment fell between these extremes. Vss was greater in all patient groups than the control group, but the magnitude of the change was smaller than for the other parameters and did not reflect the increasing severity of hepatic impairment. There were no significant changes in Cmax. There were no drug-related adverse events in the patients studied. It is recommended that the dosing frequency of ondansetron be limited to once daily in patients with severe hepatic impairment.

Bleeding time in patients with hepatic cirrhosis.

OBJECTIVE: To determine the frequency of an abnormal bleeding time in patients with cirrhosis and to relate this to known factors that affect primary haemostasis and to the severity of liver disease. DESIGN: Prospective clinical and laboratory study in patients admitted for complications or investigations of liver disease. SETTING: Royal Free Hospital hepatobiliary and liver transplantation unit. SUBJECTS: 100 Consecutive inpatients aged 17-74 with various forms of cirrhosis, including alcoholic, biliary, autoimmune, viral, and cryptogenic. At least 10 days had elapsed since any episodes of bleeding, resolution of sepsis, or alcohol intake. No patient was taking any drug known to affect primary haemostasis. MAIN OUTCOME MEASURES: Bleeding time as measured with the Simplate double blade template device. A bleeding time longer than 10 minutes was considered abnormal. Other measures were platelet count, prothrombin time, partial thromboplastin time, packed cell volume, and blood urea, serum bilirubin, and serum albumin concentrations, all measured on each subject at the same time by standard laboratory methods. RESULTS: A weak but significant correlation existed between the bleeding time and the platelet count (rs = 0.483; p less than 0.001). There were significantly lower platelet counts, longer prothrombin times, and higher blood urea and serum bilirubin concentrations in the 42 patients with bleeding times of 10 minutes or more compared with the 58 patients with bleeding times less than 10 minutes. Multiple linear regression analysis showed that the bilirubin concentration as well as the platelet count was independently correlated with the bleeding time. The combination of a platelet count greater than 80 x 10(9)/l and a prothrombin time less than 17 seconds (usually taken as safe limits for performing routine liver biopsy) did not predict a normal bleeding time. Ten of 39 patients fulfilling these criteria had a prolonged bleeding time. CONCLUSIONS: Prolonged bleeding time is common in patients with cirrhosis, even in those with prothrombin times and platelet counts within "safe limits" for invasive procedures. The severity of liver disease as assessed by the bilirubin concentration plays an important part in determining the bleeding time in cirrhosis. The bleeding time should be measured when assessing patients for invasive procedures who have a raised bilirubin concentration or poor hepatic function, even if the platelet count and prothrombin time are considered adequate.

Severe hepatitis caused by cyproterone acetate.

A case of severe acute hepatitis caused by cyproterone acetate in a 71 year old man with prostatic carcinoma is reported with a review of the literature on hepatic reactions to this drug. The association between the use of cyproterone acetate and liver abnormalities is poorly documented. This is the fourth published report of adverse hepatic reaction to cyproterone acetate and it substantiates other evidence that cyproterone acetate is potentially hepatotoxic. Monitoring of liver function tests should be mandatory in patients receiving high doses of cyproterone acetate; the drug should be withdrawn immediately if abnormal liver function tests are found.

Metabolism of exogenous S-adenosyl-L-methionine in patients with liver disease.

S-Adenosyl-L-methionine (SAMe) is an important methyl group donor for many biochemical reactions. It is widespread in body tissues, including the liver, and is metabolised via 3 main metabolic pathways: transmethyltion, trans-sulphuration and amino-propylation. In chronic liver disease these pathways are impaired, the major abnormality being a reduction in SAMe-synthetase activity. Exogenous SAMe may overcome the effects of impaired SAMe-synthetase activity. Exogenous SAMe is stable in digestive juices and, although well absorbed orally, bioavailability is reduced because of a significant first pass effect in the liver. Dose-dependent peak plasma levels are achieved within 3 to 6 hours of oral administration and plasma levels approach baseline after 24 hours. Volumes of distribution are small. The metabolism of exogenous SAMe appears to follow the known pathways of endogenous SAMe metabolism and the initial data suggest that the process is largely unaffected in patients with chronic liver disease.

2-Methyl-3,3-diphenyl-3-propanolamine (2-MDP) selectively antagonises N-methyl-aspartate (NMA).

Using electrophoretic application to rat central neurones in vivo, and bath application to frog spinal cord in vitro, 2-methyl-3,3-diphenyl-3-propanolamine was found to be a selective antagonist of N-methyl-DL-aspartate, but not of quisqualate or kainate. In this respect the (-) isomer proved to be about three times more potent than the (+) in both preparations.