Lack of effect of zinc supplementation on antipyrine clearance in alcoholic liver disease.

METHODS: The effect of zinc supplementation on antipyrine clearance was evaluated in 14 outpatients with stable alcoholic liver disease, of whom nine had biopsy proven alcoholic cirrhosis. RESULTS: There was no change in antipyrine clearance after 14 days of zinc supplementation (median 12.5 vs 12.9 ml.min-1). However, a significant increase in P-prothrombin-proconvertin was found. There was a positive correlation between S-zinc and antipyrine clearance at inclusion (rs = 0.76) as well as after zinc supplementation (rs = 0.72). CONCLUSION: No effect of zinc supplementation on antipyrine clearance was found. The positive correlation between S-zinc and antipyrine clearance could be due to the confounding effect of alcoholic liver disease.

Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987.

The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4.5%) reports and unclassifiable in four (0.4%) reports. Hepatic injuries accounted for 5.9% of all adverse drug reactions reported, and 14.7% of the lethal adverse drug reactions. A total of 47.2% were classified as acute cytotoxic, 16.2% as acute cholestatic and 26.9% as abnormal hepatic function. In 52 (4.7%) cases the hepatic injury was lethal; only 14 (1.3%) cases were chronic. Halothane accounted for 25% of the cases. The incidence of halothane-induced hepatic injury is decreasing, and only one lethal case has been reported since 1981. Next to halothane, sulfasalazine was the drug most often suspected during the last 2 years of the decade. Based on consumption data, the incidence of hepatic injury due to sulindac was estimated to be 18-fold higher than that due to ibuprofen. Paracetamol was reported to induce acute cytotoxic as well as cholestatic reactions in non-alcoholic subjects taking therapeutic doses.

Glucuronidation of oxazepam is not spared in patients with hepatic encephalopathy.

The disposition of oral oxazepam was investigated in seven patients with decompensated cirrhosis and encephalopathy and in nine healthy individuals to further examine the hypothesis of preservation of glucuronidation in liver disease. The patients showed a severe reduction in the quantitative liver function as assessed by estimation of the clearance of antipyrine; the median value was 9 ml.min-1 and the range was 6 to 12 ml.min-1. Apparent clearance of oxazepam in cirrhotic patients was 0.55 ml.min-1.kg-1, with a range of 0.46 to 1.24 ml.min-1.kg-1, compared with 1.19 ml.min-1.kg-1 and a range of 0.80 to 1.66 ml.min-1.kg-1 in the controls (p less than 0.05). The unbound clearance of oxazepam in patients was 4.1 ml.min-1.kg-1, with a range of 3.4 to 5.5 ml.min-1.kg-1, compared with 25.4 ml.min-1.kg-1, and a range of 16.7 to 43.7 ml.min-1.kg-1, p less than 0.001, in the controls. In patients with liver disease, the unbound clearance of oxazepam correlated significantly with antipyrine clearance (r = 0.88; p less than 0.05). The results suggest a reduced capacity for glucuronidation in patients with decompensated liver disease and severe hepatic failure that corresponds to the general reduction in the quantitative liver function.

Metronidazole elimination is preserved in the elderly.

1 The disposition of metronidazole and its major metabolites was compared in 11 subjects aged 86 +/- 6 years and 8 aged 30 +/- 6 years. 2 The plasma clearance of metronidazole was 1.20 +/- 0.53 and 1.25 +/- 0.22 ml min-1 kg-1, the volume of distribution 0.77 +/- 0.27 and 0.77 +/- 0.09 1 kg-1 and the half-life 7.8 +/- 1.9 and 7.2 +/- 0.9 h in elderly and young subjects, respectively (P less than 0.05). 3 The area under the plasma concentration-time curve of the hydroxy metabolite was 32 +/- 14 and 21 +/- 3 mM min-1 (P less than 0.05) whereas its half-life was 21 +/- 14 and 12 +/- 2 h (P less than 0.05) in the elderly and young subjects, respectively. 4 The recovery in the urine of metronidazole and its metabolites was 42 +/- 21% and 87 +/- 6% of dose in elderly and young subjects, respectively (P less than 0.05). With this reservation the only elimination pathways of metronidazole affected by old age were the renal excretion of unchanged compound and the hydroxy metabolite. 5 It is concluded that the ability to eliminate metronidazole is preserved in old age and that age-related dose adjustments are not necessary.

The political dimension in health care technology assessment programs.

This article considers technology assessment (TA) to be a comprehensive form of policy research. Technology assessment must then have a relation to policy-making; in the area of health care, TA must relate to such political decisions as resource allocation. Since policies are determined politically, i.e., by factors such as power and influence, technology assessment is, or should be, part of a political process. Technology assessment seems to be developing predominantly as a technical and professional activity, carried out in centers with no relation to the policy-making process. While the impact of technology on health, as well as such broader impacts as those on financial costs, is a key concern, political considerations and political decision-making must always be an important dimension in health care TA.

[Evaluation of quality in health services]. / Kvalitetsvurdering i sundhedsvaesenet.

In recent years, the population and professional people have become increasingly aware of the need for a more systematic assessment of quality in health service. On basis of this, a Danish workshop was held in 1988 concerning scientific methods of assessing quality in the health sector. This review provides an introduction to the expressions "assessment of quality" and "insurance of quality" in the health sector. The main points from the workshop are quoted and concrete examples of assessment of quality in the Danish health service are given. It is concluded that after a couple of decades in which health political analyses and decisions have primarily been concentrated on productivity and efficacy, we may consider insurance of quality as an instrument for decision-making in the current adjustment of the health service to the changes in knowledge, attitudes and technology.

Bioavailability and pharmacokinetics of oxazepam.

Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t1/2 beta) 6.7 h, total clearance (CL) 1.07 ml.min-1.kg-1, volume of distribution (Vc) 0.27 l.kg-1 (0.21-0.49) and volume of distribution at steady-state (Vss) 0.59 l.kg-1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5 ml.min-1.kg-1 and a distribution volume of 12.3 l.kg-1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t1/2 beta at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CLR) of the glucuronide metabolite was 1.10 ml.min-1.kg-1 (0.98-1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.

Consensus conferences in different countries. Aims and perspectives.

The different models of consensus development conferences (CDCs) are analyzed in relation to democratic technology assessment. In some countries CDCs are mainly concerned with influencing the quality of clinical practice and thus are dominated by medical experts. In other countries, CDCs are directed towards the public and the decision makers on the political and administrative level. The Danish experience demonstrates that CDCs may be a forceful social technology with a strong potential to influence decisions about medical as well as non-medical technology.

Metronidazole pharmacokinetics in patients with hepatic encephalopathy.

The pharmacokinetics of metronidazole and its major metabolites was investigated in eight patients with liver cirrhosis and coma of grade 2 to 4 and in eight healthy controls. In the coma patients the systemic clearance of metronidazole was reduced (29 +/- 10 versus 83 +/- 14 ml/min, mean +/- SD; p less than 0.001) and the elimination half-life prolonged (20 +/- 9 versus 7.3 +/- 0.9 h; p less than 0.001), whereas the volume of distribution at steady state was unchanged (44 +/- 9 versus 48 +/- 7 l) as compared with the healthy controls. Investigation of the major elimination pathways of metronidazole showed that the decreased rate of elimination in the patients was mainly due to impaired hepatic drug oxidation. In four patients therapeutic plasma concentrations were achieved during 6 days' treatment with 500 mg metronidazole per 24 or 48 h.

Single dose oxazepam has no effect on acetaminophen clearance or metabolism.

The metabolism of acetaminophen and oxazepam in humans is mainly dependent on the microsomal capacity for glucuronide conjugation. The clearance of acetaminophen and the formation of metabolites were evaluated in 7 patients before and during concomitant administration of oxazepam 30 mg. The subjects received a single 500 mg dose of acetaminophen i.v. and concentrations in plasma were measured for 360 minutes and in urine for 24 h in order to estimate the production of metabolites. The single therapeutic dose of oxazepam had no effect on the clearance of acetaminophen or on formation of its metabolites.

Influence of dose and route of administration on disposition of metronidazole and its major metabolites.

The influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p less than 0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.

Antipyrine clearance in pneumonia.

Antipyrine clearance was estimated by a one-sample technique in 14 patients with acute fever and clinical pneumonia. Antipyrine clearance during the acute illness was 31.4 +/- 7.6 ml/min (X +/- SD). Fourteen and 28 days later during convalescence, clearance values were higher (47.8 +/- 18.9 and 49.2 +/- 15.0 ml/min, respectively). We conclude that microsomal hepatic drug metabolism in adults is impaired during pneumonia.

Prediction of fatality in fulminant hepatic failure.

Thirty-three consecutive patients admitted to the intensive care liver unit of Rigshospitalet with acute hepatic encephalopathy induced by viral hepatitis, drugs, or pregnancy were studied. All were treated with a standard anticoma regime. The 20 patients (61%) who died had a higher bilirubin level and lower total cholic acid conjugation and glycine cholic acid conjugation (p less than 0.05) than the surviving patients. Antipyrin clearance and galactose elimination capacity tended to be lower in the non-survival group than in the survival group (p = 0.09 and 0.11, respectively). Of single variables a bilirubin level of greater than 384 mumol/l gave the best prediction of non-survival (sensitivity, 0.80; specificity, 0.69; PVpos, 0.80; PVneg, 0.69; kappa, 0.49). However, a discriminant score based on combination of variables distinguished completely between non-survivors and survivors when validated by an unbiased method in which each patient is classified on the basis of the other patients' data. It is suggested that the discriminant score is used to select patients with very low probability of survival for liver transplantation or liver assistance procedures of unknown value.

Lack of interaction between cimetidine and carbamazepine.

In order to investigate a possible interaction between cimetidine and carbamazepine (CBZ) 7 otherwise healthy epileptic patients on a long-term monotherapy with CBZ were given cimetidine (1 g daily) for 7 days. No significant alterations in steady-state plasma concentration of CBZ and the 10,11-epoxide metabolite (CBZ-E) were demonstrated.

Cholic acid conjugation test and quantitative liver function in acute liver failure.

In 33 patients with acute hepatic encephalopathy due to toxic or viral hepatitis the following analyses were performed: (24-14C)cholic acid conjugation and sulfation, plasma phenazone clearance, galactose elimination capacity, and concentrations of glycocholic acid and glycolithocholic acid sulfate in plasma. The (24-14C)cholic acid conjugation in patients with viral hepatitis was significantly lower in fatal cases than in patients who survived (p less than 0.002). In these patients the galactose elimination capacity and the plasma phenazone clearance were insignificantly lower. Tauro-(24-14C)cholic acid was the predominant metabolite of (24-14C)cholic acid in six patients, but in four patients with toxic hepatitis this metabolite was only found in trace amounts. Sulfation after 3 h of (24-14C)cholic acid accounted for 0-8.2% of the administered dose. The sulfate of glycolithocholic acid was found in the plasma of all patients. No survival limit with regard to the capacity for the (24-14C)cholic acid conjugation could be defined.