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Biomedical subjects

M Døssing

Publications and source records attributed to M Døssing.

At least 55 records · Page 3Linked to original sources
PubMed1988

Therapeutic doses of codeine have no effect on acetaminophen clearance or metabolism.

In nine healthy volunteers, the clearance and metabolism of acetaminophen 1000 mg i.v. was evaluated with and without two concomitant oral doses of codeine in order to investigate a possible interaction. Plasma acetaminophen was followed for 720 min and urine was collected for 24 h after each dose for determination of metabolites. When codeine was coadministered, the average total clearance of acetaminophen and its clearance by glucuronidation, sulphation and mercapturate formation were 0.58 to 1.12-times the control values. It is concluded that therapeutic doses of codeine do not influence the clearance or metabolism of acetaminophen.

Acetaminophen↗
PubMed1988

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%.

Administration, Oral↗
PubMed1988

Metronidazole clearance: a one-sample method and influencing factors.

After 96 administrations of metronidazole to 36 subjects, it was found that the clearance could be determined from one plasma sample, the dose, and a volume of distribution estimated from sex, age, body weight, and height, without loss of precision and accuracy compared with conventional clearance determinations (r greater than 0.97). In 230 sample pairs the plasma and saliva concentrations of metronidazole were identical (r = 0.99). In 119 subjects the one-sample clearance of metronidazole was unimodally distributed. Body weight (r = 0.28) and the alcohol consumption (r = 0.23) correlated with the metronidazole clearance. In the same subjects the consumption of tobacco (r = 0.28), alcohol (r = -0.19), coffee/tea (r = 0.27), age (r = -0.24), and sex (r = 0.28) correlated with the antipyrine clearance. The clearances of metronidazole and antipyrine were correlated (r = 0.34). The differential influence of the environmental factors on the elimination rates supports differential metabolism of metronidazole and antipyrine.

Administration, Oral↗
PubMed1988

Influence of age and consumption of tobacco, alcohol and caffeine on antipyrine clearance.

1. Antipyrine clearance and average daily consumption of tobacco, alcohol and coffee/tea were determined in 303 healthy men. 2. The antipyrine clearance was positively correlated with the consumption of tobacco (r = 0.24; P less than 0.0001) and coffee/tea (r = 0.18; P less than 0.001), and negatively with age (r = -0.14; P less than 0.05) and the alcohol consumption (r = -0.13; P less than 0.05). 3. The multiple regression coefficients suggested an increase in antipyrine clearance of 0.8% per daily cigarette or cup of tea and 1.4% per daily cup of coffee; the decrease per daily drink or year of age was 2.8% or 0.4%, respectively.

Adult↗
PubMed1987

Toluene metabolism during exposure to varying concentrations combined with exercise.

The urinary excretion of hippuric acid (HA) and ortho-cresol (O-cr) in man was measured in two studies of 7-h exposure to toluene in a climate chamber, either constant concentration of 100 ppm or varying concentrations containing peaks of 300 ppm but with a time-weighted average of 100 ppm. In Study A, four males were exposed to clean air and to constant and varying concentrations of toluene in combination with rest and with 100 W exercise in 140 min. Exercise increased end exposure excretion rate of HA and O-cr by 47 and 114%, respectively. After exposure, all excess HA was excreted within 4 h, while O-cr was eliminated with a half life of about 3 h. Alveolar air concentration of toluene varied between 21 and 31 ppm during constant exposure and between 13 and 57 ppm during varying exposure, but no difference in mean alveolar toluene concentration or in metabolite excretion was seen between the exposure schedules. In Study B, 32 males and 39 females aged between 31 and 50 years were exposed once to either clean air, constant or varying concentrations of toluene. Background excretion rate of HA was 0.97 +/- 0.75 mg/min (1.25 +/- 1.05 g/g creatinine) and rose to 3.74 +/- 1.40 mg/min (3.90 +/- 1.85 g/g cr) during the last 3 h of exposure to 100 ppm toluene. The corresponding figures for O-cr were 0.05 +/- 0.05 micrograms/min (0.08 +/- 0.14 mg/g cr), and 2.04 +/- 0.84 micrograms/min (2.05 +/- 1.18 mg/g cr). The individual creatinine excretion rate was considerably influenced by sex, body weight and smoking habits, thus influencing the metabolite concentration standardised in relation to creatinine. It is concluded that both metabolites are estimates of toluene exposure. O-cr is more specific than HA, but the individual variation in excretion of both metabolites is large, and when implementing either of them as biological exposure indices, the influence of sex, body size, age as well as consumption of tobacco and alcohol has to be considered.

Adult↗
PubMed1987

Inhibition and induction of metronidazole and antipyrine metabolism.

The effect of cimetidine, antipyrine and phenobarbitone on the pharmacokinetics of intravenous metronidazole and oral antipyrine has been examined in 7 healthy volunteers. The administration of cimetidine for 24 h before and throughout the sampling period failed to alter the total clearance of metronidazole or the rate of formation of the hydroxy metabolite, whereas the total and partial clearances of antipyrine were decreased 0.74 and 0.6-0.7-fold, respectively. Seven days of phenobarbitone or antipyrine administration increased the total clearance of metronidazole 1.51- and 1.86-fold, respectively, and the total antipyrine clearance was 1.22 or 1.46-fold increased, respectively. The rate of metronidazole hydroxylation was significantly enhanced by both enzyme inducers. The partial clearance of antipyrine to the normetabolite was significantly increased by both inducers, whereas the rate of 4-hydroxylation was significantly increased only by prior antipyrine administration. The results indicate that the hydroxylation of metronidazole is not inhibited by cimetidine, but that it is inducible by phenobarbitone or antipyrine. It is suggested that metronidazole and antipyrine are metabolized by different enzymatic pathways.

Adult↗
PubMed1987

Influence of prednisolone on antipyrine elimination in patients with obstructive lung disease.

The influence of prednisolone on the elimination of antipyrine has been investigated. The one-sample antipyrine clearance was estimated in 23 outpatients with obstructive lung disease before and after treatment with prednisolone 30 or 50 mg/day for 7 days. During prednisolone administration antipyrine clearance decreased from 54.9 +/- 14.8 to 51.7 +/- 14.6 ml/min (mean +/- SD; p less than 0.05). The results indicate that prednisolone decreases the rate of antipyrine elimination, but not to an extent suggesting a clinically important change in hepatic drug metabolism.

Antipyrine↗
PubMed1987

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.

Aged↗
PubMed1987

Increased susceptibility to liver disease in relation to alcohol consumption in women.

Sex-related differences were prospectively studied in patients with the first presentation of alcoholic liver disease. Among 42 patients the diagnosis was cirrhosis in 8 women and 15 men, alcoholic hepatitis in 4 women and 1 man, steatosis in 6 women and 6 men, and no histologic changes were found in the liver biopsy specimens from 2 men (p greater than 0.1). The median (range) antipyrine clearance was 14.6 (1.0-64) versus 17.2 (3.0-83) ml/min and the clinical score in accordance with the Pugh modification of the Child-Turcotte classification was 8 (5-13) versus 8 (5-11) in the women and men, respectively (p greater than 0.05). In 5 women and only 1 man the antipyrine clearance was less than 5 ml/min, indicating an almost total loss of functional liver mass (p less than 0.05), whereas the Pugh score was above 11 in 6 women, but not in any of the men (p less than 0.05). On an average, the men estimated their total lifetime consumption of alcohol to be 2.1 times greater and the number of days they had consumed more than 5 drinks 2.9 times higher than the women (p less than 0.05). These ratios are reduced to 1.4 and 1.7, respectively (p greater than 0.05), if the female alcohol intake is adjusted to the average male volume of distribution. The results support the concept that women may develop similar, and sometimes even more severe, liver disease after consumption of less alcohol than men. The apparent difference in susceptibility to alcohol may be partly explained by differences in volume of distribution.

Adult↗
PubMed1987

Effect of concomitant administration of cimetidine and phenobarbital on antipyrine elimination and metabolite formation.

Cimetidine 1000 mg/day and phenobarbital 100 mg/day were given to five healthy volunteers for 13 days in order to investigate the combined effect and time course of inhibition and induction on hepatic drug metabolism. The one-sample antipyrine saliva clearance (APC) and urinary metabolite profile were measured weekly, once before, two times during and four times after drug administration. On the second day of drug treatment APC was 0.7 fold and the formation clearance of the 3 oxidized metabolites 0.6 fold decreased owing to an early inhibition by cimetidine (p less than 0.05). After 8 days of concomitant drug administration, i.e. when the drug mediated inhibition and induction are supposed to be at maximum, mean APC was 0.85 times the initial value (p greater than 0.05), whereas the formation clearances of nor- and 3-hydroxymethylantipyrine were still significantly depressed. Four and 11 days after drug withdrawal, when phenobarbital, but not cimetidine could be demonstrated in plasma, APC was 1.2 times the initial value (p less than 0.05). The results suggest, that the respective effects of cimetidine and phenobarbital on antipyrine elimination are additive, when given concomitantly, but that cimetidine exerts a relatively greater inhibition in the phenobarbital induced state.

Adult↗
PubMed1986

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.

Administration, Oral↗
PubMed1986

Pulmonary disease and antipyrine clearance.

We investigated hepatic microsomal enzyme activity by the one-sample saliva test for antipyrine clearance determination in 35 homozygous, alpha 1-antitrypsin-deficient outpatients with chronic pulmonary disease. Twenty-five outpatients with chronic obstructive lung disease and comparable lung function impairment and 31 healthy volunteers served as controls. Antipyrine clearance did not differ significantly between the two groups of patients with pulmonary disease. However, the clearance was 18% lower in these two groups than in the healthy volunteers (P less than 0.01). Antipyrine clearance was lowest in patients with severe lung function impairment (P less than 0.01).

Adult↗
PubMed1986

Inhibition of antipyrine elimination by disulfiram and cimetidine: the effect of concomitant administration.

We investigated the effect of concomitantly administered disulfiram and cimetidine on antipyrine elimination. On day 1, 2, 4 and 6 of two periods of 6 days one sample antipyrine saliva clearance (APC) was measured in nine healthy volunteers. From day 2 to 6 of period I disulfiram 400 mg day-1 was administered and on day 5 and 6 cimetidine 1000 mg day-1 was added. In period II only cimetidine was given (on days 5 and 6). On day 4 of period II APC was increased 1.3 fold, probably due to self-induction by repeated antipyrine administration. Taking this into account disulfiram and cimetidine separately decreased APC 0.64 and 0.70 times, respectively. When both inhibitors were given APC was reduced 0.52 times. The results suggest that the effects of cimetidine and disulfiram on antipyrine elimination are additive.

Adult↗
PubMed1986

Repeated facial palsies after chlorocresol inhalation.

A 42-year-old woman who experienced more than 50 attacks of left-sided facial palsies after exposure to chlorocresol was studied. Only muscles around the left side of the mouth were affected. On neurophysiological testing during chlorocresol provocation the only abnormality was a loss of motor units during maximal contraction of the left orbicularis oris muscle. This could be explained by a peripheral as well as a central effect. Extensive electrophysiological examination without chlorocresol provocation excluded a preexisting generalised nerve disorder and other diagnostic procedures did not give evidence of pathology involving the left facial nerve. A hyperreactive mechanism causing a transient block of the left facial nerve is proposed.

Adult↗
PubMed1985

Occupational liver injury. Present state of knowledge and future perspective.

Epidemiological studies have mapped the occurrence of hepatitis B among health personnel with the use of specific serologic markers and thereby made rational preventive precautions possible. Follow-up studies have demonstrated the effect of this prevention, and the newly developed hepatitis B vaccine has further improved the possibilities for effective prophylaxis against occupational hepatitis B. On the other hand, there is the chemically induced occupational liver damage. Only a few of the thousands of industrially used chemicals have been sufficiently investigated for hepatotoxicity and the list of suspected and confirmed hepatotoxic agents is still growing. The worrisome example of vinylchloride-induced serious liver disease among PVC-workers, revealed after 42 years of industrial use by alert clinicians, calls for intensified activities in the field of occupational hepatotoxicity. However, the clinical, biochemical, and morphological features of liver disease are often vague and unspecific. A non-invasive, convenient quantitative liver function test is needed. Circumstantial evidence and a few epidemiological studies suggest that part of the so-called cryptogenic liver diseases, such as liver cirrhosis, may be caused by occupational exposure to chemicals. This should be further studies. Animal experiments have shown that one chemical agent may potentiate the hepatotoxic effect of another chemical agent. This should be the subject of investigations in the work environment, where exposure to various chemicals is the rule rather than the exception. Alcohol consumption may also interfere with the hepatotoxicity of occupationally used chemicals.

Chemical and Drug Induced Liver Injury↗