Search PubMed⌕ Search

Biomedical subjects

A Rane

Publications and source records attributed to A Rane.

At least 109 records · Page 6Linked to original sources
PubMed1992

N-demethylation of ethylmorphine in pregnant and non-pregnant women and in men: an evaluation of the effects of sex steroids.

1. The effects of oestrogens, testosterone, progesterone and medroxyprogesterone acetate (MPA) on the rate of N-demethylation of ethylmorphine (EM) to norethylmorphine (NEM) were studied in human adult liver microsomes. 2. N-Demethylase activity was found to be inhibited by progesterone and MPA to a similar extent while oestrogens and testosterone had no or negligible effects. 3. These findings prompted us to measure the N-demethylation of EM in relation to serum progesterone concentration in vivo in three groups of volunteers with large physiological differences in their endogenous levels of progesterone, i.e. i) pregnant women, ii) non-pregnant ovulating women and iii) men. 4. The metabolic ratio (MRP) of EM to NEM in plasma 60 min after dosage and the corresponding ratio in urine sampled for 6 h (MRU,1), measured on two occasions 14 days apart were used to reflect intraindividual variation in the rate of N-demethylation. 5. The average difference in MRP and MRU,1 between the two occasions was similar in all groups. However, the variability in MRP between individuals within a group was significantly higher in ovulating women than in men, but this had no relation to the serum concentrations of progesterone or oestradiol. 6. The cumulative 12 h urinary excretion of EM, NEM and morphine (MO) after hydrolysis with beta-glucuronidase was about 46%. There was no difference in the metabolic ratio of EM to NEM and its conjugate(s) in the urine between the luteal and the follicular phases. Our findings suggest that the menstrual cycle does not influence the rate of N-demethylation of EM.

Adolescent↗
PubMed1991

Clonazepam and 7-aminoclonazepam in human plasma.

The purpose of our study was to evaluate the hypothesis that much of the reported variability in the range of concentrations of plasma clonazepam (and also in the range of concentrations of its major metabolite, 7-aminoclonazepam) encountered in pediatric epilepsy patients is due to collection of samples at random times after dosing. High-performance liquid chromatographic analyses were performed on routinely ordered blood samples collected from chronically dosed outpatients during regular clinic visits. Thirty-six samples from 26 different children (age 0.25-19.6 years, mean 6.3 years) were analyzed. Specific dosing and sample collection times were obtained at the time of blood collection; demographic data were obtained from the clinic charts. A portion of the variation for both clonazepam and its major metabolite was accounted for by differences in daily dosage used. However, by accurate recording of dosage, administration times, and sample collection time, we graphically demonstrated that the majority of the variations in measured clonazepam and 7-aminoclonazepam concentrations was due to the time elapsed between the last dose and the time of sample collection. Thus, random sample collection times (especially during the drug distribution phase and following frequent dosing) may account, in part, for the poor correlation between plasma concentrations and reported anticonvulsant or toxic effects.

Administration, Oral↗
PubMed1991

Differential foetal development of the O- and N-demethylation of codeine and dextromethorphan in man.

1. Codeine and dextromethorphan were N-demethylated in human foetal liver microsomes at high rates which were close to the activities in adult livers. In contrast, foetal liver microsomes did not catalyze the O-demethylation of these drugs at mid-gestation. 2. The metabolic data were in accordance with the absence of P450IID6 and the presence of P450 IIIA as determined by Western blotting with anti-human P450 IID6 (MAb 114/2) and anti-rat P450 IIIA (PCN 2-13-1/C2) monoclonal antibodies, respectively. 3. The inhibitory effects of midazolam and dehydroepiandrosterone support the contention that the N-demethylase is a human foetal form of the cytochrome P450 IIIA family. Consistent with this we found that blotting with the MAb PCN 2-13-1/C2, which recognizes an epitope specific for the P450 III family, correlated well with the N-demethylase activities.

Antibodies, Monoclonal↗
PubMed1991

Mono- or polypharmacotherapy in institutionalized epileptic children with severe mental retardation? A team approach for optimizing antiepileptic therapy.

Nine severely mentally retarded patients with severe epilepsy who were living in an institution were studied during a three-year period by a multi-disciplinary team. A seizure rate serum level chart was made for each patient. It served as the basis for monthly discussions in the team about medication changes. Drug plasma concentrations were monitored monthly. Statistical comparisons between seizure frequency on different drug regimens were made by chi 2 test. Withdrawal of all medication was possible in one case and reduction to monotherapy in two cases. In the remainder of the patients a combination of two or three anticonvulsants gave the best clinical effect. We thus found polypharmacotherapy necessary for some severely retarded patients with epilepsy. Our multidisciplinary approach and chart monitoring system has many advantages and is valuable for the medical care and drug treatment of this patient category.

Adolescent↗
PubMed1991

Thiol methyltransferase in humans: development and tissue distribution.

Thiol methyltransferase (EC 2.1.1.9, TMT) activity was measured with 2-mercaptoethanol in the microsomal fraction of 12 placenta and 31 fetal and 33 adult liver specimens. TMT activity (nmol/min incubation/mg protein; mean +/- SD) was 0.61 +/- 0.25 (placenta), 0.74 +/- 0.45 (fetal liver), and 4.51 +/- 2.29 (adult liver). TMT activity was also measured in extrahepatic tissues and it was about one order of magnitude lower in fetal lungs, kidney and intestine as compared with the fetal liver. A similar distribution pattern was also observed in adult tissues except that in the kidney TMT activity was one third of the hepatic one. Studies of enzyme kinetics showed that fetal and adult hepatic TMT obeyed non-Michaelis-Menten kinetics when 2-mercaptoethanol was the varying substrate. Average values of Km for the higher and lower affinity phases were 0.03 and 14.05 mmol/l, respectively (fetal liver) and 0.005 and 14.57 mmol/l, respectively (adult liver). This paper shows that TMT develops prenatally and its distribution pattern is consistent with that of other microsomal enzymes, being preferentially associated with the liver both in the human fetus and in adult subject.

Adult↗
PubMed1991

Thiopurine methyltransferase in humans: development and tissue distribution.

Thiopurine methyltransferase (EC 2.1.1.67, TPMT) was studied with 6-mercaptopurine as substrate in the cytosolic fraction from 18 human fetal liver, 16 placental and 22 adult liver specimens. TPMT activity (pmol x min-1 x mg-1; mean +/- SD) was 33.2 +/- 15.8 (fetal liver), 19.5 +/- 11.1 (placenta) and 105 +/- 57.1 (adult liver). Fetal liver activity of TPMT is one third that in adult liver suggesting that this enzyme is well developed in the mid-gestational human fetus. The distribution of TPMT seems to be ubiquitous both in the fetus and adult subject. The kidney is an important site of methylation as suggested by the renal activity of TPMT (197 +/- 70 pmol x min-1 x mg-1) which is twice as high as the hepatic one. Fetal and adult hepatic TPMT obey nonmichaelian kinetics. Two phases, one with lower and one with higher affinity for 6-mercaptopurine, were observed. The average Km for the high affinity phase was 0.12 mmol/l (fetus) and 0.13 mmol/l (adult), whereas the Km for the lower affinity phase was 1.79 mmol/l (fetus) and 1.42 mmol/l (adult). This paper shows that TPMT develops before the second trimester of gestation in human fetus, that it has an ubiquitous distribution in the human fetus and adult subjects and the kinetic pattern of this enzyme is consistent in fetal and adult liver.

Adolescent↗
PubMed1991

Conjugation of benzoic acid with glycine in the human fetal and adult liver and kidney.

The rate of hippuric acid formation was measured in the homogenates obtained from 26 specimens of human adult liver, 9 specimens of human mid-gestational fetal liver, 5 specimens of human adult kidney and 11 specimens of human mid-gestational fetal kidney. The average (pmol/min/mg tissue +/- SD) rate of hippuric acid formation was 322 +/- 99 (adult liver), 7.6 +/- 3.6 (fetal liver), 284 +/- 117 (adult kidney) and 6.4 +/- 6.7 (fetal kidney). One third of the fetal livers and kidneys studied were inactive in the formation of hippuric acid. These findings indicate that the conjugation of carboxylic acid with glycine is poorly developed in the mid-gestational human fetus. The kinetics of the formation of hippuric acid were studied in 3 fetal and adult livers and also in 3 fetal kidneys and in 3 specimens of the cortex and medulla of adult kidneys. The transformation of the data into Eadie-Hofstee plots generated straight lines in fetal and adult livers and kidneys. The Michaelis-Menten constant for the formation of hippuric acid (mean +/- SD, mM) was 43.4 +/- 6.6 (adult liver), 27.3 +/- 10.1 (fetal liver), 33.3 +/- 6.1 (adult renal cortex), 34.7 +/- 11.3 (adult renal medulla) and 15.3 +/- 3.5 (fetal kidney). The maximum velocity of the reaction (mean +/- SD, pmol/min/mg tissue) was 204 +/- 47.8 (adult liver), 6.0 +/- 1.3 (fetal liver), 199 +/- 40.7 (adult renal cortex), 24.2 +/- 16.9 (adult renal medulla) and 6.4 +/- 1.8 (fetal kidney). The inhibitory effect of 8 drugs containing a carboxylic acid group on the rate of hippuric acid formation was studied in 3 adult livers. Salicylic acid and diflunisal were the most powerful as inhibitors. Ibuprofen, furosemide and sodium valproate were weak inhibitors, whereas ketoprofen, naproxen and captopril did not inhibit the formation of hippuric acid. The IC50 values (mean +/- SD) of salicylic acid and diflunisal on the rate of hippuric acid formation were 0.19 +/- 0.05 and 1.18 +/- 0.19 mM, respectively.

Acyltransferases↗
PubMed1991

Dopamine sulphotransferase is better developed than p-nitrophenol sulphotransferase in the human fetus.

The distribution patterns of two forms of sulphotransferase were studied in human adult and fetal tissues. One form was studied with p-nitrophenol as substrate and it is referred to as 'TS'. The other form was studied with dopamine as substrate and it is referred to as 'TL'. The activities of TS (pmol X min-1 X mg-1; mean +/- SD) were 1,077 +/- 293 (adult liver; n = 6), 97.8 +/- 26.4 (fetal liver; n = 8); 38.0 +/- 12.8 (adult kidney; n = 5), 28.5 +/- 21.5 (fetal kidney; n = 8); 78.9 +/- 21.3 (adult lung, ex-smokers; n = 5), 83.0 +/- 23.1 (adult lung, smokers; n = 5), 25.8 +/- 10.0 (fetal lung; n = 8), 140.8 +/- 18.9 (ileum; n = 5), 68.6 +/- 30.7 (ascending colon; n = 5), 28.6 +/- 10.8 (fetal gut; n = 8), 23.9 +/- 14.5 (placenta; n = 5). The adult to fetal ratios for TS were 11.0 (liver), 1.3 (kidney), 3.1 (lung) and 2.6 (gut). The activities of TL were 28.9 +/- 17.4 (adult liver; n = 6), 97.2 +/- 52.3 (fetal liver; n = 8); 10.3 +/- 4.7 (adult kidney; n = 5), 37.7 +/- 29.9 (fetal kidney; n = 8); 79.6 +/- 18.8 (adult lung, ex-smokers; n = 5), 76.3 +/- 23.7 (adult lung, smokers; n = 5), 98.2 +/- 55.0 (fetal lung; n = 8); 391.2 +/- 37.3 (ileum; n = 5), 161.5 +/- 66.0 (ascending colon; n = 5), 200.6 +/- 137.1 (fetal gut; n = 8), 21.8 +/- 13.6 (placenta; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1.

We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). The O-demethylation of codeine was highly correlated with the O-demethylation of dextromethorphan (r = 0.90). The N-demethylation of codeine was catalyzed at a considerably higher rate than the O-demethylation. The N-demethylation to O-demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate of O-demethylation of codeine (r = 0.95) and of dextromethorphan (r = 0.88) in the extensive metabolizers. The comeasurement of the O-demethylation and N-demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P-450IID1.

Antibodies, Monoclonal↗
PubMed1990

The metabolism and bioavailability of morphine in patients with severe liver cirrhosis.

1. The oral and intravenous kinetics of morphine were investigated in seven cirrhotic patients with a history of encephalopathy. The plasma concentrations of morphine and its metabolites morphine-3 (M3G) and morphine-6 (M6G) were measured by h.p.l.c. 2. The mean terminal elimination half-life of morphine was 4.2 h (95% CI 3.6-4.8) the mean volume of distribution was 4.1 l kg-1 (95% CI 2.9-5.4) and the mean plasma clearance was 11.4 ml min-1 kg-1 (95% CI 8.1-14.7). The mean oral bioavailability was 101% (95% CI 56-147). 3. The plasma clearance of morphine was significantly lower, its terminal elimination half-life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. The metabolic ratio M3G/morphine was significantly lower in the cirrhotic patients than in control subjects after oral dosing, but did not differ after intravenous dosing. 4. The average urinary recoveries of morphine plus M3G and M6G were 49.9% after i.v. and 57.7% after oral administration. There were no statistically significant differences in the urinary recovery between the two routes of administration or between the cirrhotic patients and controls. 5. Specific changes in the EEG pattern could not be detected after intravenous dosage. 6. The metabolism of morphine is impaired significantly in patients with severe cirrhosis. Clinically important findings were a high oral bioavailability and a long elimination half-life. These findings call for cautious dosing of oral and intravenous morphine in patients with severe end stage liver disease.

Administration, Oral↗