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Biomedical subjects

A Rane

Publications and source records attributed to A Rane.

At least 127 records · Page 7Linked to original sources
PubMed1990

Morphine sulphation in children.

The metabolism of morphine was studied in nine children and seven preterm neonates receiving a continuous infusion of morphine. All the neonates and three children had detectable concentrations of morphine-3-sulphate (M3S) in urine. None of the neonates or the children had detectable concentrations of morphine-6-sulphate (M6S) in urine. None of the children had detectable concentrations of M3S in plasma. The M3S/morphine ratios were significantly higher in neonates than children (P less than 0.01), suggesting that morphine sulphation decreases after the neonatal period. The amount of M3S formed, even in neonates, is low suggesting that this is a minor metabolic pathway.

Humans↗
PubMed1990

Long term high dose morphine, ketamine and midazolam infusion in a child with burns.

The metabolism of morphine and ketamine was studied in a 14 month old child with extensive burns, who received infusions of both drugs for more than 30 days. The mean plasma clearance of morphine was 29 ml min-1 kg-1 and the plasma ratios of morphine-6-glucuronide to morphine were similar to those previously reported in children. The mean plasma clearance of ketamine was 32 ml min-1 kg-1 which is greater than that previously reported in older children and adults. There were no complications despite high dose long term therapy with morphine, ketamine and midazolam.

Burns↗
PubMed1990

The rhesus monkey as a model for studies of pregnancy induced changes in metoprolol metabolism.

Five pregnant Rhesus monkeys were catheterized in the hepatic and femoral veins. They were simultaneously given 168 or 176 micrograms of 3H-metoprolol intravenously, and 9 mg of metoprolol per kg body weight orally. The same procedure was repeated a few months after delivery. Analyses of the unlabelled drug in blood were made by gas-chromatography and of the 3H-labelled metoprolol, by liquid scintillation. The apparent volume of distribution as well as the terminal half-lives of metoprolol were in the same range during pregnancy and in non-pregnancy. The oral bioavailability of metoprolol was lower (6-22%) during pregnancy than in non-pregnancy (9-49%). The apparent oral clearance and the intrinsic hepatic clearance were in a similar range although there was a greater variation in the intrinsic clearance values. The former clearance estimate was lower in the non-pregnant state only for three of the five animals. The systemic clearance varied very little and was in the same range during pregnancy and in non-pregnancy. The changes in apparent oral clearance and in oral bioavailability of metoprolol between the pregnant and non-pregnant Rhesus monkey are similar to the changes observed in pregnant women, although the absolute values are different.

Administration, Oral↗
PubMed1990

Disposition of morphine-3-glucuronide in the pregnant rhesus monkey.

Morphine-3-glucuronide (M3G) is the major metabolite of morphine and is present in the circulation of persons treated with morphine or abusing heroin. This project was designed to study the kinetics of M3G in the foeto-maternal compartment, since this metabolite may be of relevance for the abstinence syndrome observed in neonates of pregnant abusers. The kinetics of M3G were studied in two non-pregnant and four pregnant Rhesus monkeys. M3G was given as a bolus injection in four of the animals and as a long-term infusion for 12 hr in two animals. M3G passed slowly across the placenta to the foetus and amniotic fluid. After 10 hr of M3G infusion, the foetal plasma M3G concentration was measured in two cases and found to be 37% and 72%, respectively, of the maternal concentration.

Amniotic Fluid↗
PubMed1990

Transplacental transfer of morphine in man.

The transplacental transfer of morphine and morphine-3-glucuronide (M3G) was studied in five cases of suspected Rh-isoimmunization. Ultrasound-guided fetal blood sampling from the umbilical vein was carried out as a diagnostic procedure before intrauterine blood transfusion. Morphine was given as a parenteral premedication to the mother at a dose of 0.13-0.20 mg/kg bw. Fetal blood was sampled 5-74 minutes after the morphine administration. These five women were investigated on 14 different occasions. The plasma concentrations of morphine and M3G were measured in blood samples collected simultaneously from mother and fetus. The feto-maternal ratio of morphine was 0.96 at five minutes and remained close to 1.0 in most samples taken later. At 12 minutes the ratio of M3G was less than 0.002 and between 0.2 and 0.6 in the later samples. The feto-maternal plasma ratios of morphine and M3G did not change over the studied period in one woman investigated five times between gestational weeks 26 and 32. This is the first time transplacental transfer of morphine has been quantified in man. Our results demonstrate a rapid transplacental passage and equilibration of morphine between mother and fetus.

Female↗
PubMed1990

Maternal kinetics of morphine during labour.

The disposition of parenterally administered morphine was investigated in 13 nulliparous parturients in comparison with six healthy non-pregnant women of child-bearing age. Morphine was administered intravenously or intramuscularly and repeated venous blood samples were taken up to 360 minutes after the dose, or until delivery. At delivery samples were taken from the umbilical artery and vein. The plasma concentrations of morphine and M3G (morphine-3-glucuronide) were determined. The elimination half-life of morphine was shorter (43 +/- 19 versus 84 +/- 40 min) and the plasma clearance larger (3.4 +/- 1.4 versus 2.0 +/- 0.5 l/min) in the parturients than in the non-pregnant women. There was no difference in the apparent volume of distribution of morphine between those two groups. The time to peak plasma concentration of M3G was shorter (11 +/- 3 versus 21 +/- 6 min) and the M3G/morphine concentration ratio at 10 minutes higher (6.4 +/- 1.0 versus 3.4 +/- 0.6) in parturients than in non-pregnant women. In all but one infant, three of whom were born within three hours after the dose, no morphine was detectable. The rapid elimination of morphine by the parturients, resulting in only a short period of intrauterine exposure of the fetus to this drug, may be of clinical importance in the choice of obstetric analgesic agent.

Adolescent↗
PubMed1990

Therapeutic drug monitoring of anticonvulsants. State of the art.

There is considerable interindividual variation in the relationship between control of seizures and the serum anticonvulsant concentration. The minimum effective serum concentration is dependent on the type and severity of the epilepsy, and varies from patient to patient. The therapeutic range should be used as a guide to adjust the dose in order to further improve seizure control or reduce toxicity; the latter is more likely with higher serum concentrations, but can also be present when concentrations are low. A request for the serum concentration of an anticonvulsant should be made only for good clinical reasons, and an interpretation of that concentration can only be made if all the relevant clinical details are available. Indications for the measurement of serum anticonvulsant concentrations include poor seizure control, toxicity, suspected gross noncompliance, status epilepticus and seizure control, toxicity, suspected gross noncompliance, status epilepticus and the elapse of 2 to 4 weeks after the initiation of therapy. Additional drug therapy, pregnancy or illness may alter drug disposition in a well controlled patient and therapeutic drug monitoring may, therefore, help to prevent seizures secondary to these changes. The measurement of anticonvulsants in saliva as opposed to serum may be of benefit in some patients.

Anticonvulsants↗
PubMed1990

Sulphotransferase and its substrate: adenosine-3'-phosphate-5'-phosphosulphate in human fetal liver and placenta.

The activity of sulphotransferase (ST) towards 2-naphthol and the concentration of its endogenous substrate adenosine-3'-phosphate-5'-phosphosulphate (PAPS) were measured in human fetal and adult liver and in the placenta. The activity of ST (mean +/- SD; nmol/min/mg protein) was 0.28 +/- 0.06 (fetal liver); 1.82 +/- 0.44 (adult liver; p less than 0.001) and 0.021 +/- 0.014 (placenta; p less than 0.001). The concentration of PAPS (mean +/- SD; nmol/g wet tissue) was 10.1 +/- 0.9 (fetal liver); 23.4 +/- 2.4 (adult liver; p less than 0.001) and 3.6 +/- 1.1 (placenta; p less than 0.001). Both ST and PAPS were higher in fetal liver than in placenta. The difference between fetal liver and placenta was more marked for ST than for its substrate. Such a consideration was also drawn when fetal and adult liver were compared. Thus, the activity of the ST rather than the concentration of its substrate seems to be the limiting factor in sulphation.

Adenine Nucleotides↗
PubMed1989

Human fetal and adult liver metabolism of ethylmorphine. Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids.

The N-demethylation of ethylmorphine was studied in liver microsomes from human fetuses and adult patients as well as from human fetal adrenals and kidneys. Unexpectedly the reaction was catalysed at the same rate in fetal (42.3-1277.4 pmol/mg/min in 11 individuals) and adult microsomes (414-1617.8 pmol/mg/min in two individuals), which also had similar values of the apparent Km (1.50, 1.72 mM respectively) and Vmax (1.33, 1.81 nmol/mg/min respectively) in studies of the enzyme kinetics. There was a close correlation (r = 0.96) between the semiquantitative immunoblotting assessment of cytochrome P-450 HL-p in fetal liver microsomes (with the use of a monoclonal antibody against pregnenolone-16-alpha-carbonitrile induced rat hepatic cytochrome P-450) and the catalytic activity. The fetal adrenal microsomal N-demethylation was only 11-30% of the hepatic activity when compared within three fetuses in which such a comparison was possible. No activity was measurable in the kidneys. Two drugs that are believed to be substrates of the cytochrome P-450 HLp were tested as inhibitors of the ethylmorphine N-demethylation in human fetal and adult liver microsomes and in rat liver microsomes. Midazolam was a potent inhibitor (100% at 0.4 mM) of the reaction in all specimens, whereas cyclosporin A inhibited the reaction clearly only in adult liver microsomes. Endogenous steroids of importance in the fetal circulation were also tested as inhibitors. Progesterone and dehydroepiandrosterone inhibited the reaction by 75-80% at a concentration of 0.4 mM, whereas pregnenolone and 17-alpha-hydroxyprogesterone were almost devoid of inhibitory potency. These results are of interest in the discussion about the physiological role of the human fetal cytochrome P-450 HLp which has an unprecedented relative abundance in the liver.

Adrenal Cortex Hormones↗
PubMed1989

The enantioselective glucuronidation of morphine in rats and humans. Evidence for the involvement of more than one UDP-glucuronosyltransferase isoenzyme.

The formation of morphine glucuronides is enantio- and regioselective in rats and humans. In rat liver microsomes, natural (-)-morphine formed only the 3-O-glucuronide, whereas the unnatural (+)-morphine formed glucuronides at both the 3-OH and 6-OH positions, with the 6-O-glucuronide being the principal product. In human liver microsomes, both the 3-OH-and 6-OH positions were glucuronidated with each of the enantiomers, with the 3-O-glucuronide being the major product with (-)-morphine, and the 6-OH position preferred with the (+)-enantiomer. By using a series of biochemical and biological situations such as induction by xenobiotics, ontogeny, selective inhibition and genetic deficiencies, which are considered to be diagnostic of UDP-glucuronosyltransferase heterogeneity, we determined that two UDP-glucuronosyltransferase isoenzymes were responsible for the glucuronidation of morphine in rat liver. One isoenzyme (the so-called "morphine UDP-glucuronosyltransferase") was responsible for the glucoronidation at the (-)-3-OH and (+)-6-OH positions of morphine, whereas the other formed only the (+)-morphine-3-glucuronide. Evidence from enzyme induction and the genetically deficient deficient Gunn rat suggested that bilirubin UDPGT may be responsible for the (+)-morphine-3-UDP-glucuronosyltransferase activity. In human kidney, glucuronidation of both (-)- and (+)-enantiomers at the 6-OH position was deficient, whereas the activity at the 3-OH positions was still present, which indicated the involvement of two UDP-glucuronosyltransferases in the glucuronidation of morphine in man, as well as rats.

Age Factors↗
PubMed1989

Valpromide is a poor inhibitor of the cytosolic epoxide hydrolase.

The effect of the antiepileptics valpromide and sodium valproate on the cytosolic epoxide hydrolase was studied in human fetal liver, kidneys and adrenals and from human adult liver and kidneys. Trans-stilbene oxide was used as substrate. Valpromide (10 mM) lowered the activity of the epoxide hydrolase to one half of the control in all organs studied. Sodium valproate (10 mM) was less powerful as an inhibitor than valpromide; however, it exerted a significant inhibition in all tissues studied.

Anticonvulsants↗
PubMed1989

A knowledge-based information system for monitoring drug levels.

The expert system shell SMR has been enhanced to include information system routines for designing data screens and providing facilities for data entry, storage, retrieval, queries and descriptive statistics. The data for inference making is abstracted from the data base record and inserted into a data array to which the knowledge base is applied to derive the appropriate advice and comments. The enhanced system has been used to develop an intelligent information system for monitoring serum drug levels which includes evaluation of temporal changes and production of specialized printed reports. The module for digoxin has been fully developed and validated. To demonstrate the extension to other drugs a module for phenytoin was constructed with only a rudimentary knowledge base. Data from the request forms together with the S-digoxin results are entered into the data base by the department secretary. The day's results are then reviewed by the clinical pharmacologist. For each case, previous results may be displayed and are taken into account by the system in the decision process. The knowledge base is applied to the data to formulate an evaluative comment on the report returned to the requestor. The report includes a semi-graphic presentation of the current and previous results and either the system's interpretation or one entered by the pharmacologist if he does not agree with it. The pharmacologist's comment is also recorded in the data base for future retrieval, analysis and possible updating of the knowledge base. The system is now undergoing testing and evaluation under routine operations in the clinical pharmacology service. It is a prototype for other applications in both laboratory and clinical medicine currently under development at Uppsala University Hospital. This system may thus provide a vehicle for a more intensive penetration of knowledge-based systems in practical medical applications.

Data Interpretation, Statistical↗
PubMed1989

Morphine metabolism in children.

1. The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 micrograms kg-1 h-1). 2. The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min-1 kg-1, respectively) (P less than 0.01). 3. All the neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine-6-glucuronide (M6G) in plasma or urine. 4. The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P less than 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5. There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.

Adolescent↗
PubMed1989

Dextromethorphan: polymorphic serum pattern of the O-demethylated and didemethylated metabolites in man.

1. The interindividual differences in serum concentrations of dextromethorphan (DM) and its metabolites were studied in 29 healthy subjects given 120 mg orally. They were also phenotyped according to the urinary ratio of debrisoquine and 4-hydroxy-debrisoquine. 2. Four (14%) subjects were found to be poor metabolizers (PM) with a dextromethorphan/dextrorphan metabolite ratio in plasma of 3.6 or more compared with extensive metabolizers (EM) with a ratio of 0.11 or less. Significant levels of 3-hydroxymorphinan were measurable in all individuals except two, both of whom were PMs. This subdivision corresponded to the phenotype determined by the metabolic ratio of debrisoquine (r = 0.92). 3. Twelve of the 29 subjects reported adverse drug reactions after dextromethorphan administration compared with none after placebo.

Adult↗