[Heroin dependence during pregnancy - risks, clinical picture and suggestions for therapy].
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Adult↗
Biomedical subjects
A Rane
Publications and source records attributed to A Rane.
Patient-controlled dose regimen of methadone for chronic cancer pain.
Fourteen patients with severe cancer pain participated in a trial of methadone given in a fixed dose (10 mg) but at intervals selected by the patients themselves during the loading phase. The aim was to achieve rapid pain relief while avoiding the risk of toxicity from accumulation of methadone. As expected, the dosage intervals increased gradually over the first few days of treatment, the daily dose decreasing from 30-80 mg on the first day to 10-40 mg at the end of the week. Plasma concentrations of methadone varied sevenfold after four to five days (0.24 to 1.75 mumol/1; 7.4 to 54.2 microgram/100 ml). Eleven patients reported complete or almost complete pain relief and elected to continue with methadone after the study. In no case was treatment withdrawn because of intoxication. From these findings a patient-controlled dosage regimen of oral methadone may be an effective and safe alternative to parenteral narcotic medication, adjusting both for individual variation in pain intensity and for pharmacokinetics.
Adult↗
Morphine kinetics in cancer patients.
Oral and intravenous morphine kinetics were studied in seven patients with cancer who needed continuous treatment with morphine because of severe chronic pain. Single oral (20 to 30 mg) and intravenous (4 mg) doses were given on separate days, followed by repetitive blood sampling for morphine analysis by gas chromatography. Volume of distribution ranged from 0.95 to 3.75 l/kg and serum clearance from 5.0 to 16.1 ml/min/kg. Oral morphine in doses that were more than five times the intravenous dose gave concentrations (at 10 and 120 min after dose) between 38 and 112 ng/ml. During the 0.25- to 8-hr period after the oral dose serum concentrations were higher than after the intravenous dose. There was a variation in oral bioavailability of 15% to 64% and an interindividual variation in terminal half-life from 58 to 465 min. These data warrant careful adjustment of the oral dose under close supervision of the patient at the onset of therapy.
Administration, Oral↗
Relation of naproxen kinetics to effect on platelet prostaglandin release in men and dysmenorrheic women.
The purpose of our investigation was to determine kinetics of naproxen [(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid] relative to its inhibition of PGF 2 alpha release during thrombin-induced platelet aggregation in man after a single oral dose of 250 or 500 mg. Naproxen and its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid were measured by high-performance, reversed-phase liquid chromatography with fluorimetric detection. PGF 2 alpha was measured by radioimmunoassay in platelet-rich plasma (PRP). Our subjects were four healthy adult men and five dysmenorrheic women. Peak concentrations of naproxen varied between 26 and 69 microgram/ml and half-lifes varied between 9.5 and 21.9 hr, mean = 16.4 hr +/- 4.4 (SD). Naproxen plasma protein binding exceeded 99.9%. The concentration of the metabolite was less than 1% of naproxen and followed the same plasma concentration profile as the parent compound. The based concentration of PGF 2 alpha varied between 0.13 and 6.3 ng/ml, mean = 1.5 +/- 1.9 ng/ml. With no exception, there was a marked decrease in the PGF 2 alpha concentration in thrombin-stimulated PRP during therapy, and concentration was inversely correlated to the total plasma naproxen concentration.
Adult↗
Digoxin and Phenytoin analyses as part of consultations in clinical pharmacology: a study on the use of drugs.
The clinical use of digoxin and phenytoin analyses (in 405 and 152 patients, respectively) furnished by our clinical pharmacological laboratory during a five-month period was evaluated prospectively from request forms. Of first-time analyses of digoxin, 12, 38, and 50% fell above, within, and below our recommended range of 1.3-2.6 nmoles/liter, respectively. This was a significant change towards lower values compared to an earlier study. The average daily dose of digoxin was 0.22 mg, and 94% of the doses ranged between 0.13 and 0.25 mg. Thirty percent of the patients on digoxin were reinvestigated once or more, and a greater percentage of the concentrations was then within the recommended range. Mean plasma concentrations of digoxin increased significantly with age, even though the stated daily digoxin dose tended to decrease. Data from a drug surveillance study showed that 10 of 32 patients had a significant change in plasma digoxin concentration after admission to hospital, indicating deviations in compliance with the dosage regimen prior to hospitalisation. Sixty-three percent of the first-time analyses of phenytoin were below our recommended therapeutic range of 40-80 mumoles/liter. This was lower than in a previous retrospective investigation (72%). Eighty-seven percent of the doses ranged between 0.2 and 0.4 g/day, and the average daily dose was 0.3 g. High plasma concentrations were noted more frequently in patients aged 60 years or more, whilst low concentrations were noted more frequently in young patients.
Adolescent↗
Ethosuximide in human milk and in plasma of a mother and her nursed infant.
1 The concentrations of ethosuximide were measured in the milk and in the plasma of a nursing mother and her infant during a period of 4.5 months after delivery. 2 The maternal and the infant's plasma concentrations rose after delivery. 3 The milk concentration ethosuximide was similar to that in maternal plasma on the third day after delivery. During the following 2 months the average milk/maternal plasma concentration ratio was 0.80. The rise in ethosuximide concentration in milk during the first month was steeper than that in infant's plasma, which may be due to an increase in the infant's clearance of the drug. 4 Even if the infant has subtherapeutic plasma concentrations it is recommended to control the levels in infants that are nursed by ethosuximide-treated mothers when nursing has been established.
Adult↗
Phenytoin and IgA concentrations in plasma and saliva in epileptic children.
The concentrations of immunoglobulin A (IgA) and phenytoin were determined in 36 epileptic children with a mean age of 11 years. There was a good correlation between the plasma and saliva concentrations of phenytoin (r = 0.94). The concentration of phenytoin and IgA showed little variation during the dosage interval. The phenytoin treated children did not differ with respect to the concentrations of IgA in saliva in comparison to the controls.
Adolescent↗
Intestinal and hepatic morphine glucuronidation in immature and pregnant rats.
The glucuronyl transferase activity was measured in the rat liver and intestinal microsomes during the neonatal development and pregnancy using 14C-morphine as substrate. During development the hepatic glucuronyl transferase activity increased 16-fold from day 1 after birth until a maximum of 9.97 nmol/min/mg on day 20. The enzyme activity in intestinal microsomes increased only 4-fold from day 1 to 0.19 nmol/min/mg on day 30. After the peak activities were reached, there was a continuous decrease in the glucuronyl transferase activities. During pregnancy the glucuronyl transferase activity increased significantly in the liver while no change was observed in the intestinal microsomal fraction.
Aging↗
Additive clinical effect of indomethacin suppositories during salicylate therapy in rheumatoid patients.
Twelve rheumatic patients were given 2.0 and 4.5 g acetylsalicylic acid daily in two 3-week periods. On days 13 and 20 of each period the patients took a suppository containing either placebo or 50 mg of indomethacin. The study was performed double-blind. Indomethacin had a significant additive effect during ASA therapy with 2 g daily as estimated by articular index and subjective ratings of pain and morning stiffness. On the 4.5 g ASA dose there was a significant improvement only for articular index. The patients experienced less pain during maintenance therapy with 4.5 g of ASA compared with 2.0 g daily. Both ASA doses induced complete inhibition of prostaglandin PGF2 alpha release from platelets. Thus the suppression of PGF2 alpha release does not reflect the therapeutic response of these drugs. Side effects observed comprised tinnitus, dizziness and gastritis. In 2 of the patients the aminotransferase levels increased, indicating hepatotoxicity. The protein binding of salicylate decreased with increasing salicylate concentration. As the dose was increased from 2.0 to 4.5 g/day the unbound concentration increased 5 to 24 times. This reflects the combined effect of capacity-limited metabolism and capacity-limited protein binding of salicylate.
Adult↗
Glutathione S-transferases in human fetal liver.
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Cytosol↗
Glutathione and gamma-glutamyl cycle enzymes in human fetal liver.
Human fetal and adult liver were found to have similar concentrations of acid soluble sulfhydryl (SH) groups (7.4 mmol/kg) in the same range as is found in adult mouse and rat liver. The concentration was 4-fold higher than in human fetal adrenal gland tissue. Methods specific for glutathione (GSH) associated SH groups revealed that the postmortem levels of GSH is very low (0.4 mmol/kg) in relation to total SH groups. In contrast, the levels of cysteine were high (2.8 mmol/kg), indicating a rapid cleavage of GSH. Only negligible amounts of gamma-glutamylcysteine and cysteinylglycine were measured. Our findings may be explained by high fetal activity of gamma-glutamyl transpeptidase (which metabolizes GSH) that has been documented previously both in man and in experimental animals. High activities of the two GSH-synthesizing enzymes, gamma-glutamylcysteine synthetase and GSH synthetase were found in the human fetal liver (7.1 and 3.0 mukat/kg, respectively). The activities of these enzymes were in the same range as in human adult liver, whereas that of gamma-glutamyl transpeptidase was 3-fold higher in the fetal liver. Our results demonstrate the presence of high concentration of SH groups and capacity to synthesize GSH already in the first and second trimester of the human fetal gestation. This has more than theoretical interest, since we assume that the SH groups (GSH) have importance for the protection of the fetus against drugs and foreign compounds and their (toxic) metabolites, the formation of which is catalyzed by the fetus itself.
Adrenal Glands↗
Carbamazepine therapy in trigeminal neuralgia: clinical effects in relation to plasma concentration.
Seven patients with trigeminal neuralgia were treated with carbamazepine at three dose levels, each period lasting for six days. A single-blind technique was used, the patients being unaware of the dose changes. During the last three days of each dose treatment, the pain score was determined by the patients and the plasma concentrations of carbamazepine and its epoxide metabolite were measured. There was a correlation between the dose and plasma level of carbamazepine (r = .56; P < .01). At the carbamazepine doses studied (200 to 1,400 mg/day), no indication of saturation kinetics was seen. As the ratio between the plasma levels of the epoxide and carbamazepine was relatively low and constant, it was not possible to evaluate the potency of the epoxide. In six of the patients studied a plasma level-effect relationship was found. The best effect was seen at carbamazepine levels between 24 and 43 mu mole/L (5.7 and 10.1 microgram/mL). In one patient who was studied twice, the plasma level-response curve was different on the two occasions. Side effects were recorded in two patients, both with carbamazepine plasma levels above 33 mu mole/L (7.9 microgram/mL).
Carbamazepine↗
Prenatal and neonatal drug metabolism in man.
Drug oxidations are catalyzed by the liver microsomal fraction of human fetuses but not by fetal livers from most experimental animals. In contrast, glucuronidation of some substrates is catalyzed by the rat fetal liver in late gestation but not in the human fetal liver. The deficient human fetal glucuronidation seems to be compensated for by early development of sulfation activity. The inconsistency of the results from animal fetuses and human fetuses shows that animal data have little relevance for the human fetus. No generalized statements can be made about drug disposition in the newborn infant as compared to adults. Although most drugs that are oxidized have prolonged plasma half-lives in the neonatal period there are examples of drugs with half-lives similar to, or even shorter than, the average half-lives in adults. Oxazepam is conjugated with glucuronic acid in adults. The neonatal plasma half-life of this drug is considerably prolonged. This is true also for its conjugate as would be expected from the immature renal function in newborns. Adequate pharmacokinetic information is a prerequisite for rational and safe drug treatment in the neonatal period.
Adult↗
Plasma concentration-effect relationship of theophylline in treatment of apnea in preterm infants.
The relation between plasma concentration of theophylline and number of apnea preterm infants was studied in six patients. The apnea frequency was monitored after cessation of theophylline treatment and plotted against the log plasma concentration of theophylline. It was calculated that at an average plasma concentration of 40 mumol/l (7.25 micrograms/ml) the preterm infants had two or less apnea per 12 h. On the basis of our results we suggest that 40 mumol/l is the minimum plasma concentration of theophylline for optimal effect on apnea in preterm infants.
Apnea↗
Autoinduction of carbamazepine metabolism in children examined by a stable isotope technique.
Autoinduction of carbamazepine (CBZ) metabolism was investigated in 3 children (10 to 13 yr old) using tetradeuterium-labeled CBZ (CBZ-D4). Prior to treatment, CBZ and CBZ-D4 given as a mixture had almost identical kinetics in each patient. During maintenance therapy with CBZ, part of the CBZ was exchanged for CBZ-D4 on 3 occasions. The clearance of CBZ-D4 given on the second day of therapy was 0.036 +/- 0.003 1 . kg-1 . hr-1, whereas it had been 0.028 +/- 0.003 before treatment. After 17 to 32 days of treatment, clearance doubled (0.056 +/- 0.010) but during the next 4 mo there was no further increase, indicating that the autoinduction was complete within 1 mo. As a corollary there was a decrease in steady-state plasma levels.
Adolescent↗
Lack of effect of theophylline on the outcome of acute cerebral infarction.
In patients with acute ischemic stroke, dramatic but often transient improvements have been noticed after theophylline injections. Whether better results could be obtained by continuous infusion of the drug was evaluated in a double-blind study. Out of 46 patients with a mean age of 75 years, 22 got theophylline as aminophylline (bolus dose of 230 mg followed by 0.5 mg/kg/h) and 24 placebo during 3 days. The groups were comparable in all aspects at the outset of the trial. Serum theophylline concentrations were kept within the therapeutic range recommended for patients with asthma. No significant difference in outcome was noticed between the groups during the hospital period when repeated neurological assessments by two different scores and mortality were compared.
Aged↗
Metabolism of a glutathione conjugate in human fetal and adult tissues.
Human fetal and adult liver was found to catalyze the metabolism of a glutathione conjugate, acetaminophen-glutathione, to the cysteine conjugate. The activity was higher in the fetal than in the adult liver, 4.06 +/- 0.59 and 1.63 +/- 0.42 nmol/10 min/mg protein, respectively. The initial reaction was catalyzed by gamma-glutamyltransferase, as indicated by the inhibitory effect of serine-borate. The hydrolysis of the formed cysteinylglycine conjugate was extremely rapid since no conjugate was detected and an almost stoichiometric formation of acetaminophen-cysteine from acetaminophen-glutathione was observed. The human fetal kidney also metabolized acetaminophen-glutathione to the corresponding conjugate. This activity was, however, lower than in the liver from the same fetus.
Acetaminophen↗
Carbamazepine in trigeminal neuralgia: clinical effects in relation to plasma-concentration.
Seven patients (mean age 60 years) with idiopathic trigeminal neuralgia previously treated with Carbamazepine(CBZ) were studied as in patients. One patient was examined twice. CBZ (Tegretol) was given twice daily in three different dose-levels to each patient, six days on each level. A single-blind technique was used. The doses were individually chosen with previous dose requirements as a basis. Plasma samples were taken immediately before the morning dose the three last days on each dose-level. CBZ and CBZ-10, 11-epoxide were analysed using liquid chromatography. All pain paroxysms were graded and registered by the patient and pain scores were calculated. The CBZ-doses given ranged from 200 to 1 400 mg/day, the mean being 733 mg/day. In six courses of treatment, patients experienced complete or almost complete pain relief, achieved at CBZ-plasma-concentrations of 24-43 mumol/l. Patients with high pain-scores at plasma-concentrations of 30 mumol/l did not benefit from further dose increase. Small adjustments of plasma-concentration otherwise resulted in pronounced changes in pain-score. Side-effects were not reported below 34 mumol/l. No conclusions could be drawn as to the possible clinical effect of CBZ-10,11-epoxide.
Carbamazepine↗