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Biomedical subjects

J Säwe

Publications and source records attributed to J Säwe.

At least 37 records · Page 2Linked to original sources
PubMed1997

Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients.

Sirolimus is a new immunosuppressive drug that has been evaluated in animal experiments. The current study was conducted on humans with reformulated sirolimus in doses from 3 mg/m2 to 15 mg/m2. Sixteen renal transplant recipients were included in this phase I study to determine the safety, tolerance, and preliminary pharmacokinetics of increasing single doses of orally administered sirolimus. All 16 patients had stable renal graft function after a renal transplant at least 6 months before the study. Basal immunosuppression consisted of cyclosporine and prednisolone (n = 10) or cyclosporine, azathioprine, and prednisolone (n = 6). Four groups (I, 3 mg/m2; II, 5 mg/m2; III, 10 mg/m2; IV, 15 mg/m2) of four patients were assigned randomly to receive sirolimus (n = 3) or placebo (n = 1). Among the 12 patients who received sirolimus, five had mild transient study events such as headache, nausea, mild dizziness, hypoglycemia, epistaxis, and decrease in platelets. No serious adverse events occurred and no nephrotoxic effects could be related to the single dose administration of sirolimus. The only study event that was judged as probably related to sirolimus was the single case of thrombocytopenia. The other events were evaluated as possibly related. Thrombocytopenia occurred at the highest dose level (15 mg/m2 sirolimus). In two of the patients in the placebo group, slight elevations of liver enzymes and serum amylase were seen. Blood and plasma sirolimus concentrations were analyzed by an electrospray-high performance liquid/mass spectrophotometric (ESP-HPLC/MS) method Sirolimus showed an extensive red blood cell distribution with a mean blood/ plasma ratio of 49.1. The elimination half-life ranged from 43.8 to 86.5 hours (mean 56.9 hours). The Cmax and the area under the concentration versus time curves (AUC) correlated reasonably with doses from 3 to 15 mg/m2. The oral dose clearance ranged from 42 to 339 ml/h.kg. No clinically significant differences were seen in the trough concentrations of cyclosporine or the AUCs before and after the administration of sirolimus. Administration of single oral doses of sirolimus from 3 to 15 mg/m2 was safe and well tolerated in stable renal transplant recipients. Thrombocytopenia may be the dose-limiting toxicity. Additional phase II and phase III clinical trials will define the immunosuppressive efficacy of sirolimus.

Administration, Oral↗
PubMed1997

Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators.

The O-demethylation of codeine is polymorphic and catalyzed by CYP2D6. The metabolites of codeine formed through O- and N-demethylation as well as glucuronidation were quantified in the ultrarapid metabolizers of debrisoquine and compared with the normal extensive (EM) and poor metabolizers (PM). The urinary codeine and its seven metabolites were detected after 25 mg codeine in 24 healthy Caucasian subjects with low debrisoquine metabolic ratios (MR, < or = 0.11) and a group of 132 subjects tested earlier with codeine and debrisoquine including 114 EMs (MR < 12.6) and 18 PMs (MR > 12.6). Whereas the O-demethylated metabolites accounted for < 0.4% of the total recovery on average in the PMs and 1.7% to 8.7% in the EMs, they accounted for 15.3% in the 24 subjects with ultrarapid metabolism of debrisoquine. This study suggests that the ultrarapid debrisoquine hydroxylators may develop increased O-demethylated metabolite-dependent effects or side-effects of codeine.

Adolescent↗
PubMed1996

Systemic and central effects of morphine on gastroduodenal motility.

Gastrointestinal side effects still constitute a major drawback in both acute and chronic use of opioids. The exact mechanism behind the gastrointestinal effects is not known, but experimental studies indicate both central and peripheral actions. In an attempt to clarify to what extent the systemic effects of morphine after epidural administration contribute to the action on gastrointestinal motility, a study aiming to resemble the situation with epidural morphine was designed. Twenty healthy male volunteers were randomly allocated to two groups. Group one (n = 10) received intrathecal (0.4 mg) and intramuscular (4 mg) morphine (IT-IM-group). Group two (n = 10) received intrathecal (0.4 mg) morphine and i.m. saline (IT-group). Gastroduodenal activity was assessed by gastric emptying, manometry and electrogastrography. The plasma and urine concentrations of morphine and its inactive metabolite morphine-3-and active metabolite morphine-6-glucuronide were also determined. During the fasted state the gastrointestinal activity is characterised by a cyclic pattern with a duration of 80-120 min in the duodenum comprising three different phases with intense activity during Phase III. This pattern was seen in all volunteers. After the intrathecal administration the Phase III activity occurred significantly earlier in the IT-IM group (median 31 min; IR 34 min) compared to IT group (82 min; 37 min) (P < 0.01). The number of Phase IIIs was higher in the IT-IM group during the first 4 h after the morphine administration, compared to the IT group. However, after 6 h, there was no difference between the groups. The propagation velocity of Phase III decreased significantly in both groups (P < 0.001), but there was no difference between the groups. Tachygastria increased significantly with time in both groups. The acetaminophen absorption test showed that the area under the concentration curve (120 min) was significantly smaller in the IT-IM group compared to the IT group (P < 0.05). There were no measurable plasma concentrations of morphine or the glucoronidated metabolites M3G and M6G in the group that only received intrathecal morphine. This study showed that intrathecal morphine (0.4 mg) influenced gastroduodenal motility and that intramuscular morphine (4 mg) gave additional effects. These results might be applicable to the epidural situation and are indirect evidence that the gastroduodenal effects of epidural morphine are caused by both central and systemic effects of morphine.

Adult↗
PubMed1996

Disposition and analgesic effects of systemic morphine, morphine-6-glucuronide and normorphine in rat.

Morphine, morphine-6-glucuronide and normorphine were administered to male Sprague-Dawley-rats. Analgesic effect was estimated with the hot plate and spinal nociceptive reflex depression. After intraperitoneal administration the molar potency ratio of morphine-6-glucuronide/morphine was 1.7 estimated by the paw lick latency on the hot plate utilizing a linked pharmacokinetic-pharmacodynamic model. The potency ratio of morphine-6-glucuronide/morphine utilizing the spinal nociceptive reflex depression after intravenous administration was estimated to be within the earlier reported range of 1-4 after systemic administration of the drugs. In contrast to what is seen in man virtually no morphine-6-glucuronide was formed in Sprague-Dawley rats after administration of morphine, much lower levels of morphine-3-glucuronide were also seen. The molar AUC ratio of morphine-3-glucuronide/morphine was 1.8 +/- 0.5 and the corresponding ratio for normorphine/morphine was 0.2 +/- 0.06. After intraperitoneal administration of morphine, morphine-6-glucuronide and normorphine mean systemic clearance values of 413 +/- 95, 50 +/- 11 and 187 +/- 54 ml.min.kg-1 respectively were observed. Varea was 9.0 +/- 2.1, 0.8 +/- 0.2 and 4.9 +/- 1.4 L.kg-1 respectively. The slow absorption of morphine-6-glucuronide was illustrated by the mean Tmax-value of the 16 min. as compared with 9 min. for morphine and 10 min. for normorphine. It was possible to fit pharmacokinetic and pharmacodynamic data of behavioural analgesic effect of both morphine and morphine-6-glucuronide to a parametric model linking the sigmoid Emax model to standard pharmacokinetic equations.

Analgesics, Opioid↗
PubMed1995

Determination of codeine and metabolites in plasma and urine using ion-pair high-performance liquid chromatography.

A reversed-phase ion-pair high-performance liquid chromatographic method for the simultaneous determination of codeine and seven metabolites is described. The samples are purified by reversed-phase solid-phase extraction. Codeine, norcodeine, codeine-6-glucuronide, norcodeine-6-glucuronide and morphine-3-glucuronide are measured with UV detection. Detection limits are 3 nmol/l (morphine-3-glucuronide) to 20 nmol/l (codeine). Morphine, normorphine and morphine-6-glucuronide are measured with electrochemical detection. Detection limits are 0.4 nmol/1 (morphine-6-glucuronide) to 1.0 nmol/l (normorphine). Correlation coefficients better than 0.998 are normally obtained for all compounds. The method was applied to the determination of the kinetics of codeine and its metabolites in plasma and urine samples from healthy volunteers.

Calibration↗
PubMed1995

Pharmacokinetics and therapeutic drug monitoring of immunosuppressants.

Immunosuppressive drug treatment has developed considerably in recent years with new methods describing pharmacokinetic-pharmacodynamic relationships. Using in vitro models it is possible to predict the success of clinical immunosuppressive drug combinations. Furthermore, with the advances of analytical methodology it is now possible to measure minute amounts of potent immunosuppressants and to adjust dosing based on concentration measurements. Concentration control, which first was required for cyclosporine A, is being investigated for most immunosuppressive drugs in development. Characterisation of individual drug pharmacokinetics form the basis for successful immunosuppression. Among possible therapeutic drug monitoring methodologies, trough level monitoring is currently the method of choice.

Drug Monitoring↗
PubMed1995

Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects.

The CYP2D6 genotype and the debrisoquine and mephenytoin hydroxylation phenotypes were studied in 63 Oriental subjects including 21 Chinese, 21 Japanese and 21 Koreans. All subjects were extensive metabolizers of debrisoquine. The incidence of the S-mephenytoin poor metabolizer phenotype was 14% in the Chinese, 24% in the Japanese and 24% in the Korean population, respectively, which is similar to previous reports. The CYP2D6 genotype was analysed by Xba I and Eco RI RFLP, and by allele-specific PCR analysis for the presence of several allelic variants of the CYP2D locus. No CYP2D6A or CYP2D6B alleles, two of the most common defect alleles among Caucasians, were found among the Oriental subjects. The frequency of the CYP2D6D allele was similar to that in Caucasian populations and consistent with the low incidence of the poor metabolizer phenotype in all three Oriental populations. The CYP2D6L2-allele with duplication of an active CYP2D6L gene was identified in one Korean and one Chinese allele in association with high CYP2D6 activity. The CYP2D6Ch alleles CYP2D6Ch1 and Ch2, identified by RFLP and PCR for the -1338C-->T and 188C-->T mutations, were the most frequent allelic variants in all three populations studied, and were related to a decreased CYP2D6 activity as previously shown in Chinese. In conclusion, the present pilot study revealed major similarities in the polymorphic CYP2D locus between Korean, Japanese and Chinese populations.

Adult↗
PubMed1995

Cyclosporin A in fat emulsion carriers: experimental studies on pharmacokinetics and tissue distribution.

In the commercially available intravenous formulation of Cyclosporin A (Sandimmun), polyoxyethylated castor oil (Cremophor EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor EL with a soybean oil-based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil-cyclosporin A was compared to that of Sandimmun. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half-lives. Moreover, the tissue distributions of soybean oil-cyclosporin A and Sandimmun were compared in rats. These studies also included two additional lipid-based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.

Animals↗
PubMed1994

Carbamazepine and cigarette smoking induce differentially the metabolism of codeine in man.

The inducibility of codeine metabolism by carbamazepine (CBZ) and cigarette smoking has been investigated. A single oral dose of 25 mg of codeine was given to seven epileptic patients before and after 3 weeks' regular CBZ treatment (400-600 mg per day). Codeine was also given to nine volunteers who were heavy smokers (20 cigarettes per day) and to nine non-smokers as controls. All subjects were found to be extensive metabolizers of codeine by O-demethylation. Urine was collected over 8 h following codeine intake. Codeine and the metabolites were analysed with HPLC. CBZ significantly increased the urinary excretion of the N-demethylated metabolite, norcodeine (NC) which led to a significant decrease in the metabolic ratio (MR) for N-demethylation. The O-demethylation was not significantly altered. The excretion of normorphine, an active metabolite formed through both O- and N-demethylation of codeine increased by almost three-fold after CBZ treatment. Contrary to CBZ treatment, cigarette smoking slightly but significantly induced the glucuronidation of codeine as shown by a decreased MR for glucuronidation in the smokers, while the O- and N-demethylations were not significantly changed as indicated by the similar MRs in smokers and in non-smokers. These results suggest that CBZ and cigarette smoking selectively induce different metabolizing enzymes. The polymorphic O-demethylation is relatively stable to these factors.

Adolescent↗
PubMed1993

On the intraindividual variability and chronobiology of cyclosporine pharmacokinetics in renal transplantation.

The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0-12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0-12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t1/2, tmax and Cmax were more variable than the AUC (0-12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng.ml-1 versus 223 ng.ml-1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.

Adult↗
PubMed1993

Quinidine inhibition of debrisoquine S(+)-4- and 7-hydroxylations in Chinese of different CYP2D6 genotypes.

Pronounced differences in the CYP2D6 gene between Chinese and Caucasians have previously been described. There was a low frequency of detrimental mutations in the Chinese CYP2D6 gene causing the poor metabolizer (PM) phenotype. In contrast to Caucasians where the Xba I 44 kb allele is almost always associated with the PM phenotype, Chinese with the 44/44 kb RFLP pattern are extensive metabolizers (EM). In order to evaluate whether the debrisoquine hydroxylation seen in subjects with this haplotype is catalysed by a functionally similar enzyme to CYP2D6 or is catalysed by another type of P450 isozyme, product selectivity of the 4-hydroxylation was studied in 27 Chinese. The inhibition of CYP2D6 by quinidine was also investigated. In the 26 Chinese EM the S(+)-4-hydroxy enantiomer was found to be the major urinary metabolite of debrisoquine with an enantiomeric excess of 96.8-100%, which is similar to that in Caucasians. A correlation between the amount of S(+)-4-hydroxy and the minor 7-hydroxy metabolites excreted in urine (r = 0.72; p < 0.001) was seen. The amount of these two metabolites excreted was less in Chinese EM of debrisoquine with the 44/44 kb RFLP pattern, than in those with the wild type 29/29 kb pattern (p < 0.01). The stereoselectivity was very high in both groups. All Chinese homozygous for the 44 kb fragment (n = 5) were transformed to apparent PM after a single 100 mg dose of quinidine similarly to five Caucasian EM. Both the S(+)-4- and 7-hydroxylations of debrisoquine were inhibited by quinidine in both populations. This study shows that the cytochrome P450 catalysing the 4- and 7-hydroxylations of debrisoquine in Chinese EM has the same properties (product stereoselectivity and inhibition by quinidine) as the CYP2D6 in Caucasian EM.

Asian People↗
PubMed1993

Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations.

Morphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72 h after administration of single intravenous 5 mg and oral 20 mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of morphine was on average 21.1 +/- 3.4 ml/min/kg (1.27 +/- 0.20 L/h/kg), volume of distribution was 2.9 +/- 0.8 L/kg and oral bioavailability was 29.2 +/- 7.2%. Clearance of morphine to form M3G and M6G comprised 57.3% and 10.4%, respectively, and renal clearance comprised 10.9% of total systemic plasma clearance; hence, more than one-fifth of a dose (20.8%) remained as unidentified residual clearance. On the basis of the area under the plasma concentration-time curves determined after oral and intravenous administration, the ratios of M6G:morphine were 3.6 +/- 1.2 and 0.7 +/- 0.3, respectively. The corresponding figures for M3G:morphine were 29.9 +/- 6.8 and 7.7 +/- 1.4. Differences in metabolic ratios between the parenteral and oral routes could be attributed solely to differences in morphine concentrations as evidenced both by plasma concentrations and amounts excreted in urine. An oral:parenteral potency ratio of 1:3 may, thus, be due to differences in circulating amounts of morphine since the proportions of an administered dose found as M6G and M3G after administration by both routes were equal. A major finding was a slowly declining terminal phase of morphine and metabolites that was evident both in plasma and in urinary excretion versus time curves, where the half-lives of morphine, M3G and M6G were 15.1 +/- 6.5 h, 11.2 +/- 2.7 h and 12.9 +/- 4.5 h, respectively. The terminal half-life of normorphine was 23.9 +/- 10.1 h after oral administration. Comparison of oral with intravenous excretion curves showed that a greater part of morphine and metabolites were excreted during the slowly declining phase after the oral dose than the intravenous dose, which is highly suggestive of enterohepatic cycling. The renal clearance of M6G and morphine was seen to exceed creatinine clearance, possibly due to an active secretion process.

Administration, Oral↗
PubMed1992

A randomized pilot study of cyclosporin G in renal transplantation.

Animal studies have suggested that the analogue cyclosporin G (CyG) may be less nephrotoxic than cyclosporin A (CyA). A pilot study was therefore performed in 10 primary cadaveric renal allograft recipients who were randomized to receive posttransplant immunosuppression with either CyA or CyG. The follow-up time was a minimum of 1 year. One graft was lost in each group. All patients in both groups experienced at least one acute rejection episode. Episodes of acute nephrotoxicity were observed in both groups. Renal function, as assessed by determinations of the serum creatinine level and chromium-ethylene diamine tetra-acetic acid (Cr-EDTA) clearance, did not differ between the two groups. Renal allograft biopsies showed a significantly higher degree of fibrosis in the CyG group than in the CyA group. All CyG-treated patients evidenced laboratory signs of acute liver toxicity, which was dose-dependent and reversible. Today, all CyG-treated patients have been switched to CyA. This study shows that immunosuppression after renal transplantation in man is possible with CyG; however, it does not seem to have any advantages over CyA.

Adult↗
PubMed1991

Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine.

The Far Eastern and Caucasian populations are strikingly different with respect to the debrisoquine/sparteine hydroxylation polymorphism. The number of poor metabolizers, as defined for Caucasians, is very low among Chinese and Japanese. We investigated the molecular basis for this difference by analysis of the CYP2D6 gene in 115 Chinese subjects, combined with phenotypic classification of codeine and debrisoquine metabolism. A correlation between the rates of metabolism of these two drugs and genotype, as analyzed by RFLP using XbaI, was observed among the Chinese. A high frequency (37%) of alleles indicative of gene insertions (reflected by XbaI 44kb fragments) was recorded in the Chinese, but was not associated with the poor metabolizer phenotype, as it is in Caucasians. PCR amplification of part of the CYP2D6 gene with mutation specific primers for CYP2D6A (29A) and CYP2D6B (29B) allelic variants revealed that the XbaI 44kb fragment in Chinese apparently contains a functional CYP2D6 gene, in contrast to the situation among Caucasians. The results provide a molecular explanation of the interethnic difference in the metabolism of drugs affected by the debrisoquine hydroxylation polymorphism.

Adolescent↗
PubMed1991

Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients--a comparison of two oral formulations.

The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC. There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The tmax was 3.3 h for the tablets compared to 1.1 h for the solution. After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively. Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer tmax and greater fluctuation in morphine concentrations after the controlled-release tablets.

Adenocarcinoma↗