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F Sjöqvist

Publications and source records attributed to F Sjöqvist.

At least 19 recordsLinked to original sources
PubMed1992

[Genotyping for drug metabolism capacity can give valuable clinical information].

There is pronounced individual variation in the human metabolism (eg, acetylation and hydroxylation) of drugs, in many cases due to genetic factors. The genetic basis of cytochrome P4502D6 gene defects has recently been elucidated, for instance. The cytochrome P4502D6 is absent from 7 percent of the Caucasian population, usually owing to the presence of either of two different mutations in the corresponding gene. PCR amplification of genomic DNA with allele-specific primers enables rapid prediction of the patient's drug metabolism capacity and the individualization of drug treatment with respect to dosage.

Cytochrome P-450 Enzyme System↗
PubMed1992

Clinical pharmacology and the provision of drug information.

Clinical pharmacologists have a service role in the provision of drug information to individuals both in hospitals and primary health care. We present here a systematic approach in answering questions in a drug information centre (DIC), and describe the working method and the documentation of the work in a question answer (Q/A) data base. Drugline is a full-text data base offering problem-oriented drug evaluation comparable to a clinical consultation. The drug information is produced in a non-commercial drug information centre sponsored by the national health care sector and the National Corporation of Swedish Pharmacies, and run jointly by clinical pharmacologists and pharmacists. A minor part of Drugline is available in English for online searching, in parallel with Medline at the database host, the Medical Information Centre at the Karolinska Institute Library and Information Centre, and the users represent mainly medical libraries, hospital pharmacies, university clinics, and the pharmaceutical industry. A network of DICs has been organized in Swedish university hospitals with access to Drugline for searching and the storage of questions and answers. This network has the potential for expansion throughout Europe. It offers the unique possibility of complementing drug product information with problem-oriented drug information emerging from cases in the real world of prescribing.

Clinical Pharmacy Information Systems↗
PubMed1992

The use of drugs in Estonia compared to the Nordic countries.

Wholesale data from Estonia covering all drug supplies during the period 1983-1989 have been studied using the defined daily dose (DDD) methodology. The use of all major pharmacological groups was compared with the corresponding statistics from the Nordic countries. The patterns of drug use showed large differences between the Nordic countries and Estonia. Many drugs were used in large quantities in Estonia although they are no longer considered to be first-line medications in the Nordic countries because of their high risk to benefit ratio. These included the pyrazolones (phenylbutazone, aminophenazone), chloramphenicol, aminoglycoside antibiotics, and Rauwolfia alkaloids. On the other hand, several groups of effective drugs were available in Estonia only in limited amounts, including the histamine (H2) receptor antagonists, hormonal contraceptives, beta-adrenoceptor antagonists, angiotensin converting enzyme inhibitors, and cephalosporins. There were also differences in the use of non-steroidal anti-inflammatory drugs, blood pressure lowering agents, and anti-asthmatic drugs. Amongst the factors influencing drug usage it appears that economic status, the ordering and invoicing routines of the pharmaceutical services, and therapeutic traditions were the main reasons for the differences found.

Denmark↗
PubMed1992

Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population.

The molecular basis of polymorphic debrisoquin hydroxylation was studied in 223 Swedish white subjects, 187 extensive metabolizers and 36 poor metabolizers phenotyped with debrisoquin and desipramine. Restriction fragment length polymorphism (RFLP) analysis of the CYP2D6 gene revealed that 52% of unrelated poor metabolizers were homozygous for Xba I 29 kb fragment, and only 8% had two mutant alleles detected with RFLP. Allele-specific polymerase chain reaction (PCR)-based DNA amplification, however, revealed that all but one of the poor metabolizers had two mutant alleles of the CYP2D6A or CYP2D6B type or both. Extensive metabolizers who were heterozygous for wild-type and CYP2D6B genes had metabolic ratios for debrisoquin and desipramine that were higher than those of subjects who were homozygous for the wild-type gene. The 16 + 9 kb Xba I RFLP pattern was associated with the poor metabolizer phenotype and CYP2D6B mutations. Three extremely rapid metabolizers of debrisoquin had a 44 kb Xba I fragment that did not carry either CYP2D6A or CYP2D6B mutations. In conclusion, in the Swedish population studied, allele-specific PCR amplification allowed prediction of the debrisoquin hydroxylation phenotype with 99% accuracy.

Adolescent↗
PubMed1992

Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin.

The frequency of poor metabolizers of debrisoquin was low and similar in four different native Chinese nationalities. In a total sample of 695 Chinese subjects, only seven (1.01%) had a urinary ratio between debrisoquin and 4-hydroxydebrisoquin greater than 12.6, which is the antimode between poor metabolizers and extensive metabolizers in white populations. This is significantly lower than the 6.82% found in 1011 white Swedish healthy subjects (p less than 0.0001). Admixture analysis indicated the occurrence of two distributions within extensive metabolizers among both Chinese and white subjects. The mean of the distribution of metabolic ratios among Chinese extensive metabolizers was shifted toward higher values compared with Swedish extensive metabolizers (p less than 0.01). The frequency of poor metabolizers of S-mephenytoin was higher in 137 Chinese (14.6%) than in 488 Swedish (3.3%) subjects (p less than 0.0001). Our findings imply that drugs metabolized by these two polymorphic hydroxylases should be prescribed in different dosages to Chinese and white subjects.

China↗
PubMed1992

Genetic polymorphism of cytochromes P450: interethnic differences and relationship to incidence of lung cancer.

The cytochromes P450 participate in the metabolic activation of precarcinogens. Recent results reveal that many P450 genes are polymorphically distributed. Different investigators have tried to link polymorphic variants of the CYP1A1, CYP2D6 and CYP2E1 genes to the incidence of cancer, particularly lung cancer, in Asian and Caucasian populations. In the current overview we briefly summarize this research. It appears that interesting functionally linked interindividual differences in the CYP1A1 gene have been found and could be of importance in understanding differences in susceptibility to lung cancer. On the other hand, the data presented regarding CYP2D6 and CYP2E1 are less promising. We also describe interethnic differences in the P450 gene structures as a major obstacle for extrapolation of results between different ethnic groups.

Cytochrome P-450 CYP1A1↗
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

Treatment of depression with E-10-hydroxynortriptyline--a pilot study on biochemical effects and pharmacokinetics.

The major metabolite of nortriptyline, i.e. E-10-hydroxynortriptyline (E-10-OH-NT), was given as a racemate in increasing doses from 75 to 225 mg/day to five patients with major depressive episode. Plasma concentrations of both the (-)- and (+)-enantiomers were linearly related to the doses. The mean ratio between them was 3.6 +/- 0.53, indicating stereospecific kinetics during maintenance treatment. Lumbar punctures were performed in four of the patients before and after 3 weeks of E-10-OH-NT treatment. There was a 18% mean decrease (P less than 0.01) in the noradrenaline metabolite HMPG in cerebrospinal fluid (CSF), supporting previous in vitro data showing that E-10-OH-NT inhibits noradrenaline uptake in vivo. During treatment, the median depression score measured by the Montgomery-Asberg Depression Rating Scale declined from 32 to 14 (P less than 0.05). As the study was open, the clinical outcome is not conclusive but does not contradict the hypothesis that E-10-OH-NT has antidepressant properties. If present at all, side effects were mild and did not interfere with the treatment.

Adult↗
PubMed1991

Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype.

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators. The side-chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmax values, but comparable AUC. The thioridazine ring-sulphoxide attained higher Cmax and 3.3-fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4-hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring-sulphoxide is probably formed mainly by another enzyme.

Adult↗
PubMed1991

A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators of debrisoquine.

1. The kinetics of codeine and metabolites were studied in eight unrelated healthy Chinese subjects following a single oral dose of 50 mg codeine phosphate. The data were compared with those from eight Caucasian subjects who were matched with the Chinese group according to their metabolic ratio (MR) of debrisoquine. 2. Mean values of Cmax (445 nmol l-1) and AUC (1660 nmol l-1 h) of codeine in the Chinese were significantly higher than those in the Caucasians (292 nmol l-1 and 1010 nmol l-1 h). Thus plasma clearance was significantly lower (P less than 0.02) and the plasma half-life was longer (P less than 0.05) in the Chinese. 3. Partial clearance by glucuronidation was significantly lower (0.79 +/- 0.14 s.d. vs 1.42 +/- 0.48 s.d. 1 h-1 kg-1) in Chinese than in Caucasians. 4. The total urinary recovery of drug-related material in 48 h urine was similar in Chinese (82.2%) and Caucasians (84.4%). The recovery of unchanged codeine was significantly higher in Chinese (5.7%) than in Caucasians (3.3%). 5. The AUC ratios of codeine relative to its 6-glucuronide, morphine and norcodeine were 1:9, 35:1 and 4:1, respectively in Chinese. The corresponding ratios in Caucasians were 1:15, 50:1 and 6:1. 6. There was no significant difference between Chinese and Caucasians in the renal clearances of codeine and its primary metabolites. 7. Large interethnic differences in the kinetics of codeine have been shown. The Chinese are less able to metabolise codeine mainly because of a lower efficiency in glucuronidation.

Administration, Oral↗
PubMed1990

Determination of metrifonate and dichlorvos in whole blood using gas chromatography and gas chromatography-mass spectrometry.

Analytical methods for determining metrifonate and dichlorvos in whole blood and a sampling procedure suitable for pharmacokinetic studies in man are described. Metrifonate concentrations were determined after chloroform extraction using gas chromatography-nitrogen-phosphorus detection. The within-assay coefficients of variation were 4 and 9% at 19.4 and 0.8 mumol/l (limits of determination), respectively. Dichlorvos was determined using gas chromatography-mass spectrometry of toluene extracts. The within-assay coefficients of variation were 2 and 5% at 225 and 50 nmol/l (limits of determination), respectively. Since both substances are chemically unstable, the blood was collected by dripping it directly from the vein into 0.74 M phosphoric acid.

Chromatography, Gas↗
PubMed1990

Clinical pharmacology and primary health care in Europe--a gap to bridge. The WHO Working Group on Clinical Pharmacology in Europe.

A group of senior European clinical pharmacologists presents a position paper on the possible role of clinical pharmacology (CP) in bridging the gap between academic drug evaluation and drug prescribing in primary health care (PHC). As a teaching, research and service discipline CP has developed in academic or other major hospitals while 80% of all drugs are prescribed in PHC. CP therefore has to extend its functions to PHC. Examples are given of how joint ventures between clinical pharmacologists and PHC physicians may improve the quality of drug research and increase the clinical relevance of drug information in PHC, thereby contributing towards rational drug utilization in PHC. Colleagues in PHC are invited to respond to this call for collaboration.

Drug Prescriptions↗
PubMed1990

Prescription monitoring of drug dosages in the county of Jämtland and Sweden as a whole in 1976, 1982 and 1985.

Prescribed doses of drugs for which individualisation of dosage is deemed necessary were recorded from one national and one local Swedish prescription monitoring study for the years 1976, 1982 and 1985. Dose patterns were analysed in order to determine whether the practice of individualising drug doses had become more widely adopted by physicians. Amongst drugs eliminated primarily by metabolism, (propranolol and amitriptyline were prescribed in highly variable doses (30-fold or more). The three commonest doses of these agents accounted for about 60% of the prescriptions. In general, doses decreased with increasing patient age. Prescribing practices for piroxicam differed markedly from those of propranolol and amitriptyline, with one fixed dose of piroxicam accounting for about 90% of all prescriptions. For drugs eliminated mainly by renal excretion (digoxin, cimetidine and atenolol) there was an 8-10-fold variation in the prescribed doses. The most frequent dose of these drugs accounted for 40-60% of the prescriptions. Doses of cimetidine and atenolol were lowered only in the oldest patients. The doses of digoxin decreased more evenly with increasing age, and were reduced in elderly patients on long-term maintenance therapy. The difference in digoxin dose between young and old patients increased during the study period. Prescription monitoring as a method for following-up drug usage may be instrumental in evaluating the effect of drug educational efforts.

Adolescent↗
PubMed1990

Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects.

A single oral 5 mg dose of diazepam was given to 16 healthy native Chinese Han volunteers. Eight volunteers were extensive metabolizers of S-mephenytoin, and eight were poor metabolizers of S-mephenytoin. Plasma levels of diazepam and its demethyl metabolite were determined by HPLC in blood samples drawn during 4 weeks. There was no difference in diazepam disposition between the two phenotypes. However, the plasma half-life of demethyldiazepam was longer in poor metabolizers than in extensive metabolizers of mephenytoin (mean +/- SD: 161 +/- 37 and 116 +/- 29 hours, respectively; p less than 0.02). The plasma concentrations of demethyldiazepam at 7, 14, and 21 days after intake of diazepam were significantly higher in poor metabolizers than in extensive metabolizers. We compared the pharmacokinetic parameters of diazepam in Chinese subjects with our previously reported data from white subjects. The mean plasma half-life values of diazepam in Chinese extensive metabolizers (85.1 hours) and poor metabolizers (88.3 hours) were very similar to those in white subjects who were poor metabolizers (88.3 hours), and more than twice those in white subjects who were extensive metabolizers (40.8 hours). In parallel, the mean clearance of diazepam in Chinese subjects (independent of phenotype) was similar to that in white subjects who were poor metabolizers, but half that in white subjects who were extensive metabolizers. Chinese subjects had a slightly larger volume of distribution of diazepam than white subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Nonstereoselective disposition of ethosuximide in humans.

The total concentration of ethosuximide varied between 80 and 770 mumol/L in plasma samples obtained from 33 patients on long-term treatment with the racemic drug. The ratios between the two enantiomers measured by chiral gas chromatography in the same samples were close to unity (mean +/- SD = 1.06 +/- 0.14; range = 0.76-1.39). This suggests that the disposition of ethosuximide in humans is not stereoselective and that the measurement of total concentrations of ethosuximide is sufficient for therapeutic monitoring.

Adolescent↗
PubMed1990

A prospective study of cyclosporine concentration in relation to its therapeutic effect and toxicity after renal transplantation.

1. Cyclosporine (CsA) concentrations in plasma and whole blood were monitored prospectively in 66 consecutive kidney transplant recipients for 6 months after transplantation or until graft loss. Immunosuppression was based on treatment with CsA and prednisolone in 27 patients and CsA, azathioprine and prednisolone in 39 patients. 2. Whole blood and plasma samples (separated at 37 degrees C) were collected 10-12 h after CsA dosage twice weekly over the first 3 months and thereafter once weekly. CsA concentrations were measured by high pressure liquid chromatography (h.p.l.c.) in plasma, by specific and non-specific monoclonal radioimmunoassays (r.i.a.) in whole blood, and by polyclonal r.i.a. and polyclonal fluorescence polarization immunoassay (f.p.i.a.) in whole blood and plasma. 3. There were no differences between the treatment schedules regarding graft or patient survival, occurrence of acute rejection, nephrotoxicity or infection. 4. CsA concentrations were significantly lower at the time of acute rejection than one week earlier based on all of the analytical methods used except f.p.i.a. 5. The lowest CsA concentration, recorded during the first month after transplantation, was significantly lower in patients with than in patients without experience of acute rejection episodes when the CsA concentrations were measured by polyclonal r.i.a. in whole blood and plasma and by specific and non-specific monoclonal r.i.a. in whole blood, but not by h.p.l.c. in plasma or polyclonal f.p.i.a. in whole blood or plasma. 6. The highest CsA concentration recorded during the second post-transplantation month, was higher in patients with acute nephrotoxicity than in those without nephrotoxicity when CsA was measured by specific monoclonal r.i.a. in whole blood (471 +/- 409 ng ml-1 vs 327 +/- 150 ng ml-1, P less than 0.05), but not by the other methods. 7. The mean plasma h.p.l.c. concentration of CsA measured by h.p.l.c. during the first month after transplantation was significantly higher in patients who suffered from systemic infection than in patients who did not (116 +/- 70 ng ml-1 vs 82 +/- 52 ng ml-1; P less than 0.05). 8. Thus, significant relationships between CsA concentrations and clinical events were apparent using assay methods specific for CsA as well as using polyclonal r.i.a., but not using polyclonal f.p.i.a. When h.p.l.c. was used, however, plasma drug concentrations were often below the limit of determination. Our results suggest that specific analysis of CsA in whole blood allows the best distinction between patients who respond favourably and less favourably to treatment with CsA.

Adolescent↗