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F Sjöqvist

Publications and source records attributed to F Sjöqvist.

At least 19 recordsLinked to original sources
PubMed2001

[Quality assurance of drug prescription in primary health care. A new database software makes the drug therapy surveillance easier].

Quality assurance of drug prescription is a pre-requisite for rational drug use. From 22 health-care centres in the south-western area of the Stockholm County Council region, drug-prescription data were obtained from the patients' computerised medical recordings. This could be done with the aid of a specially designed database program. The drug-prescription data from the 22 health-care centres were collected and compiled in a central unit. Thereafter the results were brought back to the health-care centres, in which the quality assurance of drug prescription could be started.

Community Health Centers↗
PubMed2001

The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro.

INTRODUCTION: The polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) catalyses the metabolism of many drugs including S-warfarin, acenocoumarol, phenytoin, tolbutamide, losartan and most of the non-steroidal anti-inflammatory drugs. Diclofenac is metabolised to 4'-hydroxy (OH), the major diclofenac metabolite, 3'-OH and 3'-OH-4'-methoxy metabolites by CYP2C9. The aim of the present study was to clarify the impact of the CYP2C9 polymorphism on the metabolism of diclofenac both in vivo and in vitro. SUBJECTS, MATERIALS AND METHODS: Twenty healthy volunteers with different CYP2C9 genotypes [i.e. CYP2C9*1/ *1 (n = 6), *1/*2 (n = 3), *1,/*3 (n = 5), *2/*3 (n = 4), *21*2 (n = 1), *31*3 (n = 1)] received a single 50-mg oral dose of diclofenac. Plasma pharmacokinetics [peak plasma concentration (Cmax), half-life (t 1/2) and area under the plasma concentration-time curve (AUCtotal)] and urinary recovery of diclofenac and its metabolites were compared between the genotypes. Diclofenac 4'-hydroxylation was also analysed in vitro in 16 different samples of genotyped [i.e. CYP2C9*1/*1 (n = 7), *1/*2 (n=2), *1/*3 (n = 2), *2/*3 (n = 2), *2/*2 (n = 2), *31/*3 (n = 1)] human liver microsomes. RESULTS: Within each genotype group, a high variability was observed in kinetic parameters for diclofenac and 4'-OH-diclofenac (6- and 20-fold, respectively). No significant differences were found between the different genotypes either in vivo or in human liver microsomes. No correlation was found between the plasma AUC ratio of diclofenac/4'-OH-diclofenac and that of losartan/ E-3174, previously determined in the same subjects. CONCLUSION: No relationship was found between the CYP2C9 genotype and the 4'-hydroxylation of diclofenac either in vivo or in vitro. This, together with the lack of correlation between losartan oxidation and diclofenac hydroxylation in vivo raises the question about the usefulness of diclofenac as a CYP2C9 probe.

Adult↗
PubMed2001

CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages.

OBJECTIVE: This review aimed to provide distinct dose recommendations for antidepressants based on the genotypes of cytochrome P450 enzymes CYP2D6 and CYP2C19. This approach may be a useful complementation to clinical monitoring and therapeutic drug monitoring. METHOD: Our literature search covered 32 antidepressants marketed in Europe, Canada, and the United States. We evaluated studies which had compared pharmacokinetic parameters of antidepressants among poor, intermediate, extensive and ultrarapid metabolizers. RESULTS: For 14 antidepressants, distinct dose recommendations for extensive, intermediate and poor metabolizers of either CYP2D6 or CYP2C19 were given. For the tricyclic antidepressants, dose reductions around 50% were generally recommended for poor metabolizers of substrates of CYP2D6 or CYP2C19, whereas differences were smaller for the selective serotonin reuptake inhibitors. CONCLUSION: We have provided preliminary average dose suggestions based on the phenotype or genotype. This is a first attempt to apply the new pharmacogenetics to suggest dose-regimens that take the differences in drug metabolic capacity into account.

Antidepressive Agents↗
PubMed2001

Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers.

This investigation describes the expression and interindividual variability in transcript levels of multiple drug efflux systems in the human jejunum and compares the expression profiles in these cells with that of the commonly used Caco-2 cell drug absorption model. Transcript levels of ten-drug efflux proteins of the ATP-binding cassette (ABC) transporter family [MDR1, MDR3, ABCB5, MRP1-6, and breast cancer resistance protein (BCRP)], lung resistance-related protein (LRP), and CYP3A4 were determined using quantitative polymerase chain reaction in jejunal biopsies from 13 healthy human subjects and in Caco-2 cells. All genes except ABCB5 were expressed, and transcript levels varied between individuals only by a factor of 2 to 3. Surprisingly, BCRP and MRP2 transcripts were more abundant in jejunum than MDR1 transcripts. Jejunal transcript levels of the different ABC transporters spanned a range of three log units with the rank order: BCRP approximately MRP2 > MDR1 approximately MRP3 approximately MRP6 approximately MRP5 approximately MRP1 > MRP4 > MDR3. Furthermore, transcript levels of 9 of 10 ABC transporters correlated well between jejunum and Caco-2 cells (r2 = 0.90). However, BCRP exhibited a 100-fold lower transcript level in Caco-2 cells compared with jejunum. Thus, the expression of a number of efflux protein transcripts in jejunum are equal to, or even higher than, that of MDR1, suggesting that the roles of these proteins (in particular BCRP and MRP2) in intestinal drug efflux have been underestimated. Also, we tentatively conclude that the Caco-2 cell line is a useful model of jejunal drug efflux, if the low expression of BCRP is taken into account.

ATP-Binding Cassette Transporters↗
PubMed2000

CYP2D6 genotype and antipsychotic-induced extrapyramidal side effects in schizophrenic patients.

OBJECTIVE: In order to evaluate whether poor metabolizers (PM) of debrisoquine are overrepresented among patients with acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs, the CYP2D6 genotype was determined in schizophrenic patients. METHODS: Allele status for CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 as well as gene duplication was determined by allele-specific PCR, long-PCR and restriction fragment length polymorphism analysis (RFLP) in 119 schizophrenic patients (99 males and 20 females). All subjects were treated with antipsychotics metabolized, at least partially, by this isozyme. Sixty-three of the patients (52.9%) had a history of extrapyramidal side effects (EPS), while 56 (47.1%) had not experienced such problems (controls). RESULTS: Sixty-five patients (54.6%) were homozygous for a functional CYP2D6*1 allele, 44 (37.0%) were heterozygous for detrimental alleles, and 4 (3.4%), who carried two detrimental alleles, were classified as PM. In six patients (5.0%) duplication of a functional CYP2D6 gene was found, and they were consequently classified as ultrarapid metabolizers (UM). Homo- and heterozygous extensive metabolizers (EM) as well as UM were equally distributed between patients with and without EPS, whereas all the PM had a history of EPS. No significant differences in allele frequencies between the two groups were found. CONCLUSION: Although the results cannot be considered conclusive due to the small number of PM patients in our study, the PM genotype may be a predisposing factor for antipsychotic-induced EPS. Knowledge of the CYP2D6 genotype, before starting antipsychotic therapy, might be useful in identifying subjects at risk of developing EPS.

Adult↗
PubMed2000

Workplace drug testing (WDT) likely to increase in Europe. Report from the First European Symposium on WDT including selected abstracts.

Will it take a series of drug-related accidents that have already occurred in the USA before workplace drug testing (WDT) becomes accepted in Europe as a preventive measure? Currently, the development of WDT in most European countries lags some 10-15 years behind that in the USA. Labour authorities in Europe now ought to take initiatives to demand a mandatory programme for accrediting drug analytical laboratories for WDT. Companies should realise that illicit drug use is no longer only a problem at street corners, and that having a testing system in place is important, not just for public health, but also for their reputations as responsible societal actors. Improved networking among police and regulatory authorities is required to keep pace with the rapid appearance and dissemination of new substances of abuse. European research collaboration, including the newly formed European Workplace Drug Testing Group, is needed to assess the impact of drug-testing policies on accidents and other outcome variables, and thereby to convince the general public and politicians that drug testing is beneficial and necessary. A 1993-1994 survey of quality analysis in some 200 European laboratories reported from Institut Municipal d'Investigació Medica (IMIM), Spain, showed good agreement between nominal and found concentrations but that only 10% of the laboratories could both screen, identify and quantify samples. Experiences from Italy show that proficiency testing schemes lead to improved accuracy of results. These were some major conclusions of the First European Symposium on Drug Testing held at Huddinge University Hospital in Stockholm, Sweden, 30 March to 1 April 1998, organised by Karolinska Institute, with participants from 22 countries.

Europe↗
PubMed2000

Drug safety in relation to efficacy: the view of a clinical pharmacologist.

The number of registered drugs, and drug expenditure are increasing rapidly in Europe, and within the European Union (EU) there are no longer any regulations requiring that new drugs have to be better than old ones. At the same time, pharmacoepidemiological studies in Europe and USA show that adverse drug reactions now may account for up to 10% of the admissions of patients to internal medicine wards at a cost of hundreds of millions of US dollars annually. This represents a considerable increase compared to 20 years ago. A partial explanation is the many shortcomings of many clinical trials and their relevance for health care. Adverse drug reactions are often poorly studied and documented in these studies and very seldom included in health economical analyses of the value of new drugs. Pharmacovigilance is product- rather than utilization-oriented and quite invisible in clinical medicine. This is regrettable, since up to 50% of adverse drug reactions (ADRs) are dose-dependent and thus preventable. Hopefully, the rapid progress in molecular and clinical pharmacogenetics will provide new tools for clinicians to choose and dose drugs according to the individual needs of patients.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics.

A short review of the metabolism of psychoactive drugs and the pharmacogenetic factors regulating the enzymes involved is presented here. The potential clinical usefulness of phenotyping and genotyping individuals, with regard to their drug metabolic capacity, is discussed. Indications for genotyping CYP2D6 and a flow scheme for the combined use of conventional therapeutic drug monitoring (TDM) and pharmacogenetic methods for optimizing dosage-schedules of psychoactive drugs are suggested.

Antidepressive Agents↗
PubMed1999

Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population.

Cytochrome P450 2C9 (CYP2C9) catalysis the metabolism of important drugs such as phenytoin, S-warfarin, tolbutamide, losartan, torasemide, and nonsteroidal anti-inflammatory drugs. A functional polymorphism of the CYP2C9 gene has been described. The variant alleles include CYP2C9*2 having a point mutation in exon 3 causing an Arg144Cys exchange, and CYP2C9*3 with a point mutation in exon 7 resulting in an Ile359Leu exchange. Genotyping of these variant forms was carried out in 430 Swedish healthy volunteers and three different methods were compared. Sequence analysis of the different PCR products revealed that other genes in the CYP2C locus were co-amplified in one of the methods applied, whereas the other two methods were specific for CYP2C9. The frequencies of the CYP2C9*1, CYP2C9*2 and CYP2C9*3 alleles in the population examined were found to be 0.819, 0.107, and 0.074, respectively. The need for careful evaluation of the genotyping procedure by sequence analysis of PCR products is emphasised.

Adult↗
PubMed1999

Lack of polymorphism of the conversion of losartan to its active metabolite E-3174 in extensive and poor metabolizers of debrisoquine (cytochrome P450 2D6) and mephenytoin (cytochrome P450 2C19).

OBJECTIVE: Losartan was given to subjects with known phenotypes of the polymorphic enzymes CYP2D6 and CYP2C19 to study any possible influence on the metabolism of the drug. METHODS: Plasma concentrations of losartan and E-3174 were studied after oral intake of 50 mg losartan in 24 healthy, male, Swedish Caucasian subjects who were extensive or poor metabolizers (EM/PM) of debrisoquine [cytochrome P450 2D6 (CYP2D6)] or mephenytoin [cytochrome P450 2C19 (CYP2C19)]. RESULTS: The areas under the curve (AUCinfinity) of losartan and E-3174 did not differ between poor and extensive metabolizers of debrisoquine or mephenytoin, respectively. CONCLUSION: About 14% of the antihypertensive drug losartan is metabolized to the active carboxylic acid metabolite E-3174, which contributes to the effect of losartan. The present study suggests that CYP2D6 and CYP2C19 are not involved to any major extent in the in vivo conversion of losartan to E-3174.

Adult↗
PubMed1999

The past, present and future of clinical pharmacology.

Four decades of clinical pharmacological research (1960-2000) have emphasized different aspects of the discipline from controlled clinical trial and drug metabolism during the early 1960s to molecular pharmacogenetics and pharmacoeconomy during the late 1990s. Clinical pharmacology is not only a research discipline, but also a clinical specialty in its own right with functions in health care that focus on the rational use of drugs by physicians and patients. Clinical pharmacology should bridge the gap between product specialists and prescribers by emphasizing both pharmacological and medical aspects of drug treatment. A recent review of the development of the discipline in Europe shows satisfactory progress in several countries, but active recruitment of young physicians to the discipline is necessary to avoid a shortage of clinical pharmacologists in the future.

Europe↗
PubMed1998

Drug utilization 90%--a simple method for assessing the quality of drug prescribing.

OBJECTIVES: To describe a simple method for assessing the quality of drug prescribing. METHODS: We tested the idea that the number of drugs accounting for 90% of drug use--drug utilization 90% (DU90%)--may serve as an indicator of the quality of drug prescribing. We ranked the drugs by volume of defined daily doses (DDD) and determined how many drugs accounted for the DU90% segment. We also compared this segment with the pharmacotherapeutic guidelines issued by the Regional (local) Drug Committee to determine the adherence to its recommendations (index of adherence). The cost per DDD within the DU90% segment and for the remaining 10% was also calculated. The utilization of drugs based on prescriptions purchased during April 1995 was determined for 24 primary health care (PHC) centres in southwestern Stockholm. RESULTS: The number of different products, defined as all products marketed under a single brand name within an ATC (anatomic therapeutic chemical) category, in the DU90% segment varied twofold (81-164) between the 24 PHC centres. Differences in the number of GPs per PHC centre accounted for a third of this variation. The compliance with the Drug Committee recommendations varied between 54% and 78%. There was no relationship between the number of products accounting for the DU90% segment and the adherence to local prescription guidelines, i.e. prescribing more products did not increase the adherence. The costs for the DU90% drugs varied from 2.26 SEK/DDD in one PHC centre to 3.75 in another one, with an average cost of 2.87 SEK/DDD, while for the remaining 10% it was the double (6:54 SEK/DDD). In all, the DU90% drugs made up 80.8% of the total cost as compared with 19.2% for the remaining 10%. In the DU90% segment, there was no clear relationship between adherence to the guidelines and the cost/DDD, i.e. following the evidence-based guidelines appeared to provide a higher quality of prescribing rather than cheaper prescribing. CONCLUSIONS: The DU90% is an inexpensive, flexible, and simple method for assessing the quality of drug prescribing in routine health care. The number of products in the DU90% segment and adherence to prescription guidelines may serve as general quality indicators. The method may be adapted to provide comparative data between PHC centres, hospitals, regions etc. that may be cross-sectional and longitudinal. Other quality criteria, specific for each class of drugs, should complement these general indicators.

Catchment Area, Health↗
PubMed1998

Drug use in Estonia in 1994-1995: a follow-up from 1989 and comparison with two Nordic countries.

OBJECTIVE: To determine the patterns of drug use in Estonia for the years 1989 and 1994 1995, i.e. for the years before and after the pharmaceutical services in the country changed from a state monopoly to a competitive market. METHODS: The wholesale data from Estonia and the defined daily doses methodology were used. For comparison, national statistics on medicines from Finland and Sweden for the years 1994-1995 are shown. RESULTS: The general sales of drugs in Estonia decreased almost twofold in all major pharmacological groups from 1989 to 1994 and subsequently increased by 10%-30% in 1995. Substantial differences in patterns of drug use between Estonia and the two Nordic countries were observed. The amount of prescription-only medicines used in Estonia was approximately 25% of that used in Finland and Sweden. The amount of over-the-counter drugs used was 61% of that used in Finland and 58% of that used in Sweden. In the drug use patterns in Estonia, some common trends can be noted: (1) persistent traditions, such as the low use of diuretics, beta-blockers, antithrombotics and inhalant anti-asthmatic drugs; (2) changes in prescription preferences--central anti-adrenergic drugs, pyrazolones, aminoglycosides and barbiturates are being replaced by calcium channel blockers and angiotensin-converting-enzyme inhibitors, propionic acid derivatives, cephalosporins and benzodiazepines, respectively; (3) rapidly increasing use of drugs not prescribed in the 1980s, such as hormonal contraceptives, opioids and antiulcer drugs, which strongly improves the quality of pharmacotherapy in Estonia. CONCLUSION: The general trends in Estonia and the two Nordic countries are similar--the use of newer and more effective drugs is increasing and that of older ones decreasing. The changes are more rapid in Estonia than in Finland and Sweden, but, because of a short observation period, the use of newer drugs not yet prevailing. The international differences in drug utilization observed in this study may possibly be related mainly to the prescription preferences (e.g. therapeutic traditions) and less dependent on the respective health care systems (e.g. reimbursement schemes) and economic state of the country.

Drug Prescriptions↗