Biomedical subjects

L S Steijns

Publications and source records attributed to L S Steijns.

7 recordsLinked to original sources

PubMed2001

[Maintenance dose requirement for phenytoin is lowered in genetically impaired drug metabolism independent of concommitant use of other antiepileptics].

OBJECTIVE: To investigate the effect of genetically determined impaired drug metabolism and of the use of comedication on phenytoin maintenance dose requirement. DESIGN: Descriptive. METHOD: In 60 patients on long-term phenytoin therapy the concentration of phenytoin in serum was measured and CYP2C9 genotyping was performed (mutant alleles of CYP2C9 are associated with impaired phenytoin metabolism). In addition, the use of other antiepileptics concurrently with phenytoin was reviewed: phenobarbital, carbamazepine and valproic acid. CYP2C9 genotype and comedication were connected to phenytoin daily dose requirement. The 60 patients were 38 men and 22 women, between 16 and 74 years of age, and all mentally disabled. RESULTS: Genotyping revealed that of the 60 patients 38% (n = 23) carried at least one mutant CYP2C9 allele. Their mean dose of phenytoin was 199 mg dd, while the mean required maintenance dose in non-carriers (n = 37) was 287 mg dd (p < 0.01). When the use of comedication was taken into account, it appeared that the mean phenytoin daily doses in the different comedication groups did not differ significantly. CONCLUSION: Patients with a genetically determined impaired phenytoin metabolism required on average a 30% lower dose than those with a normal metabolism, while the concomitant use of other antiepileptics appeared to have no effect on phenytoin dose requirement.

Adolescent↗

PubMed2001

The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement.

The cytochrome P450 enzyme CYP2C9 catalyses the metabolism of numerous therapeutic agents, including the anti-epileptic drug phenytoin. CYP2C9 is genetically polymorphic: two allelic variants are known, CYP2C9*2 and CYP2C9*3, differing from the wild-type CYP2C9*1 by a single point mutation. Both mutant alleles are associated with markedly impaired metabolic capacity for many CYP2C9 substrates compared to the wild-type, resulting in raised serum drug levels upon a given dose. Because this may be relevant in treatment with phenytoin, we studied the effect of CYP2C9 genotype on phenytoin dose requirement in a group of 60 epileptic patients on long-term phenytoin therapy. CYP2C9 genotyping was performed by polymerase chain reaction analysis, phenytoin serum concentrations were measured by high-performance liquid chromatography analysis and related to the maintenance doses. For patients carrying at least one mutant CYP2C9 allele (n = 17), the mean phenytoin dose required to achieve a therapeutic serum concentration was about 37% lower than the mean dose required by wild-type individuals (199 mg/day versus 314 mg/day; P < 0.01). A low maintenance dose (< 200 mg/day) sufficed for 47% of carriers, while 58% of normals required a high dose (> 300 mg/day) for an effective serum level. The results show that there is a strong association between CYP2C9 allelic variants and phenytoin dose requirement. Since phenytoin has a narrow therapeutic index and genotyping may be carried out rapidly and at low cost, dosage adjustment based on CYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent drug intoxications in carriers.

Adolescent↗

PubMed1999

Cytochrome P450 enzyme system: genetic polymorphisms and impact on clinical pharmacology.

The cytochrome P450 (CYP) enzyme system is involved in the metabolism and elimination of numerous widely used drugs. The capacity of this system varies from one person to another, leading to variable drug excretion rates and intersubject differences in the final serum drug concentrations. For this reason, therapeutic response and side-effects vary widely between patients treated with the same dose of drug. The intersubject variability in metabolic rate is largely determined by genetic factors. Some CYP enzymes, including CYP2D6 and CYP2C19, are genetically polymorphic. Several mutant alleles have been described, Environmental factors such as smoking, diet and co-administration of medications might also influence the CYP enzyme activity. By the use of genotyping or phenotyping methods every individual can be classified as either a poor, an intermediate, an extensive or an ultrarapid metabolizer. If this could be performed prior to drug therapy, the knowledge could be applied to drug selection and dose adjustment in order to reach therapeutic serum drug levels.

Cytochrome P-450 Enzyme System↗

PubMed1998

Ultrarapid drug metabolism: PCR-based detection of CYP2D6 gene duplication.

The enzyme debrisoquine 4-hydroxylase (CYP2D6), which metabolizes many widely used drugs, is highly polymorphic. The activity of the enzyme ranges between subjects from ultrafast to a complete absence. Therefore, metabolic capacity varies, producing intersubject differences in therapeutic efficacy and side effects at standard recommended doses. Up to 7% of Caucasians may demonstrate ultrarapid drug metabolism (UM) because of inherited alleles with multiplicate functional CYP2D6 genes, causing an increased amount of enzyme to be expressed. Identification of UM subjects is of potential clinical importance for adjustment of doses in drug therapy, as well as to avoid misidentification of noncompliance. In our study, we tested recently designed PCR assays for the detection of the UM genotype. We found a 3.5% prevalence of UMs carrying duplicate active CYP2D6 genes in a population consisting of 202 psychiatric patients.

Cytochrome P-450 CYP2D6↗

PubMed1996

Evaluation of nonisotopic binding assays for measuring vitamin B12 and folate in serum.

We report the evaluation of the microparticle enzyme immunoassay (MEIA) for estimating vitamin B12 and the ion capture (IC) assay for estimating folate in serum. The assays were performed with the Abbott IMx analyzer. Intra-assay coefficients of variation were from 3.4% to 8.0% for vitamin B12 and from 1.5% to 4.2% for folate, respectively. Interassay coefficients of variation ranged from 6.3% to 8.8% for vitamin B12 and from 3.9% to 11.3% for folate, respectively. Linearity was satisfactory, with an analytical recovery of 119 +/- 4% for vitamin B12 and 95 +/- 8% for folate. The detection limit was 56.2 pmol/l for vitamin B12 and 1.9 nmol/l for folate. Results of these assays correlated well with those from the cloned enzyme donor immunoassay (CEDIA), our current routine method: r = 0.97 for vitamin B12 (n = 47) and r = 0.97 for folate (n = 50). The MEIA and the IC assay were easy to perform with the IMx analyzer.

Folic Acid↗

PubMed1996

[Apolipoprotein E polymorphism and Alzheimer disease].

At present a reliable and specific diagnostic test of Alzheimer's disease is not available. Thus far, diagnosis is based on clinical criteria despite their occasional inadequacy. Post mortem search for neuropathological hallmarks can establish the diagnosis with certainty. In the present case control study we performed an apoE genotyping for 21 patients, divided into an Alzheimer-positive and an Alzheimer-negative group after neuropathological search. As described in the literature, the apoE-epsilon 4 allele was overrepresented in the Alzheimer-positive group, while in the Alzheimer-negative group the apoE-epsilon 3 allele dominated. The epsilon 4 allele of the apoE gene may be considered as a biological risk factor for the development of Alzheimer's disease. Especially in geriatric patients with cognitive impairment, apoE genotyping seems to be a supplementary tool for risk assessment.

Aged↗

PubMed1992

Effect of ploidy on transcription levels in cultured rat aortic smooth muscle cells.

Aging and hypertension increase the number of polyploid smooth muscle cells (SMC) in a blood vessel. We assessed the effect of ploidy on the transcription of several genes in SMC cultures derived from newborn and adult rats. In diploid and tetraploid subcultures of SMC from newborn rats, RNA expression of the genes assayed is linked with ploidy. However, when phenotypically different SMC cultures derived from newborn and adult rats were compared, transcription levels varied from gene to gene and not linked with the ploidy. Thus, differences in gene expression due to polyploidy are superimposed on those due to other phenotypical features.

Actins↗