PubMed Health⌕ Search

Biomedical subjects

A Llerena

Publications and source records attributed to A Llerena.

At least 19 recordsLinked to original sources
PubMed2001

Determination of clozapine and its N-desmethyl metabolite by high-performance liquid chromatography with ultraviolet detection.

A rapid high-performance liquid chromatographic method has been developed for the simultaneous determination of the atypical antipsychotic drug clozapine and its principal metabolite, N-desmethyl clozapine in human plasma. After liquid-liquid extraction the compounds were separated in a reversed-phase column and measured by ultraviolet absorption at 230 nm. For both compounds inter-day variations were <3.8%, and, based on a plasma sample volume of 2 ml, the limits of quantification were 25 ng/ml. Analytical interference from coadministered psychoactive drugs and their metabolites was also studied, and no interference was found from the most commonly used antidepressants and antipsychotic drugs. The assay is sufficiently sensitive and easy to use for the analysis of plasma samples in human clinical trials and therapeutic drug monitoring.

Antipsychotic Agents↗
PubMed2001

[Optimizing pharmacologic therapy for the elderly].

The authors analyze the most important aspects one should bear in mind regarding medication in elderly patients. The authors study the pharmaco-kinetic and pharmaco-dynamic changes which occur with aging and how these influence variations in therapeutic responses and their most frequent adverse reactions among the elderly. The authors conclude that it is necessary to draw up individualized therapeutic plans for these patients. The authors also analyze the general recommendations made for administering and prescribing medications for the elderly. Considering that the administration of medication and the evaluation of adverse reactions are some of the most important responsibilities nurses have, the authors recommend specific programs be drawn up to evaluate the efficiency-risk binomial and to keep a close watch on adverse reactions in these patients.

Aged↗
PubMed2000

Clozapine withdrawal symptoms after change to sertindole in a schizophrenic patient.

A 30-year-old male patient with paranoid schizophrenia was on clozapine therapy for more than five years. Discontinuation of clozapine and an attempt to change his medication to sertindole has led to serious psychotic and somatic symptoms. After readministration of clozapine the psychotic symptoms rapidly disappeared. The patient was monitored by BPRS and PANSS positive and negative scale. Also clinical and labor parameters of the patient were monitored. The change of his medication from clozapine to sertindole was unsuccessful. This case report suggests that although atypical antipsychotics may be generally different from the classical neuroleptic drugs, there are also significant differences among the atypical antipsychotic drugs in their effects on the receptors of the central nervous system. Therefore the change of clozapine to another atypical antipsychotic medication in the clinical practice should be cross-tapered and the symptoms of withdrawal closely monitored.

Adult↗
PubMed2000

Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity.

Thioridazine is metabolized in humans by CYP2D6 to mesoridazine, which is an active metabolite. Two or more CYP2D6 substrates are seldom given simultaneously to elderly patients because potentially dangerous metabolic interactions may occur. It may be valuable to know the CYP2D6 metabolic capacity of such patients to avoid drug interactions, which depend on the metabolic phenotype. The goal of this study was to evaluate the use of the mesoridazine/thioridazine ratio for the estimation of CYP2D6 enzyme capacity. A sensitive and reliable method has been developed for the determination of thioridazine and its metabolites, mesoridazine and sulforidazine. Commonly used central nervous system (CNS) comedications do not interfere with the method. A group of 27 chronic patients with mental illness receiving monotherapy with thioridazine were studied. There were 23 men and 4 women between 37 and 80 years old (mean +/- SD: 61.2 +/- 10.2). The thioridazine/mesoridazine ratio correlated with the debrisoquine metabolic ratio (r = 0.74, p < 0.001). Therefore, the authors suggest that the measurement of thioridazine and its metabolite might be a useful tool to assess CYP2D6 activity during treatment.

Adult↗
PubMed1999

Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients.

This study investigated to what extent fluvoxamine affects the pharmacokinetics of thioridazine (THD) in schizophrenic patients under steady-state conditions. Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma samples obtained from 10 male inpatients, aged 36 to 78 years, at three different time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2 weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD concentrations relative to time point A significantly increased approximately threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004). The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time point C, but despite fluvoxamine discontinuation for 2 weeks, three patients continued to exhibit elevated concentrations of THD and its metabolites. In conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware of the potential for a clinical drug interaction between both compounds, and careful monitoring of THD levels is valuable to prevent the accumulation of the drug and resulting toxicity.

Adult↗
PubMed1998

Influence of genetic admixture on polymorphisms of drug-metabolizing enzymes: analyses of mutations on NAT2 and C gamma P2E1 genes in a mixed Hispanic population.

OBJECTIVES AND STUDY DESIGN: The genetic basis of two polymorphisms of drug- and carcinogen-metabolizing enzymes, NAT2 (arylamine N-acetyltransferase-2) and CYP2E1 (cytochrome P450 2E1), was studied in genomic deoxyribonucleic acid from 137 healthy, unrelated subjects from a mixed Nicaraguan population. RESULTS: Six point mutations were identified at the coding region of the NAT2 gene, including the most common alleles NAT2*4 (41.6%), NAT2*5B (31.4%), and NAT2*6A (16.8%). The percentage of carriers of two defective genes was 49.6%. The Nicaraguan population studied was in Hardy-Weinberg's disequilibrium for the NAT2 genotype (p < 0.01) and the allele frequencies were significantly different from those of other populations, being intermediate between those of pure Central American Indians and Spanish persons. The frequency of CYP2E1 alleles mutated at the RsaI site (c2 allele; 16.5%) was intermediate between that of Spanish white and Asian subjects. About 5% of the subjects were homozygous for the c2 allele. CONCLUSIONS: These findings indicate a high impact of genetic admixture of populations of Asian origin (Central American Indians) and white persons (Spaniards) on the genetic polymorphisms studied here and suggest that among mixed Hispanics a high heterogeneity of genotypes and phenotypes can be expected depending on the degree of genetic admixture of every subgroup. Therefore different subgroups of mixed Hispanic subjects can exhibit different results when treated with drugs that are inactivated through polymorphic enzymes.

Arylamine N-Acetyltransferase↗
PubMed1998

Antibiotic use in 3 European university hospitals.

The use of antibiotic drugs was studied in university teaching hospitals in Tartu, Estonia, Huddinge, Sweden and Badajoz, Spain. Data on drug deliveries to hospital wards during 1992 are presented in defined daily doses (DDD) per 100 bed-days (DDD/100 bed-days). In addition, the time trends of antibiotic use in Tartu University Hospital from 1992 to 1995 are shown. The total amount of antibiotic drugs used for systemic treatment in 1992 was similar in the 3 hospitals, 41 DDD/100 bed-days in Tartu vs. 51 DDD/100 bed-days in Badajoz and 47 DDD/100 bed-days in Huddinge. The antibiotics used most frequently were tetracyclines and aminoglycosides in Tartu, broad-spectrum penicillins and cephalosporins in Badajoz and narrow-spectrum penicillins and cephalosporins in Huddinge. Injectable preparations accounted for one-half of the antibiotics used. Among the medical departments, the total use of antibiotics varied up to 3-fold (from 19 to 61 DDD/100 bed-days), less than among the surgical departments (18-94 DDD/100 bed-days). The frequency of antibiotic use was very similar in departments of similar profile in the 3 hospitals (i.e. in departments of neurology, urology, etc.). The use of antibiotic drugs in intensive care units was twice as high in Huddinge (243 DDD/100 bed-days) as in Badajoz (106 DDD/100 bed-days) and Tartu (135 DDD/100 bed-days) in 1992. In conclusion, the international differences in the use of antibiotics in hospital were not in the frequency of use, but in the predominant prescription preferences in the hospital.

Anti-Bacterial Agents↗
PubMed1995

References used in a drug information centre.

The literature sources used in 461 consecutive problem-oriented questions submitted during 1993 to a Drug Information Centre were reviewed retrospectively. Journals were the most frequently used literature source (36% of all quotations). Commonly used medical and clinical pharmacology journals, together with standard textbooks, provided the necessary information to solve more than 50% of drug information requests. Most questions could be answered by including the complementary use of the question/answer database Drugline. Drug information access is important for the improvement of rational use of drugs. According to the present study, this activity is possible with a fairly limited number of sources.

Bibliometrics↗
PubMed1995

Patterns of drug treatment of schizophrenic patients in Estonia, Spain and Sweden.

1. Patterns of drug treatment and the use of polypharmacy in schizophrenic in-patients were compared and evaluated in the University Teaching Hospitals of Psychiatry in Badajoz, Spain, Huddinge, Sweden, and Tartu, Estonia. 2. The medical records of up to 100 consecutively admitted patients were retrospectively reviewed using a standardized data form. 3. The male patients were significantly younger than females in all study locations, but there were no age differences between the locations. The length of stay was equal for the two series in the same hospital, but considerably longer in Tartu than in Badajoz and Huddinge. 4. The neuroleptic drugs used most commonly in Badajoz and Tartu were similar in prescription frequency and in the doses prescribed, but different from those used in Huddinge. Haloperidol was the most frequently prescribed neuroleptic in Badajoz and Tartu, accounting for one third of all neuroleptic prescriptions. In Huddinge the choice of neuroleptics was more evenly spread over several compounds. Intramuscular injections other than depot preparations were commonly used in Tartu and Badajoz, but not in Huddinge. 5. At least two neuroleptics were prescribed simultaneously on 73% of treatment days in Badajoz and 46% in both Huddinge and Tartu. The average cumulative daily doses of concomitant multiple neuroleptic treatment, expressed in chlorpromazine equivalents, were lower in Huddinge than in the other study locations and higher for male patients in Badajoz and Tartu. 6. Anticholinergics were used together with neuroleptics in 42% of treatment days in Badajoz and 30% in Huddinge as compared with 75% in Tartu. The use of anticholinergics increased in parallel to the increase in the number and the cumulative dose of concomitant neuroleptics in all study locations. 7. About 15% of patients in Badajoz and Tartu, but only 1% in Huddinge, received concomitant treatment with antidepressant drugs. The simultaneous use of antidepressants and benzodiazepines was inversely related to the number and the cumulative dose of neuroleptics in Badajoz and Tartu. In contrast, the cumulative dose and number of neuroleptics were greater, when additional benzodiazepines were prescribed in Huddinge. 8. The study in schizophrenic in-patients revealed that polypharmacy with concomitant multiple neuroleptics, additional anticholinergics and other psychotropics is an international phenomenon.

Adult↗
PubMed1994

Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms.

A large interindividual variability has previously been demonstrated in the bioavailability, steady-state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S-mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10-fold interindividual variation in Cmax and a 14-fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol l-1 and the mean AUC(0,24) value was 890 (711) nmol l-1 h. The value of t1/2,z varied 3-fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S-mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.

Administration, Oral↗
PubMed1994

Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test.

In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (rs = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. N1- and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.

Administration, Oral↗
PubMed1993

Frequency of S-mephenytoin hydroxylation deficiency in 373 Spanish subjects compared to other Caucasian populations.

We have investigated the prevalence of poor metabolisers (PM) of S-mephenytoin in 373 unrelated, healthy Spanish Caucasian subjects, based on the enantiomeric S/R mephenytoin ratio in urine collected 0-8 h and 24-32 h after intake of the racemic drug. Five of the subjects were PM (1.34%, 95% confidence interval 0.18-2.59%), a prevalence lower than in 6 other Caucasian populations, but only significantly lower than in studies in France and Switzerland (P < 0.01). We suggest that this difference might be due to the use of different phenotyping procedures.

Adolescent↗
PubMed1993

Relationship between personality and debrisoquine hydroxylation capacity. Suggestion of an endogenous neuroactive substrate or product of the cytochrome P4502D6.

We administered the Karolinska Scales of Personality to 225 healthy subjects in Spain selected from a group of 925 individuals previously phenotyped with regard to their capacity to hydroxylate debrisoquine. A significant relationship was found between the scores in as many as 4 of the 15 subscales (psychic anxiety, psychasthenia, inhibition of aggression and socialization) and the debrisoquine hydroxylation capacity. Poor metabolizers were more anxiety-prone and less successfully socialized than extensive metabolizers of debrisoquine. This and a previous study among subjects in Sweden suggest that there may be a relationship between personality and the activity of the enzyme hydroxylating debrisoquine (cytochrome P4502D6). This polymorphic enzyme may have an endogenous neuroactive substrate or product, such as a biogenic neurotransmitter amine.

Adolescent↗
PubMed1993

Reproducibility over time of mephenytoin and debrisoquine hydroxylation phenotypes.

Mephenytoin and debrisoquine hydroxylation phenotypes were determined twice in 15 Spanish healthy volunteers with an interval of about one year. The phenotype assignment did not change in any subject for either debrisoquine or mephenytoin. Among extensive metabolisers of mephenytoin, there was a slight increase (P = 0.04) of the mephenytoin-S/R enantiomeric ratio over the study period. The family members of a poor metaboliser of mephenytoin were phenotyped, and the heterozygous extensive metabolisers were found to have higher mephenytoin-S/R ratios than other extensive metabolisers suggesting a correlation between the genotype and the S/R ratio.

Adult↗