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Biomedical subjects

Jose de Leon

Publications and source records attributed to Jose de Leon.

At least 73 records · Page 4Linked to original sources
PubMed2003

Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report.

Clozapine is mainly metabolized by the cytochrome P450 1A2 (CYP1A2), which may be inhibited by serious respiratory infections. This case report supports that a serious respiratory infection may increase clozapine levels and contribute to side effects. Plasma clozapine and norclozapine levels were monitored 17 times during 1 year. The concentration-to-dose ratio (C/D), an index of metabolic activity, was obtained by dividing the sum of plasma clozapine and norclozapine concentration (total clozapine concentration) by clozapine dose. The coefficient of variation (CV) of the total clozapine concentrations was calculated at different doses to provide a measure of the noise associated with determining clozapine concentrations in clinical practice. During a respiratory infection, the patient was taking 600 mg/day of clozapine. Clozapine levels were 1245 ng/ml (norclozapine 472 ng/ml), reflecting a decrease in clozapine metabolism by approximately a factor of 2. The high clozapine levels were associated with side effects (myoclonus and increased sedation). The C/D during the infection was 2.9, while the rest of C/Ds ranged between 1.0 and 1.6. CVs before and after the infection, at different doses, were always lower than 20%. When the level during the infection was included to calculate the CV on 600 mg/day, the CV increased to 54%. The theophylline literature, a prior case report and this case all suggest that if a clozapine patient develops a severe respiratory infection with fever, the psychiatrist must pay particular attention to any signs suggestive of major clozapine toxicity associated to a decrease in clozapine metabolism. If any of these signs appear, the psychiatrist may need to consider cutting the clozapine dose in half until the patient has recovered from the infection.

Adult↗
PubMed2003

Exploring brief measures of nicotine dependence for epidemiological surveys.

A score > or = 6 in the Fagerström Test for Nicotine Dependence (FTND), identifying high nicotine dependence, was compared with three briefer classifications: (1) Item 4: heavy smoking (more than 30 cigarettes per day); (2) Item 1: high early smoking (smoking within 30 min of waking up); and (3) a score > or = 4 by combining Items 1 and 4. The FTND scores from 1642 smokers from five samples in the US and Spain were analyzed. Heavy smoking had low sensitivity. High early smoking had low specificity. A score > or = 4 by combining Items 1 and 4 had relatively good sensitivity (94%) and specificity (88%). Researchers needing definition of nicotine dependence briefer than FTND may want to only use Items 1 and 4 of FTND with a cutting score > or = 4.

Health Surveys↗
PubMed2003

Glucuronidation enzymes, genes and psychiatry.

The phase I cytochrome P450 (CYP) isoenzymes have received substantial attention in the pharmacogenetic literature. Researchers are beginning to examine the role of the phase II UDP-glucuronosyltransferase (UGT) enzymes, which produce products that are more water-soluble, less toxic and more readily excreted than the parent compounds. Several reasons may have contributed to neglect of UGTs (compared to CYPs) including: (1) the overlapping activity of UGTs and lack of selective probes; (2) the complexity of the glucuronidation cycle; and (3) the difficulty in developing analytic methods to measure glucuronides. Current CYP knowledge is used as a model to predict advances in UGT knowledge. At least 24 different UGT human genes have been identified and are classified in two families (UGT1 and UGT2) based on sequence homology. The UGT1A subfamily (genes located on chromosome 2) glucuronidates bilirubin, thyroid hormones, and some medications. UGT1A4 metabolizes tricyclic antidepressants and some antipsychotics. The UGT2B subfamily (genes located on chromosome 6) glucuronidates sexual steroids and bile acids. Oxazepam and lorazepam are mainly metabolized by glucuronidation. Anti-epileptics with mood-stabilizing properties are frequently metabolized by UGTs. Opioid and nicotine addiction may also be influenced by glucuronidation. Glucuronidation of serotonin may be important during fetal development. UGTs appear to be in small concentrations in brain tissue (and higher concentrations at brain capillaries). However, UGTs may be localized in certain brain areas to provide a neuroprotective function. This review illustrates the importance of glucuronidation and the implications for psychiatry.

Animals↗
PubMed2003

Serum antimuscarinic activity during clozapine treatment.

This study attempts: (1) to verify that serum antimuscarinic activity is related to clozapine dose, and more importantly to clozapine plasma concentrations; (2) to explore whether norclozapine has serum antimuscarinic activity; (3) to explore whether antimuscarinic activity is related to clozapine side effects; and (4) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics. In 39 patients participating in a double-blind clozapine study, the [3H]QNB assay was used to measure serum antimuscarinic activity: (1) on baseline medications; (2) after a 4-week haloperidol trial; (3) after a 16-week clozapine trial of either 100, 300, or 600 mg/d; and (4) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders. Clozapine levels predicted serum antimuscarinic activity better than clozapine dose. At the end of the 1st clozapine trial, the correlation with the levels explained 69% of the variance of serum antimuscarinic activity (r = 0.83, P < 0.001, N = 34). Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d. After correcting for clozapine levels, the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant (r = 0.54, F = 26.7, df = 1.65, P < 0.001). Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial. Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians. In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment.

Antipsychotic Agents↗
PubMed2003

Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships.

BACKGROUND: There have been no published reports comparing the CYP450 GeneChip microarray assay with more standard methods of genetic testing. METHODS: We collected 20-mL blood samples from 236 volunteers for DNA isolation and testing before each individual ingested 60 mg of dextromethorphan, and collected their urine. CYP2D6 alleles *3 to *7, *9, *17, and *41, and multiple CYP2D6 gene copies were tested by allele-specific PCR (AS-PCR), whereas alleles *2 to *4 and *6 to *11 were tested by the Affymetrix CYP450 GeneChip assay. Five of the CYP2D6 alleles (*3, *4, *6, *7, and *9) were tested by both AS-PCR and the CYP450 GeneChip assay in an independent and blinded fashion in 232 of the 236 healthy volunteers. The combined CYP2D6 genotype from both methods was used to divide the population into four subgroups, poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs), based on their relative function and ability to express the CYP2D6 gene. The urinary elimination of dextromethorphan was assessed in each of these CYP2D6 subgroups. RESULTS: The CYP2D6*3, *4, *6, *7, and *9 alleles showed a high degree of concordance between the CYP450 GeneChip and AS-PCR methods (>99% concordance). The mean (SD) of the log[dextromethorphan metabolic ratio (MR)] in the four CYP2D6 subgroups was PM = 0.49 (0.38); IM = -1.24 (0.53); EM = -2.35 (0.61); and UM = -2.43 (0.38). CONCLUSIONS: Oligonucleotide microarray technology is an efficient and reliable way to test for CYP2D6 gene variation based on five alleles compared by separate methods. The methodology is influenced by the quality and amount of DNA present. The log(dextromethorphan MR) is a highly variable index that appears to reflect the crude nature of the dextromethorphan MR as an indicator of CYP2D6 in vivo enzyme activity.

Cytochrome P-450 CYP2D6↗
PubMed2002

Polydipsia and schizophrenia in a psychiatric hospital: a replication study.

A prior study in a US state hospital suggested that schizophrenia, smoking and long hospitalization were associated with polydipsia. This study, in another US hospital, attempts to (1) replicate that schizophrenia and smoking are associated with polydipsia, and (2) rule out that this relationship is partly explained by alcohol and drug use. Both studies have similar methodologies. The second sample included 588 inpatients. Models of variables associated with polydipsia were developed using logistic regression. In the second study, after correcting for other factors, the association between polydipsia and schizophrenia showed a borderline significance, while polydipsia and smoking displayed a significant association. Neither organic brain lesions, nor alcohol or drug use, were associated with polydipsia. An analysis combining both samples showed that: (1) schizophrenia, long hospitalization, smoking and heavy smoking were significantly associated with polydipsia, and (2) male gender and Caucasian race (but not smoking) increased the risk of developing water intoxication in polydipsic patients. These two studies in severely mentally ill patients suggest that the association of polydipsia with schizophrenia, smoking and chronicity is consistent and independent from the definition of polydipsia (by staff, a biological method or the combination of both). Psychiatric medications do not appear to explain most cases of polydipsia in these patients.

Analysis of Variance↗
PubMed2002

Schizophrenia and tobacco smoking: a replication study in another US psychiatric hospital.

A prior study in a US state hospital suggested that schizophrenia is more closely associated with tobacco smoking when compared with other severe mental illnesses. This second study, in a neighborhood hospital, tries to (1) replicate that schizophrenia is associated with smoking and heavy smoking, and (2) rule out that this relationship is explained by substance use. The methodology was very similar to the first study. The sample included 588 inpatients. Logistic regression was used to develop models of variables associated with smoking or heavy smoking. The frequency of current smoking for the total, schizophrenic and non-schizophrenic samples were respectively 71, 75, and 55%. The sequence of frequencies from the highest to lowest was the same as in the first study: male schizophrenic patients, male non-schizophrenic patients, female schizophrenic patients and female non-schizophrenic patients. This second study consistently replicated the relationship between schizophrenia and smoking (after correcting for other variables) including history of alcohol and drug abuse or dependence. Only one of two definitions of heavy smoking showed a significant association with schizophrenia. In summary, these two studies suggest that schizophrenia is strongly associated with smoking. Neither substance use, antipsychotics, nor institutionalism can explain this relationship.

Adult↗
PubMed2002

Initiation of daily smoking and nicotine dependence in schizophrenia and mood disorders.

This study replicates, using more refined methodology, the indications of prior studies that patients with schizophrenia show a greater frequency of tobacco smoking than patients with mood disorders. The sample included 66 patients with schizophrenia and 51 patients with a mood disorder who were admitted at a state hospital in Kentucky. The control group included 404 community subjects. Ever daily smoking was studied using logistic regression. Survival analyses of age of onset of daily smoking (AODS) were performed controlling for several variables including education level. Nicotine dependence was measured with a scale. The prevalence of ever and current daily smoking was respectively 92 and 83% for patients with schizophrenia, 78 and 65% for patients with mood disorders, and 47 and 26% for controls. Before the age of 20, the three populations appear to have a similar risk of smoking initiation. However, after the age of 20, the initiation rate of daily smoking for patients with schizophrenia was higher than in patients with a mood disorder, or controls. Among daily smokers, there were no differences in nicotine dependence between patients with schizophrenia and those with a mood disorder. Schizophrenia was associated with a greater probability of ever daily smoking than mood disorders and with higher rates of initiation of daily smoking after 20 years old.

Adult↗
PubMed2002

A gender-specific association between the serotonin transporter gene and suicide attempts.

This pilot study tested the gender-specificity of the association between suicide attempts and a polymorphism in the promoter area of the serotonin transporter with two allelic variants, a long (1) variant and a short (s) variant. In a Spanish general hospital, 180 suicide attempters (121 women and 59 men) and 212 control blood donors (93 women and 119 men) were recruited. Subjects were classified as S individuals (s/s or s/l) with low expression of the serotonin transporter, and L individuals (l/l) with high expression. S individuals were significantly overrepresented (or L, underrepresented) in female attempters when compared with female controls and male attempters. Lethality appeared to have a significant influence on the effects of the genotype in suicide since S females were overrepresented among non-lethal female attempters. Further studies are needed to replicate that the serotonin genotype polymorphism may influence suicide attempts only in females.

Carrier Proteins↗
PubMed2002

How safe are psychiatric medications after a voluntary overdose?

PURPOSE: This study assessed psychiatric medications and their potential lethality in a representative sample of suicide attempts. MATERIALS AND METHODS: During 1996-98, 563 suicide attempts were studied in a general hospital in Madrid (Spain). Medication overdose was used in 456 suicide attempts (81%). The ratio between dose taken and maximum prescription dose recommended was used to evaluate the medication toxicity. RESULTS: Benzodiazepines were the drugs most often used in self-poisoning (65% of overdoses), followed by new antidepressants (11%), tricyclic antidepressants (TCAs) (10%), and antipsychotics (8%). An overdose with any of the three latter psychiatric medications was significantly more frequent in patients prescribed those medications. The overdoses for TCA were potentially lethal in 47% of the cases. However, all patients who overdosed on psychiatric medications recovered well and were discharged without any sequelae. DISCUSSION: This study suggests that psychiatric medications, particularly benzodiazepines, new antidepressants and antipsychotics, are relatively safe when they are used for self-poisoning. If patients with mental illnesses are under treated, there is a clear and documented higher risk for suicide. CONCLUSION: It is better to prescribe psychiatric medications, particularly the new ones, rather than withhold them due to an exaggerated fear of a lethal overdose

Adult↗
PubMed2002

Total cotinine in plasma: a stable biomarker for exposure to tobacco smoke.

Determination of plasma cotinine concentration is the predominant assay employed to quantify smoking and exposure to environmental tobacco smoke in epidemiological studies. However, cotinine is biotransformed into secondary metabolites. This pilot study determined plasma concentrations of cotinine, cotinine glucuronide, 3-hydroxycotinine, and 3-hydroxycotinine glucuronide. Total cotinine concentration was determined by summation of all four metabolites. The goals of this study were (1) to explore the stability and validity of total cotinine concentration as a measure of tobacco smoking and as a measure of exposure to environmental tobacco smoke in nonsmokers, (2) to explore the stability of plasma concentrations of each of the four nicotine metabolites in smokers by performing a.m. and p.m. measures, and (3) to explore the stability of indices of glucuronidation as measures of possible markers for enzymatic activity. The subject sample included 76 white volunteers (32% smokers and 68% nonsmokers). Plasma total cotinine concentration appeared to be very stable, suggesting that total cotinine concentration may be a good measure for epidemiological studies employing a single plasma sample. Moreover, plasma total cotinine concentration also reflected exposure to environmental tobacco smoke more accurately than did plasma cotinine concentration, which would have not identified 27% of passive smokers. 3-Hydroxycotinine glucuronide and 3-hydroxycotinine plasma concentrations were almost as stable as cotinine concentrations. However, cotinine glucuronide and its indices of glucuronidation were unstable, suggesting that cotinine glucuronide undergoes deconjugation. New studies of total cotinine in plasma using more than two blood collections during the day are needed to definitively establish that it is a stable biomarker for epidemiological studies.

Adult↗
PubMed2002

The association between high nicotine dependence and severe mental illness may be consistent across countries.

BACKGROUND: Studies all over the world suggest that severe mental illness, including schizophrenia and mood disorders, is associated with tobacco smoking. This study, combining samples from the United States and Spain, had 3 objectives: (1) to test the hypothesis that severely mentally ill patients who smoke are more likely to have a high nicotine dependence when compared with control smokers, (2) to compare frequencies of high nicotine dependence in controls in both countries, and (3) to compare frequencies of high nicotine dependence in severely mentally ill patients in both countries. METHOD: Scores on the Fagerström Test for Nicotine Dependence (FTND) for 4 samples of current daily smokers were analyzed. The sample sizes of the U.S. and Spanish control groups were 129 and 646 subjects, respectively. The diagnoses for the U.S. patients were DSM-IV schizophrenia, 74% (89/120), and DSM-IV mood disorders, 26% (31/120). The diagnoses for the Spanish patients were DSM-IV schizophrenia, 87% (173/199), and DSM-III-R mood disorders, 13% (26/199). High nicotine dependence (FTND score > or = 6) was the dependent variable in 5 logistic regression analyses. RESULTS: The main findings were that (1) severely mentally ill patients had significantly higher frequencies of high nicotine dependence than controls (odds ratio [OR] = 10.59, 95% CI = 7.31 to 15.34) even after controlling for gender, country, interaction between country and mental illness, and age; (2) U.S. controls had significantly higher frequencies of high nicotine dependence than Spanish controls (OR = 3.18, 95% CI = 2.02 to 5.00); and (3) U.S. and Spanish patients did not have significantly different frequencies of high nicotine dependence. CONCLUSION: New studies, specially designed to test for transcultural differences in nicotine dependence, are needed to verify that nicotine dependence in severely mentally ill patients is consistently high and similar in different countries.

Comorbidity↗
PubMedDate not supplied

Toxicity of dipyridyl compounds and related compounds.

Five dipyridyl isomers, 2,2'-, 2,3'-, 2,4'-, 3,3'-, and 4,4'-dipyridyl, are products resulting from the pyrolytic degradation of tobacco products and degradation of the herbicide paraquat, and therefore may be present in the environment. In this article, the toxicological properties of these dipyridyl isomers in humans and animals are reviewed. Epidemiological studies suggest that cancerous skin lesions in workers involved in the manufacturing of paraquat may be associated with exposure to dipyridyl compounds. Experimental animal studies suggest that dipyridyl isomers may have several toxicological effects. Three of the dipyridyl isomers (the 2,2', 2,4', and 4,4' isomers) appear to be inducers of some metabolic enzymes. The 2,2'-dipyridyl isomer, an iron chelator, appears to influence vasospasm in primate models of stroke. The cytotoxic effects of 2,2'-dipyridyl on several leukemia cell lines have been reported, and a potent teratogenic effect of 2,2'-dipyridyl has been observed in rats. Based on the results of paraquat studies in experimental animal models, it has been proposed that paraquat may have deleterious effects on dopaminergic neurons. These findings support the epidemiological evidence that paraquat exposure may be associated with the development of Parkinson's disease. Studies designed to determine an association between paraquat exposure and Parkinson's disease are complicated by the possibility that metabolic changes may influence the neurotoxicity of paraquat and/or its metabolites. Preliminary unpublished data in mice show that 300-mg/kg doses of 2,2'-dipyridyl are neurotoxic, and 300-mg/kg doses of 2,4'- and 4,4'-dipyridyls are lethal. These results are consistent with earlier studies in Sherman rats using high 2,2'- and 4,4'-dipyridyl doses. New studies are needed to further explore the toxicological properties of dipyridyls and their potential public health impact.

2,2'-Dipyridyl↗
PubMedDate not supplied

Association between the menses and suicide attempts: a replication study.

OBJECTIVE: In our prior (first) study, suicide attempts were associated with the menses. The main hypothesis of this replication (second) study is that the proportion of suicide attempters during the menses is significantly higher than the expected probability in the general population. METHODS: Using the same methodology and setting, this replication naturalistic study included 120 fertile female suicide attempters with regular menstrual cycles during a 1-year period in the emergency room of a general hospital in Madrid, Spain, serving a catchment area of 500,000 people. RESULTS: The significant increase in probability of attempting suicide during the menses for the first study was 1.61; for the second study, 1.72; and for both studies combined, 1.68 (95% confidence interval, 1.27-2.09). Thus, using the combined results, the probability of attempting suicide during the menses was 1.68 times higher than the overall probability of attempting suicide for any fertile women. In the catchment area, the population rate of fertile women arriving at the hospital after a suicide attempt was 166 per 100,000. The probability for women during the menses arriving at the hospital after a suicide attempt was significantly higher, 279 per 100,000 (1.68 x 166 per 100,000). The 95% confidence interval was 211 to 347 per 100,000. CONCLUSIONS: Despite inherent limitations, this naturalistic study replicates a small but significant increase of suicide attempts during the menses.

Adult↗