Correspondence between the CYP2C19 and CYP3A4 genotypes with the inferred metabolizer phenotype by omeprazole administration in Mexican healthy children.

WHAT IS KNOWN AND OBJECTIVE: CYP2C19 genotypes presumably allow the prediction of the metabolizer phenotypes: poor (PMs), extensive (EMs) and ultra-rapid (UMs). However, evidence from previous studies regarding this predictive power is unclear, which is important because the benefits expected by healthcare institutions and patients are based on this premise. Therefore, we aimed to complete a formal evaluation of the diagnostic value of CYP2C19 and CYP3A4 genes for predicting metabolizer phenotypes established by omeprazole (OME) administration in 118 healthy children from Jalisco (western Mexico). METHODS: The genotypes for CYP3A4*1B and CYP2C19*2, *3, *4, *5 and *17 alleles were determined. CYP2C19 and CYP3A4 phenotypes were obtained after 20 mg OME administration and HPLC quantification in plasma to estimate the Hydroxylation Index (HI = OME/HOME) and Sulfonation Index (SI = OME/SOME), respectively. RESULTS AND DISCUSSION: The distribution of genotypes and phenotypes for CYP2C19 and CYP3A4 was similar to previous studies in Mexico and Latin America. We estimated the CYP2C19 UM, EM and PM phenotype frequency in 0.84%, 96.61% and 2.54%, respectively. Although differences in the HI distribution were observed between CYP2C19 genotypes, they showed a poor diagnostic ability to predict the CYP2C19 metabolizer phenotype. Similarly, the number of CYP2C19 and CYP3A4 functional alleles was correlated with the HI distribution, but also their diagnostic ability to predict the CYP2C19 phenotype was poor. WHAT IS NEW AND CONCLUSION: The CYP2C19 phenotype is not predicted by the number of functional alleles of CYP2C19 and CYP3A4 genes. Phenotyping is still the most valuable alternative to dose individualization for CYP2C19 substrate drugs.

CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards.

Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in California than in Spaniards (SP). This was assumed to be related to the low CYP2C9*2 and *3 allele frequencies in Orientals. This study was therefore aimed at analyzing whether there were also differences in CYP2C9 allele frequencies between Mexican-Tepehuanos (MT) and Mexican-Mestizos (MM) living in northwestern Mexico and SP. The CYP2C9*2 frequency was expected to be lower in the indigenous MT than in the two other groups, and lower in MM than in SP as in our earlier study. CYP2C9 genotypes and allele frequencies of two populations of healthy volunteers, MT (n=99) and MM (n=102), were compared with a population of SP (n=327). The data were also compared with our previously published population of Mestizo-Mexican-Americans (MA). The CYP2C9 genotypes among the studied populations were in equilibrium. The frequencies of CYP2C9*2 were 0.01, 0.07, 0.08, and 0.16 for MT, MM, MA, and SP subjects, respectively. In agreement with our hypothesis, CYP2C9*2 was significantly lower in the Mexican populations than in the SP (P<0.05), and among Mexicans in the MT than in the MM and MA groups (P<0.05), which presented similar frequencies. Moreover, the frequency of CYP2C9*3 was found to be lower (P<0.05) in MM (0.015) and MT (0.015) than in MA (0.06) and SP (0.08). Finally, the CYP2C9*6 allele was present just in one MM subject, and CYP2C9*4 and *5 were not found in the studied populations. Therefore, these findings add further evidence about CYP2C9 genetic diversity within Hispanic populations with regard to their ancestry. Considering that CYP2C9*2 and CYP2C9*3 alleles have altered catalytic activities relative to CYP2C9*1, the present data suggest the need for pharmacogenetic studies to optimize drug dosages in different populations.

Serum level of scorpion toxins, electrolytes and electrocardiogram alterations in Mexican children envenomed by scorpion sting.

The scorpion Centruroides limpidus limpidus (C.l.l.) is endemic in México, producing hundreds of accidents in humans; children being one of the most susceptible targets. Few studies reported that severe envenoming by scorpion venom induces cardiac damage and electrolytes abnormalities in children, but the relationship of envenoming severity and toxic blood levels is unknown. The aim of this study was to determine the relationship among clinical status of envenoming, serum electrolyte, electrocardiographic abnormalities, and serum toxin levels in 44 children stung by scorpion over a period of 6 months in the State of Morelos, Mexico. The patients were said to be asymptomatic, when they presented just local symptoms, and were said to be symptomatic when showing local symptoms and at least one systemic symptom. The clinical status was evaluated at the admission at the emergency room of the Hospital, and 30 min after the administration of polyspecific F(ab')2 anti-scorpion therapy to symptomatic children. Forty-one percent of the children were asymptomatic and 59% symptomatic. Potassium and sodium imbalance and an elongation of the QT interval were detected; the rate of hypokalemia was higher in symptomatic than on asymptomatic children (50% and 6%, respectively). Hypokalemia persisted in 19% in symptomatic patients, whereas sodium reached normal levels 30 min after anti-venom therapy. The hypokalemia statistically correlated with elongation of the QT interval. The concentration of the toxic components of C.l.l in serum was significantly higher in symptomatic than asymptomatic children, and the serum levels of the toxic component significantly decreased to undetectable levels after the application of anti-venom therapy. Despite the small size of the sample, this study establishes that severity of envenoming was statistically related to potassium imbalance in serum, QT interval and the concentration of toxic components in serum, which decreased at undetectable levels after specific treatment with the anti-scorpion venom, correlating with clinical disappearance or greatly reduction of symptoms of envenomation.

Pharmacokinetics of metronidazole in severely malnourished and nutritionally rehabilitated children.

A comparison of the pharmacokinetics of oral metronidazole, after a single dose of 30 mg/kg body weight, was done in two groups of subjects: group I consisted of 10 severely malnourished children, aged 4 to 43 months; group II consisted of 10 children, aged 3 to 25 months, who were studied after nutritional rehabilitation. The biologic half-life of elimination was significantly longer (p less than 0.01) in severely malnourished children (median, 10.21 hours; range, 4.89 to 22.93 hours) than in rehabilitated children (median, 5.09 hours; range, 2.61 to 8.75 hours). Metabolic clearance of metronidazole was significantly lower in group I (p less than 0.01; median, 0.077 L/kg/hr; range, 0.033 to 0.192 L/kg/hr) than in nutritionally rehabilitated children (median, 0.166 L/kg/hr; range, 0.105 to 0.300 L/kg/hr). Volume of distribution was not different between groups I and II, although both showed higher values than the values reported for children who were not malnourished. These findings suggest that the dose of metronidazole should be reduced in malnourished children, and the therapeutic regimen should be individualized for each patient.

Influence of nutritional status on the pharmacokinetics of acetylsalicylic acid and its metabolites in children with autoimmune disease.

BACKGROUND: It is unknown whether nutritional status associated with autoimmune disease alters the pharmacokinetics of acetylsalicylic acid (ASA) and its metabolites. OBJECTIVE: We studied the effects of the nutritional status of children with autoimmune disease on the disposition of ASA and its metabolites. DESIGN: A prospective, open-label study was performed with 21 children aged 3-15 y who required ASA therapy. Children received 25 mg ASA/kg orally. Blood samples were drawn before and 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, and 24.0 h after ASA administration; urine samples were collected at different intervals. ASA and its metabolites were measured in plasma and urine. Nutritional status was assessed previously. RESULTS: The ASA maximum plasma concentration, area under the curve, and total clearance were significantly lower in underweight children than in normal-weight children. The elimination rate constants of gentisic acid (GA), salicyluric acid (SUA), and salicylic acid (SA) in plasma were slower for underweight children than for normal-weight children. The distribution volume of SUA increased significantly (r = 0.92) when the deficit percentage in weight-for-height increased. Underweight children excreted less GA and SA, but more SUA, than did normal-weight children. CONCLUSIONS: These observations suggest a decrease in the hydrolysis and oxidative reactions of the metabolic pathway of ASA and its metabolites in underweight children. The study illustrates the need for pharmacokinetic data to establish the individual doses of drugs, particularly in conditions that alter nutritional status.

Pharmacokinetics of cyclosporine as a function of energy--protein deficiency in children with chronic renal failure.

The present study was conducted to determine whether malnutrition in patients with chronic renal failure requiring cyclosporine therapy for renal transplantation has some effect on the clinical pharmacokinetics of cyclosporine. Eleven pediatric patients were enrolled in this study before renal transplantation and divided into two groups (group I: six well-nourished patients with a deficit in weight/height ratio < or = 7%; group II: five malnourished patients with a deficit in weight/height > 8%). The patients received a single oral dose of cyclosporine (3.0 mg/kg). Blood samples were collected for a 26-hour period, and serum concentrations of cyclosporine were measured using fluorescence-polarization immunoassay technology. The results suggest that, when malnutrition is present, the median Cmax of cyclosporine decreases by almost threefold (from 387.5 ng/mL in group I to 136.1 ng/mL in group II). An observed 52% reduction in AUC0-infinity (from 2,856.0 ng/mL/hr in group I to 1,481.4 ng/mL/hr in group II) was caused by the increased volume of distribution (from 4.6 L/kg in group I to 11.1 L/kg in group II). The elimination half-life (t1/2) was longer in group II compared with that of group I (12.4 hr for group II; range, 7.8-13.5 hr versus 8.9 hr for group I; range, 5.2-16.0 hr). Differences in t1/2 were not statistically significant at 5% confidence intervals. The effects of energy malnutrition on the pharmacokinetics of cyclosporine could explain in part some of the interindividual variability. This study provides pharmacokinetic guidelines for the use of cyclosporine.

Plasmatic levels of theophylline in asthmatic patients. Comparative evaluations of two different methods.

BACKGROUND: There are several criteria to choose an analytical method for drug monitoring. Such methods have to comply with standard values and quality control as well as other subjective features such as cost and the time consumed to obtain quantification (TCOQ). The purpose of this work was to compare two methods used to quantify plasmatic levels of theophylline in asthmatic patients as support to choose the best method. METHODS: We analyzed plasma samples from 30 asthmatic pediatric patients at the pediatric service of the Hospital General de México, who were under treatment with theophylline and whose monitoring of drug levels was indicated. Plasma samples were analyzed by liquid chromatography (HPLC) and by enzyme immunoassay (EMIT), and were then compared with respect to reliability, as well as cost and TCOQ. RESULTS: The difference of the plasmatic levels of theophylline quantified by both methods was not significant (p > 0.05); both showed a good correlation index (r = 0.995), and both were reliable based on other validity parameters. However, TCOQ for HPLC was 20.0 +/- 5.5 min (mean +/- SD) for each sample analyzed, and 2.3 +/- 0.5 for EMIT. With respect to the cost of each analysis, HPLC required 2.3 +/- 0.5 USD (mean +/- SD) and EMIT 4.5 +/- 0.3 USD. CONCLUSIONS: Analytical methods used to quantify plasmatic levels of theophylline based on HPLC and EMIT proved to be suitable, because they fulfilled the criteria and standard values regarding quality control, although laboratorists have to select subjectively the best method according to cost and TCOQ, since HPLC was less expensive, and EMIT was more rapid.

Kinetic effects of trimethoprim-sulfamethoxazole in children with biliary atresia: a new dosing regimen.

Pharmacokinetics for combination trimethoprim/ sulfamethoxazole (TMP/SMX) was studied in only four patients with biliary atresia (BA): three girls, 6.2,8.0 and 8.2 years of age and one boy 8.4 years of age, as this is an uncommon obstructive anomaly of the extrahepatic biliary system and has been described as having a poor prognosis. These four patients are the survivors of 27 initial children who were operated on previously. They have been receiving 2.3 +/- 0.5 mg/kg TMP, and 11.5 +/- 2.6 mg/kg SMX every 12 h since 2 weeks after surgical treatment for biliary atresia performed at 2-2.5 months of age. The patients have suffered some episodes of cholangitis during their short lives, most of them after interrupting temporally the chemotherapy. Nevertheless, they have achieved a favorable quality of life. TMP/SMX disposition was well characterized by a one compartment open pharmacokinetic model. Wide interpatient variability was observed for all pharmacokinetic parameters with coefficients of variation for t1/2 el, ClT, and Vd of 33.2, 49.6, and 26.3%, respectively, for SMX and 108.9, 52.1, and 71.0%, respectively, for TMP. A marked difference in the pharmacokinetics of TMP and SMX was observed, for example; (ClT: mean +/- SD; 90.3 +/- 47.0 ml/kg/g for TMP and 13.7 +/- 6.8 ml/kg/h for SMX), (t1/2 el with 7.93 +/- 8.64 h for TMP and 10.51 +/- 3.49 h for SMX). In order to develop dosage schedules that would reliably achieve peak serum concentrations of TMP/SMX in the therapeutic range, we found that established dose leads to high fluctuations at steady state between C(max), ss and C(min), ss, without maintaining therapeutic levels. Recommended maintenance dose varied from 8 to 30 mg/kg for SMX with a mean of 21.9 +/- 10.89 mg/kg/12 h, and from 0.8 to 4.5 mg/kg/12 h with a mean of 3.2 +/- 1.7 mg/kg/12 h. The present study illustrates the need for pharmacokinetic studies for the individualization of drug dosing in patients with BA.

Bacterial mutagens in the urine of patients under tinidazole treatment.

Tinidazole is an antiparasitic drug belonging to the 5-nitroimidazole family. It is prescribed against protozoal infestations and is widely used in Mexico as well as other underdeveloped countries where infectious diseases are the first cause of children mortality. The drug is a direct mutagen in Salmonella typhimurium TA100 strain and the presence of S9 mixture did not modify its mutagenic effect. At low doses no mutagenicity was detected with strains TA100NR, TA98 or UTH8414 (Uvr+ derivative of TA100). Urine from four patients under tinidazole treatment exhibited a mutagenic activity on strain TA100, greater than the expected from the tinidazole concentrations determined by high-performance liquid chromatography (HPLC). Components from the urine samples were separated on thin-layer chromatography (TLC) plates, and their mutagenic effects tested by direct application of the Salmonella assay onto sections of the developed chromatoplate. The Rf of one component (0.62) corresponded to the one obtained for a tinidazole standard and showed the expected mutagenicity, while a second component with an Rf=0.39, exhibited a mutagenic potency slightly greater than the observed for tinidazole; however, as in the case of the drug itself, reduction of the nitro group was necessary for a mutagenic activity.

Patterns of drug consumption in relation with the pathologies of elderly Mexican subjects resident in nursing homes.

PURPOSE: To describe the patterns of drugs consumed by the male and female elderly living in Mexican private and public nursing homes. METHODS: Three hundred and fifty elderly participants from four nursing homes (2 private and 2 public) were selected for the six month study: 108 subjects were excluded; the remaining 242 were between 65 and 100 years old; 123 were females and 119 males. A complete clinical history was taken and clinical files were reviewed. RESULTS: Of the 242 elderly studied, 193 took diverse medications and 28.5% were at risk of some type of drug interaction. The groups of drugs more frequently consumed were vitamins and anti-anemic medications, followed by cardiovascular drugs. Females consumed greater number of drugs. They also consumed more drugs simultaneously. CONCLUSIONS: There is a need to monitor the elderly for their drugs pattern use.

Nutritional state of beta-carotene and retinol in institutionalized elderly individuals of México City.

A study of the nutritional status of beta-carotene and retinol of 228 institutionalized elderly individuals, in four elderly homes of México City was carried out. Subjects varied between 61 and 101 years of age (151 were females and 77 were males). High pressure liquid chromatography was used to quantitate retinol and beta-carotene. Ninety eight percent of elderly individuals showed beta-carotene levels less than acceptable (at risk); 85.2% were deficient (high risk), and 12.9% were low (medium risk), only 1.85% had acceptable values (low risk). Ninety two percent of subjects had acceptable values (low risk) of retinol, while 6.0% and 2.0% were low (medium risk) and deficient (high risk) respectively. There were not significant differences among the four elderly homes. No significant correlation with age was found for any of the two vitamins. No sex related difference (p > 0.05) was observed in serum vitamin A and beta-carotene in either group.

[Cefuroxime Bayesian pharmacokinetics in severely ill septic children]. / Farmacocinética bayesiana de cefuroxima en niños infectados gravemente enfermos.

OBJECTIVE: To estimate the cefuroxime pharmacokinetic parameters in critically ill pediatric septic patients using a Bayesian pharmacokinetic method and three serum drug assays per patient. DESIGN: Cross-sectional study of critically ill pediatric patients undergoing therapeutic monitoring of cefuroxime serum concentrations. SETTING: Tertiary care center. PATIENTS: Nine critically ill pediatric patients with sepsis and septic shock treated with cefuroxime. METHODS: Timed serum concentrations of cefuroxime were obtained in each patient. The Vd (volume of distribution) and the Kel (constant of elimination) were estimated by means of a Bayesian iterative two-stage algorithm, using the information of three serum drug concentrations per patient at optimal times. The parameters were also estimated by the traditional method of non linear least square regression in eight samples. RESULTS: The Bayesian Vd was very similar to the traditional Vd with a correlation coefficient of 0.99 and a small bias of -0.04 L/kg whereas the Kel had a correlation of 0.90 and bias of -0.29 h-1. The mean Bayesian Vd was 0.68 L/kg, a larger value than that reported in non critically ill patients. CONCLUSIONS: We offer a tentative cefuroxime pharmacokinetic model for critically ill pediatric septic patients which may be useful for the control of cefuroxime serum concentrations. Also, our study underscored the potential usefulness of a Bayesian pharmacokinetic approach as a tool for therapeutic drug monitoring in critically ill patients.

[Bayesian prediction of chloramphenicol blood levels in children with sepsis and malnutrition]. / Predicción bayesiana de las concentraciones séricas de cloranfenicol en niños con sepsis y desnutrición.

OBJECTIVE: To validate the population pharmacokinetic parameters of chloramphenicol in pediatric patients with sepsis and malnutrition (PPSM) using a bayesian forecasting program. DESIGN: Retrospective evaluation of predictive performance of a bayesian program in PPSM. SETTING: Tertiary care center. PATIENTS: Fifteen MPSP and ten NMPSP that receiving treatment with chloramphenicol. METHODS AND MAIN RESULTS: In the first part of the study, the medical records of 10 MPSP and 10 NMPSP who had received treatment with chloramphenicol were reviewed. The population pharmacokinetic parameter values for each group were estimated using a nonparametric expectation maximization algorithm (NPEM). In the second part, data gathered from five other MPSP receiving chloramphenicol were entered into a bayesian program. Chloramphenicol pharmacokinetic values for each of these five patients were estimated, first using the values of NMPSP as a priori distribution and then repeating the analysis using the MPSP values. The bayesian serum chloramphenicol concentrations predicted for each population model were compared with the actual peaks and troughs. The specific model for MPSP permitted forecasting the peak and trough serum chloramphenicol concentrations with less bias and a better precision compared with the NMPSP population model. CONCLUSIONS: These data indicate that chloramphenicol pharmacokinetics in PPSM can be predicted with minimal bias and good precision using a bayesian forecasting program, allowing a better control of the chloramphenicol serum concentrations. In addition, the limited number of samples required by the bayesian method may represent an important economical benefit for the patient.

[Dose-effect of the administration of ferrous fumarate in aged persons with iron deficiency]. / Dosis efecto de la administración de fumarato ferroso en personas ancianas con deficiencia de hierro.

BACKGROUND: Anemia is the most prevalent hematological problem in elderly persons, affecting 14% of the males and 6% of the females of the population over 60 years of age in Mexico City. OBJECTIVE: To determine the effect produced by the prolonged administration of ferrous fumarate in elderly persons with iron deficiency. METHOD: In a population of 178 subjects, aged between 65 to 100 years, iron deficiency was diagnosed in 51 (28.6%), who had serum iron concentrations below 80 micrograms/dL for men and 60 micrograms/dL for women, but only 21 patients (11.8%), accepted to participated in the study. The response to a 6 months oral administration of ferrous fumarate were studied with a daily oral dose of 5 mg/kg of elemental iron. The patients were classified in 3 groups according to the abnormal parameters of iron metabolism (group 1 = 10.9% anemia, group 2 = 28.0% and group 3 = 63.0% anemia). RESULTS: The efficacy of treatment was evaluated by quantification of the changes occurred in serum iron concentrations, hemoglobin, ferritin and transferrin saturation index, at 0, 30, 90 and 180 days of treatment. This study showed that the treatment of oral ferrous fumarate in elderly patients with iron deficiency, produces a quantifiable improvement in measures of iron parameters within 6 months. CONCLUSIONS: The results of this study suggest the usefulness of prolonged treatment with ferrous fumarate in elderly patients with iron deficiency, to avoid therapeutic failure as a consequence of non-compliance as is common in elderly patients.

[Pharmacogenetics and its importance in the clinical]. / La farmacogenética y su importancia en la clínica.

Therapeutic inefficacy and pharmacologic toxicity has frequently been seen in the clinical use of drugs or medicines in individuals under pharmacological treatment. Due to the presence of drug metabolizing enzymes, medicines may participate as substrate inhibitors or enzyme inductors. Their activity may vary among individuals. This enzymatic variability may be assessed through the analysis of recombinant DNA, using restriction analysis of the genomic DNA (fragment restriction of polymorphic length) and the enzymatic amplification of DNA through PCR (polymerase chain reaction). This technology has been used in clinical studies which allow us to know the mechanisms of inherited variations in response to drugs regulated by each individual's genes dependent on different races. These enzymatic differences may also be influenced by nutritional habits or environmental factors. This study deals with the importance of understanding the metabolism of drugs applied to the therapeutic management of individuals with therapeutic inefficacy or pharmacologic toxicity.

A new dosing regimen for metronidazole in malnourished children.

The use of metronidazole for the treatment of intestinal parasitosis has increased markedly, particularly in developing countries, where the association of malnutrition and parasitosis is very common. Since biotransformation of metronidazole is significantly affected by severe malnutrition, and undesirable effects of the drug seem to be related to its plasma concentration, it was decided to carry out a study to establish a dosing-regimen of metronidazole in severely malnourished children. A single dose of 30 mg/kg body weight, and computer simulation of a steady-state was studied in 10 malnourished and in 10 patients undergoing nutritional rehabilitation. Due to ethical considerations (refusal of parents to allow a second dose of metronidazole) acute malnourished children and rehabilitated patients are 2 distinct groups. The results indicate that a predicted drug cumulation would occur in malnourished children with the ordinary dosage regimen (30 mg/kg/day). Based on the clearance data, daily maintenance doses for pediatric patients with severe malnutrition should be 12.0 mg/kg/day, corresponding to a 60% reduction of the common dose calculated to achieve and maintain a plasma concentration of 6.0 micrograms/ml of metronidazole. The study illustrates the need for pharmacokinetic data to establish the individual dose of a drug particularly under conditions that alter biotransformation processes.

Relationship between clinical and biologic variables and chloramphenicol pharmacokinetic parameters in pediatric patients with sepsis.

OBJECTIVE: To evaluate the influence of several clinical and biologic factors on the disposition kinetics of oral chloramphenicol in pediatric patients and to determine the usefulness of this information to predict chloramphenicol serum concentrations. STUDY DESIGN: The clinical, biologic, and pharmacokinetic data of 30 consecutive pediatric patients diagnosed with sepsis and admitted to a tertiary care center were analyzed retrospectively. The patients were randomly assigned to a study group and a validation group. The model was developed by a three-step approach involving Bayesian estimation of pharmacokinetic parameters, selection of covariates by principal component analysis, and final selection by stepwise multiple linear regression. The model was tested in the study group and compared with a general population model using a prediction error analysis. RESULTS: Regression analysis revealed that weight, albumin, and white blood cell (WBC) count were the most important determinants for chloramphenicol distribution volume, whereas age, WBC count, and serum creatinine were the most important determinants for chloramphenicol clearance. The performance of the constructed population model improved significantly in terms of both bias and precision compared with the general model when tested in the validation group. CONCLUSIONS: Clinical and biologic factors may significantly influence chloramphenicol's disposition in pediatric patients with sepsis and therefore should be considered in programming dosage regimens.