Detection of cocaine exposure in the neonate. Analyses of urine, meconium, and amniotic fluid from mothers and infants exposed to cocaine

Cocaine and its metabolites were measured in urine, meconium, and amniotic fluid specimens collected from 30 maternal-infant pairs with histories of prenatal cocaine use. Cocaine, benzoylecgonine, and ecgonine methyl ester were measured by isotope dilution gas chromatography-mass spectrometry. Mothers were interviewed at delivery regarding their cocaine use during pregnancy. There was qualitative agreement between the results of drug determinations in maternal urine, amniotic fluid, infant urine, and meconium. Although all of the mothers in this study admitted to using cocaine during their pregnancy, cocaine or its metabolites were detected only in the 20 cases in which cocaine was used within 3 weeks before delivery. We conclude that when sufficiently sensitive analytic methods are used, maternal urine, infant urine, and meconium analyses yield equivalent results for detection of prenatal cocaine exposure. Importantly, neither meconium nor urinary drug measurements detected cocaine exposure when the last reported use was prior to 3 weeks before delivery.     

Partial and complete correlations of fetal maturity with ultrasonographic and enzymatic measurements

The computer-aided enzymatic and ultrasonographic method of pregnancy monitoring takes into account ultrasound measurements of fetal parameters (BPD, HC, AC, FL) and oxytocinase (CAP1) and isooxytocinase (CAP2) levels in maternal blood. In this paper we decided to verify which one of this values have the major influence on fetal maturity prediction. 385 pregnancies, after sterility treatment, were studied where ultrasound measurements and enzymes levels were estimated simultaneously as well as current fetal maturity were established using computer-aided method by M. Klimek. There are high sample correlations between current fetal maturity and the number of remaining days to labor (r = -0.8) as well as ultrasound measurements (BPD r = 0.87, HC r = 0.89, AC r = 0.90, FL r = 0.81). Fetal maturity correlations with enzymatic values (CAP1, CAP2) were smaller 0.55, 0.52 respectively. The partial correlation pictures this relations much stronger -0.29, 0.28, 0.22, 0.30, 0.46, -0.06, 0.13 respectively.     

Clinical pharmacokinetics of carboplatin in children

The present study was undertaken to evaluate in children the plasma pharmacokinetics of free carboplatin given at different doses and schedules and to evaluate the inter- and intrapatient variability and the possible influence of schedule on drug exposure. A total of 35 children (age range, 1-17 years) with malignant tumors were studied. All patients had normal renal function (creatinine clearance corrected for surface body area, above 70 ml min-1 m-2; range, 71-151 ml min-1 m-2) and none had renal involvement by malignancy. Carboplatin was given at the following doses and schedules: 175, 400, 500, and 600 mg/m2 given as as a 1-h infusion; 1,200 mg/m2 divided into equal doses and infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m2 given as a 5-day continuous infusion. A total of 57 courses were studied. Carboplatin levels in plasma ultrafiltrate (UF) samples were measured both by high-performance liquid chromatography and by atomic absorption spectrophotometry. Following a 1-h infusion, carboplatin free plasma levels decayed biphasically; the disappearance half-lives, total body clearance, and apparent volume of distribution were similar for different doses. In children with normal renal function as defined by creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we found at each dose studied a limited interpatient variability of the peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) and a linear correlation between the dose and both Cmax (r = 0.95) and AUC (r = 0.97). The mean value +/- SD for the dose-normalized AUC was 13 +/- 2 min m2 l-1 (n = 57).2+ The administration schedule does not seem to influence drug exposure, since prolonged i.v. infusion or bolus administration of 1,200 mg/m2 achieved a similar AUC (13.78 +/- 2.90 and 15.05 +/- 1.44 mg ml-1 min, respectively). In the nine children studied during subsequent courses a limited interpatient variability was observed and no correlation (r = 0.035) was found between AUC and subsequent courses by a multivariate analysis of dose, AUC, and course number. The pharmacokinetic parameters were similar to those previously reported in adults; however, a weak correlation (r = 0.52, P = 0.03) between carboplatin total body clearance and creatinine clearance varying within the normal range was observed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of three types of half-limb casts on in vitro bone strain recorded from the third metacarpal bone and proximal phalanx in equine cadaver limbs

This open-label, non-randomized, parallel-group trial investigated the pharmacokinetics of raltitrexed (Tomudex, formerly ZD1694) after a single intravenous dose of 3.0 mg m(-2), comparing eight cancer patients with mild to moderate renal impairment (creatinine clearance 25-65 ml min(-1)) with eight cancer patients with normal renal function (creatinine clearance >65 ml min(-1)). The primary end points were area under the plasma raltitrexed concentration-time curve from the start of the infusion to the last determined concentration (AUC(0-tldc)) and AUC to infinity (AUC(0-infinity)); secondary end points were peak concentrations of raltitrexed (Cmax) and elimination half-life (t(1/2gamma)). The groups were compared statistically using analysis of covariance. The AUCs were greater for patients with renal impairment than for patients with normal renal function (2452.2 compared with 1247.3 ng h ml(-1) for AUC(0-tldc) (ratio 1.97; 95% CI 1.36-2.84); 2961.5 compared with 1457.0 ng h ml(-1) for AUC(0-infinity) (ratio 2.03; 1.25-3.29). These differences were statistically significant (P = 0.002 and P = 0.008 for AUC(0-tldc) and AUC(0-infinity) respectively. Terminal half-life was longer for the renally impaired patients (271.2 compared with 143.3; P = 0.030). There was no significant statistical difference between the groups for Cmax (652.9 compared with 564.7 ng ml(-1) for patients with impaired and normal renal function respectively: ratio 1.16; 0.91-1.46; P = 0.204). There was a clear relationship between raltitrexed clearance and creatinine clearance. Adverse events, severe (WHO grade 3 or 4) toxicity and hospitalization due to adverse events were more frequent in the group with renal impairment. Therefore, a reduction in raltitrexed dose and increased interval between doses is recommended for patients with mild to moderate renal impairment.     

Single- and multiple-dose pharmacokinetics of riluzole in white subjects

Riluzole is a novel neuroprotective agent that has been developed for the treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to establish its pharmacokinetics on single- and multiple-dose administration in young white male volunteers. The mean absolute oral bioavailability of riluzole (50-mg tablet) was approximately 60%. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) values were linearly related to dose for the range studied. Cmax occurred at 1.0 hour to 1.5 hours after administration. Plasma elimination half-life appeared to be independent of dose. After repeated administration of 100 mg riluzole for 10 days, some intraindividual variability in bioavailability was seen. A high-fat meal significantly reduced the rate (tmax = 2 hours compared with 0.8 hours; Cmax = 216 ng.mL-1 compared to 387 ng.mL-1) and extent of absorption (AUC = 1,047 ng.hr.mL-1 versus 1,269 ng.hr.mL-1). With multiple-dose administration, riluzole showed dose-related absorption, although the terminal plasma half-life was prolonged slightly. Steady-state plasma concentrations were achieved within 5 days. Steady-state trough plasma concentrations were significantly higher with a 75-mg dose twice daily than with a 50-mg dose three times daily, although AUC values did not differ.     

Epidemiology of oral cavity tumors

In this study we aimed at evaluating the modifications in the pharmacokinetic profile of cyclosporin A (CyA) after conversion from standard formulation (CyA-ST) to a new formulation (CyA-NF, Sandimmun Neoral) in patients with rheumatoid arthritis (RA). It was an open, crossover study that involved 15 RA patients who were on stabilized treatment with CyA-ST. The patient continued receiving CyA-ST (mean dose of 3.0 +/- 0.7 mg/kg per day) for 3 weeks and then converted 1:1 to CyA-NF for a further 3 weeks. CyA pharmacokinetics were established on day 1 (CyA-ST evaluation) and +21 (CyA-NF evaluation). The results showed that the bioavailability of CyA-NF was greater than that of CyA-ST (AUC tau, bss: 3335 +/- 1300 vs 2667 +/- 1155 ng.h/ml, P = 0.0073; AUC tau, bss ratio 1.26 +/- 0.40 vs 1.0 as reference, P < 0.05), with higher and earlier peak blood concentrations (Cmax: 677 +/- 256 vs 475 +/- 213 ng/ml, P = 0.0329; tmax: 1.5 +/- 0.7 vs 2.6 +/- 1.6 h, P = 0.0720). The pharmacokinetic profile of CyA-NF showed greater between-patient reproducibility (lower CV% for all of the considered parameters). In conclusion, when using CyA-NF instead of CyA-ST, greater and more constant exposure to CyA should be expected.     

Pharmacokinetics of gentamicin at traditional versus high doses: implications for once-daily aminoglycoside dosing

Two doses of gentamicin (2 and 7 mg/kg of body weight) were administered to 11 healthy volunteers in a randomized, crossover single-dose study to compare their pharmacokinetics. Doses were infused over 1 h with a syringe infusion pump, and 14 concentrations in sera were obtained over an 8-h period. Concentration in serum versus time data were fitted to a two-compartment pharmacokinetic model. In addition, to mimic the clinical setting, subjects' data were fitted by the Sawchuk-Zaske method. Distributional and postdistributional peak concentrations, along with the last obtained concentration in serum, were utilized to compare the following pharmacokinetic variables: volume of distribution at steady state (Vss), half-life, clearance (CL), and maximum concentration in serum (Cmax). With two-compartment pharmacokinetic fitting, significant differences in distribution half-life (average, 21.8 and 41.6 min [P < or = 0.05]) and gentamicin CL (76.6 +/- 6.6 and 67.2 +/- 4.2 ml/min/1.73 m2 [P < or = 0.001]) were found between traditional-dose and high-dose groups, respectively. When the data for concentrations in sera were fitted to a one-compartment pharmacokinetic model by using either the distributional or the postdistributional Cmax, statistically significant differences (P < or = 0.001) were found between Vss, half-life, CL, and Cmax values for both dosage groups. The results show that the pharmacokinetics of gentamicin at a large dose differ significantly from those at the traditional dose. This information has direct implications for once-daily aminoglycoside (ODA) literature when the Cmax values reported are distributional and therefore show falsely high Cmax/MIC ratio estimates. In addition, ODA nomogram dosing tools developed with distributional Cmax values are probably inaccurate.     

Differential changes in copy numbers of rice mitochondrial plasmid-like DNAs and main mitochondrial genomic DNAs that depend on temperature

OBJECTIVE: The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months) after the start of antipsoriatic therapy. METHODS: Ten male and female psoriatic patients who failed to respond to previous conventional therapy were treated with 15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the same occasions, MTX accumulation in erythrocytes obtained before MTX administration was investigated. Pharmacodynamics of MTX were evaluated using the psoriasis area and severity index (PASI) score. RESULTS: There were marked intersubject differences (range of coefficients of variation 34.9-76.3%) in the area under the curve (AUC), peak concentration (Cmax) and clearance (CL) of MTX. Total CL was proportional to renal clearance (CLR) (r2 = 0.735, P < 0.0001) which accounted for 73 (19)% of the former. There was a strong linear relationship (r2 = 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of drug administration, the urinary excretion of MTX was 46-99% of the dose, while that of 7-OH MTX was 1.5-8.6%. In 8 of 10 patients, more than 70% of the MTX dose was recovered. No intraindividual variations of MTX kinetic parameters during treatment were observed. MTX concentrations in erythrocytes reached the steady-state concentration in the range 40.7-170 nmol.l(-1) after 2 months of therapy. Pharmacodynamic measurement versus pharmacokinetics revealed a significant inverse relationship between PASI score and MTX AUC (rs = -0.912, P < 0.002) and between PASI score and erythrocytic MTX (rs = -0.988, P < 0.002). CONCLUSION: The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration.     

Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease

BACKGROUND: Recent clinical trials have demonstrated that methotrexate may have an important therapeutic role in the treatment of patients with inflammatory bowel disease, who are either refractory or intolerant to traditional medical therapy. The aim of this study was to evaluate the pharmacokinetics of low-dose oral methotrexate in patients with inflammatory bowel disease. METHODS: Methotrexate (12.5 mg) was given orally to nine patients with inflammatory bowel disease: five with Crohn's disease, and four with ulcerative colitis, and to six patients with rheumatoid arthritis who served as a control group. Blood samples were drawn at specific intervals to evaluate methotrexate plasma levels. RESULTS: Methotrexate was rapidly absorbed in all patients. Peak concentrations (Cmax) varied considerably, ranging from 0.25-0.87 micro M. The mean Cmax values were similar in all patient groups (0.59 +/- 0.12, 0.69 +/- 0.16 and 0.54 +/- 0.18 micro M, P not significant) for Crohn's disease, ulcerative colitis and rheumatoid arthritis, respectively. The mean area under curve in 120 min (AUC0-120) was also similar in all patient groups (32.9 + 11.3, 43.6 + 9.9 and 41.8 + 14.9 ng.min/mL, P not significant) for Crohn's disease, ulcerative colitis and rheumatoid arthritis, respectively. The mean time to reach Cmax, (tmax), varied between patient groups (84, 112 and 95 min, respectively, with a significant difference, P < 0.02, between the Crohn's disease and ulcerative colitis groups. A negative correlation was found between methotrexate dosage/kg and Cmax (r = -0.74) only in Crohn's disease patients but not in the other patient groups. CONCLUSIONS: Orally administered methotrexate is well absorbed in patients with inflammatory bowel disease including those with severe small bowel disease or resection. If methotrexate is proven to be effective in inflammatory bowel disease, it should be administered orally.     

Genetic influences on plasma catecholamines in human twins

We examined the relative genetic and environmental influences on the variability in plasma epinephrine, norepinephrine, and dopamine levels in 109 twin pairs. Epinephrine levels were lower in females (P = 0.048). The norepinephrine concentration increased with age (r = 0.40; P < 0.001). Blood pressure (BP) was not associated with epinephrine levels in either sex or with norepinephrine levels in females. In males, there was a positive association between norepinephrine concentration and diastolic BP (r = 0.31; P = 0.020). A negative association between dopamine levels and systolic and diastolic BP in females (r = -0.22; P = 0.014 and r = -0.20; P = 0.027, respectively) was not maintained after accounting for age, body mass index, and sex. Using path analysis and maximum likelihood model fitting, genetic, unique environment, and age effects contributed 57% (P < or = 0.001), 27% (P < or = 0.001), and 16% (P < or = 0.001) to the variability in norepinephrine, respectively. Genetic effects explained 64% (P < 0.1) and 74% (P < 0.1) of the variability in epinephrine concentrations in females and males, respectively. Unique environmental influences explained the remainder. Genetic and unique environmental effects explained 72% (P < 0.01) and 28% (P < or = 0.001) of the variability in dopamine levels. These results indicate a substantial genetic influence on plasma catecholamine levels. Although consistent associations between plasma catecholamines and BP were not evident in this study, the observed genetic influence on circulating catecholamines may be relevant to the potential role of the sympathetic nervous system in the early stages of essential hypertension.     

A field test comparison of hiking stick use on heartrate and rating of perceived exertion

A case is presented involving a young woman on several illicit drugs (heroin, cocaine and cannabis) as well as two medications and a solvent used for their anesthetic and narcotic properties: thiopental, ketamine and chloroform. This complex drug use was supported by hair analysis over a 10.5 cm segment of the hair taken at autopsy. The average measured concentrations in hair were: thiopental = 5.3 ng/mg, pentobarbital = 10.0 ng/mg, ketamine = 11.3 ng/mg norketamine = 1.0 ng/mg, diazepam = 1.2 ng/mg, nordiazepam = 0.1 ng/mg, 6-acetylmorphine = 4.4 ng/mg, morphine = 3.4 ng/mg, codeine = 1.2 ng/mg, cocaine = 5.5 ng/mg, benzoylecgonine = 1.5 ng/mg and methylecgonine ester = 1.0 ng/mg. While the ketamine/norketamine ratio is consistent with that already reported on drug detection in hair, the thiopental/pentobarbital ratio seems to be inverted.     

Time course of cocaine in rabbit hair

The accurate interpretation of analytical results from hair testing for drugs of abuse continues to be a complex and difficult problem since many questions still remain unanswered. In this paper an animal model was developed to ascertain the time course for the appearance and disappearance of cocaine and its metabolite benzoylecgonine (BE) in hair. Female Fauve Bourgogne red-haired rabbits (n = 6) were intraperitoneally administered a single dose of cocaine at 5 mg/kg. Animal hair was shaved just before drug administration and the newly grown back hair was subsequently shaved and collected daily over a period of two weeks. Samples were analyzed for cocaine and BE by gas chromatography-mass spectrometry (GC-MS). The profiles were quite similar for parent drug and metabolite. Cocaine and BE appeared in the first sampling (day 1), with peak concentration appearing that same day. 1.01 ng/mg and 0.51 ng/mg for cocaine and BE, respectively. Levels declined rapidly on day 2, remaining detectable for ten days after drug administration. This study demonstrates that the initial incorporation of cocaine compounds in rabbit hair is very rapid (24 h). A small fraction of the drug is detected ten days after exposure, at a time when concentrations in other biological specimens (blood or urine) are not detectable.     

Pantoprazole does not interact with the pharmacokinetics of carbamazepine

OBJECTIVE: Pantoprazole is a H+/K+-ATPase inhibitor with a minimized potential of interaction with the cytochrome P450 system. Imidazole derivatives such as cimetidine and omeprazole have been shown to markedly interact with carbamazepine, a major anticonvulsant with a narrow therapeutic range. Therefore, the influence of steady-state pantoprazole on the pharmacokinetics of carbamazepine was investigated. SUBJECTS AND METHODS: N = 20 healthy volunteers (12 male/8 female) completed a double-blind, placebo-controlled, randomized crossover study. During the test period they received 40 mg pantoprazole p.o. once daily for 11 days and concomitantly a single oral dose of 400 mg carbamazepine on day 5. In the reference period placebo was administered instead of pantoprazole. RESULTS: Serum concentrations of carbamazepine and its active metabolite carbamazepine-10,11-epoxide were measured until day 11. Geometric means of AUC (extent characteristic) and Cmax/AUC (rate characteristic) of carbamazepine were 292 and 287 mgxh/l, and 0.0150 and 0.0144 l/h (reference and test), respectively. Point estimates and 90% confidence intervals of the ratios were 0.98 (0.95, 1.01) for AUC, and 0.96 (0.92, 1.00) for Cmax/AUC, respectively. Since the 90% confidence intervals of the primary characteristics, AUC and Cmax/AUC were entirely within the predefined equivalence range of 0.80 - 1.25, lack of interaction of pantoprazole with the pharmacokinetics of carbamazepine was demonstrated. Equivalence was also demonstrated for carbamazepine-10,11-epoxide using the characteristics AUC and Cmax. CONCLUSION: No dose adjustment of carbamazepine is therefore required during concomitant treatment with pantoprazole.     

Longitudinal changes in maternal serum leptin concentrations, body composition, and resting metabolic rate in pregnancy

OBJECTIVE: We sought to evaluate the longitudinal changes in maternal serum leptin concentrations, body composition, and resting metabolic rate during pregnancy. STUDY DESIGN: Ten women were evaluated before pregnancy, in early pregnancy (12 to 14 weeks), and in late pregnancy (34 to 36 weeks). Leptin concentrations were measured by radioimmunoassay, body composition with hydrodensitometry with adjustment for total body water, and resting metabolic rate by use of indirect calorimetry. RESULTS: Using analysis of variance with repeated measures from pregravid to late pregnancy, a 66% increase (mean +/- SD) was found in leptin concentrations (in nanograms per milliliter) (before pregnancy, 25.4 +/- 19.9; in early pregnancy, 37.5 +/- 26.2; and in late pregnancy, 38.4 +/- 27.3, p = 0.003); a 9% increase in body fat (in kilograms) (before pregnancy, 29.4 +/- 15.7; in early pregnancy, 28.7 +/- 14.0; in late pregnancy, 31.4 +/- 14.6; p = 0.04); a 28% increase in oxygen consumption (in milliliters of oxygen per minute) (before pregnancy, 221.2 +/- 29.5; in early pregnancy, 230.4 +/- 42.9; in late pregnancy, 285.3 +/- 51.9; p < 0.0001); and a 9% increase in oxygen consumption (milliliters of oxygen per kilogram per minute) (before pregnancy, 3.02 +/- 0.43; in early pregnancy, 3.05 +/- 0.30; in late pregnancy, 3.31 +/- 0.37, p = 0.002) with advancing gestation. A significant positive correlation was present between leptin and body fat before pregnancy (r = 0.90, p < 0.0001), in early pregnancy (r = 0.91, p < 0.0001), and in late pregnancy (r = 0.87, p = 0.0005) and between leptin and oxygen consumption before pregnancy (r = 0.80, p = 0.004), in early pregnancy (r = 0.92, p < 0.0001), and in late pregnancy (r = 0.62, p = 0.06). When oxygen consumption was adjusted for maternal and fetal tissue mass, a significant negative correlation was found between leptin and oxygen consumption before pregnancy (r = -0.96, p < 0.0001), in early pregnancy (r = -0.80, p = 0.0034), and in late pregnancy (r = -0.70, p = 0.02). CONCLUSION: We conclude that leptin increases significantly during early pregnancy before any major changes in body fat and resting metabolic rate. These data suggest that pregnancy represents a leptin-resistant state.     

Lack of effect of cocaine on lysine and alanine uptake in human placental villi or transfer in perfused human placenta

The effect of cocaine on lysine and alanine uptake in human placental villi and transfer across the dually perfused placenta was studied. Uptake (in terms of the intracellular to extracellular distribution ratio) of alanine and lysine was 2.81 +/- 0.30 (n = 5) and 1.45 +/- 0.24 (n = 5) respectively and was unaffected by cocaine (50-500 ng mL(-1) in the incubation medium. In the dually perfused placenta, the clearance index (ratio of amino acid to antipyrine clearance) was 0.35 +/- 0.03 and 0.30 +/- 0.05 and the transfer index (ratio of amino acid to L-glucose clearance) was 2.20 +/- 0.07 and 1.89 +/- 0.29 for lysine and alanine respectively. Cocaine at concentrations of 100 ng mL(-1) or 250 ng mL(-1) had no effect on the clearance of either amino acid. The results of this study indicate that concentrations of cocaine likely to be encountered in vivo do not affect uptake of lysine or alanine by placental villi or transfer across the perfused placental lobule, in contrast with the report that cocaine reduces uptake of alanine by placental vesicles. Experimental models must be critically evaluated before accepting the results as pertinent to a clinical situation.     

Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin

BACKGROUND: Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions. METHODS: The effects of rifampin on the pharmacokinetics of tamoxifen (study I) and toremifene (study II) were examined in 2 randomized, placebo-controlled crossover studies. Ten (study I) or 9 (study II) healthy male volunteers took either 600 mg rifampin or placebo orally once a day for 5 days. On the sixth day, 80 mg tamoxifen or 120 mg toremifene was administered orally. Blood samples were collected up to 336 hours after drug administration. RESULTS: Rifampin reduced the area under the plasma concentration-time curve (AUC) of tamoxifen by 86% (P < .001), peak plasma concentration (Cmax) by 55% (P < .001), and elimination half-life (t1/2) by 44% (P < .001). The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin. During the rifampin phase, the AUC of N-demethyltamoxifen was 38% (P < .001) and the AUC of N-demethyltoremifene was 20% (P < .01) of that during the placebo phase. CONCLUSIONS: Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.     

Interaction of citrus juices with pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy subjects

OBJECTIVES: The study was conducted to investigate whether oral co-administration with citrus juices significantly affects the pharmacokinetics and/or pharmacodynamics of pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy male subjects. Grapefruit juice and orange juice, which were both commercially available, were used in this study. METHODS: Sixteen healthy male Japanese subjects participated in this study and were divided into two groups for grapefruit juice and orange juice treatment. The study followed an open-labelled crossover design, comparing the effects of a single oral dose of 2 mg pranidipine taken together with 250 ml citrus juice or 250 ml water. Serum pharmacokinetics of pranidipine, adverse reactions, blood pressure, heart rate, 12-lead ECG, haematology, clinical chemistry and urinalysis were measured throughout the study. RESULTS: For grapefruit juice, mean Cmax and AUC0-24 h were significantly higher than those of water (P=0.0003 and 0.0005, respectively, ANOVA) with the ratios of log transformed values being 1.50 and 1.74, respectively. There were no differences in tmax and t1/2 between the juice and water treatments. A significant increase in heart rate (P=0.0240, ANOVA with repeated measurements) was observed in the juice treatment whereas there were no significant differences in systolic and diastolic blood pressure between the two treatments. For orange juice, a small decrease in mean Cmax was observed compared with water (P=0.0218, ANOVA) with the ratio being 0.86, but there was no significant difference in AUC0-24h between the two treatments. No marked differences were observed in tmax and t1/2. Oral pranidipine administration with orange juice did not affect heart rate, systolic and diastolic blood pressures or other parameters for safety evaluation. CONCLUSIONS: Oral co-administration with grapefruit juice and pranidipine was associated with increased bioavailability and changed the pharmacodynamics of pranidipine, particularly with regard to heart rate. Orange juice intake with pranidipine did not markedly affect the pharmacokinetics and no clinically significant changes were observed in the pharmacodynamics and safety evaluation.     

Measurement of substrate oxidation in man

Human hair analysis is now recognized for evaluating someone exposure to xenobiotics: drugs of abuse, pharmaceuticals and polluants. This paper describes analytical methods than can be used by biologists. For drugs of abuse after decontamination, hydrolysis of hair, selective extraction and derivatization, determinations are performed by gas chromatography-mass spectrometry (GC/MS). Calibration uses deuterated standards. The cut-off value is 0.5 ng/mg for 6-monoacetylmorphine (heroin) and amphetamines and a benzoylecgonine/cocaine ratio > 0.05 for cocaine. Measurement of metabolites from endogenous metabolism sign the exposure (6-monoacetylmorphine and morphine for heroin, benzoylecgonine for cocaine, delta 9-tetrahydrocannabinol carboxylic by-product for cannabis). For drugs, after selective extraction, determinations are performed by GC/MS or liquid chromatography coupled to a diode array detector. Main applications concern drug monitoring to complement blood determinations or when blood collection is missing, as evidence of hidden, illicit or criminal drug exposure. Finally it is a powerfull tool for clinical diagnosis especially when late biological investigations are performed.     

Cocaine and metabolites in amniotic fluid may prolong fetal drug exposure

OBJECTIVE: Cocaine and metabolites can be found in the amniotic fluid after maternal use, presumably as a result of fetal urination. The fetus may be repeatedly exposed to the effects of these drugs through contact with amniotic fluid that contains these substances. The purpose of this study was to determine whether the naive fetal lamb generates detectable fetal blood levels of cocaine and metabolites when cocaine is placed directly into the amniotic fluid and, if so, whether fetal swallowing accounts for these findings. STUDY DESIGN: Six pregnant ewes with singleton fetuses of 120 to 125 days' gestation were chronically catheterized for daily sampling of cocaine and metabolite levels in maternal venous plasma, fetal venous plasma, and amniotic fluid over a 7-day period. Esophageal ligation was performed in three additional animals similarly instrumented to evaluate the role of fetal swallowing in the distribution of amniotic fluid cocaine and its metabolites. In each case, at the time of surgery, an Alzet osmotic pump delivering cocaine at 0.5 mg/kg estimated fetal weight per hour into the amniotic fluid was secured to the fetal back. Cocaine and metabolites (benzoylecgonine, ecgonine methyl ester, and norcocaine) were measured daily in material and fetal plasma, amniotic fluid, and meconium by solid-phase extraction and derivatization and quantified by high-performance gas chromatographic techniques. RESULTS: The concentrations of ecgonine methyl ester were highest in the amniotic fluid followed by cocaine and benzoylecgonine. In the normal and esophagus-ligated groups, cocaine, benzoylecgonine, and norcocaine were found in fetal plasma in concentrations of approximately 3% that of amniotic fluid. Ecgonine methyl ester was not detected in fetal plasma from either group. Meconium samples from sheep with and without esophageal ligation demonstrated high levels of norcocaine. CONCLUSION: We conclude that cocaine and metabolites in amniotic fluid enter the fetal circulation to produce detectable plasma levels through routes other than swallowing. Moreover, the results of meconium analyses in the two groups of fetuses suggest that fetal swallowing is not the primary mechanism by which cocaine and metabolites enter the intestine.