BackgroundEvidence is conflicting regarding the relationship between low maternal alcohol consumption and birth outcomes. This paper aimed to investigate the association between alcohol intake before and during pregnancy with birth weight and gestational age and to examine the effect of timing of exposure.MethodsA prospective cohort in Leeds, UK, of 1303 pregnant women aged 18–45 years. Questionnaires assessed alcohol consumption before pregnancy and for the three trimesters separately. Categories of alcohol consumption were divided into ≤2 units/week and >2 units/week with a non-drinking category as referent. This was related to size at birth and preterm delivery, adjusting for confounders including salivary cotinine as a biomarker of smoking status.ResultsNearly two-thirds of women before pregnancy and over half in the first trimester reported alcohol intakes above the Department of Health (UK) guidelines of ≤2 units/week. Associations with birth outcomes were strongest for intakes >2 units/week before pregnancy and in trimesters 1 and 2 compared to non-drinkers. Even women adhering to the guidelines in the first trimester were at significantly higher risk of having babies with lower birth weight, lower birth centile and preterm birth compared to non-drinkers, after adjusting for confounders (p<0.05).ConclusionsWe found the first trimester to be the period most sensitive to the effect of alcohol on the developing fetus. Women adhering to guidelines in this period were still at increased risk of adverse birth outcomes. Our findings suggest that women should be advised to abstain from alcohol when planning to conceive and throughout pregnancy.

This animal model demonstrates that an increase in lysosomal turnover and hence urine NAG activity, occurs when increased protein is presented to the tubular cells. Urine NAG activity is thus a measure of altered function in the renal tubules and not simply an indicator of damage.

Aims Although methadone is widely used to treat opiate dependence, guidelines for its dosage are poorly defined. There is increasing evidence to suggest that a strategy based on plasma drug monitoring may be useful to detect non-compliance. Therefore, we have developed a population-based pharmacokinetic (POP-PK) model that characterises adaptive changes in methadone kinetics. Methods Sparse plasma rac-methadone concentrations measured in 35 opiate-users were assessed using the P-Pharm software. The final structural model comprised a biexponential function with first-order input and allowance for time-dependent change in both clearance (CL) and initial volume of distribution ( V ). Values of these parameters were allowed to increase or decrease exponentially to an asymptotic value. Results Increase in individual values of CL and increase or decrease in individual values of V with time was observed in applying the model to the experimental data. Conclusions A time-dependent increase in the clearance of methadone is consistent with auto-induction of CYP3A4, the enzyme responsible for much of the metabolism of the drug. The changes in V with time might reflect both up-and downregulation of a 1 -acid glycoprotein, the major plasma binding site for methadone. By accounting for adaptive kinetic changes, the POP-PK model provides an improved basis for forecasting plasma methadone concentrations to predict and adjust dosage of the drug and to monitor compliance in opiate-users on maintenance treatment.

Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac‐methadone were given to 13 drug‐naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P‐Pharm software. Results Comparison of kinetic models incorporating mono‐ or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h−1 (5.3±1.2 s.d. l h−1 using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h−1, P<0.001); 95% CI for the difference=−3 to −6 l h−1 and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half‐life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half‐life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

General Practitioners and hospital doctors should recognise the significant benefits of prescribing methadone for heroin-dependent women during pregnancy. We recommend that if a pregnant opioid user complains of methadone withdrawal symptoms (i.e. that the methadone dose does not "hold" them) the prescribing clinician takes this observation seriously and considers a more detailed assessment. Further work on key factors undergoing changes during pregnancy accounting for differences in methadone metabolism in the mother, fetus and neonate are required.

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Caffeine is a commonly consumed drug during pregnancy with the potential to affect the developing fetus. Findings from previous studies have shown inconsistent results. We recruited a cohort of 2643 pregnant women, aged 18-45 years, attending two UK maternity units between 8-12 weeks gestation from September 2003 to June 2006. We used a validated tool to assess caffeine intake at different stages of pregnancy and related this to late miscarriage and stillbirth, adjusting for confounders, including salivary cotinine as a biomarker of smoking status. There was a strong association between caffeine intake in the first trimester and subsequent late miscarriage and stillbirth, adjusting for confounders. Women whose pregnancies resulted in late miscarriage or stillbirth had higher caffeine intakes (geometric mean = 145 mg/day; 95% CI: 85 to 249) than those with live births (103 mg/day; 95% CI: 98 to 108). Compared to those consuming <100 mg/day, odds ratios increased to 2.2 (95% CI: 0.7 to 7.1) for 100-199 mg/day, 1.7 (0.4 to 7.1) for 200-299 mg/day, and 5.1 (1.6 to 16.4) for 300+ mg/day (P trend =0.004). Greater caffeine intake is associated with increases in late miscarriage and stillbirth. Despite remaining uncertainty in the strength of association, our study strengthens the observational evidence base on which current guidance is founded.

Objective-To examine the composition of illicitly manufactured "ecstasy" tablets sold on the UK drugs market. Methods-Analysis by gas chromatography of 25 jl) were analysed by gas chromatography with flame ionisation detection. Samples were injected onto a silated glass (1.5 m x 4 mm internal diameter) column packed with 2% potassium hydroxide and 10% Apiezon L on Chromosorb-w-(AW) 100-120 mesh. Nitrogen at a flow rate of 60 ml/min was the carrier gas; hydrogen flow was at 1.0 kg/cm2 and air flow 1.2 kg/cm2. Analysis for the presence of amphetamine, methylamphetamine, methyldioxyamphetamine (MDA), MDMA, methyldioxyethamphetamine (MDEA), and a range of other drugs took place over a temperature gradient held at 1 55°C for 10 min followed by an increase of 8°C/min to a final temperature of 195°C. Temperatures of the injection and detector ports were 200°C and 190°C respec-tively. Extracts of tablets and quality control samples were measured against known concentrations of standards (10 gg/ml) and the detector recalibrated after every 10th sample. Paracetamol and caffeine were assayed by enzyme colorimetric assay and ketamine by using an in-house gas chromatography-mass spectrometry procedure. ResultsEach of the ecstasy samples in the present study was in tablet form, except for one, rhubarb and custard, which was a red and yellow capsule containing powder. Weights and dimensions of the tablets varied (see table 1). Of the 25 tablets handed in, doves (small white tablets embossed with a dove shape on one side) were the most common (n=7) and all contained MDMA (range 19-140 mg). One of these dove tablets also contained traces of caffeine. A further five tablets (love heart, MDMA tablet, New Yorker, purple heart, and the rhubarb and custard capsule) also contained doses of MDMA (range 2-105 mg). One of these five tablets (purple heart) contained traces of caffeine and another (MDMA tablet) contained 39 mg of caffeine. The only capsule, 194 on 7 June 2019 by guest. Protected by copyright.