Samuel B. Lucas

The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs

The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until 6 years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (VPA) (6/50, 12.0%; aOR 6.05, 95%CI 1.65 to 24.53, p=0.007) and in those exposed to polytherapy with sodium VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005) compared with control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium VPA exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium VPA is a treatment option.

Comparison of a genetic algorithm neural network with logistic regression for predicting outcome after surgery for patients with nonsmall cell lung carcinoma

Neural networks have been used to predict outcome in cancer patients. Their accuracy compared with standard statistical methods has not been fully assessed.

Clinical pharmacology of oral and intravenous 4-demethoxydaunorubicin

SummaryThe clinical pharmacology of 4-demethoxydaunorubicin (4-DMDNR) was studied in 28 patients with advanced breast cancer, using a sensitive reverse-phase HPLC technique. All patients had normal renal and hepatic function. The serum levels of 4-DMDNR after a single i.v. bolus injection followed a triple exponential decay curve (T1/2α=9.6 min, T1/2β=3.2 h and T1/2γ=34.7 h) and conformed to a three-compartment model. Comparison of the area under the curve (AUC) and urinary excretion for the oral and i.v routes suggests an oral bioavailability of approximately 24%. In patients treated with a schedule of weekly oral administration for periods of up to 12 months there was no significant alteration in either AUC or elimination half-life for the parent drug or its principal metabolite 13-OH4DMDNR. Moreover, there was no evidence of accumulation of the metabolite although measurable amounts were present 7 days after administration of 4-DMDNR.

The pharmacokinetics of 7-hydroxymethotrexate following medium- dose methotrexate therapy

SummaryAn unambiguous and specific HPLC assay was used to determine the pharmacokinetics of 7-hydroxymethotrexate (7-OHMTX) following the administration of moderate-dose methotrexate (MTX) 100 mg·m-2 to 37 patients with advanced head and neck cancer. There was marked interpatient variation but patient exposure to 7-OHMTX was considerable. There was, however, no correlation between the amount of 7-OHMTX produced and either tumour response or patient toxicity.

Pharmacokinetics of high-dose cyclophosphamide in patients with metastatic bronchogenic carcinoma

SummaryCyclophosphamide (CP) was administered to eight patients with metastatic bronchial carcinoma in escalating doses of 1.5, 2.5, and 3.5 g/m2 at intervals of 3 weeks. The proportion of the administered dose converted into alkylating metabolites was similar for each dose and there was no evidence to suggest that the enzyme system responsible for activating CP was saturated even with the highest dose. Considerable between-patient variation in drug metabolism was observed, but within each patient the fraction metabolised remained constant.

Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer.

SummaryRecombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC∞ with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.

Adjustment of Carbamazepine Dose to Offset the Effects of the Interaction with Remacemide Hydrochloride in a Double‐Blind, Multicentre, Add‐On Drug Trial (CR2237) in Refractory Epilepsy

Summary: Purpose: The efficacy of remacemide hydrochloride (REM) as an antiepileptic drug (AED) was tested in a double‐blind, add‐on trial in patients with refractory epilepsy. Concurrent drugs included carbamazepine (CBZ). The interfering effects of the pharmacokinetic interaction between REM and CBZ were offset by the monitoring of plasma CBZ concentration and the appropriate reduction of CBZ dose by an unblinded observer.

Measurement of effective HCl diffusion coefficients through aqueous and gel films by a pH jump technique

Direct measurement of HCl diffusion coefficients in low ionic strength media have not been reported owing to the practical difficulty of controlling pH gradients in two compartments of a diffusion chamber with minimal or no inclusion of buffer. Here we report a single-compartment system in which effective HCl diffusion to a membrane-mounted glass pH electrode can be measured under conditions approaching neutrality. A strong pH-dependent response of the membrane- or gel-mounted pH electrode was observed. Comparison of effective DHCl values in the presence of a mounted gel and/or membrane showed a clear decrease to that of a liquid film over the pH range studied (3.5–9.5). However, the study also demonstrated effective DHCl values to be strongly pH dependent with a minimum around neutrality.

Genetic Evolution of Neural Network Architectures

Feed forward back-propagation artificial neural networks (ANNs) have been used to predict outcomes in a variety of biomedical settings [1],[2]. Their advantages and disadvantages compared with standard statistical methods (SSMs) relate to different appraisals of three major problems that are common to all methods for estimation: (1) agreement, (2) stability and (3) transparency. In this chapter we consider these problems and propose a method which addresses some of them using procedures called genetic algorithms. Our arguments are illustrated by comparing the performance of the various prediction methods in predicting the occurrence of depression after mania [3].