Central nervous system anomalies associated with meningomyelocele, hydrocephalus, and the Arnold-Chiari malformation: reappraisal of theories regarding the pathogenesis of posterior neural tube closure defects.

Complete gross and microscopic neuropathological examinations of 25 children who died with meningomyelocele, the Arnold-Chiari malformation, and hydrocephalus revealed a wide range and frequency of associated central nervous system malformations. The most remarkable of these anomalies were hypoplasia or aplasia of cranial nerve nuclei (20%), demonstrable obstruction of cerebrospinal fluid flow within the ventricular system (92%), cerebellar dysplasia (72%), a disorder of migration of cortical neurons (92%), fusion of the thalami (16%), agenesis of the corpus callosum (12%), and complete or partial agenesis of the olfactory tract and bulb (8%). The anomalies associated with posterior neural tube closure defects can no longer be considered secondary, but rather must be considered part of a spectrum of malformations caused by an unidentified primary insult to the central nervous system. The frequency and pattern of brain malformations associated with neural tube defects of some children with meningomyelocele suggest that such malformations may seriously affect intellectual outcome.

4'-Hydroxylated derivatives as urinary metabolites of two barbiturates.

4'-Hydroxybutobarbitone and 4'-hydroxypentobarbitone have been synthesized. These 4'-hydroxy derivatives have been quantified in the urine of volunteers following single doses of butobarbitone, and single and multiple doses of pentobarbitone. The corresponding aldehydes have also been synthesized, and shown to be excreted in minor quantities. The excretion of an ingested dose of 4'-hydroxybutobarbitone, and its oxidation products, has also been followed over 24 h.

Multidose studies in the human metabolism of pentobarbitone.

The metabolism of pentobarbitone has been investigated in two healthy volunteers, and the urinary excretion of unchanged drug, and the products of omega- and (omega-1)-oxidation, quantified for four days after each of three doses to each volunteer. The rates of excretion are discussed in terms which include enzyme induction effects.

A multi-dose study on the human metabolism of amylobarbitone.

1. The metabolism of amylobarbitone has been investigated in two healthy male volunteers, and the urinary excretion of unchanged drug, and the products of omega and omega-1 oxidation, quantitatively determined for four days after each of three doses to each volunteer. 2. In contrast to observations with butobarbitone, amylobarbitone was shown to have little effect on the rate of its own metabolism. 3. The t 1/2 for urinary excretion of the parent drug was 16.3 h while that for the two metabolites was 22.2 h.

Control of the composition of gentamicin sulphate by proton magnetic resonance spectrometry.

The proportions of the main components present in gentamicin sulphate complex, gentamicins C1, C1a and C2, can be monitored by 1H nuclear magnetic resonance (nmr) spectrometry. The method depends on measurement of the peak heights of signals for N-methyl and C-methyl groups present in all three components and of those present in C1 and C2 only, followed by calculation of peak height ratios to control composition within acceptable limits. The precision and reproducibility of the method have been established through two collaborative studies each involving seven laboratories. In the second study, with an improved procedure, the mean variance between laboratories with 10 samples was 3.4 X 10(-4) for the N-methyl ratio of the peak at delta 2.75 to that at delta 2.95, and 1.25 X 10(-3) for the C-methyl ratio of the peak at delta 1.25 to that at delta 1.35. Within laboratories the mean variance for triplicate determinations was 7.4 X 10(-5) and 8.9 X 10(-5) respectively. The data presented here form the experimental basis for the test controlling the composition of gentamicin sulphate in the British Pharmacopoeia 1973: Addendum 1975, and for the introduction into the British Pharmacopoeia of nmr spectrometry as an analytical technique. The reference standards and all batches of gentamicin sulphate intended for therapeutic use in the United Kingdom examined by this procedure comply with the limits laid down.

The synthesis and urinary estimation of N-hydroxyaprobarbitone.

N-Hydroxyaprobarbitone (I) has been synthesized by oxidation of aprobarbitone, characterized, and a method developed for its estimation in urine. It has shown to be no more than a minor metabolite (less than 4%) in the human metabolism of aprobarbitone.

A study of the human metabolism of secbutobarbitone.

The urinary excretion of secbutobarbitone (I) and its metabolites has been studied quantitatively using combined gas chromatography-mass spectrometry. After a single oral dose was given to healthy male volunteers, unchanged drug (5-9%), 2'-hydroxysecbutobarbitone (II, 1.7-3.2%), 2'-oxosecbutobarbitone (III, less than 1%), and the carboxylic acid (IV, 24-34%) were found. The kinetics of the excretion process were studied.

Metabolism of quinalbarbitone.

The human metabolism of (+/-)-5-allyl-5-(1'-methylbutyl) barbituric acid (I), quinalbarbitone, taken orally, has been studied. Comparison of g.c. and g.c.-m.s. data from derivatized extracts of urine with similar data from synthetic samples confirmed the presence of the two diastereoisomeric forms of 5-allyl-5-(3'hydroxy-1'-methylbutyl)barbituric acid (II), 5-allyl-5-(3'-oxo-1'-methylbutyl)barbituric acid (III), 5-allyl-5-(1'-methyl-3'-carboxypropyl)barbituric acid (IV), and 5-(2',3'-dihydroxypropyl)-5-(1'-methylbutyl)barbituric acid (V) in the urine. There was no evidence for the urinary excretion of unchanged drug. The rate of excretion of these metabolites has been examined in some detail, and rate-limited kinetics shown to apply for excretion of the acid (IV) and the diol (V).