Biomedical subjects

W L Gent

Publications and source records attributed to W L Gent.

At least 19 recordsLinked to original sources

PubMed1992

Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients.

An HPLC method is described for measurement of plasma hydrazine (Hz) concentrations (CHz) at the same time as isoniazid (INH) levels (CINH). Study has been made of CHz during 2-5 after dose in healthy adults (A, n = 34), in adult pulmonary TB patients (B, n = 18) and in paediatric tuberculous meningitis patients (C, n = 25). Although the population has about equal proportions of 'slow' (52%) and 'fast' acetylators, in none of the groups could a correlation be shown between CHz levels or rates of Hz accumulation and any measure of acetylator type. Consequently Hz must be derived both from INH and from its metabolites during the first hours post-dose. For group A and ca. 70% of groups B and C a constant and maximal fraction of dose (ca. 0.6% for adults and 0.4% for paediatric patients) appeared as Hz at 4-5 h. For group B patients small pre-dose concentrations increased with duration of treatment. Four patients in group B showed the highest levels of CHz and rates of Hz accumulation some three times greater than the rest; all four had been identified as alcoholics and one showed evidence of hepatotoxicity at CHz (5 h) = 1.3% of dose. Amongst group C (9/25) episodes of high CHz greater than 0.5% of dose occurred during the first weeks of treatment and one developed CHz ca. 100 ng/ml = 1.3% of dose coincidentally with indications of hepatic damage.

Acetylation↗

PubMed1992

Cerebrospinal fluid isoniazid concentrations in children with tuberculous meningitis: the influence of dosage and acetylation status.

Cerebrospinal fluid (CSF) and plasma isoniazid (INH) concentrations were determined on 96 occasions in 38 children (median age 1.5 years) with tuberculous meningitis, and the effects of INH elimination status and test dosages of 10 mg/kg body weight and 20 mg/kg body weight was studied. Maximum cerebrospinal fluid INH concentrations were reached during the period 2 to 4 hours after dosing and cerebrospinal fluid and plasma INH concentrations did not differ significantly during this period. Cerebrospinal fluid INH concentrations following a dosage of 10 mg/kg (4.6 +/- 2.4 micrograms/mL) were, however, significantly lower than those following a dosage of 20 mg/kg (11.6 +/- 2.7 micrograms/mL). Cerebrospinal fluid INH concentrations in faster acetylators at a dosage of 10 mg/kg (3.2 +/- 1.1 micrograms/mL) were significantly lower than in slower acetylators (7.7 +/- 1.3 micrograms/mL), as was the case with a dosage of 20 mg/kg, where faster acetylators had cerebrospinal fluid INH concentrations of 10.5 +/- 2.5 micrograms/mL compared with 14.1 +/- 1.4 microgram/mL in slower acetylators. Following dosages of both 10 mg/kg and 20 mg/kg, INH concentrations in excess of the minimal inhibitory concentration for Mycobacterium tuberculosis persisted in the CSF 12 to 14 hours later. Despite the patients' being young and frequently malnourished, suffering from advanced forms of tuberculous meningitis, and receiving high dosages of INH, rifampicin, and pyrazinamide, none developed any clinical signs of hepatotoxicity and in only one child did the serum bilirubin level rise to 19 micrograms/mL.

Acetylation↗

PubMed1989

Experimental values of the ionization constants for L-3,5-di-iodotyrosine and a model for ionic interactions of thyroid hormone (T3) and its nuclear receptor.

Ionization characteristics of L-3,5-di-iodotyrosine have been measured under various conditions. These data, which correct an erroneous report of pK3 in the literature, have been used to estimate the ionization constants of the thyroid hormone L-3',3,5-tri-iodothyronine (T3). On this basis a reinterpretation has been made of the pH-dependent binding of the hormone to its solubilized rat liver nuclear receptor (Wilson BD and Gent WL, Biochem J 232: 663-667, 1985). The interaction may depend on the ionization of the phenolic group of T3 and an acidic group (pK'7.6) in the receptor site, leading to the formation of a hydrogen bond between the two groups. The changes of the number of binding sites with pH must then result independently from alterations in the conformation of the receptor protein.

Diiodothyronines↗

PubMed1985

Effects of pH and ionic strength on the binding of L-tri-iodothyronine to the solubilized nuclear receptor.

K'A (apparent association constant) and Bmax. (total receptor concentration) describing the interaction of tri-iodothyronine (T3) and its solubilized rat liver nuclear receptor (R) are found to be moderately consistent in successive preparations, but both quantities diminished after a few days. To achieve comparability in the effects of ionic strength (I) and of pH on K'A and Bmax, appropriate measurements have been made simultaneously on single preparations. K'A and Bmax. were found to be effectively unchanged over the range I0.05-0.60. Both parameters have been measured over the range pH 6.4-9.0 and the values of K'A analysed in terms of the 4'-OH ionization of T3 and that of a cationic acidic group, shown to require pK' = 7.6. This group could be identified either with the terminal alpha-NH3+ of T3 or with a group (RH+) in the receptor site. On the balance of evidence the first possibility is the more likely, in which case the variation of Bmax. with pH is ascribed to conformational changes in the receptor protein.

Animals↗

PubMed1984

The binding of thyroid hormone receptors to DNA.

The behaviour of tri-iodothyronine (T3)- and thyroxine (T4)-receptor complexes when bound to native DNA-cellulose is reported. Equal and large proportions of both T3- and T4-receptor complexes bind to DNA but although T3-receptor complexes are 99% recoverable by 0.5 M NaCl buffer elution, only 60-70% of the T4-receptor complexes are regained. The balance appears as free T4, apparently released as the T4-receptor complexes bind to the DNA whilst the corresponding receptor remains bound. This effect is independent of T4-receptor complex/DNA ratio up to ca. 4 fmol/micrograms DNA, of the presence of an equal amount of unoccupied receptor and of an eight-fold concentration range of both T4-receptor complex and DNA at a fixed ratio, in the cellulose matrix. Pre-formed receptor-DNA material, likewise, only accepts some 60% of the expected quantity of T4 whereas the capacity for T3 appears to be similar to that of free receptors.

Animals↗

PubMed1973