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Biomedical subjects

W M Watkins

Publications and source records attributed to W M Watkins.

179 records · Page 10Linked to original sources
PubMedDate not supplied

Pharmacokinetics of phenytoin following intravenous and intramuscular administration of fosphenytoin and phenytoin sodium in the rabbit.

The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration may not be feasible.

Animals↗
PubMedDate not supplied

A comparative study of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine and dapsone) as chemoprophylactics against malaria in Gambian children.

A comparison has been made of Lapudrine (chlorproguanil) and Maloprim (pyrimethamine +dapsone) as malaria chemoprophylactics when given every two weeks for 3 years to Gambian children under the age of 5 years. Both drugs produced falls in spleen and malaria parasite rates and an increase in packed cell volume. Maloprim, but not chlorproguanil, significantly reduced the incidence of episodes of fever accompanied by malaria parasitaemia. Children who received Maloprim, but not those who received chlorproguanil, grew better than children in the placebo group. This finding suggests that brief clinical episodes of malaria are more important in impairing growth than more prolonged periods of asymptomatic parasitaemia. No serious side-effect attributable to either drug was observed. After chemoprophylaxis had been given for 3 malaria transmission seasons the level of resistance of Plasmodium falciparum to pyrimethamine and to chlorproguanil was about 10%.

Animals↗
PubMedDate not supplied

Variability in the metabolism of proguanil to the active metabolite cycloguanil in healthy Kenyan adults.

Extensive metabolizers (EM) and poor metabolizers (PM) of the malaria chemoprophylactic drug proguanil have been identified by measuring the proguanil/cycloguanil ratio in urine following a single dose of the pro-drug. The pharmacokinetic characteristics of proguanil were similar in 8 EM and 8 PM subjects, but there were significant differences between the 2 groups with respect to cycloguanil pharmacokinetics. In none of the PM subjects could cycloguanil be detected in whole blood samples at any time after proguanil dosage. Plasma cycloguanil was measureable in only 2 of 8 PM subjects, despite an analytical sensitivity in the high-performance liquid chromatographic assay of 1 ng/ml cycloguanil. A comparatively high proportion of Black Kenyan adults appear to metabolize proguanil poorly, possibly because they lack the specific mixed function oxidase which will accept proguanil as substrate.

Adult↗
PubMedDate not supplied

Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life.

In an area of continuing transmission of Plasmodium falciparum on the Kenya coast, children treated with pyrimethamine-sulfadoxine experienced rapid parasite clearance, although a high proportion became reinfected within a short time. The frequency of pyrimethamine resistance in vitro in new infections was higher during the elimination phase of drug from a previous treatment. In infections which occurred at times when predicted residual drug concentrations were no longer inhibitory, incidence of pyrimethamine resistance was no different from the natural or background frequency. These results are discussed in terms of the selective pressure for resistance which is exerted by drugs with long elimination half-lives and a consideration of possible ways by which the problem might be addressed.

Animals↗
PubMedDate not supplied

A single dose of intramuscular sulfadoxine-pyrimethamine as an adjunct to quinine in the treatment of severe malaria: pharmacokinetics and efficacy.

It has been suggested that sulfadoxine-pyrimethamine (SD/PM) may be useful in the treatment of severe malaria since it could enhance the killing of parasites by quinine (QN) and it can be given as a single intramuscular injection. Eighty Kenyan children with severe malaria were allocated at random to receive either intramuscular QN alone (quinine dihydrochloride 20 mg salt/kg as a loading dose, followed by 10 mg salt/kg 12 hourly for a total of 6 doses) or the same QN regimen plus one intramuscular injection of SD/PM (sulfadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg). There was no difference in time to defervescence, aparasitaemia, or 50% reduction in parasitaemia, parasite elimination half-life, or mortality between the 2 groups. In addition, the concentrations of SD and PM were measured in 14 children and of QN in 8 of these children. Concentrations needed to achieve synergy against PM-resistant strains of Plasmodium falciparum were achieved in all of the children with severe malaria within the first hour and maintained for more than 72 h. SD/PM did not perturb the pharmacokinetics of QN.

Acute Disease↗
PubMedDate not supplied

Daily chlorproguanil is an effective alternative to daily proguanil in the prevention of Plasmodium falciparum malaria in Kenya.

To test the efficacy of chlorproguanil prophylaxis, 156 malaria-free schoolchildren in the coastal region of Kenya were allocated at random to receive either 7.5 mg chlorproguanil daily, 50 mg chlorproguanil weekly, 100 mg proguanil daily, or 100 mg calcium lactate weekly (placebo). The children were followed up daily for 169 d, by which time Plasmodium falciparum parasitaemia had occurred in 92% of the placebo group, 31% of the daily proguanil group, 38% of the daily chlorproguanil group and 55% of the weekly chlorproguanil group. There was significant reduction (P < 0.001) in the risk of parasitaemia in all the groups receiving chemoprophylaxis. Daily chlorproguanil and daily proguanil were equally effective, and significantly more effective than weekly high dose chlorproguanil. No significant toxicity was reported or observed. Thus daily chlorproguanil 20 mg/60 kg is a cheap and effective alternative to proguanil for chemoprophylaxis.

Child↗
PubMedDate not supplied

Towards optimal regimens of parenteral quinine for young African children with cerebral malaria: unbound quinine concentrations following a simple loading dose regimen.

Nine children with severe falciparum malaria were treated with an intravenous quinine regimen which did not require burettes or infusion pumps, to determine its practicability and to ensure that therapeutic drug concentrations were achieved and maintained throughout the dose interval. The regimen comprised quinine dihydrochloride (15 mg/kg; 12.5 mg/kg of the free base), which was added to a bag of intravenous fluid (after wastage of all but 100 mL), and given via standard giving sets over 2 h. Blood was drawn sequentially during the infusion, and for 12 h thereafter; plasma water was obtained by ultrafiltration of samples at the bedside, and quinine concentration was measured, in plasma and plasma water, by high performance liquid chromatography. Drug administration was practicable without burettes or infusion pumps; unbound drug concentrations exceeded the 99% inhibitory concentration for local parasites within 0.5 h, and remained within the therapeutic range for the entire dose interval. This loading dose regimen can now be recommended for young children in African hospitals; maintenance doses of 10 mg/kg should be given at 12 h intervals until oral antimalarial drugs are possible. These recommendations will need to be modified if susceptibility to quinine declines.

Child↗
PubMedDate not supplied

A malariometric survey in Turkana District, Kenya: chemosensitivity in vivo of Plasmodium falciparum infections and identity of the vector.

We have carried out a limited survey in vivo of the efficacy of chloroquine (n = 39) and pyrimethamine-sulfadoxine (n = 29) as treatments for falciparum malaria in Kaling, Turkana District, northern Kenya. Both treatments were effective, achieving clinical cure (> 75% reduction in parasitaemia on day 2 with clinical improvement, and negative blood slide on day 7) in both children and adults. A limited entomological survey suggested that the main malaria vector in this area was Anopheles arabiensis.

Adolescent↗
PubMedDate not supplied

The disposition of intramuscular artemether in children with cerebral malaria; a preliminary study.

The disposition of intramuscular artemether (AM) was studied in 26 Kenyan children with cerebral malaria. Antimalarial activity determined by bioassay was compared with total plasma AM plus dihydroartemisinin (DHA) determined by high power liquid chromatography (HPLC). Therapeutic levels were achieved in most subjects (21/26) within 1 h of receiving intramuscular AM (3.2 mg/kg), with close correlation between bioassay and HPLC measurements (r = 0.706). However, there was marked inter-individual variation, antimalarial activity was undetectable in 5 subjects ('non-absorbers'), and plasma concentrations were lower in subject with respiratory distress. The 50% parasite clearance time was significantly longer in non-absorbers (mean = 13.1 h, SD = 10.8 vs. mean = 7.8 h, SD = 5.5; P = 0.013). We conclude that the bioavailability of intramuscular AM in children with severe malaria may be highly variable, particularly in the presence of respiratory distress, and may be associated with an inadequate therapeutic response.

Antimalarials↗
PubMedDate not supplied

Unravelling the biochemical basis of blood group ABO and Lewis antigenic specificity.

The ABO blood-group polymorphism is still the most clinically important system in blood transfusion practice. The groups were discovered in 1900 and the genes at the ABO locus were cloned nearly a century later in 1990. To enable this goal to be reached intensive studies were carried out in the intervening years on the serology, genetics, inheritance and biochemistry of the antigens belonging to this system. This article describes biochemical genetic investigations on ABO and the related Lewis antigens starting from the time in the 1940s when serological and classical genetical studies had established the immunological basis and mode of inheritance of the antigens but practically nothing was known about their chemical structure. Essential steps were the definition of H as the product of a genetic system Hh independent of ABO, and the establishment of the precursor-product relationship of H to A and B antigens. Indirect methods gave first indications that the specificity of antigens resided in carbohydrate and revealed the immunodominant sugars in the antigenic structures. Subsequently chemical fragmentation procedures enabled the complete determinant structures to be established. Degradation experiments with glycosidases revealed how loss of one specificity by the removal of a single sugar unit exposed a new specificity and suggested that biosynthesis proceeded by a reversal of this process whereby the oligosaccharide structures were built up by the sequential addition of sugar units. Hence, the primary blood-group gene products were predicted to be glycosyltransferase enzymes that added the last sugar to complete the determinant structures. Identification of these enzymes gave new genetic markers and eventually purification of the blood-group A-gene encoded N-acetylgalactosaminyltransferase gave a probe for cloning the ABO locus. Blood-group ABO genotyping by DNA methods has now become a practical possibility.

ABO Blood-Group System↗