Browsing by Author "Du Preez, Marie J."

Now showing 1 - 2 of 2

An investigation into the effects and possible mechanisms of action of cimetidine and ranitidine on the sexual behaviour of male rats.
(1985) Badri, Roopram.; Du Preez, A. L.; Du Preez, Marie J.
The development of a new class of antihistamines, the H2-receptor antagonists, introduced a new era in the treatment of peptic ulcer diseases. Cimetidine, the first clinically effective H2-blocker, was introduced in 1976. Recently ranitidine, a second member approved for clinical use, has been found to be as effective as cimetidine in the management of peptic ulcer diseases. Soon after the introduction of cimetidine several reports of loss of libido, impotence and gynaecomastia were described in male patients who were on normal or high therapeutic doses of cimetidine. A few unsubstantiated reports of loss of libido and gynaecomastia attributed to ranitidine therapy have also appeared in literature. This study was undertaken to examine in detail the effects of acute and subchronic treatment with cimetidine and ranitidine on mating behaviour in sexually active male rats. Motor activity counts were recorded immediately before sexual behaviour observations. The animals were tested on every third day and observations were terminated after the first intromission of the next series of copulations. In the single dose study, mating behaviour tests were commenced 2 hours after treatment; mating tests during the subchronic dose studies were done 4 to 7 hours after the 6hOO dose. The following measures were used in the analysis of data: mount latency, intromission latency, mount frequency, intromission frequency, ejaculation latency, and the postejaculatory intromission latency. At the termination of the subchronic dose studies blood samples were collected by cardiac puncture and the animals were subsequently autopsied. Cauda epididymal sperm counts and motility were determined, testes and accessory sex organs were weighed, and one testis was processed for histological examination. Cimetidine in the low dose, 128.6 mg/kg, significantly shortened the ejaculatory latency and to a lesser extent the postejaculatory intromission latency. At the higher dose, 257.1 mg/kg, cimetidine markedly prolonged the postejaculatory intromission latency and to a lesser extent increased the ejaculation latency. The inhibitory effect of cimetidine on copulatory behaviour at the higher dose level was accompanied by significant depression in motor activity. At the conclusion of the subchronic dose studies marked reductions in serum testosterone levels and decreased testes and accessory organ weights were observed in the cimetidine group. No significant changes in sperm counts were observed, although the sperm counts in the cimetidine group were lower than the control values. Histological examination of testes showed apparently normal spermatogenesis in all three treatment groups. However, in spite of the reduced testosterone levels and decreased testes and accessory sex organ weights in the cimetidine group, no impairment in mating behaviour was observed. In both the acute and the subchronic dose studies, similar to placebo, treatment with ranitidine showed no effect on mating behaviour. On final analysis of the results it is concluded that cimetidine, and not ranitidine, disrupts sexual behaviour in male rats. Furthermore, it is concluded that the effect of cimetidine on sexual behaviour is not related to H2-receptor blockade as equipotent doses of ranitidine did not produce similar effects. The mechanism of cimetidine-induced impairment of sexual performance in the male rat may possibly be attributed to some non-specific, direct or indirect action of cimetidine on some neurotransmitter system responsible for the control of sexual behaviour. It is further suggested that the effect may possibly be mediated by a blockade of central dopamine receptors. However, it must be stressed that further experimentation is necessary to elucidate the mechanism of action of cimetidine on sexual behaviour.
The pharmacokinetics/pharmacodynamics of theophylline in premature neonates during the first few days after birth.
(2000) Du Preez, Marie J.; Botha, Julia Hilary.; McFadyen, Margaret Lynn.
Theophylline is one of the few preparations available for the treatment of apnoea of prematurity. Currently little data is available on the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationships of theophylline for premature neonates during the first few days of life, a time when neonates undergo profound physiological changes and when the drug is most often used. Furthermore, the influence of theophylline on hypoxaemic episodes has not yet been quantified. The study aimed to investigate optimal theophylline dosing in this group by establishing pharmacokinetic parameters, assessing the effectiveness of the drug in abolishing apnoea and hypoxaemic episodes and investigating the concentration/effect relationship. The project was conducted in the neonatal wards of King Edward VIII Hospital, Durban, South Africa. The study group comprised a total of 105 Black, apnoeic, premature neonates, with respiratory distress syndrome, who were receiving intravenous theophylline. Serum samples (263), collected from patients during routine care, were analysed for theophylline. Forty-six patients were monitored before and after theophylline therapy with a neonatal capnograph linked to a data acquisition. Apnoea incidents were classified into total (all apnoea <_5 seconds) and pathologic (all apnoea >_20 seconds) and a hypoxaemic episode was defined as a >_10% fall for >10 seconds in peripheral oxygen saturation. Within each of these groups patients were assessed as responders (>_50% reduction in the clinical effect from baseline to the last recording) and non-responders. Patient characteristics were identified as possible markers of non-response to theophylline therapy. The Nonlinear Mixed Effects Model (NONMEM) was used to derive population pharmacokinetic models and parameters for theophylline as well as to assess the concentration-effect relationship. The pharmacokinetic analysis estimated a low clearance and volume of distribution, with oxygen support enhancing clearance. Relatively high inter-individual and residual variability values were obtained prompting testing for inter-occasion variability. This resulted in a decrease of inter-individual variability for clearance and volume of distribution as well as in residual variability. In the theophylline doses used, a significant reduction in total and pathologic apnoea but not in hypoxaemic episodes occurred over the first three days after birth. The most positive improvement was seen on the first day of treatment after the loading dose. A statistically significant increase in the average pulse rate and a decrease in episodes of bradycardia from baseline to all three days of monitoring were recorded. Most patients responded at serum theophylline concentrations of 3 to 9 mg/L. Most serum theophylline concentration measurements were also in this range and it was not possible to clearly define a concentration-effect relationship. The cumulative percentage of non-responders was relatively high for total apnoea (48%) and hypoxaemic episodes (45%), but low for pathological apnoea (13%). Being one of a set of twins was identified as a marker of poor response for both total apnoea and hypoxaemic episodes. Other possible markers for poor response, in terms of total hypoxaemic episodes, were being born by caesarean section and having more than the 75th percentile pathologic apnoea per hour at baseline. It was interesting to note that, with regard to total apnoea, there were some features that seemed to predict a favourable response to theophylline. These were birth weight and 5 minute Apgar score below the 25th percentile, and patients with baseline total apnoea counts above the 75th percentile. The cumulative graphs of the responders and non-responders resembled the fixed effect model, which is the simplest model to explain drug-effect relationships. More sophisticated analysis of the concentration-effect relationship, using NONMEM and the count model proved difficult. None of the models tested were found to be satisfactory, but that which included the influence of a hypothetical respiratory depressant factor gave the most realistic value of EC50. It is suggested that further even more complex modelling may be required to accurately define the concentration-effect relationship (and hence the therapeutic range) for theophylline in neonatal apnoea.