Ivan Havlik

Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum

The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.

Longitudinal Changes in Pituitary-Adrenal Hormones in South African Women With Burnout

The author’ goal was to document baseline pituitaryadrenal hormonal and related metabolic variables in 16 female patients with burnout. Then, following stress management intervention, to compare the changes with an equal number of untreated control subjects. At monthly intervals for 4 mo, 24-h urine samples were obtained for determination of free cortisol excretion. In addition, fasting blood samples were analyzed for levels of cortisol, dehydroepiandrosterone sulfate (DHEAS), ACTH, aldosterone, and catecholamines. Other biochemical measurements included growth hormone, prolactin, insulin, glucose, and lipid components. The Maslach Burnout Inventory, General Health Questionnaire-28, and Zung depression rating scale were completed on each consecutive visit. The most striking finding was the reduction of urine free-cortisol excretion in the patients compared with controls. Initial urinary free cortisol was significantly lower in the patients (mean ± SEM=47.2 ± 11.0 vs 79.0 ± 6.8 nmol/L, P=0.02) and remained significantly reduced at 4 mo (mean ± SEM=44.0 ± 6.1 vs 91.1 ± 8.8 nmol/L, p=0.0001). There were no significant changes in the other hormonal and biochemical data. We conclude that there is functional hypocortisolism in burnout, which is not immediately restored on stress management intervention despite clinical and psychological improvement.

Comparison of the Pharmacokinetic Profiles of Soluble Aspirin and Solid Paracetamol Tablets in Fed and Fasted Volunteers

The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.

Plasmodium falciparum: effects of amantadine, an antiviral, on chloroquine-resistant and -sensitive parasites in vitro and its influence on chloroquine activity

The lysosomotropic nature of amantadine suggested potential as an antimalarial. Sensitivity tests to amantadine hydrochloride alone and in combination with chloroquine were carried out in 96-well microtitre plates using the tritiated hypoxanthine uptake method to measure parasite growth. Amantadine alone has antimalarial activity. Amantadine is more potent against chloroquine-resistant strains. Combinations of amantadine and chloroquine result in slight synergy in both resistant and sensitive strains.

Endogenous heparin levels in the controlled asthmatic patient

BACKGROUND Since heparin possesses anti-inflammatory properties, it is hypothesised that asthmatic patients have decreased levels of circulating heparin compared with healthy individuals. DESIGN We compared endogenous heparin levels in controlled asthmatic patients (53 adults) from the Asthma Clinic at Johannesburg General Hospital with those of healthy controls (26 adults) from the general population. Heparin levels in the blood samples were tested using the Chromogenix Coatest Heparin kit. RESULT The blood of the patients contained significantly lower levels of endogenous heparin compared with that of the healthy individuals, indicating that the anti-inflammatory properties afforded by heparin are absent in these patients.

In vitro drug interaction between amantadine and classical antimalarial drugs in Plasmodium falciparum infections

The interactions of amantadine with classical antimalarial drugs were evaluated against a chloriquine-resistant and a chloroquine-sensitive strain of Plasmodium falciparum in vitro. Amantadine potentiated the effect of chloroquine and quinine in both strains; it also potentiated the effect of mefloquine, halofantrine and primaquine in the chloroquine-resistant strain but had no effect in the chloroquine-sensitive strain. Amantadine had no effect on the response to pyrimethamine of either strain. Amantadine does not interfere with the activity of these compounds and may possibly enhance it.

Addition of clonidine and fentanyl to epidural blockade with 0.5% bupivacaine

To the Editor: Clonidine, an alpha2 agonist produces variable analgesia when given epidurally 1.2 but without respiratory depression. 2,3 Synergy between epidural opioids and clonidine in producing analgesia has also been reported. 2 In a double-blinded, randomised study, 26 patients undergoing major gynaecological surgery received lumbar epidural block with 17 ml 0.5% plain bupivacaine. In addition, to evaluate the extent of the synergy, they received epidurally: Group I Group 2 saline 0.9% 2 ml clonidine 150 Isg made up to 2 ml with 0.9% saline Group 3 fentanyl 100 Ixg (2 ml) or Group 4 clonidine 75 ~tg plus fentanyl 50 ~tg made up to 2 ml with 0.9% saline No patient had received any analgesia for at least 24 hr before surgery. All were premeditated with diazepam 10 m g p o two hours before surgery. In no group was analgesia sufficient for surgery produced. Most patients required general anaesthesia. The duration of analgesia (min) from completion of the epidural block until patients required further analgesia in the four groups is shown in the Table.