Browsing by Author "Van Jaarsveld, P. P."

Now showing 1 - 5 of 5
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    Endogenous immunoreactive digitalis-like substance in neonatal serum and placental extracts
    (Health & Medical Publishing Group, 1984) Beyers, A. D.; Spruyt, L. L.; Seifart, H. I.; Kriegler, A.; Parkin, D. P.; Van Jaarsveld, P. P.
    Therapeutic levels of digoxin in the serum of untreated neonates delivered to mothers who had not received the drug prenatally were detected by radio-immunoassay. Digoxin levels in neonates should be interpreted with care because of the unknown contribution by the endogenous digitalis-like substance (DLS) to the level of the drug. Three commercially available radio-immunoassay kits were compared with regard to their sensitivity and reproducibility in detecting the endogenous DLS. The kit from Clinical Assays (Cambridge, Mass., USA) was selected for further investigations. In a series of 35 paired samples of maternal and cord blood the average DLS values in terms of digoxin were 0.52 ± 0.07 and 0.81 ± 0.27 ng/ml respectively. This difference is statistically highly significant. In the case of infants with DLS values of 1-1.5 ng/ml in terms of digoxin, approximately 1 week was required to reach non-therapeutic digoxin levels, i.e. below 0.5 ng/ml. Gel chromatography showed that the DLS in neonatal serum was more closely associated with protein than is authentic digoxin. In placental extracts it followed the elution profile of the protein completely, but it shifted to fractions with a lower molecular weight than haemoglobin after trypsinization. The level of DLS in neonatal serum was also increased by more than half its original value by trypsinization. Proteolysis therefore seems to have a releasing effect on DLS. The molecular size of this substance is probably in the same range as that of polypeptides, since it was not dialysable from trypsinized and untreated samples through a membrane with a 22,000 dalton molecular weight cut-off point.
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    Immunoreactive digitalis-like substance in pre-eclampsia
    (Health & Medical Publishing Group, 1986) Odendaal, H. J.; Beyers, A. D.; Van Heyningen, C. F.; Spruyt, L. L.; Kotze, T. J. van W.; Van Jaarsveld, P. P.
    An endogenous digitalis-like substance (DLS) may be involved in the pathogenesis of essential hypertension and pre-eclampsia. The digoxin levels in maternal and cord blood of 504 randomly selected patients were determined. Since none of the patients received digoxin, these levels indicated a cross-reacting substance (immunoreactive DLS). DLS levels were significantly higher in the cord blood of pre-eclamptic patients than in the cord blood of controls. DLS levels in cord blood increased with the severity of pre-eclampsia, and levels were higher in primigravidas than in multigravidas. The structure and biological activity of DLS must be determined before definite conclusions about its role in the pathogenesis of pre-eclampsia can be made.
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    Intra-ocular concentration-time relationships of subconjunctivally administered gentamicin
    (Health & Medical Publishing Group, 1991) Van Rooyen, M. M. B.; Coetzee, J. F.; Du Toit, D. F.; Van Jaarsveld, P. P.
    Eighty-nine patients scheduled for cataract removal or lens implantation were divided randomly into three groups. Each received 5, 10 or 20 mg gentamicin subconjunctivally at times varying between 0,2 and 19 hours pre-operatively. At surgery a sample of aqueous humour was obtained and analysed for gentamicin concentration. The data for each group were subjected to non-linear regression analysis to fit an open one-compartment pharmacokinetic model with first-order kinetics. A statistically acceptable fit was obtained. The average values of the pharmacokinetic parameters obtained from the single doses were used to simulate multiple-dose kinetics. The average target intra-ocular gentamicin concentrations and dosage interval were specified in the computer program, which subsequently allowed calculation of the dose required. This allowed the construction of a simple linear nomogram that can be used to read off the dose needed for handling specific clinical situations.
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    The pharmacokinetic behaviour of hypoxoside taken orally by patients with lung cancer in a phase I trial
    (Health & Medical Publishing Group, 1995) Albrecht, C. F.; Kruger, P. B.; Smit, B. J.; Freestone, M.; Gouws, L.; Miller, R.; Van Jaarsveld, P. P.
    Objective. To study the pharmacokinetic behaviour of hypoxoside taken orally by 24 patients with lung cancer. Design. Randomised open study with three single doses of 1 600, 2 400 and 3 200 mg standardised Hypoxis plant extract (200 mg capsules) and a multiple-dose. study on the first 6 patients taking 4 capsules 3 times daily for 11 days. Participants and setting. Patients with histologically proven squamous, large-cell or adenocarcinoma were hospitalised at the Radiation Oncology Ward, Karl Bremer Hospital, Bellville, W Cape. Methods. Blood was drawn at regular intervals up to 75 hours after single doses and the concentrations of metabolites of the aglucone of hypoxoside, rooperol, were measured with a high-performance liquid chromatography method. For the multiple-dose study blood was drawn before the first dose each day. Concentration-time relationships were analysed according to a conventional single open-compartment model and also by using the NONMEM digital computer programme. Results. Neither hypoxoside nor rooperol appear in circulation. This is due to complete phase II biotransformation to diglucuronide, disulphate and mixed glucuronide-sulphate metabolites, of which the latter is the major component. Considerable interpatient variation in concentration-time relationships was found in the singledose studies. It was due to an active enterohepatic recirculation in some patients and a distinct lag phase in others together with zero-order rate of formation of rooperol in the colon. Computer modelling indicated a single open-compartment model in which the mass of the patient did not influence volume of distribution and clearance because formation of the metabolites is dependent on the metabolising capacity of the patient. However, the elimination of the metabolites follows first-order kinetics with half-lives ranging from 50 hours for the major metabolite to 20 hours for the two minor metabolites. Multiple-dose studies also showed large interpatient variation. Conclusion. In order to reach metabolite levels near 100 μg/ml, which have been shown to be tumouricidal after enzymatic deconjugation to rooperol, maintenance doses need to be individualised for each patient. For most patients, however, a daily dose of 2 400 mg was sufficient.
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    A phase I trial of hypoxoside as an oral prodrug for cancer therapy : absence of toxicity
    (Health & Medical Publishing Group, 1995) Smit, B. J.; Albrecht, C. F.; Liebenberg, R. W.; Kruger, P. B.; Freestone, M.; Gouws, L.; Theron, E.; Bouic, P. J. D.; Etsebeth, S.; Van Jaarsveld, P. P.
    Objective. To assess the toxicity of hypoxoside taken orally by 24 patients with lung cancer. Design. Open study with patients taking 1 200 - 3 200 mg standardised Hypoxis plant extract (200 mg capsules) per day divided in 3 doses in order to maintain metabolite blood levels near 100 μg/ml. Participants and setting. Patients with histologically proven squamous, large-cell or adenocarcinoma were hospitalised initially at the radiation oncology ward, Karl Bremer Hospital, Bellville, W. Cape. Thereafter they returned every 2 weeks for full clinical examinations. Methods. Routine biochemical and haematological measurements were done. Patients underwent regular full clinical examinations including radiographs and computed tomography scanning according to the discretion of the principal investigator. Results. Nineteen patients on hypoxoside therapy survived for an average of 4 months with progression of their primary tumours and metastases, while 5 survived for more than a year. One of them survived for 5 years and histological examination of the primary lesion showed absence of cancer. No toxic effects, in clinical examinations or biochemical or haematological measurements, were found that could be ascribed to the ingestion of hypoxoside. Only one occasion of possible drug intolerance, with anxiety, nausea, vomiting and diarrhoea, was noted. Conclusion. The absence of toxicity warrants further investigation of hypoxoside as an oral prodrug, especially in patients with slow-growing necrotising tumours that are inoperable and have high concentrations of β-glucuronidase and sulphatase as high sensitivity for rooperol.