Research Articles (Clinical Pharmacology)

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Browsing Research Articles (Clinical Pharmacology) by Author "Albrecht, C. F."

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    Morphological characterisation of the cell-growth inhibitory activity of rooperol and pharmacokinetic aspects of hypoxoside as an oral prodrug for cancer therapy
    (Health & Medical Publishing Group, 1995) Albrecht, C. F.; Theron, E. J.; Kruger, P. B.
    Hypoxoside is the major diglucoside isolated from the corms of the plant family Hypoxidaceae, It contains an. unusual E-pent-l-en-4-yne 5-carbon bridging unit with two distal catechol groups to which the glucose moieties are attached, It is non-toxic for BL6 mouse melanoma cells in tissue culture on condition that the fetal calf serum in the medium is heat-inactivated for 1 hour at 56°C in order to destroy endogenous beta-glucosidase activity. The latter catalyses hypoxoside conversion to its cytotoxic aglucone, rooperol, which, when tested as a pure chemical, caused 50% inhibition of BL6 melanoma cell growth at 10 μg/ml, Light and electron microscopy revealed that the cytotoxic effect of rooperol manifested as vacuolisation of the cytoplasm and formation of pores in the plasma membrane. Indications of apoptosis were also found. Pharmacokinetic studies on mice dosed intragastrically with hypoxoside showed that it was deconjugated by bacterial beta-glucosidase to form rooperol in the colon, Surprisingly, no hypoxoside or rooperol was detectable in the serum, Only phase II biotransformation products (sulphates and glucuronides) were present in the portal blood and bile, In contrast, however, in human serum after oral ingestion of hypoxoside, the metabolites can reach relatively high concentrations, Rooperol metabolites isolated from human urine were non-toxic for BL6 melanoma cells in culture up to a concentration of 200 μg/ml. In the presence of betaglucuronidase, which released rooperol from the metabolites, 50% growth inhibition was achieved at a 75 μg/ml metabolite concentration, The supernatant of a human melanoma homogenate could also cause deconjugation of the metabolites to form rooperol,It can be concluded from these findings that rooperol has promising properties as an oral prodrug for cancer therapy in humans given its complete first-pass metabolism into non-toxic conjugates which may be activated in tumours with high deconjugase activity, Rodent cancer models are, however, not applicable since rooperol metabolites are completely sequestered in the bile.
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    Origin of the enigmatic, circular, barren patches ('Fairy Rings') of the pro-Namib
    (Academy of Science of South Africa, 2001) Albrecht, C. F.; Joubert, J. J.; De Rycke, P. H.
    We have studied the enigmatic, circular, barren patches on the edge of the pro-Namib Desert in Namibia. An aerial photograph of the Wolwedans area (25°4.5′S, 15°59.5′E) showed that the patches had an average diameter of 6.1 m and an ordered distribution with an R-value of 1.68, suggesting a termite-associated origin. We postulate that there is an active evolutionary process of circular patch formation, involving genesis, growth, maturation and extinction. Stipagrostis uniplumis seedlings growing in the moist inner soil of barren patches, after rains, appeared to lack root side-hairs when compared to similar plants growing outside the patch and these seedlings invariably died when the rains subsided. Growth experiments with Cynodon dactylon in inner and outer soil samples showed that these grass seedlings could survive cycles of dehydration and hydration only when growing in outer soil. Seedlings in the inner soil collapsed and died under similar conditions. This suggested that there is a biological factor in the inner soil, which inhibits resistance to dehydration, possibly through inhibition of side-root growth and/or maintenance. We postulate that termites are linked to this biological factor in some unknown manner and that the barren patches have an evolutionary advantage for the termites by acting as water traps. Direct experiments showed five-fold more water in soil samples from the barren patches than between them. Preliminary attempts to indicate or isolate the putative abiosis factor with HPLC were not successful and more sophisticated analytical techniques are called for.
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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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    Smoking, oncogenes and human lung cancer. A review of recent laboratory evidence linking smoking and lung cancer
    (Health & Medical Publishing Group, 1988) Albrecht, C. F.; Theron, E. L.
    Recent molecular genetic experiments conducted in the USA and The Netherlands have isolated specific mutations in human lung cancer cells. These data implicate the activation of the K-ras oncogene in the pathogenesis of adenocarcinoma of the lungs of heavy smokers and the deletion of DNA from the short arm of chromosome 3 in small-cell and non-small-cell carcinoma of the lung. The implications of these results are discussed and explained in the light of current DNA-manipulative technology which is now available in RSA.