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The influence of HPTP : a tetrahydropyridine analog of haloperidol on the metabolism of amino, organic and fatty acids in baboons

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dc.contributor.advisor Bergh JJ, Dr en
dc.contributor.advisor Mienie LJ, Prof en
dc.contributor.author Van Staden E en
dc.date.accessioned 2016-09-22T07:17:25Z
dc.date.available 2016-09-22T07:17:25Z
dc.date.submitted 1997 en
dc.identifier.uri http://hdl.handle.net/20.500.11892/11320
dc.description.abstract Haloperidol {4-(4-chlorophenyl)-4-hydroxy-1-piperidino-4-fluorophenyl-1- an antipsychotic neuroleptic drug, causes side effects in about 30 percent of patients. Early treatment is often characterised by extrapyramidal effects (parkinsonian manifestations, acute dystonic reactions and akathisia), while chronic therapy sometimes results in irreversible tardive dyskinesia. Recent studies indicated that some relationship may exist between neurodegenerative processes and deficient cellular energy production which in turn is frequently linked to metabolic diseases and therefore to the presence of specific metabolites. The neurodegenerative effects of the parkinsonian-inducing agent, 1-methyl-4-phenyl- l, 2, 3, 6-tetrahydropyridine (MPTP), are thought to be caused by its pyridinium metabolite, MPP+, which inhibits mitochondrial respiration by interfering with the electron transport chain, causing destruction of the dopaminergic neurones in the substantia nigra. Haloperidol and its tetrahydropyridine analogue, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1, 2, 3, 6-tetrahydropyridine (HPTP), are biotransformed to the pyridinium metabolites, RHPP+ and HPP+ which are both structurally related to MPP+. It may be argued that side effects such as tardive dyskinesia associated with haloperidol may be mediated by these pyridinium metabolites. Both HPP+ and RHPP+ are known inhibitors of complex I in the mitochondrial respiratory chain. This investigation was launched to gather information about the metabolic defects caused by compounds such as RPTP and to establish if any alternative inhibition of the electron transport chain occurs. It was postulated that depletion of ATP resulting from this inhibition is likely to cause changes in the levels of certain metabolites, especially organic and fatty acids. HPTP and not haloperidol was used to investigate these metabolic disorders because it was found that animals treated with haloperidol became - severely catatonic and suffered from emaciation due to loss of appetite. Two experiments were conducted. In experiment one; samples were collected after treatment was terminated. Four baboons were injected intramuscularly three times a week with HPTP (8 mg/kg) for 12 months while four baboons were injected with placebo and acted as controls. Three months after cessation of treatment, samples were collected following a 12 hour fasting period. In experiment two, baboon 9 and 10 were treated identically to the experimental animals in experiment 1 but the samples were collected during treatment: After six weeks of treatment, the baboons were fasted for 12 hours after which they were injected with the regular dose. The urine samples were collected in six hourly portions for 48 hours. Baboons 9 and 10 served as their own controls and were injected with placebo prior to treatment with HPTP. Quantitative analyses were performed on: (1) organic acids in urine and cerebrospinal fluid, (2) amino acids in urine and (3) fatty acids in blood. The amino acid, p-fluorophenylglycine, which is speculated to act as a phenylalanine hydroxylase inhibitor, was detected in the urine of treated baboons. The organic acids, however, provided the most interesting results. The profiles of normal organic acids in the baboon agreed favourably with those of humans, the only exceptions being the higher concentration of phenylacetic acid in the baboon and the presence of free benzoic acid, the latter phenomenon being very rare in humans. The most significant results came from baboons 9 and 10 evaluated during treatment. Abnormal metabolites (ethylmalonic, methylsuccinic, adipic, suberic, sebacic and glutaric acid; isobutyrylglycine, isovalerylglycine and 2-methylbutyryiglycine), associated with glutaric aciduria type II and Jamaican vomiting sickness in humans were found in the urine of these animals. These results suggest that HPTP, in addition to complex I, may also inhibit any one or more of the reactions involving electron transfer of the fatty acids and amino acid catabolic pathways to coenzyrne Q. It may be speculated that HPTP treatment in the baboon - primarily through inhibition of cellular mitochondrial respiration - may lead to a lowered ATP concentration and, via the resulting elevated fatty acid concentrations, promote further depletion of ATP, thereby compounding the cellular toxicity. en
dc.language English en
dc.subject Medical sciences: Pharmacology and therapeutics en
dc.subject General en
dc.title The influence of HPTP : a tetrahydropyridine analog of haloperidol on the metabolism of amino, organic and fatty acids in baboons en
dc.type Masters degree en
dc.description.degree MSc en


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