title: Non-human primate SPECT model for determining cerebral perfusion effects of cerebrovasoactive drugs acting via multiple modes of pharmacological action.
abstract: Increasing clinical and experimental evidence implicate cerebral hypoperfusion during increased ageing and points to chronic cerebrovascular ischemia as a vital component of the neuropathological progression of dementia. In vivo cerebral perfusion animal models can greatly contribute to the evaluation of drugs and to the screening of drug interactions. This study describes a baboon Papio ursinus model under anaesthesia, for in vivo cerebral blood flow (CBF) determinations, using Single Photon Emission Computed Tomography (SPECT) following the split-dose method with 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO). Perfusion studies with acetazolamide as intervention clearly showed that the non-human primate model under aneasthesia is sufficiently sensitive to serve in the evaluation of other cerebrovasoactive drugs for induced perfusion changes with significant increases of the R-value (+40%) for comparative measurement when compared to the control value (2.53+/-0.15 vs. 1.79+/-0.13). These findings stimulated investigations of several drugs, i.e. pentifylline (phosphodiesterase inhibitor); nimodipine (calcium channel blocker); sumatriptan (serotonin receptor agonist) and nicotinic acid (vasodilator) for CBF effects. Increases in the cerebral perfusion in some cases more than +30% for nimodipine (2.51+/-0.14 vs. 1.79+/-0.13), acetazolamide and +29% for the combination of pentifylline and nicotinic acid (2.31+/-0.19 vs. 1.79+/-0.13) were observed. Drug interaction studies revealed an attenuation of increased CBF due to nimodipine, with sumatriptan (-25%) and acetazolamide (+22%) in combination with nimodipine. Drug interactions with clinical implications may result during simultaneous use of cerebrovasoactive drugs in managing patients with cerebrovascular disorders. This study further showed that the CBF non-human primate model under anaesthesia is useful for the investigation of vasoactive drugs acting via various pharmacological modes of action.
authors.affiliation: Pharmacology Potchefstroom University for CHE, Faculty of Health Sciences, P/Bag X6001, Potchefstroom 2520, South Africa. fkldwo@puknet.puk.ac.za
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Oliver
authors.forename: Irene C
authors.initials: IC
authors.lastname: Dormehl
authors.forename: Werner K A
authors.initials: WK
authors.lastname: Louw
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004347:Drug Interactions; D008297:Male; D009525:Niacin / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D010215:Papio; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D019690:Technetium Tc 99m Exametazime; D013805:Theobromine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015899:Tomography, Emission-Computed, Single-Photon; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D010726:Phosphodiesterase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009525:Niacin; D019690:Technetium Tc 99m Exametazime; D009553:Nimodipine; D018170:Sumatriptan; C007942:pentifylline; D013805:Theobromine