Cerebral blood flow dynamics is an essential component for preserving
cerebral integrity. Cerebral blood flow abnormalities are often seen in patients
with central nervous system pathologies such as epilepsy, migraine,
Alzheimer's Disease, vascular dementia, stroke, and even HIV/AIDS. There is
increasing clinical and experimental evidence implicating cerebral
hypoperfusion during ageing. The determination of cerebral perfusion has
therefore become an important objective in physiological, pathological,
pharmacological, and clinical investigations. The knowledge of regional
cerebral blood flow further provides useful diagnostic information and/or data
for a better understanding of the complex clinical presentations in patients with
neurological and psychiatric disorders. Several cerebrovasoactive drugs have
found application in the clinical setting of cerebrovascular diseases such as
migraine and dementia.
Due to the similarities between humans and non-human primates with
respect to their brains, both structurally and behaviourally, numerous studies
have been conducted and several non-human primate models have been
developed for physiological, pathological, pharmacological, and clinical studies,
amongst others in Parkinson's disease and diabetes. The relatively large size
of the Cape baboon Papio Ursinus with a weight of 27-30 kg for a large male,
makes this primate especially suitable for in vivo brain studies using
radiotracers and Single Photon Emission Computed Tomography (SPECT).
The main aim of the current study was therefore to develop a suitable
radiotracer (99m Tc-hexamethylpropylene amine oxime (HMPAO) or 99m Tc_ethyl_cysteinatedimer (ECD) or 123l-iodoamphetamine (IMP)) for adapted in vivo
cerebral blood flow measurements in a non-human primate (Papio ursinus) as
an investigative model. The model was to be validated and applied in various
drug studies for the evaluation of pharmacological interventions. The study
design made use of split-dose methodology, whereby the radiopharmaceutical
(radiotracer) was administered twice during each study. The first administration
was injected soon after the induction of the anaesthesia, and was followed by
the first SPECT data acquisition. The second administration of the radioligand,
a double dose of radioactivity with respect to the first radioligand injection, was
done at a specific time during the study, which took into account the
pharmacodynamics of the drug. A second SPECT data acquisition followed
subsequently. The drugs that were included in the study were acetazolamide,
a carbonic acid anhydrase inhibitor (often used in nuclear medicine to
determine cerebral reserve); sumaptriptan, a 5-HT (serotonin) agonist used for
treatment of migraine; sodium valproate (an anti-epileptic drug); nimodipine, a
calcium channel blocker and nitro-glycerine, a vasodilator used for angina.
Arterial blood pressures were recorded from a catheter in the femoral artery
and heart rates were concurrently monitored.
The split-dose method was successfully applied to develop a non-human
primate cerebral blood flow model under anaesthesia. The model showed
differences in cerebral perfusion of the different anaesthesia regimes. These
anaesthesia data sets were suitable as control/baseline results for drug
intervention studies. Acetazolamide evaluation through the split-dose method
in the baboon confirmed the sensitivity of the model by presenting comparable
perfusion. This result compared to those already familiar prompted the model
to be applied in pharmacological intervention studies. Subsequent results of
these investigations showed increases in perfusion for single drug nimodipine
treatment (25%). However, nimodipine attenuated the increases in perfusion
when administered in combination with acetazolamide. Sumatriptan was able
to decrease and normalise the increased perfusion after long duration
anaesthesia. Decreased cerebral blood flow was observed for combinations of
nimodipine with sodium valproate suggesting drug-drug interaction with
important clinical implications. Similar decreases were found also for
sumatriptan and nitro-glycerine when administered in combination with
nimodipine.
Studies with the various tracers (99m Tc_HMPAO or 99m Tc_ECD or 123l_IMP)
showed clear differences in the perfusion data, confirming variation in the
biochemical performance of the tracers. These differences, if not taken into
consideration, caution for inappropriate clinical conclusions and subsequent
erroneous therapeutic decisions. Improvement of radiotracer efficacy was
subsequently attempted through application of the cyclodextrine complexation
approach. Although cyciodextrine technology did not markedly improve the
brain disposition of the 99m Tc-ECD, protection of the tracer against degradation
was demonstrated. This study encouraged further exploration of this method for
protection of the tracer against chemical and metabolic degradation.
The current study was aimed to develop and effectively apply a non-human
primate model with nuclear medicine technology for cerebral blood flow
determinations after pharmacological interventions. This was achieved through
the split-dose method and dedicated computer programming, which yielded a
successful model with the non-human primate under anaesthesia. The model
was validated with the application of acetazolamide to confirm familiar
cerebrovascular reserve results, indicating that the model is sensitive to CBF
changes. The model was also effectively applied in several pharmacological
intervention studies, whereby cerebropharmacodynamics of selected drugs
were investigated and established.
This unique model of a non-human primate, Papio ursinus for cerebral blood
flow determinations has served pharmacological research successfully during
the past 12 years and could do so in the future, with scope to investigate new
frontiers with improved technologies. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/435 |
| Date | January 2003 |
| Creators | Oliver, Douglas William |
| Publisher | North-West University |
| Source Sets | North-West University |
| Detected Language | English |
| Type | Thesis |
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