Non-human primate SPECT model for determining cerebral perfusion effects of cerebrovasoactive drugs acting via multiple modes of pharmacological action.

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.

Comparison of the predicted in vivo behaviour of the Sn(II)-APDDMP complex and the results as studied in a rodent model.

In a quest for more effective radiopharmaceuticals for pain palliation of metastatic bone cancer, this paper relates results obtained with ((117m)Sn labelled) Sn(II) complexed to the bone seeking bisphosphonate, N,N-dimethylenephosphonate-1-hydroxy-3-aminopropylidenediphosphonate (APDDMP). APDDMP is synthesised from the known bone cancer pain palliation agent 1-hydroxy-3-aminopropylidenediphosphonate (APD, Pamindronate). This work is performed to utilise the idea that the low bone marrow radio toxicity of (117m)Sn could afford a highly effective radiopharmaceutical in pain palliation but also in the curative treatment of bone metastasis. Complex-formation constants of APDDMP with the important blood plasma metal-ions, Ca(2+), Mg(2+), Zn(2+) as well as the added metal ion, Sn(2+) were measured by glass electrode potentiometry at 25 degrees C and I = 150 mM. Blood plasma models were constructed using the computer code ECCLES and the results compared with those gathered from tests on a rodent model. The ((117m)Sn-labelled) Sn(II)-APDDMP complex was found to have only some liver and bone uptake although a high trabecular to normal bone ratio was recorded. From the blood plasma model this was shown to be primarily due to the high affinity of APDDMP for Ca(II) causing some of the Sn(II)-APDDMP complex to dissociate. High kidney uptake and excretion as well as high bladder uptake was recorded which was shown to be due to the dissociation of the Sn(II)-APDDMP complex in blood plasma. Animal model observations could be explained by the blood plasma modelling.

Biodistribution and pharmacokinetics of variously molecular sized 117mSn(II)-polyethyleneiminomethyl phosphonate complexes in the normal primate model as potential selective therapeutic bone agents.

In the search for a cure for metastatic bone cancer, 117mSn with its conversion electrons and low energy photons both of discrete energies shows little bone marrow toxicity, providing the opportunity to increase the administered dose. Selective accumulation in lesions would capitalise on this advantage. The 10-30 kDa fraction of the water-soluble polymer polyethyleneimine, functionalised with methyl phosphonate groups (PEI-MP) and labelled with 99mTc, has shown selective uptake into bone tumours. Furthermore using speciation calculations it was predicted that the Sn(II)-PEI-MP complex would remain intact in the blood plasma. Because of this positive indication animal experiments were carried out to test this prediction. This paper relates the labelling, biodistribution and pharmacokinetics of various fractions of 117mSn-(II) PEI-MP in the normal primate model, and points to promising therapeutic possibilities.

Cerebral blood perfusion after treatment with zolpidem and flumazenil in the baboon.

Previous studies have shown that zolpidem (CAS 82626-48-0) can lead to improved perfusion in damaged brain tissue. Zolpidem belongs to the imidazopyridine chemical class and it illicits its pharmacological action via the gamma-aminobutyric acid (GABA) receptor system through stimulation of particularly the omega 1 receptors and to a lesser extent omega 2 receptors. Previously it was reported that no cerebral blood flow effects were observed in normal baboons after treatment with zolpidem, whereas an asymmetric regional increase in cerebral blood flow was observed in a neurologically abnormal baboon. In this study, the effect of a combination of the benzodiazepine receptor antagonist flumazenil (CAS 78755-81-4) and zolpidem on brain perfusion was examined by the 99mTc-hexamethyl-propylene amine oxime (99mTc-HMPAO) split dose brain single photon emission computed tomography (SPECT). Four normal baboons and the neurologically abnormal baboon from the previous zolpidem study were examined. In the current study the asymmetric changes observed after zolpidem--only treatment in the abnormal baboon was attenuated by flumazenil intervention. A decreased brain blood flow was observed after combination treatment of zolpidem and flumazenil in the normal baboons. The involvement of the omega receptors is suggested by these results. Up- or down-regulation of omega receptors may also contribute to the observed responses in the abnormal baboon and a brain injured patient.