No abstract

An ideal radiopharmaceutical for the treatment of neoplastic and inflammatory (benign) bone disease would be a radiolabelled compound that predominantly accumulates in bone lesions with limited access to normal bone and other organs. Neoplastic tissue's abnormal blood supply (increased permeability) and lack of lymphatics will selectively accumulate radiolabelled macromolecules. This enhanced permeability and retention effect forms the basis of this study, using various molecular sizes of the radiolabelled macromolecule polyethyleneiminomethyl phosphonic acid (PEI-MP) for increased selectivity of the bone-seeking radiopharmaceutical. PEI-MP was synthesized by condensation of polyethyleneimine, phosphonic acid and formaldehyde, followed by fractionation into different molecular sizes by membrane ultrafiltration. Labelling efficiency to 99mTc (as radiotracer) was approximately 99% with complexes stable for 24 h. The pharmacokinetics and biodistribution of various 99mTc-PEI-MP fractions were investigated using 4 experimental baboons (Papio ursinus) per fraction. Scintigraphy was performed on the baboons under general anaesthesia of pentobarbital i.v. After an i.v. bolus of 99mTc-PEI-MP (approximately 185 MBq) both dynamic studies (30 x 1 min frames), and static studies (2 min acquisition every hour for 4 h) were done, as well as blood samples and urine collected. From the results macromolecules with sizes ranging between 30-300 kDa were characterized by excessive liver (21%-57% retained activity) and kidney (40% retained activity) uptake and accompanying long residing times (t1/2 up to 24 h). The percentage bone uptake averaged at 8% for these particles excluding sizes 100-300 kDa where very little bone uptake was seen (< 1%). In this case the blood clearance was also slow (t1/2 approximately 2 h). The fraction size 10-30 kDa had comparatively low accumulation and short residence times in the liver and kidneys (resp. 20%, t1/2 = 22 +/- 4 min; 17.5%, t1/2 = 20 +/- 3 min) and although the bone uptake of 18% in this case was high, it is still low for a bone-seeking agent. These particles cleared the blood with t1/2 = 25 +/- 2 min and seemed suitable for labelling with a therapeutic radioisotopic agent.

A recent report showed that zolpidem (CAS 82626-48-0) can lead to the arousal of a semi-comatosed patient. Zolpidem is clinically used for the treatment of insomnia. It belongs to the imidazopyridine chemical class and is a non benzodiazepine drug. It illicits its pharmacological action via the GABA receptor system through stimulation of particularly the omega 1 receptors. In this study, the effect of zolpidem on brain perfusion was examined by 99mTc hexamethyl-propylene amine oxime (HMPAO) split dose brain SPECT on four normal baboons and in one baboon with abnormal neurological behaviour. The global and regional brain perfusion was not significantly affected in the normal brains. In some regions of the abnormal baboon brain, however, there was a disproportionate increase in perfusion after zolpidem.

Bosman H, Dormehl IC, Hugo N, Redelinghuys IF, Theron JJ. The effect of intravenous administration of melatonin on cardiovascular parameters of the baboon (Pupio ursinus). J . Pineal Res. 1991: I1:179-Abstract: Melatonin (0.3 to 0.4 mgikg) dissolved in 0.5 ml dirnethylsulphoxide (DMSO) was injected i.v. into six baboons, and their cardiovascular parameters were monitored. Left ventricular end-diastolic and end-systolic volumes, stroke volume, cardiac output, and left ventricular ejection fraction were measured, using conventional radionuclide ventricuiography, and compared to normal values previously established. These parameters were also measured after an i.v. administration of only DMSO. The only statistical significant change due to melatoqin was the increase in the cardiac output and left ventricular ejection fraction. With the reduced heart rate the increase in cardiac output implies a positive inotropic action on the heart by melatonin. There are indications that DMSO possibly suppresses I cardiovascular actions of melatonin.

A water-soluble polymer, polyethyleneimine functionalised with methylene phosphonate groups (PEI-MP) and labelled with 99m Tc, has shown selective uptake into bone tumours. Apparent formation constants for the complexation of important blood plasma metal-ions and metal-ions of radionuclides used in therapeutic radiopharmaceuticals (excluding Tc) with PEI-MP were measured potentiometrically. These were added to the ECCLES data base in order to construct a blood plasma model for PEI-MP. From this model it could be predicted that the polymer would not deliver the therapeutic radionuclides 153 Sm, 166 Ho, 212 Pb, 213 Pb and 89 Sr to bone. This was clinically verified for 153 Sm. However good uptake of 99m Tc-PEI-MP could be demonstrated in dogs. Due to the similar chemistry of Re as compared to Tc, it can be expected that PEI-MP labelled with 186 Re or 188 Re could result in effective therapeutic radiopharmaceuticals for bone cancer.