Irene C. Dormehl

Evaluation of samarium-153 and holmium-166-EDTMP in the normal baboon model

Bone-seeking radiopharmaceuticals such as ethylenediaminetetramethylene phosphonate (EDTMP) complexes of samarium-153 and holmium-166 are receiving considerable attention for therapeutic treatment of bone metastases. In this study, using the baboon experimental model, multicompartmental analysis revealed that with regard to pharmacokinetics, biodistribution, and skeletal localisation, 166Ho-EDTMP was significantly inferior to 153Sm-EDTMP and 99mTc-MDP. A more suitable 166Ho-bone-seeking agent should thus be sought for closer similarity to 153Sm-EDTMP to exploit fully the therapeutic potential of its shorter half-life and more energetic beta radiation.

Effect of Pseudomonas aeruginosa-derived pyocyanin and 1-hydroxyphenazine on pulmonary mucociliary clearance monitored scintigraphically in the baboon model

The effect of products of the bacterium Pseudomonas aeruginosa on mucociliary lung clearance has been monitored in vivo in the baboon model by scintigraphy. Clearance was found to be inhibited by both 1-hydroxyphenazine and pyocyanin, and a dose-effect was illustrated by the former. This confirms previous in vitro results as well as results from work on guinea-pigs, and holds good prospects for the use of the baboon model under anesthesia in such investigations.

GUANIDINES: FROM MOLECULE TO PRIMATE

Guanidine-like compounds have been investigated since the first observations of their therapeutic potential some 30 years ago in fields of cancer and virology. Guanidine-type compounds that reached clinical status include amongst others the potassium channel opener, pinacidil and the histamine H2-receptor antagonists (e.g. cimetidine). Recent research on guanidines has focused on enzyme systems such as xanthine oxidase and nitric oxide synthase. Our studies demonstrated an in vivo cardioprotection effect of (N-(3,4,-dimethoxy-2-chlorobenzylideneamino)-guanidine: ME10092) in ischaemic reperfusion injury in the rodent. The present investigation in the normal non-human primate, Papio ursinus baboons showed cardiovascular negative chronotropic effects and transient decreases in blood pressure, which correspond to those observed in the in vivo cardioprotection studies in the rodent.

SPECT monitoring of improved cerebral blood flow during long-term treatment of elderly patients with nootropic drugs

PURPOSE In normal aging persons, oxygen and glucose consumption progressively decreases with reduced cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A data processing model with the use of Tc-99m SPECT of the human brain has been developed and found to be sensitive for monitoring the effects of drugs that increase CBF. In this study, the effect of two vasodilator drugs (the combination of pentifylline and nicotinic acid versus piracetam) was compared with the effect of placebo on CBF. MATERIALS AND METHODS Thirty elderly volunteers had three different procedures using the Peelproc method to spatially standardize and compare CBF patterns by SPECT before and after drug intervention. The 30 patients were divided into five groups of six persons each who were randomly assigned in a 1:1 ratio to the treatment sequences consisting of three phases: the combination of pentifylline and nicotinic acid (C), piracetam (N), and placebo (P), or C-N-P; P-N-C; P-C-N; N-C-P; C-P-N; or N-P-C. Phases 1 to 3 each consisted of a baseline recording of parameters (day 0), treatment for 60 days (days 1 to 60), and recording of parameters after treatment (day 61). RESULTS In elderly human volunteers (ages, 52 to 70 years), after 2 months of oral treatment with a combination of pentifylline and nicotinic acid (800 mg pentifylline, 200 mg nicotinic acid daily), SPECT results for the Peel-proc program indicated a statistically significant improvement in CBF of the total brain, with a more pronounced improvement in the cerebellum and frontal regions, where a definite shift from abnormal to normal blood flow was detected. Spontaneous communication from most of the volunteers suggested that they experienced an improvement in memory and general well-being from the combination treatment. After 2 months of oral treatment with piracetam (2.4 g daily) in elderly human volunteers, SPECT results indicated a regional improvement in CBF, particularly in the cerebellum. However, no beneficial effects with this drug were spontaneously reported. CONCLUSION The in vivo method to quantitatively monitor the progress of long-term drug therapy on CBF described here could be useful to assess and even direct changes in therapy.

Metal-ion speciation in blood plasma incorporating the water-soluble polymer, polyethyleneimine functionalised with methylenephosphonate groups, in therapeutic radiopharmaceuticals

Summary A water-soluble polymer, polyethyleneimine functionalised with methylene phosphonate groups (PEI-MP) and labelled with 99mTc, 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 153Sm, 166Ho, 212Pb, 213Pb and 89Sr to bone. This was clinically verified for 153Sm. However good uptake of 99mTc-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 186Re or 188Re could result in effective therapeutic radiopharmaceuticals for bone cancer.

Radiopharmaceuticals for Bone Metastasis Therapy and Beyond: A Voyage from the Past to the Present and a Look to the Future

Bone cancer can be divided into primary and secondary (metastatic) bone cancer. Osteosarcoma is the most common type of primary bone cancer, but still is a rare cancer. The development of bone metastases is a common event for the cancer patient and the main cause of treatment failure and death, being chronic pain syndrome the most important complication. There are currently several therapeutic modalities for the treatment of metastatic bone disease, including radiation therapy. Treatment with radionuclides (β- and α-particle emitters and Auger electron cascades) is a safe and effective tool of medicine. There is a great deal of interest in diphosphonic acids in nuclear medicine as ligands for radiometals in bone-seeking diagnostic and therapeutic agents. Several radiopharmaceuticals have been designed with the phosphonates as ligands. A recent approach to develop an effective radiopharmaceutical for therapy of bone cancer was the design of a water-soluble polymer that would exploit the disrupted vasculature in tumors according to the enhanced permeability and retention effect. To enhance the effect of radionuclide therapy on the cancer cells, new strategies have recently been investigated, such as the combined radionuclide and chemotherapy, high-dose radionuclide therapy, and repeated radionuclide therapy.

An evaluation of the diagnostic efficacy of phase analysis of data from radionuclide ventriculograms in patients with Wolff-Parkinson-White syndrome

It has been suggested that phase analysis of radionuclide ventriculograms may be of value for detecting and localising the abnormal sequence of ventricular contraction secondary to Wolff-Parkinson-White (WPW) syndrome. The present study was undertaken to test this hypothesis. The space-time sequences of right- and left-ventricular action obtained from radionuclide ventriculograms obtained during rest studies were evaluated in 8 patients with WPW syndrome (confirmed by 12-lead surface electrocardiography) and compared to those of 14 normal subjects. All of the latter showed a consistent ventricular activation pattern, i.e. the first site of ventricular activity in the upper septal region followed by a second site either at the base of the left ventricle or located apically. It was possible to diagnose 11 of the 14 normal subjects (specificity, 79%) and 7 of the 8 patients (sensitivity, 88%). The 4 patients who had been classified as having a left-sided accessory bundle by surface electrocardiography were likewise diagnosed by phase analysis, as were the 2 patients with a confirmed right-sided bypass tract. Two patients with septal posterior accessory pathways could not be identified by phase analysis. Furthermore, cases with an activation pattern which closely resembled that of the 2 patients with right-sided accessory bundles were found to be normal from their ECGs. It is now necessary to evaluate phase analysis against invasive electrophysiological methods in such patients.

Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study.

Haloperidol (HP) and its tetrahydropyridine dehydration product 4-(4-chlorophenyl)-[4-(fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyrid ine (HPTP) are both metabolized in vivo to several pyridinium metabolites with potential neurotoxic properties similar to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The effect of long-term HPTP treatment on the central nervous system of baboons (Papio ursinus) was studied using [123I]iodobenzamide (IBZM) and single photon emission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment. Striatal dopamine receptor binding was measured semiquantitatively by calculating the IBZM count rate ratios of the basal ganglia to frontal cortex and basal ganglia to cerebellum. Relative striatal perfusion was assessed by similar 99mTc-HMPAO (hexamethylpropylene amine oxime) ratios. Time activity curves of IBZM from the brain structures suggest that HPTP treatment results in a marked reduction in central dopamine ligand binding, and in particular D2-like receptor binding. Increased washout of the ligand from all the brain structures investigated was seen in the HPTP-treated animals, also consistent with reduced binding. Cerebral blood flow in the control and HPTP-treated groups was similar, indicating that this did not account for the reduced dopamine receptor binding of the IBZM ligand. These data suggest that treatment with HPTP induces significant effects on dopamine receptor binding that may contribute to some of the neurological disorders observed in humans undergoing chronic HP treatment.

The effect of an oral gold preparation on the gastrointestinal tract motility in two species of experimental animals

The oral gold preparation, auranofin, used in rheumatoid arthritis has been reputed to cause chronic diarrhea. To investigate this the G.I. tract motility was measured before auranofin therapy and after 1, 3, and 5 weeks of therapy using scintigraphy following indium-111-labeled meals in three beagle dogs. The gastric emptying times of the dogs accelerated throughout the duration of the experiment, although the large bowel transit times did not seem to be affected. The affect of auranofin on the stools of the baboon Papio ursinus was also noted. The baboon stools were observed for any change in consistency. Sigmoidoscopic examination including mucosal biopsies was carried out monthly over a 6-month period. The baboons stools were noted to become very soft in consistency, but histology indicated no mucosal changes.

The detection and evaluation of drug-induced changes in the gastrointestinal motility of beagle dogs using a 111In-labelled resin mixed into a standard meal as tracer

An investigation was performed to establish the usefulness of 111In-labelled polymer beads mixed into a standard meal as a tracer of gatrointestinal(GI)-motility changes due to the influence of various drugs. The labelled polymer beads were well mixed into the food, which was then fed to healthy beagle dogs undergoing drug therapy. GI motility was monitored using a gamma camera and data processor. The results were compared to those obtained from corresponding placebo studies on the same dogs. A significant acceleration of gastric emptying and colon transit was noted under the influence of a gastric and intestinal prokinetic coded R 51619. No influence on GI motility could, however, be detected after the administration of a calcium-blocking agent to the dogs.