Werner Louw

Metal-ion speciation in blood plasma incorporating the tetraphosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropilydenediphosphonate (APDDMP), in therapeutic radiopharmaceuticals

In a quest for more effective radiopharmaceuticals for pain palliation of metastatic bone cancer, this paper relates results obtained with 166Ho and 153Sm complexed to the bone seeking phosphonate, N,N-dimethylenephosphonate-1-hydroxy-4-aminopropylidenediphosphonate (APDDMP). APDDMP is synthesised from the known bone cancer pain palliation agent 1-hydroxy-3-aminopropylidenediphosphonate (APD) and was complexed to lanthanide trivalent metal ions. This work is performed to utilise the idea that the energetic beta-particle emitter, 166 Ho, coupled with phosphonate ligands such as APD and APDDMP could afford a highly effective radiopharmaceutical in the treatment of bone cancer. Complex-formation constants of APDDMP with the important blood plasma metal-ions, Ca2+, Mg2+, and Zn2+ and the trivalent lanthanides Ho3+ and Sm3+ were measured by glass electrode potentiometry at 37 degrees C and I = 150 mM. Blood plasma models were constructed using the computer code ECCLES and the results compared with those gathered from animal tests. The 166Ho-APDDMP complex was found to have little liver or bone uptake while 153Sm-APDDMP had a moderate bone uptake. This was primarily due to the high affinity of APDDMP for Ca(II). Clinical observations could be explained by the blood plasma modelling.

Metal-ion speciation in blood plasma incorporating the bisphosphonate, 1-hydroxy-4-aminopropilydenediphosphonate (APD), in therapeutic radiopharmaceuticals.

In the quest for more effective pain palliation radiopharmaceuticals for metastatic bone cancer, this paper relates results obtained with 166Ho complexed to the bone-seeking bisphosphonate, 1-hydroxy-4-aminopropililydenediphosphonate (APD). APD is itself a bone cancer pain palliation agent and this work was therefore driven by the idea that the energetic beta-particle emitter, 166Ho, coupled with APD could afford a highly effective radiopharmaceutical in the treatment of bone cancer. Complex-formation constants for important blood plasma metal-ions were measured by potentiometry or polarography at 37 degrees C and I = 150 mmol dm-3. The latter technique was used for systems where precipitates formed at ligand-to-metal ratios appropriate for potentiometry. For trivalent lanthanides, neither electrochemical technique could be used. Animal tests showed that the 166Ho-APD complex was taken up primarily by the liver due to precipitation or colloid formation.

Thermodynamic and biodistribution studies of Zn(ii), Ca(ii), Gd(iii) and Cu(ii) complexes of 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioximeCopper anti-inflammatory drugs in rheumatoid arthritis. Part 6.1

The thermodynamic equilibria of copper(II), zinc(II), calcium(II) and gadolinium(III) with 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime (L1) have been studied at 25 degrees C and an ionic strength of 0.15 mol dm(-3). Copper and gadolinium form stable complexes with the ligand while the corresponding zinc species are more than 9 log units less stable. No complexes between calcium and the ligand were detected. The low binding strength of L1 towards zinc is attributed to the square-planar coordination geometry forced on the metal ion by the ligand as revealed by molecular mechanics calculations and molecular dynamics simulations. Speciation calculations, using a computer model of blood plasma, indicate that, despite the high concentration of zinc(II) and calcium(II) in vivo, L1 is able to increase the low-molecular-mass fraction of copper in plasma. Octanol/water partition coefficient of [CuL1H(-1)] indicates that although this species is largely hydrophilic, approximately 6% of the complex goes into the octanol phase and hence may promote dermal absorption of copper by the same amount. The dermal penetration rate is calculated to be 4.0 x 10(-4) mm h(-1). The [CuL1H(-1)] complex, which predominates at pH 7.4, is a poor mimic of native copper-zinc superoxide dismutase. Biodistribution experiments using the 64Cu-labelled [CuL1H(-1)] complex indicate an initial high uptake of this species in the liver followed by redistribution into muscle. Only a small amount is excreted through the urine.

A thermodynamic approach, using speciation studies, towards the evaluation and design of bone-seeking radiopharmaceuticals as illustrated for 117mSn(II)-PEI-MP

Blood plasma modeling has proved effective in the evaluation of clinical observations recorded for baboon and rat tests with 153Sm- ethylenediaminetetraphosphonic acid (EDTMP) as well as for 166Ho-EDTMP. In the search for a cure for metastatic bone cancer, 117mSn with its conversion electrons of discrete energies shows low bone marrow toxicity, providing the opportunity to increase the administered dose. Selective accumulation in lesions would capitalize on this advantage. The 10-30 kDa fraction of the water-soluble polymer polyethyleneimine, functionalized with methylene phosphonate groups (PEI-MP) and labeled with 99mTc, has shown selective uptake into bone tumours. This paper relates the speciation of Sn(II)-PEI-MP and other known 117mSn(II) containing bone-seeking radiopharmaceuticals in blood plasma. Apparent formation constants for the complexation of SnII with PEI-MP, DTPA, HEDP and other important blood plasma ligands were measured potentiometrically or estimated by linear free energy relationships (LFER). These data were added to the ECCLES database in order to construct a blood plasma model for SnII. From this model it is predicted that SnII will remain bound to the polymer (PEI-MP) in blood plasma and therefore, have only slight reticuloendothelial uptake. Preliminary primate studies indeed proved that the complex between SnII and PEI-MP remains intact in blood plasma, which is consistent with the observation for PEI-MP labeled with 99mTc. From these data, it was also possible to explain in retrospect the lower bone uptake, the slow blood clearance and the liver uptake of the agents 117mSn(II) DTPA and 117mSn(II) HEDP agents as reported in the literature.

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.

Nucleoid Sedimentation Analysis of DNA Superstructure, γ-Radiation-induced Damage and Repair in Human and Chacma Baboon (Papia Ursinus) Peripheral Lymphocytes

The use of the chacma baboon (Papio ursinus) in radiobiological investigations justifies special attention because it answers many of the criteria of parallelism to the human. The present study was undertaken to establish whether in vitro gamma-radiation effects in chacma baboon and human lymphocytes are comparable. The sensitive and rapid nucleoid sedimentation technique was employed to evaluate in vitro DNA superstructure, damage and repair in readily obtainable radiosensitive peripheral lymphocytes. Dose-response curves after 60Co gamma-irradiation were obtained, and by applying single-hit kinetics of the target theory, an estimation of molecular masses of the supercoiled domains was made. The baboon and human lymphocytes produced analogous results, while an ethidium bromide intercalation study also revealed a similarity in average DNA superhelical density. Lymphocyte DNA repair after 0.5-4.0 Gy gamma-irradiation and repair times from 0.5 to 5.0 h were evaluated. The repair data obtained from baboon and human cells after 2.0 Gy irradiation compared favourably in extent of DNA repair as well as the profiles of the kinetic curves. These findings indicate that the chacma baboon would be a useful and relevant model for further in vivo radiobiological studies on lymphocytes. The effects of sedimentation conditions and advantages of using vertical-tube rotors in the nucleoid sedimentation technique are also discussed.

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.