Peter M. May

Speciation studies of adriamycin, quelamycin and their metal complexes

Abstract The formation constants for complexes formed between Adriamycin and some transition metals are reported. They are used to calculate the probable complex species concentrations present in gastro-intestinal fluids following Adriamycin and Quelamycin administration and to estimate the influence of the two agents upon the low-molecular-weight complexes normally present in blood plasma. Adriamycin forms a range of complexes in intestinal fluid and blood plasma, e.g. CaAd and FeAdOH. The former suggests that Adriamycin may affect calcium metabolism whereas the latter suggests that co-administering ferric ions could interfere with this inhibition.

Metal-ligand complexes involved in rheumatoid arthritis—IV: Formation constant and species distribution considerations for copper(II) -cystinate, -oxidised penicillaminate and -oxidised glutathionate interactions and considerations of the action of penicillamine in vivo☆

Glutathione was found to form the following (GssG)p4−.(histidinate)p′−.Cuq2+.Hr+ complexes, pp′qq = 1010, 2010, 1020, 1011, 1012, 1110, 1111 and 1112. Ternary complexes formed with glutathione are capable of effecting a cupresis compatible with that of Trien following intravenous administration of the peptide. ECCLES models of blood plasma show that under physiological conditions oxidised penicillamine is unable to increase the amount of copper(II) in the low molecular weight fraction i.e. the drug does not act upon the labile copper equilibria in blood as a chelating agent per se. Rather its mode of action is probably one of increasing the total amount of exchangeable copper in plasma by liberating copper from metalloprotein. A reassessment of biological and chemical data reported in the literature concludes that penicillamine therapy probably produces antiinflammatory activity through more than one mechanism; it possibly has a destructive effect upon proteins that produce inflammation and also by transferring metalloprotein-bound copper into the labile pool of copper in plasma. The latter is additionally instrumental in controlling the amount of inflammation as found in part I of this series.

Computer simulation of metal ion equilibria in biofluids. Part 3. Trace metal supplementation in total parenteral nutrition.

Computer simulation models have been developed to investigate the effect of intravenous infusions of nutritive amino acid solutions metal equilibria in plasma. The distribution of Ca(II), Mg(II), Zn(II), Cu(II), and Mn(II) among the ligands in the nutritive fluid is calculated and used to estimate the amounts of each metal that should be included in future preparations.

Metal-ligand complexes involved in rheumatoid arthritis—I: Justifications for copper administration

Abstract The role of copper in rheumatoid arthritis is discussed both from historical and experimental viewpoints. Reasons supporting the hypothesis that the administration of low molecular weight complexes of copper is beneficial are listed and supported with experimental evidence: (a) Calculations of the bioavailability, in terms of cell membrane transmission, of a series of copper amino-acid mixtures are compared with animal screen results of the effect of such mixtures upon rat paw oedema caused by λ carrageenan injection. For subcutaneous administration, the degree of antiinflammatory activity is directly proportional to the quantity of copper injected. (b) The concentrations of ternary copper complexes in serum can be correlated with their protective influence upon the denaturation of serum proteins. The predominant complexes affording protection are copper histidinate.cystinate − and copper histidinate.cystinate.H.

Metal binding by pharmaceuticals. Part 1. Copper(II) and zinc(II) interactions following ethambutol administration.

Formation constants for copper(II) and zinc(II) complexes of dextro-2,2′-(ethylenediimino)-di-1-butanol (ethambutol) and its metabolic oxidation product, 2,2′-(ethylenediimino)-dibutyric acid (EDBA) have been measured potentiometrically at 37°C, I=0.15 mol dm−3 [NaCl]. The constants are used in computer models to assess the extent of the formation of these complexes in vivo. These simulations indicate that whereas ethambutol forms metal complexes only to a limited extent in vivo, EDBA competes effectively under physiological conditions for copper(II) and zinc(II). This study suggests that zinc(II) binding by EDBA may account for a number of side effects of ethambutol treatment.

Computer simulation of metal ion equilibria in biofluids. IV: Plutonium speciation in human blood plasma and chelation therapy using polyaminopolycarboxylic acids

An investigation by computer simulation into the nature of Pu(IV) binding to low-molecular ligands in human blood plasma is described. Particular consideration is given to the interactions of various chelating agents which have been or might be used for treating plutonium intoxication. Formation constants of EDTA and DTPA with Cu(II), Mg(II), Mn(II), Zn(II), and Cd(II) have been measured under biologic conditions of temperature and background electrolyte. The relative ability of these and other chelating agents to cause excretion of plutonium and the concomitant loss of certain essential trace metals has thus been assessed.

Metal-ligand complexes involved in rheumatoid arthritis—VI: Computer models simulating the low molecular weight complexes present in blood plasma for normal and arthritic individuals

Computer simulation of the complexing conditions occurring in biofluids has been used to assess Sorensons biological activity data for copper chelate antiarthritic agents. A list of properties desirable for maximum activity and minimum stomach ulceration is reported. When the complexes are administered subcutaneously, the reduction in inflammation is found to be proportional to the total amount of copper injected. For oral administration, the presence of a neutral copper complex at stomach pH pootects against ulcer formation. Models of blood plasma show that the administered copper complexes release their copper to serum albumin. Some agents (namely aspartate, carboxyisoquinolate, histamine, lysinate, penicillaminate (oxidised) and tryptophanate) also redistribute the copper amongst low molecular weight complexes producing additional uncharged ternary complexes at the expense of [Cu.cystinate.histidinate]−. In general administered copper complexes are effective because they increase the concentrations of complexes which are able to pass through membranes thereby distributing the copper into tissue. This study has produced a strategy for improved rheumatoid arthritis therapeuticals.

Metal complexing ability of two inducers of reverse transformation

Abstract The metal complexing properties of sodium thiazolidine-4-carboxylate and 2-amino-2-thiazoline hydrochloride with H + , Mg 2+ , Ca 2+ , Ni 2+ , Mn 2+ , Cu 2+ and Zn 2+ have been investigated. These agents have been reported to be a new type of anticancer agent wich induce reverse transformation. Computer simulations of blood plasma suggest that this type of ligand drug disturbs the normal biochemistry of manganese and, to a lesser extent, zinc.

Metal binding by pharmaceuticals. Part 4. A comparative investigation of the interaction of metal ions with hydralazine, prizidilol and related compounds

The metal complexing properties of two antihypertensive drugs, hydralazine (1-hydrazinophthalazine) and prizidilol (a hydrazinopyridazine), and some related ligands, have been studied using potentiometry, elemental analysis, spectrophotometry and computer simulation. The coordination chemistry of 1-hydrazinophthalazine and the hydrazinopyridazines is similar in that Ca(II), Mg(II), and Mn(II) complexes are not formed, whereas Zn(II), Cu(II) and Fe(II)/Fe(III) complexes are produced. Both kinds of ligand react with Fe(II) to form a brightly coloured tetrazene complex which is insoluble for hydralazine but soluble for prizidilol. Computer simulation studies indicate that the most prevalent metal complex of prizidilol in blood plasma is [Fe2+(Priz−H+]2+ but that this only forms at very high drug concentrations. It is concluded that prizidilol is unlikely to have any direct effects on the metabolism or distribution of the trace elements listed here.

Computer Analysis of Low Molecular Weight Copper Complexes in Biofluids

There is agreement in research reports concerning two aspects of rheumatoid arthritis: it involves malfunctions in the autoimmune system1–3 chemically it results in copper imbalances. The biochemistries of how the immune system errs and the exact details of how plasma cerulo-plasmin rises whilst low-molecular-weight copper complexes in the biofluid become depleted are not yet certain.