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Biomedical subjects

M W Whitehouse

Publications and source records attributed to M W Whitehouse.

At least 19 recordsLinked to original sources
PubMed1992

Zinc monoglycerolate--a slow-release source of therapeutic zinc: solubilization by endogenous ligands.

A combination of 65Zn-tracer determinations, oxidative analyses for glycerol, and a bioassay for uncomplexed Zn2+ have shown that: (i) zinc monoglycerolate (ZMG) dissolves in aqueous salt solutions/physiological media by dissociation into zinc ions and glycerol, but the rate and extent of ZMG dissolution depend upon pH, and/or concentration and complexing efficiency of zinc-ligands; (ii) under physiological conditions certain ligands present in skin and blood (e.g. citrate, lactate, albumin, histidine, glutathione and other thiols and, to a lesser extent, amino acids) accelerate ZMG dissolution; and (iii) there is a general correlation between the conditional stability constants (pH 7.3, 25 degrees C) of zinc-ligand complexes and the ability of given ligands to (a) solubilize ZMG in vitro and (b) mask the irritancy of Zn2+ in vivo. These observations indicate a mechanism for the transformation of ZMG applied transdermally or subcutaneously, to bioactive zinc (anti-arthritic nutritional supplement, etc.).

Animals↗
PubMed1992

Changes in plasma zinc, copper, iron, and hepatic metallothionein in adjuvant-induced arthritis treated with cyclosporin.

The early changes in hepatic metallothionein (MT) and plasma zinc (Zn), copper (Cu), and iron (Fe) were investigated during the induction of adjuvant (AJ) arthritis in rats in conjunction with cyclosporin (CsA) treatment. Plasma Zn decreased after AJ injection (60% of control values at 8 h), and this was associated with a 4.5-fold increase in hepatic MT at 8 h. Plasma Zn was lowest at 16 h (40% of control), whereas hepatic MT concentrations increased to a maximum of 20-fold at 16 h. Changes in plasma Fe paralleled those of Zn, whereas plasma Cu levels were increased. Plasma metal and hepatic MT concentrations returned toward normal from d 1-7. At d 14, when marked paw swelling was apparent, hepatic MT and plasma Cu were again increased and plasma Zn decreased. Administration of CsA decreased MT induction in rats injected with AJ and also caused a marked recovery in plasma Zn and Fe levels. These changes were small but significant even in the early stages (up to 24 h) after AJ injection and were followed by a sustained improvement in all parameters, corresponding to the nonappearance of clinical arthropathy in CsA-treated rats. TNF-alpha and IL-6 production by peritoneal macrophages isolated from AJ-injected rats was significantly decreased by CsA treatment at d 7 and 14. The inhibition of hepatic MT induction during acute and chronic inflammation by cyclosporin emphasizes the role of the immune system in altered metal homeostasis in inflammation.

Animals↗
PubMed1992

Anti-ulcer activity of a slow-release zinc complex, zinc monoglycerolate (Glyzinc).

A slow-release zinc complex, zinc monoglycerolate (ZMG) was examined for its potential gastroprotective activity in various gastric ulcer models. These models comprised (a) oral or parenteral non-steroidal anti-inflammatory drugs (NSAIDs) given to rats whose gastrointestinal mucosa was pre-sensitized by prior development of arthritis, oleyl alcohol-induced inflammation and cold exposure, (b) oral ethanol (12.5-100%) with and without added 4% HCl, (c) intraperitoneal reserpine (5 mg kg-1) in arthritic and normal rats and in normal mice, (d) oral NSAIDs given to mice in which acid and pepsin production was stimulated by co-administration of intraperitoneal bethanechol chloride (5 mg kg-1) to enhance ulcer development, and (e) NSAIDs given to carrageenan-inflamed rats to determine effects of ZMG on paw inflammation. In these models, ZMG given orally was effective in preventing development of gastric lesions, except with propionic acid NSAIDs; the effective doses being apparently dependent on the severity of the mucosal injury. In many of the models ZMG was superior to zinc sulphate and other zinc salts or metal ion complexes investigated but was slightly more effective or equipotent compared with zinc acexamate. ZMG did not impair the anti-oedemic effects of NSAIDs. ZMG is thus an effective agent in preventing ulcer development in a wide range of model systems and may be more effective than zinc salts because of the controlled slow-release of zinc from the complex.

Animals↗
PubMed1992

The prostaglandin E1 analogue, misoprostol, regulates inflammatory cytokines and immune functions in vitro like the natural prostaglandins E1, E2 and E3.

We examined whether some immune functions related to the action and production of cytokines could be regulated by the natural prostaglandins E (PGE) and the PGE1 (ester) analogue, Misoprostol. PGE1,2,3 and Misoprostol inhibited: (1) the mitogenic activity of interleukin-1 (IL-1) for mouse thymocytes; (2) spreading of mouse macrophages on glass; (3) tumour necrosis factor (TNF) (alpha and beta) production by human peripheral blood mononuclear cells and rat macrophages; (4) IL-1 production by rat and mouse peritoneal macrophages; and (5) interferon-gamma (IFN-gamma) production by human peripheral blood mononuclear cells. These PGE had little effect on IL-1 production by human monocytes. By contrast, they all enhanced IL-6 production by rat and mouse macrophages and human monocytes. These effects were noted at concentrations below 500 nM (even as low as 10 nM). The relative potency of the prostanoids tested for both inhibitory and stimulatory effects was PGE1 = PGE2 = or greater than PGE3 greater than Misoprostol greater than PGA2 much greater than PGF1-alpha = PGF2-alpha = PGD2 (no effect). There is strong evidence that PGE1,2,3 and Misoprostol bind to the same receptor(s) and trigger the second messenger, cAMP, since dibutyryl cAMP (a lipophilic analogue of cAMP) had the same effects as the PGE. These PGE also induced elevated intracellular cAMP levels in and competed with [3H]PGE2 for binding to human and rat cells with the same relative potencies as described above.

Animals↗
PubMed1991

Transdermal delivery of inorganic complexes as metal drugs or nutritional supplements.

The gastro-intestinal tract presents a significant barrier to the efficient absorption of both orally administered metal drugs and dietary essential trace minerals. Absorption can be compromised by competition between alimentary metal ions, by an excess of dietary ligands (e.g. polyphosphates), or by disease (e.g. chronic inflammation). Alternative delivery by injection can be expensive, painful, often promotes systemic toxicity and usually leads to rapid elimination through excretion (bile, urine), as a consequence of bolus dosing. By contrast, our new observations indicate that presenting trace metals or metal drugs in lipophilic forms which can penetrate the dermis, permits their slow release from the skin with more efficient (relative to incipient toxicity) systemic delivery. Examples are given from our own research of dermal application of copper(II), zinc(II), titanium(IV), platinum(II) and gold(I) complexes to treat chronic inflammatory disease. Some of these compounds are also anti-cancer agents. Physical and biological constraints to transdermal (percutaneous) drug delivery are discussed together with some chemical principles governing selection of complexes as metal drugs or dietary supplements.

Administration, Cutaneous↗
PubMed1991

The effects of some anti-arthritic drugs and cytokines on the shape and function of rodent macrophages.

Non-steroidal antiinflammatory drugs (NSAID) enhanced the spreading of mouse and rat peritoneal macrophages attached to either plastic or glass. This was probably due to drug inhibition of prostaglandin E2 (PGE2) production since spreading was also inhibited by adding exogenous PGE2. Corticosteroids (dexamethasone, cortisol and prednisolone) and some immunosuppressants (6-mercaptopurine, methotrexate, but not cyclosporin-A) also enhanced in-vitro spreading of murine peritoneal macrophages. Some recombinant cytokines (human tumour necrosis factor alpha and beta, murine tumour necrosis factor alpha, and murine interferon gamma, but not human interferon gamma) also enhanced the spreading of mouse peritoneal macrophages in vitro. Scanning electron microscopy revealed significant differences in morphology of cells induced to spread by these drugs and cytokines. NSAID treatment also enhanced macrophage clumping in vitro, indicating that cell spreading may play an important role in the resolution of inflammatory processes and/or the formation of multinucleated giant cells.

Adrenal Cortex Hormones↗
PubMed1990

The cyclo-oxygenase inhibitor, piroxicam, enhances cytokine-induced lymphocyte proliferation in vitro and in vivo.

The effects of Piroxicam on the production and activity of lymphoproliferative cytokines (LC) produced by mononuclear phagocytes (MNP) were examined. In vitro, Piroxicam did not affect IL-1 induced thymocyte proliferation (LAF assay). However, the LAF activity from lipopolysaccharide (LPS)-treated MNP cultures was increased after Piroxicam (0.1-20 mumol/L) treatment. The increase in apparent LC activity was largely due to suppression of prostaglandin E2 (PGE2) production. Peripheral blood, spleen and thymus lymphocytes from animals predosed with Piroxicam (5 mg/kg per day for 3 days) synthesized more DNA than untreated mice (as measured by [3H]-thymidine uptake ex vivo). MNP from Piroxicam-treated animals produced significantly more LC. Piroxicam had similar effects in both inflamed and non-inflamed mice. Piroxicam and other non-steroidal anti-inflammatory drugs (NSAID) may therefore stimulate or modulate the immune functions requiring lymphoproliferation by suppressing the formation of PGE2, a natural inhibitor of both LC production and LC-induced lymphoproliferation.

Animals↗
PubMed1978

Copper and inflammation.

Bonta, Sorenson and others have shown that Cu(II) derivatives are effective anti-inflammatory agents. Some chemical and pharmacological properties of Cu(I) and metallic Cu are discussed. Thio complexes of Cu(I) were prepared and shown to be useful anti-inflammatory agents in rats. Hypotheses are stated concerning the possible therapeutic value of copper in its various oxidation states.

Animals↗
PubMed1978

Lymphocyte surface poisons: disulfides and thiolsulfonates.

Eight disulfides (I-VIII) and a thiolsulfonate (IX) were promising blocking agents of lymphocytes in graft-versus-host reactions (GvHR) without comensurate intracellular effects. The blocking effects were assayed through inhibition of the local GvHR after parental lymphocytes had been incubated with agents at suitable concentrations and then inoculated into F1 hybrid offspring. The intracellular effects were assessed beforehand by measuring the inhibition of [6-3H]thymidine incorporation by lymphocytes in the presence of a wide range of concentrations of agents. Concentration levels which induced no greater than approx. 50% inhibition of the [6-3H] thymidine incorporation were considered to reflect sufficiently small intracellular effects and were used for the subsequent GvHR comparisons. Cellular survival always was 90% or more for the GvHR tests (unless stated otherwise), even when inhibition of thymidine incorporation was as high as 50%; hence the thymidine data are useful not only as guides for dose levels in the GvHR but also as leads to new agents that may show immunosuppressive or anti-leukemic activity through intracellular effects. Structural specificity of the active compounds as cell-surface poisons is evidenced by little or no activity (less than 30% inhibition of GvHR) of 28 other disulfides, 2 trisulfides, 2 Bunte salts, and 8 other thiolsulfonates. Active agents may owe this function to replacement of the H of SH in cell-surface thiol receptors by an SR group. Glutathione did not significantly inactivate agents, probably because the products of reaction also are active disulfides. When two agents (III, IX) were given orally or intraperitoneally to F1 hybrid recipients of untreated parental cells, doses of 10--15 mg/kg produced a GvHR inhibition of 17--53%.

Animals↗
PubMed1978

About some common biochemical and pharmacological properties of bile salts and non steroidal anti-inflammatory drugs.

Glyco- and tauro-deoxycholate, -chenodeoxycholate, -dehydrocholate and -cholate uncouple the mitochondrial oxidative phosphorylation in this order of potency. They also induce pseudo-energized mitochondrial swelling and lymphocyte swelling in the same order of potency. Similar swelling properties were observed for glyco- and tauro-lithocholate. Glyco- and tauro-deoxycholate induce alkalinization of the intra-mitochondrial space as determined on bromothymol blue pre-loaded mitochondria. These two bile salts conjugates also increase the amount of -SH groups available on lymphocyte membranes for sulfhydryl-disulfide interchange reactions. All these biochemical properties have been described for non-steroidal anti-inflammatory drugs. They could thus be implicated in the jaundice remission observed in various inflammatory states.

Animals↗