Biomedical subjects

M M Jones

Publications and source records attributed to M M Jones.

At least 127 records · Page 7Linked to original sources

PubMed1990

Structural influences on intracellular cadmium mobilization by dithiols.

An examination of 5 dithiols, N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA), benzene-1,2-dithiol (BDT), toluene-3,4-dithiol (TDT), alpha, alpha'-dimercapto-o-xylene (DOX), and 4,5-dimethyl-alpha,alpha'-dimercapto-o-xylene (DDOX), reveals that these compounds are all inferior to previously reported compounds as agents for the in vivo mobilization of cadmium from its intracellular sites, although all possess sulfhydryl groups capable of reacting with cadmium. The results demonstrate the considerable importance of those parts of the molecule which do not participate directly in the formation of chelate rings in the determination of the ultimate behavior of such compounds in vivo.

Animals↗

PubMed1990

Schedule dependency of a cadmium-complexing dithiocarbamate analog in mice.

A number of dosing regimens was assessed to determine the optimum schedule of administration of N-(4-methoxybenzyl)-N-dithiocarboxy-D-glucamine (MeOBDCG) in depleting whole-body, renal and hepatic levels of metallothionein-bound cadmium (Cd) in mice. A comparison of 4.0 mmol/kg given as a single injection versus 0.5 mmol/kg given as 8 hourly injections revealed the latter regimen to be superior in reducing renal Cd levels, but less effective than a bolus dose in lowering hepatic Cd concentrations. Administration of 1.33 mmol/kg for 3 consecutive days or 0.8 mmol/kg for 5 days effected a more extensive depletion of renal Cd concentrations than did a single injection of 4.0 mmol/kg. Three injections of 1.0 mmol/kg given at 4- to 7-day intervals were generally more effective in reducing renal Cd concentrations than were 3 consecutive daily injections in mice which had low or moderately high total Cd burdens. The lowest effective dose of MeOBDCG in lowering whole-body, liver and kidney Cd levels when given repetitively was about 0.2 mmol/kg. While schedule variations did not alter appreciably the whole-body Cd reductions at any given total dose of MeOBDCG, repetitive dosing schedules in which injections were given at intervals of several days rather than daily were typically more effective in reducing renal Cd levels. Based upon consideration of pharmacological response as influenced by body surface area, it was calculated that doses of MeOBDCG of the order of 2.0 g/d may be effective in reducing renal Cd levels in individuals with chronic renal dysfunction secondary to chronic Cd intoxication.

Animals↗

PubMed1990

Increased elastase secretion by peripheral blood monocytes in cystic fibrosis patients.

Morbidity and mortality in cystic fibrosis (CF) is predominantly due to destruction of pulmonary tissue. The host immune response may, in part, play a pathogenic role in pulmonary destruction in these patients. To further understand host immune response in CF, we examined the state of activation of peripheral blood monocytes in CF. Baseline elastase activity was 2.2-fold greater in the CF monocytes than in controls. Pseudomonas aeruginosa mucoid exopolysaccharide (MEP) and high molecular weight polysaccharide (HMP) increased elastase activity in both control and CF monocytes, with a greater absolute increase in the CF monocytes. There was no difference in baseline or MEP-stimulated secretion of interleukin-1 (IL-1) or interleukin-6 (IL-6) between CF and control monocytes. Ibuprofen enhanced both MEP and HMP-stimulated elastase activity, whereas dexamethasone suppressed both baseline and stimulated elastase activity greater than 20% in both CF and control monocytes. These results suggest that circulating monocytes in CF are stimulated in vivo, resulting in a remarkably elevated elastase activity in vitro. Elevated elastase release by peripheral blood monocytes as they enter the lung in response to chemotactic stimuli may contribute to lung destruction in CF.

Adolescent↗

PubMed1990

Structural factors in the in vivo chelate mobilization of aged cadmium deposits.

The role of structural factors in determining the relative efficacy of dithiocarbamates as chelating agents for the in vivo mobilization of aged cadmium deposits is examined for 23 newly synthesized compounds of this type. The critical feature in determining the efficacy of the compounds in mobilizing intracellular cadmium is the balance between hydrophobic and hydrophilic groups. This balance also governs the other properties of these compounds such as the organ specificity of action and the relative propensity to carry cadmium to the brain. The transport of cadmium to the brain by dithiocarbamate can be greatly reduced by the incorporation of appropriate hydrophilic groups that prevent the formation of lipid-soluble cadmium complexes that pass readily into the brain. If the chelating agents carry an additional ionic charge, their ability to pass through cellular membranes and react with intracellular deposits of cadmium is significantly reduced, with other structural factors being equal. The structural features that optimize mobilization of cadmium from the kidney do not appear to be identical with those that optimize its mobilization from the liver. The correlation of cadmiummobilizing properties of these chelating agents with the sum of the Hansch pi constants for the parts of the molecular structures other than the dithiocarbamate grouping (sigma pi) is reasonably good for the removal of renal cadmium by derivatives of D-glucamine and D-xylamine. Another aspect of the molecular structure that appears to play a role is the presence of uncharged polar groups having the ability to form hydrogen bonds. The relevance of these factors in designing chelating agents to enhance the excretion of other toxic metals from their intracellular sites is discussed.

Animals↗

PubMed1990

Glutathione status, glutathione monoisopropyl ester, and cadmium metabolism in mice.

Glutathione monoisopropyl ester (GSHMI) was synthesized for an investigation of its interactions with cadmium (Cd) in mice. When administered ip prior to the injection of lethal doses of Cd given by the ip or sc route, it did not reduce Cd-induced mortality. When given to Cd-bearing mice it did not promote mobilization of Cd from metallothionein-bound stores in liver, kidneys, spleen, testes, pancreas, or brain. When given at a dose of 6.0 mmol/kg 2 hr prior to administration of Cd, GSHMI enhanced Cd accumulation in kidneys, liver, spleen, and testes, and reduced the accumulation of the metal in brain. When 4.0 mmol/kg of the ester were given at various intervals prior to Cd administration, the major actions observed were substantial increases in Cd concentrations ultimately attained in kidneys and liver at most time intervals examined. Reductions of Cd accumulation were found only in liver and pancreas, and only when GSHMI treatment preceded Cd administration by 30 min. Reduction of endogenous GSH levels by administration of L-buthionine-(S,R)-sulfoximine (BSO) led to moderate increases in Cd accumulation in kidneys and pancreas; Cd deposition was reduced in spleen, testes, heart, lungs, and brain. BSO pretreatment led to only slight or no change in liver Cd accumulation. Sephadex G-75 gel filtration chromatography revealed that GSHMI pretreatment led to only a moderate and transient increase in hepatic Cd-metallothionein content when measured 2 hr after Cd administration; when assessed 1 hr and 3 hr post-Cd, elution profiles of extracts from livers of GSHMI-pretreated mice were indistinguishable from control profiles. We conclude that GSHMI is not an effective agent for the control of Cd toxicity.

Animals↗

PubMed1989

The rate of the in vivo dithiocarbamate-induced mobilization of hepatic and renal cadmium deposits.

The dithiocarbamate-induced removal of aged cadmium from intracellular sites in the kidneys and liver of mice has been followed as a function of time. The processes are quite rapid with the entire course of the cadmium-removal process being completed in 60-90 min. An examination of the rates at which a dithiocarbamate removes cadmium from hepatic and renal deposits in vivo and from metallothionein in vitro, suggests strongly that the processes are similar. A common mechanism is proposed for both processes which involves the direct attack by the dithiocarbamate on cadmium ion incorporated into metallothionein. Such a mechanism is consistent with the similarities in rates and the degree of overall mobilization of cadmium by the same dithiocarbamate both in vitro and in vivo. The administration of 1 mmol/kg of sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate (MeOBDCG) to cadmium-loaded mice leads to a reduction of in vivo renal and hepatic cadmium levels of 45% and 30%, respectively, over a period of only 1 h. Previously the incubation of metallothionein in vitro in the presence of 1 mmol/l of MeOBDCG was found to lead to the reduction of the cadmium content of metallothionein of approximately 60% over a period of 1 h. The administration of higher doses of this compound (2 mmol/kg and 4 mmol/kg) to cadmium-loaded mice led to an even more rapid and more extensive removal of cadmium from both the liver and the kidney. The major factors which limit the ability of dithiocarbamates to mobilize cadmium from in vivo sites appear to be molecular structural features which hinder or prevent the access of the dithiocarbamates to the intracellular sites at which the majority of aged cadmium deposits are held.

Animals↗

PubMed1989

The mobilization of intracellular cadmium by butyl and amyl esters of meso-2,3-dimercaptosuccinic acid.

The esters of the general structure, [CH(SH)COOR]2, i.e., Di-BDMS, R = CH2CH(CH3)2; Ds-BDMS, R = CH(CH3)CH2CH3; Di-ADMS, R = CH2CH2CH(CH3)2; and D3-ADMS, R = CH(CH2CH3)2 from the reaction of meso-2,3-dimercaptosuccinic acid with isobutyl, sec-butyl, isoamyl, and 3-amyl alcohols, respectively, have been prepared, characterized, and examined as chelating agents for the removal of cadmium from its aged intracellular deposits. All of these compounds depleted cadmium from such deposits and significantly reduced the whole body levels of cadmium. In the case of three (Ds-BDMS, Di-BDMS, and Di-ADMS) of these compounds, the reductions achieved are equal to or greater than that produced by 2,3-dimercapto-1-propanol (BAL) under similar circumstances. None of these compounds caused any redistribution of cadmium to the brain, and two of them (Di-BDMS and Di-ADMS) caused a very much larger reduction in the liver levels of cadmium than BAL. None was as effective as BAL in reducing kidney levels of cadmium. These compounds are not soluble in water and are administered as solutions in peanut oil. A comparison of the behavior of these compounds with others which have been reported to be effective in reducing body burdens of cadmium in chronic cadmium intoxication reveals that they are among the most effective. An analysis of the manner in which mobilizing efficacy changes with structure indicates that higher, purely alkyl analogs are not expected to be superior to these compounds, though other structural variations may be.

Animals↗

PubMed1989

Control of nephrotoxicity in the rat during repeated cis-platinum treatments.

The nephrotoxicity of cis-platinum (CDDP) in the rat can be controlled throughout a series of weekly administrations of CDDP (each of 5 mg kg-1, i.v.) for at least three weeks by a combination of protective measures involving pretreatment with dithiocarbamates and diuretics and the administration of appropriate dithiocarbamates given 1 h after the CDDP. The use of dithiocarbamates with polar substitutents is effective in removing both renal and hepatic deposits of platinum from rats subsequent to its administration and in this respect these compounds are significantly superior to meso-2,3-dimercaptosuccinic acid (DMSA) in the rate at which platinum is removed and in the amounts removed. The most effective of the dithiocarbamates remove ca. 70% of the platinum from the kidneys and the liver; the least effective remove ca. 50% of the platinum from these organs when given at a level of 1.57 mmol kg-1 i.p. for 6 days subsequent to the administration of CDDP. Acetazolamide was shown to be much less effective in preventing renal damage than the dithiocarbamates and was not effective in reducing renal or hepatic levels of platinum. Pretreatment with sodium diethyldithiocarbamate 12 h prior to the administration of the CDDP was more effective in preventing renal damage than the administration of this compound 30 min before the cis-platinum. Several dithiocarbamates are found to be superior to sodium diethyldithiocarbamate in reducing renal platinum burdens of rats given CDDP at the level of 6 mg kg-1, and dose-response curves for the removal of renal and hepatic platinum were determined for sodium N-methyl-D-glucamine dithiocarbamate (NaG).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Dithiocarbamate-induced biliary platinum excretion and the control of cis-platinum nephrotoxicity.

Treatment with any one of six different dithiocarbamates subsequent to the administration of cis-platinum (CDDP) is shown to promote the biliary excretion of platinum. The administration of the most effective of these compounds, sodium diethyldithiocarbamate (DDTC) at 1.57 mmol/kg, led to a 30-fold increase in the biliary excretion of platinum. For the other dithiocarbamates investigated, a similar dosage led to increases ranging from approximately 5-fold for sodium iminodiacetic acid dithiocarbamate, to 26-fold for sodium sarcosine dithiocarbamate. The presence of alkyl groups on the nitrogen of the dithiocarbamate increased the effectiveness of the compounds. There is no increase in the platinum levels of the brain when DDTC is used in this manner. A histopathological evaluation of the kidneys of rats given 15 mg CDDP/kg in 6.3% saline with and without the use of dithiocarbamates for renal protection shows significant additional protection due to the use of the dithiocarbamates. Dithiocarbamates given at an appropriate dosing schedule can lead to a significant reduction in the renal damage which is revealed by microphotographs. It is suggested that part of the renal protection obtained by the use of dithiocarbamates may be due to this shift of platinum excretion to the bile which obviates additional renal exposure to platinum. It was also found that the simultaneous injection of a dithiocarbamate with the cis-platinum has no obvious effect on the anti-cancer action of cis-platinum against the Walker 256 carcinosarcoma in rats.

Animals↗

PubMed1989

Thermodynamics of the interaction of sodium-n-dodecyl sulphate with Aspergillus niger catalase in high ionic strength aqueous solutions.

The thermodynamic parameters for the interaction between sodium n-dodecyl sulphate (SDS) and Aspergillus niger catalase in aqueous solution at pH 3.2 and 6.4 have been measured by microcalorimetry and equilibrium dialysis over a range of ionic strength from 0.05 to 0.2 at 25 degrees C. Binding isotherms have been interpreted in terms of theoretical models (Hill equation and Wyman binding potential). The Gibbs energies of interaction become increasingly negative with increase in ionic strength and the entropies of interaction become increasingly positive. The ionic strength dependence of the Gibbs energies are much greater than predicted by the Debye-Hückel limiting law indicating a strongly ionic strength dependent hydrophobic contribution to the interactions.

Aspergillus niger↗

PubMed1989

Mechanistic aspects of the dithiocarbamate-induced mobilization of cadmium.

The examination of some of the species involved in the in vivo processes in which dithiocarbamates mobilize cadmium from its intracellular deposits indicates that several competing reactions occur. Rates of hydrolytic decomposition of a series of dithiocarbamates capable of mobilizing cadmium in vivo have been determined, and the solubility behavior and nuclear magnetic resonance (NMR) spectra of their cadmium complexes have been examined. Some of the dithiocarbamates most effective in this mobilization process are shown to undergo slow conversion to oxazolidine-2-thiones in the presence of cadmium. All of the cadmium complexes involved in the mobilization process are shown to undergo rapid ligand exchange. While dissociative mechanisms based on the turnover of metallothionein are inconsistent with the experimental data, at least two associative mechanisms are possible. These involve attack on the metallothionein by the dithiocarbamate itself or by a compound derived from it by known metabolic processes.

Animals↗

PubMed1989

N,N-disubstituted dithiocarbamates as cadmium antagonists: N-(4-methoxybenzyl)-N-dithiocarboxy-D-glucamine.

The newly synthesized dithiocarbamate analog, N-(4-methoxybenzyl)-N-dithiocarboxy-D-glucamine (MeOBDCG) reduced whole-body cadmium levels 66% in cadmium-laden mice when given as 3 injections at 1.0 mmol/kg. Renal and hepatic Cd concentrations were reduced 78 and 85%, respectively. After 6 injections, the whole-body cadmium burden was reduced 71%, while renal and hepatic levels were lowered 84% and 91%, respectively. Mobilized cadmium was excreted almost exclusively by the fecal route. There was no evident toxicity consequent to treatment as judged by mouse body weights and by gross appearance of organs upon dissection. On a molar dose basis, MeOBDCG was more effective than N-benzyl-N-dithiocarboxy-D-glucamine (BDCG) in removing cadmium from both renal and hepatic deposits. An in-vitro assessment of the interaction of MeOBDCG, BDCG and N-methyl-N-dithiocarboxy-D-glucamine with murine cadmium-metallothionein (Cd-MT) revealed a direct relationship between the extent of cadmium depletion from Cd-MT and the relative in-vivo efficacies of the 3 analogs.

Animals↗

PubMed1989

Idiopathic pelvic pain. The relationship to depression.

Episodic and chronic idiopathic pelvic pain is enigmatic for both physician and patient. Antidepressant drug therapy combined with behavior modification techniques is beneficial in improving the functional status of some patients. Whether the decrease in frequency, intensity, and duration of pelvic pain complaints results from treatment of underlying depression or analgesic effects of the antidepressant drugs is difficult to determine. Addressing the psychological component of idiopathic pelvic pain through education and counseling is essential to long-term resolution of symptoms.

Abdomen↗

PubMed1989

Mobilization of lead by esters of meso-2,3-dimercaptosuccinic acid.

An examination was made of the relative efficacies of 2,3-dimercapto-1-propanol (BAL) and three diesters ( [CH(SH)COOR]2; DMDMS, R = CH3; DEDMS, R = C2H5; and Di-PDMS, R = CH(CH3)2] of meso-2,3-dimercaptosuccinic acid (DMSA) in mobilizing freshly injected lead from mice. These diesters, like BAL, reduced the lead levels resulting from freshly injected lead in both the soft tissues (liver, kidneys, spleen, and brain) and the bone (tibia). After treatment with the dimethyl (DMDMS), the diethyl (DEDMS), and the diisopropyl (Di-PDMS) esters the lead content of each of the organs was significantly less than that present in the untreated controls. Each of the diesters reduced lead levels in the kidneys, liver, and spleen significantly below those levels found after BAL treatment. The action of the diesters in reducing brain lead levels was comparable to that of BAL. Di-PDMS was the most effective of these compounds and was significantly superior to BAL. Each of the esters was also significantly more effective than BAL in reducing the whole body level of lead.

Animals↗

PubMed1989

Effect of chelating agent structure on the mobilization of cadmium from intracellular deposits.

An examination of the efficacy of several structural types of chelating agents in the removal of cadmium from its intracellular deposits in mouse liver and kidneys reveals that of the structural types examined, only dithiocarbamates and a vicinal dithiol were able to mobilize cadmium from such intracellular sites. Esters of L-cysteine, a macrocyclic thioether, and a disulfide of a dithiocarbamate were unable to cause any appreciable decrease in either renal or hepatic cadmium levels. Charged groups such as carboxylic acid groups reduce the efficacy as well as the toxicity of the structural types that can otherwise mobilize such cadmium. It was also found that the administration of a cadmium-binding polymer ip leads to only a very slight net excretion of cadmium, while the po administration of this polymer leads to no net additional cadmium excretion. Of the compounds newly reported here, some are approximately equal in cadmium-mobilizing efficacy to the most effective of previously reported compounds.

Animals↗

PubMed1989

Effects of dithiocarbamates on intestinal absorption and organ distribution of cadmium chloride in mice.

Earlier publications have demonstrated that diethyldithiocarbamate (DDC) antagonizes the acute toxicity of injected CdCl2 but enhances the acute toxicity of orally administered CdCl2, most likely due to the high lipophilicity of DDC and the complex formed with the Cd++ ion. This study demonstrates that the hydrophilic dithiocarbamates dihydroxyethyldithiocarbamate (DHE-DTC) and N-methyl-N-glucamyl dithiocarbamate (NMG-DTC) also enhance the intestinal absorption of orally administered CdCl2 in mice, although less efficiently than DDC. After oral as well as intraperitoneal administration 15 min. after a single oral dose of CdCl2 the dithiocarbamates tested enhanced the intestinal cadmium uptake with a relative efficiency, DDC greater than DHE-DTC greater than NMG-DTC, which correlated to the lipophilicity of both the dithiocarbamates and the complexes formed with the Cd++ ion. Intraperitoneal administration of DDC induced extensive changes in the relative organ distribution of absorbed cadmium, compared to the distribution of CdCl2 administered alone. However, the only noticeable effect of administration of DHE-DTC and NMG-DTC was decreased gastrointestinal deposition of cadmium, irrespective of the administration route of the dithiocarbamates. Earlier studies have demonstrated that DDC and various other dithiocarbamates are capable of mobilizing intracellular cadmium deposits, presumably due to some lipophilicity. This study demonstrates that these dithiocarbamates may also enhance the intestinal absorption of cadmium.

Administration, Oral↗

PubMed1989

Population of the diaphragm by mast cells in growing rats.

The mast cell content of the diaphragm of the rat was examined using electron microscopy, and using light microscopy in material stained with Alcian blue. The concentration and diameters of the mast cells were estimated in animals at regular time intervals from 16 days gestation to 14 weeks of age and compared to the mast cell content of muscles of the calf and anterior abdominal wall. The results were discussed in relation to the origin of mast cells. It was proposed that if mast cells develop in haemopoietic sites that they may populate adjacent tissues by migrating within the connective-tissue spaces.

Aging↗

PubMed1989

Relationship of hypergammaglobulinemia, circulating immune complexes, and histocompatibility antigen profiles in patients with cystic fibrosis.

Among patients with cystic fibrosis (CF), those in the subset who develop hypergammaglobulinemia and circulating immune complexes often have relatively severe disease and a decreased likelihood of survival. Because Fc receptors have an important role in the removal of immune complexes and because defective Fc receptor function has been associated with inheritance of the histocompatibility antigens HLA DR2 and HLA DR3, we postulated that HLA DR2 and/or HLA DR3 might be genetic markers for this subset of patients with CF. However, in a group of 20 carefully documented patients with CF, we found no association of HLA DR2 or HLA DR3 with serum immunoglobulin, immune complex levels, or evidence of rapidly progressive disease.

Adolescent↗