Biomedical subjects

M M Jones

Publications and source records attributed to M M Jones.

At least 271 records · Page 15Linked to original sources

PubMedDate not supplied

An in vitro model for the in vivo mobilization of cadmium by chelating agents using 113Cd-NMR spectroscopy.

An in vitro method, based on 113Cd-NMR spectroscopy, that provides an alternative to the use of animals for an initial screening of cadmium antagonists is presented. The relative values of the effective stability constants of potential chelating antagonists for cadmium are estimated by using 113Cd-NMR spectroscopy to determine the concentrations of the cadmium species involved in appropriate competitive equilibria. This is accomplished via an examination of the competition between the proposed antagonist and EDTA (ethylenediaminetetraacetic acid) for cadmium-113; previously, EDTA has been shown to be capable of removing cadmium from such in vivo binding sites as metallothionein. The reactions proceed via the stepwise addition of three dithiocarbamate groups to the cadmium accompanied by the concurrent stepwise release of donor groups from the EDTA. The resulting 113Cd-NMR data allow for the determination of the overall stability constant for the complex formed between cadmium and N-methyl-D-glucamine dithiocarbamate, iminodiacetic acid dithiocarbamate, proline dithiocarbamate, sarcosine dithiocarbamate. The use of 113Cd-NMR spectroscopy has the potential for providing direct evidence on the effectiveness of chelate antagonists to compete with endogenous ligands for other toxic metal ions. This technique could prove very useful for other compounds that are not stable enough toward acid and/or base to be examined by standard titrimetric methods.

Cadmium↗

PubMedDate not supplied

The reactions of cis-[Pt(NH3)2(H2O)2]2+ with L-(+)-cystathionine and seleno-L-methionine: potential relevance to the molecular basis of cisplatin toxicity.

NMR spectroscopic studies indicate that the hydrolysis product of cisplatin, cis-[Pt(NH3)2-(H2O)2]2+, reacts readily with the important intracellular thiol L-(+)-cystathionine and the amino acid derivative seleno-L-methionine. In both cases, the formation of six-membered mononuclear S,N- or Se, N-chelate rings was established on the basis of [1H], [13C], [77Se], [195Pt], and [13C]-(1H) DEPT (distortionless enhancement by polarization transfer), COSY (correlation spectroscopy), heterocorrelation, and NOE (nuclear Overhauser effect) difference NMR experiments. The formation of these products suggests that related in vivo processes may play a significant role in the toxicity of cisplatin. The potential loss of NH3 in such platinum complexes may lead to additional products over time.

Cisplatin↗

PubMedDate not supplied

Design of in vivo cadmium-mobilizing agents: synthesis and properties of monobenzyl meso-2,3-dimercaptosuccinate.

A novel method for the synthesis of monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) is presented which utilizes the reaction of the vicinal sulfhydryl-protected anhydride with the corresponding alcohol in the presence of a base. The product is then treated successively with mercuric chloride to remove the protecting group and form the mercuric complex, and hydrogen sulfide to regenerate thiol groups by removal of mercury as HgS. This strategy was exploited to synthesize monobenzyl meso-2,3-dimercaptosuccinate (MBzDMS), C6H5CH2O(O)CCH(SH)CH(SH)C(O)OH, and demonstrates a feasible synthesis of monoesters difficult to obtain by direct esterification, via the use of the reactive anhydride. The resultant compound was found to be an effective cadminum-mobilizing agent when used with cadmium-exposed rats or mice and when administered by any one of several routes (ip, iv, po). This monobenzyl ester (MBzDMS) of DMSA was found to be somewhat less effective than the corresponding monoisoamyl ester (Mi-ADMS) in mobilizing cadmium from such cadmium deposits. The ability of MBzDMS to mobilize cadmium into the urine is significantly decreased by the coadministration of p-aminobenzoic acid, in support of the hypothesis that MBzDMS enters renal cells via an anion transport system. An analysis of the structural features of vicinal dithiols examined as antagonists for chronic cadmium intoxication allows a hypothesis to be formulated indicating essential features required for the design of effective new cadmium antagonists of this type.

Administration, Oral↗

PubMedDate not supplied

Molecular-modeling design of cadmium-mobilizing agents: a novel biscarbodithioate.

This report describes the design, synthesis, characterization, and in vivo cadmium-mobilizing properties of a novel biscarbodithioate chelating agent, namely, disodium N,N'-diglucosyl-1,9-nonanediamine-N,N'-biscarbodithioate+ ++ (C9G2DTC), HOCH2(CHOH)4CH2(CS2Na)N(CH2)9N(CS2-Na)CH2( CHOH)4CH2OH, which can coordinate to a single cadmium ion with both of its carbodithioate groups (CS2Na) in its folded configuration. When evaluated for its cadmium efficacy at 1.0 mmol/kg x 5 ip in 109Cd-pretreated rats against sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as standard, the biscarbodithioate was found to reduce the whole-body levels of cadmium more rapidly in the rat than BGDTC which contains only one CS2Na group. The whole-body Cd depletions after the first ip injection of the new and the standard compound were 52% and 23%, respectively. The C9G2DTC was found to be more effective in removing cadmium from the liver (% Cd reductions compared to controls: C9G2DTC, 94, and BGDTC, 85), but slightly less effective in reducing renal cadmium levels (% Cd-reductions: C9G2DTC, 44, and BGDTC, 60). The ip LD50 of the bis-DTC was estimated to be slightly in excess of ca. 4.0 mmol/kg in the rat. A molecular model of this chelating agent indicates that, because of the flexibility of the nonane chain, both carbodithioate groups can approach closely enough to each other to permit complexation with the same cadmium ion to give a resulting structure without significant strain. A mechanism for the removal of Cd from CdMT by C9G2DTC is also proposed.

Animals↗

PubMedDate not supplied

Structure/activity relationships affecting the ability of monoanionic 3-hydroxyprid-4-ones to mobilize iron.

Current attempts to remove iron from individuals suffering from iron overload have encountered difficulty due to the toxicity of the administered chelating agent. In a search for iron chelators of potentially reduced toxicity, nine monoanionic compounds have been examined. To determine the chemical features which govern their ability to induce the excretion of iron, the compounds were administered to female Sprague-Dawley rats. All carboxylate derivatives were tested for biliary excretion following iv injection, as well as for urinary excretion following iv or po injection. Sulfonate derivatives were tested for biliary and urinary excretion as well, but only one representative compound was tested po. The biological activity of the new pyridinones was compared to that of 1,2-dimethyl-3-hydroxypyrid-4-one, L1, which served as the standard. While none of the chelators was able to surpass L1 in both urinary and biliary iron excretion, all of the chelators at least equaled L1 in one of these two areas following iv administration. Two derivatives surpassed the standard in mobilizing iron into the bile, and all others were statistically equivalent. In terms of urinary excretion, two compounds were equivalent to L1 after iv administration, although none of the compounds equaled L1 when administered orally. The structure of (1,4-dihydro-3-hydroxy-2-methyl-4-oxo-1- pyridyl)methanecarboxylic acid was determined by X-ray diffraction, as this compound showed higher activity than previously reported by other investigators. We speculate that these chelators utilize organ-specific, monoanionic transport systems in the liver and kidneys to mobilize iron and that their toxicity may be substantially less than that of their neutral analogs.

Animals↗

PubMedDate not supplied

Effects of some chelating agents on urinary copper excretion by the rat.

In order to estimate the potential advantages of new chelating agents which can enhance copper excretion in the chronic copper intoxication arising in Wilson's disease, the relative ability of none chelating agents to induce the urinary excretion of copper was compared with that of D-penicillamine (DPA) and triethylenetetramine.2HCl (TRIEN), all given ip at 1 mmol/kg to male Sprague-Dawley rats. The compounds examined were as follows: tris(2-aminoethyl)-amine.3HCl (TREN), tetraethylenepentamine.5HCl (TETREN), pentaethylenehexamine.6HCl (PENTEN), 1,4,7,11-tetraazaundecane.4HCl (TAUD), 1,5,8,12-tetraazadodecane.4HCl (TADD), 1-N-benzyltriethylenetetramine.4HCl (BzTT), 4,7,10,13-tetraazatridecanoic acid.2H2SO4 (TTPA), 1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane.4HCl (BPTETA), and N,N-bis(2-pyridylmethyl)-4-(aminomethyl)benzoic acid (4ABA). Of these, BzTT, TTPA, and 4ABA are new chelating agents not previously reported. The factors by which these chelating agents enhanced copper excretion over control (untreated) levels were as follows: DPA, 7.2; TREN, 1.6; TRIEN, 4.0; TETREN, 10.1; PENTEN, 7.8; TAUD, 7.8; TADD, 2.6; TTPA, 5.6; BzTT, 1.8; and 4ABA, 5.5. The results indicate that it may well be possible to develop additional chelating agents which are equal or superior to those now used in the treatment of Wilson's disease, as well as structural types whose immunological properties may be significantly different from DPA or TRIEN, the compounds currently used in the clinic for this disorder.

Analysis of Variance↗

PubMedDate not supplied

In vivo cadmium mobilization by three novel bis(carbodithioates).

Four novel cadmium-chelating agents N,N'di(D-glucosyl)alkanediamine-N,N'-bis(carbodithioates) 4a-e were prepared as disodium salts of the general formula (CH2)n[N(CS2Na)CH2(CHOH)4CH2OH]2, where n = 7, 8, 10, and 12. They were synthesized by the reductive coupling of 2 mol of alpha-D-(+)-glucose (1) with 1 mol of the corresponding alkanediamines 2a-e followed by reaction with CS2 in a basic medium. The elemental analyses of the Cd complexes 5a, b, d, and e prepared revealed that these bis(carbodithioates) form 1:1 complexes with Cd2+. The in vivo cadmium-mobilizing efficacy of three of the new chelators (4a, b, and d) was determined in rats pretreated ip with CdCl2.H2O containing 2 microCi of 109Cd (74 kBq), and comparable data were obtained on a previously reported member of this series (4c, n = 9), and with BGDTC (sodium N-benzyl-D-glucamine-N-carbodithioate, 6), all given once at 1.0 mmol/kg ip. The compound with n = 12 (4e, C12G2DTC) proved to be too toxic in the preliminary study and was not evaluated further. A single injection of the 4a, b, and d caused a reduction in Cd levels of the whole body to ca. 50% and liver to ca. 12% of control levels. Comparable experimental data on BGDTC resulted in a reduction of whole-body cadmium to only 78% of the control levels and a reduction in liver cadmium to only 56% of control. After one and six injections at the same dosage, the new chelators (4a, b, and d) and C9G2DTC (4c, n = 9) significantly surpassed BGDTC for whole-body and liver Cd depletion but caused only a very modest depletion of renal Cd. While these compounds were designed to allow the two dithiocarbamate groups to coordinate to the same Cd2+ in vivo, the data do not prove that the two > NCS2Na groups bind to the same cadmium ion in vivo. The very rapid reduction in liver cadmium levels following only a single injection indicates that these -2 anions rapidly gain access to intracellular hepatic sites by some transport system.

Animals↗

PubMedDate not supplied

Chelate antidotes for sodium vanadate and vanadyl sulfate intoxication in mice.

Eighteen different chelating agents, including all of those previously shown to have a protective action in vanadium intoxication, have been compared as antidotes for acute vanadium intoxication using mice. Of these compounds, those found to be effective antidotes for both vanadate (VO3(-3)) and vanadyl (VO2+) include ascorbic acid, deferoxamine, D-penicillamine, sodium calcium diethylenetriaminepentaacetic acid (Na3CaDTPA), Na2CaEDTA, glutathione, Tiron, and ethylenediaminetetra(methylene phosphonate). Of the compounds examined, ascorbic acid appeared to be the most promising for human use. When administered at the levels used in this study, it is an effective antidote for intoxication due to either the vanadate or the vanadyl ion. Certain compounds are able to act as antidotes for vanadate solely by virtue of their action as a reducing agent; when these compounds are unable to form complexes with the reduction product (vanadyl ion), they are effective antidotes for the higher oxidation state only when the concentration of vanadyl produced is less than the level that results in toxic effects.

Animals↗

PubMedDate not supplied

In vivo screening of potential antidotes for chronic cadmium intoxication.

Nineteen chelating agents have been screened under identical conditions of metal loading in an attempt to establish their relative ability to mobilize cadmium from the liver and kidney in mice with chronic cadmium intoxication. The compounds investigated were divided into five groups: polyaminocarboxylic acids, monothiols, dithiols, macrocycles, and a miscellaneous category. Only 2,3-dimercaptopropanol (BAL) and sodium diethyldithiocarbamate (NaDDTC) were able to produce a statistically significant (at the 95% level) reduction in the cadmium content of the kidney. The closely related dithiols sodium 2,3-dimercaptopropane-1-sulfonate and 2,3-dimercaptosuccinic acid produced statistically significant increases in the liver cadmium contents, as did N-(2-mercaptopropionyl)-glycine. The reduction in kidney cadmium levels produced by both BAL and NaDDTC was just under 40%.

Animals↗

PubMedDate not supplied

Paramagnetic NMR contrast agents. Development and evaluation.

Paramagnetic ions could be theoretically used as NMR contrast agents because of their effect upon T1. However, the toxicity of these ions prevents their application. By the formation of appropriate chemical complexes with these ions, the toxicity of these agents can be substantially reduced while maintaining the paramagnetic effect. Two potential NMR contrast agents, one for oral use and one for intravenous administration, were developed and evaluated both in vitro and in vivo. The effect upon T1 in vitro of these paramagnetic compounds was determined using a JEOL FX-90Q NMR spectrometer. These agents were evaluated in vivo in dogs with a Technicare 0.3 tesla superconducting magnet system and in rabbits with the Aberdeen 0.04 tesla resistive NMR imager. Using calculated T1 NMR images, a nontoxic dose of gadolinium oxalate provided visualization of the gastrointestinal tract. Intravenous administration of chromium EDTA provided enhancement of the kidneys, ureters, and bladder, thereby potentially allowing for the evaluation of renal function with magnetic resonance imaging. Stable paramagnetic complexes can serve as effective, nontoxic, oral and intravenous NMR contrast agents.

Administration, Oral↗

PubMedDate not supplied

Infantile subglottic hemangiomas. An update.

Between 1913 and 1985, 323 cases of infantile subglottic hemangiomas have been reported in the English language literature. The purpose of this study is to review these cases, to report The Johns Hopkins Hospital experience with ten additional cases, and to compare the various methods of treatment in an attempt to identify the regimens associated with the best outcome. The majority of the patients presented before the age of 6 months with respiratory distress, most commonly inspiratory stridor. There was a 2:1 female to male preponderance. The diagnosis was established by endoscopy in the majority and confirmed by biopsy in one third, without serious bleeding complications. A plethora of treatment methods have been described, including the following: corticosteroids, tracheotomy, radiation therapy, radioactive implant therapy, surgical excision, cryotherapy, and carbon dioxide laser. These methods were reviewed and their results compared to our own. We conclude that several methods are effective, each having its advantages and disadvantages. We believe that immediate tracheotomy should be performed in cases with severe airway obstruction. Smaller lesions may be vaporized with the carbon dioxide laser without tracheotomy if postoperative care is provided in a pediatric intensive care unit. Corticosteroids may be used alone or in combination with other modalities. External radiation therapy and injection of sclerosing agents are not advised.

Female↗

PubMedDate not supplied

An interdisciplinary mock trial involving pharmacy, law, and ethics.

OBJECTIVE: To describe an innovative, interdisciplinary approach to illustrate the relationship between healthcare ethics and law. METHODS: A mock trial was created for students enrolled in the Samford University McWhorter School of Pharmacy and Department of Paralegal Education. The trial served as the starting point to discuss confidentiality in health care in general and pharmacy in particular. Students from both programs served on the jury and rendered a verdict after the case had been presented. The Alabama statute concerning exceptions to confidentiality is reviewed. The students' assignment and lessons learned are also described. SUMMARY: Students thoroughly enjoyed this method of teaching and learning. The mock trial provided an interesting way to exemplify the often complex relationship between healthcare ethics and law.

Confidentiality↗

PubMedDate not supplied

Coadministration of dimethyl sulfoxide reduces cisplatin nephrotoxicity.

The administration of dimethyl sulfoxide with cisplatin at a mole ratio of 200:1 results in a considerable reduction in the nephrotoxicity produced when cisplatin alone is administered to Sprague-Dawley rats at 7.5 mg/kg. Observed measures of nephrotoxicity which were significantly improved by the coadministration of cisplatin and DMSO over the values found for cisplatin alone include BUN, serum creatinine, creatinine clearance and histopathological evidence of renal damage. The weight loss associated with cisplatin administration was also significantly reduced by DMSO coadministration. The use of DMSO did not result in any observable loss in antitumor activity of cisplatin against the Walker 256 carcinosarcoma.

Animals↗

PubMedDate not supplied

Thioether suppression of cisplatin nephrotoxicity in the rat.

Six compounds containing a thioether group were examined as agents for the reduction of the nephrotoxicity caused by cisplatin (CDDP) in the rat. Of these, five were able to reduce the CDDP- induced nephrotoxicity when administered simultaneously with CDDP (8.0 mg/kg, iv). The compounds capable of reducing CDDP toxicity were L-methioninamide, cystathionine, methionyl-L-alanine, (methythio) acetic acid and 4-(methylthio) benzoic acid. Indices used to evaluate toxicity included body weight changes, BUN and serum creatinine levels and the histopathological examination of renal tissue. The platinum levels of renal tissue were determined but were found not to correlate well with other measures of renal function. Oral administration of the more effective of these compounds was found to provide a reduced level of protection against the nephrotoxicity caused by iv CDDP. The most effective of these compounds caused a very modest reduction in the anti-tumor activity of CDDP as measured against the L1210 murine leukemia.

Animals↗

PubMedDate not supplied

Thiol and thioether suppression of cis-platinum-induced nephrotoxicity in rats bearing the Walker 256 carcinosarcoma.

An examination of eighteen thiols and thio ethers revealed that the simultaneous administration of several of these with cis-platinum (CDDP) at 7.5 mg/kg (25 mumols/kg) iv, as a single injection to rats bearing the Walker 256 carcinosarcoma led to significant reduction in the nephrotoxicity typically found with cis-platinum, and no apparent interference in its anti-neoplastic action towards this tumor. The thiols and thiol ethers were administered at a twenty-fold molar excess to the CDDP and were combined with the CDDP immediately prior to administration. The most effective compounds in suppression nephrotoxicity were D-, and L-methionine, methyl and ethyl L-methioninate, and N-acetyl-D, L-methionine.

Animals↗

PubMedDate not supplied

Combination and individual antitumor effects of hyperthermia, cisplatin, and selected dithiocarbamates.

The antitumor effects produced by combinations of cisplatin (Pt), substituted dithiocarbamates (dimethyldithiocarbamate [DmDTC] and sodium N-methyl-D-glucamine dithiocarbamate [NMGDTC]) and hyperthermia (H) were measured and compared to those produced by single agents alone in C3H/HeN mice bearing the transplantable radiation-induced fibrosarcoma, RIF-1, in one or both hind feet. The average tumor volumes of control and treatment groups were compared periodically after treatment with H. Combinations of H and Pt completely resolved established foot tumors in 10/13 mice. However, evidence of long-term nephrotoxicity and gastrointestinal (GI) toxicity became evident causing death of these mice within 120 to 122 days after tumor inoculation. Hyperthermia plus DmDTC resolved tumors in heated and non-heated feet in 3/8 mice, thus demonstrating both ipsilateral and contralateral anti-tumor activity. Furthermore, H-Pt-NMGDTC produced complete tumor resolution in 7/13 mice; these mice survived and were tumor-free 180 days post inoculation and autopsies revealed no appreciable nephro- or GI toxicity. In addition, 4/8 mice underwent complete tumor resolution in heated left feet plus dramatic retarding of tumor growth in unheated right feet (ipsilateral and contralateral anti-tumor effects). Five heat-treated left foot tumors resolved in the H-Pt-DmDTC group with one mouse demonstrating resolution of tumor in both feet. Advanced foot tumors were treated with H-DmDTC and H-Pt-DmDTC. Hyperthermia and Pt were administered on day 0 of the experiment and DmDTC on days 0 through 3; dramatic tumor shrinkage continued through day 6 for a total of 75 to 80 percent reduction of tumor volume in both groups. The concurrent administration of DmDTC or NMGDTC with H and Pt prevented or greatly reduced nephrotoxicity and GI toxicity in all experiments without retarding anti-tumor efficacy.

Animals↗

PubMedDate not supplied

Toxicity of chelated mercury.

The oral and iv acute toxicities of several mercury chelates were determined in mice in a search for relationships bearing on the effectiveness of various chelating agents in therapy. It was found that the toxicity was independent of the stability constant for the mercury chelate when the toxicity was expressed on a molar basis. For the mercury chelates of sulfhydryl containing chelating agents, the oral toxicity was unexpectedly low, presumably due to the poor absortion of these materials from the G.I. tract. The results suggest that the toxicities of mercury complexes are independent of the stability constant of the complex over the range of stability constant from 10(23) on down, provided chelation does not drastically alter the distribution of the complex in the body.

Animals↗

PubMedDate not supplied

Mechanism of diethyldithiocarbamate, dihydroxyethyldithiocarbamate, and dicarboxymethyldithiocarbamate action of distribution and excretion of cadmium.

Diethyldithiocarbamate (DEDC), dihydroxyethyldithiocarbamate (DHDC), and dicarboxymethyldithiocarbamate (DCDC) were assessed for their relative efficacies in mobilizing metallothionein-bound cadmium (Cd) from selected organs and tissues of mice and in promoting Cd excretion. The DHDC was effective but less so than DEDC in mobilizing Cd from liver, kidney and spleen. However, while DEDC effected a redistribution of Cd which resulted in higher levels in lungs, testes, heart, and brain, DHDC after 13 injections reduced the levels of Cd in all four of these organs. The DCDC analog did not alter the Cd load of any organ. Bone Cd content was most effectively reduced by DEDC; DCDC was somewhat less active, and DCDC was without effect. Skin Cd burden was enhanced markedly after treatment with DEDC but was reduced by treatment with DHDC or DCDC. Treatment with DEDC increased the muscle Cd content about 250 percent over control values; treatment with DHDC reduced it significantly, while DCDC was without effect. Both DEDC and DHDC reduced the whole body Cd burden, but DCDC was ineffective. The initial rate of fecal excretion of Cd was much greater following DHDC treatment than after DEDC treatment, while DCDC did not promote excretion to any detectable extent. The pattern of mobilization, redistribution, and excretion of Cd following treatment with each chelator was related to the organic/aqueous partition coefficient of each dithiocarbamate-Cd complex.

Animals↗