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Biomedical subjects

M J Kelner

Publications and source records attributed to M J Kelner.

70 records · Page 4Linked to original sources
PubMed1986

Inhibition of erythrocyte superoxide dismutase by diethyldithiocarbamate also results in oxyhemoglobin-catalyzed glutathione depletion and methemoglobin production.

N,N-Diethyldithiocarbamate (DDC), a copper-chelating agent, not only inhibits superoxide dismutase activity in the red cell, but also depletes glutathione and promotes the production of methemoglobin, sulfhemoglobin, and small amounts of lipid peroxidation products. DDC reacts with oxyhemoglobin to yield disulfiram, hydrogen peroxide, and methemoglobin. Disulfiram and hydrogen peroxide both convert GSH to GSSG, while DDC reduces methemoglobin to oxyhemoglobin. Although disulfiram also reacts with the hemoglobin sulfhydryl groups, this reaction does not play a role in the conversion of GSH to GSSG. Other hemoglobin derivatives, ferrous, and ferric ions do not catalyze the oxidation of GSH by DDC. These results support the conclusion that DDC reacts with the super-oxo-ferriheme complex of oxyhemoglobin to generate hydrogen peroxide and disulfiram and that the cyclic conversion of oxyhemoglobin to methemoglobin and DDC and disulfiram results in the net oxidation of GSH. Thus, damage to DDC-treated erythrocytes exposed to a putative superoxide-generating toxin, such as 1,4-naphthoquinone-2-sulfonate, may actually be due to diminished GSH concentration and hemoglobin oxidation rather than to superoxide radicals. Glucose added to the incubation medium of DDC-treated erythrocytes fully prevented glutathione depletion but not the oxidation of oxyhemoglobin to methemoglobin. Several other copper-chelating agents either failed to inhibit the activity of purified superoxide dismutase or when incubated with erythrocytes produced more extensive GSH depletion and hemoglobin oxidation than DDC. It is concluded that the interpretation of results with erythrocytes exposed to copper-chelating agents must consider their effects on GSH and hemoglobin as well as on superoxide dismutase inhibition. Moreover, one must be mindful of the interference by DDC in the analysis of GSH with 5,5'-dithiobis-(2-nitrobenzoic acid) in the absence of sufficient quantities of metaphosphoric acid to destroy DDC and that contamination of DDC with trace quantities of disulfiram may be a significant problem.

Copper↗
PubMed1986

In vitro oxidation of uric acid in serum by methylene blue.

Methylene blue oxidizes uric acid to allantoin in vitro, analogous to the reaction between uric acid and phosphotungstate, although the rate is considerably slower. The reaction requires oxygen and produces hydrogen peroxide. As little as 10 micromol of methylene blue per liter in a serum sample will produce a measurable difference in the apparent uric acid concentration within 4 h at room temperature. Methylene blue may be administered for various medical reasons. If uric acid is to be measured in such sera, the procedure should be performed within 30 min, whatever method of analysis is used.

Aerobiosis↗
PubMed1985

Methylene blue directly oxidizes glutathione without the intermediate formation of hydrogen peroxide.

Methylene blue stimulates the oxidation of glutathione in red blood cells in vitro and in vivo. This oxidation has been attributed to hydrogen peroxide that is generated from the autooxidation of leucomethylene blue arising from the reduction of methylene blue by NADPH. In this report we present evidence that methylene blue directly oxidizes glutathione and that oxidation of glutathione by hydrogen peroxide is a secondary reaction. Moreover, superoxide dismutase has no effect on the oxidation. Under aerobic conditions, methylene blue oxidizes glutathione 30 times faster than the spontaneous autooxidation of glutathione. Under anaerobic conditions the stoichiometry of the reaction of methylene blue with glutathione supports a direct chemical reaction. The reaction rates between glutathione and methylene blue suggest a second order reaction over the conditions tested. That neither oxygen radical formation nor significant amounts of hydrogen peroxide are produced by methylene blue, even in the presence of added glucose, is further confirmed by the failure to detect significant amounts of lipid peroxidation products, or hemolysis, in red blood cells incubated with the dye.

Chemical Phenomena↗
PubMed1985

Rapid separation and identification of myoglobin and hemoglobin in urine by centrifugation through a microconcentrator membrane.

Urinary myoglobin (Mr = 16 500) is readily separated from hemoglobin (Mr = 64 000) by centrifugation through a microconcentrator membrane with a 30 000-Da cutoff. Myoglobin, but not hemoglobin, will pass through the membrane, after which each fraction may be separately analyzed by spectrophotometry. This technique is advantageous over direct spectrophotometry of urine because it is not restricted to analyzing the oxy forms of these hemoproteins and obviates the difficulty of discriminating small (3 nm) differences in their spectra. In addition, this method of separation is more complete than that attained by differential "salting out" with ammonium sulfate, and it is simpler than gel filtration or ultrafiltration under reduced pressure.

Centrifugation↗
PubMedDate not supplied

On the mechanism of toxicity of illudins: the role of glutathione.

Illudin M and illudin S, antitumor sesquiterpenes from Omphalotus illudens, have been found to react with thiols in a pH-dependent manner. The optimum pH values for reaction of illudin M with methyl thioglycolate, cysteine, and glutathione were 5.8, 5.6, and 6.1, respectively, and pseudo-first-order rate constants at 25 degrees C (10-fold excess of thiol) were 44 x 10(-3), 11.5 x 10(-3), and 11.3 x 10(-3) min-1. In all cases, thiol added to the alpha, beta-unsaturated ketone giving an unstable intermediate. Subsequent loss of the tertiary hydroxyl and opening of the cyclopropane ring afforded a stable aromatic product. The toxicity of illudin S to HL60 cells was increased by lowering glutathione levels in the cells and vice versa. General toxicity and antitumor activity of illudins are discussed in the light of these results.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Regulation and legislation of the dying process: views of health care professionals.

Because of radical changes that have been effected by medical advances in the process of dying, it is now frequently necessary for patients to make an explicit decision on whether to forego life-prolonging medical therapies. We report physicians' and nurses' perceptions of the need for, feasibility of, and value of regulations and legislation to govern the dying process. In-depth, semistructured interviews were conducted with a sample of 20 physicians and 20 nurses at a large teaching hospital. There was little unanimity in their attitudes toward whether it is advisable or feasible to devise adequate legal safeguards for physicians and nurses who assist patients to hasten their deaths. Some believed such regulations were needed, but others believed they would seriously compromise good patient care. There was also disagreement as to who should develop guidelines. There was, however, clear opposition among most participants to the involvement of lawyers in the process of clarifying the content of regulations and legislation on the dying process.

Adolescent↗
PubMedDate not supplied

Propylene glycol as a cause of lactic acidosis.

Propylene glycol (PG) concentrations were measured in 35 sera and eight cerebrospinal fluids (CSF) from five patients receiving intravenous medications containing PG as a vehicle. Serum concentrations ranged from 6 to 711 mg/L, and CSF concentrations from 11 to 566 mg/L. The CSF concentrations were as high as 85% of the serum concentrations. In several instances, PG was also measured in urine and pleural fluid. Lactate concentrations ranged up to 24.1 mEq/L (217 mg/dL) and showed statistically significant correlation (r = 0.921) with the PG concentrations in serum (p less than 0.01). The PG:creatinine clearance ratios in two patients were 35.5% and 48.8%. Serum half-lives in two patients were 4.7 and 5.6 hrs. Propylene glycol administration may be an important cause of lactic acidosis in the hospitalized patient.

Acidosis↗
PubMedDate not supplied

Ethchlorvynol ingestion: interpretation of blood concentrations and clinical findings.

Thirty-eight patients who ingested ethchlorvynol were seen at our institution over an 8.7 year period. Eleven involved ethchlorvynol alone ("pure") while the remainder included at least one other drug ("mixed"). Twenty-three of the patients were women. Six patients required hospitalization. Five patients were chronic users of the drug. Admission ethchlorvynol blood concentrations ranged from 3 to 46 mg/L ("pure") and from 3 to 75 mg/L ("mixed"). For the "pure" cases the most common physical findings were depressed level of consciousness (10 cases), dysarthria (7), mydriasis (6), nystagmus (6), areflexia (4), tachycardia (4), and hypotension, ataxia, and respiratory depression (2 cases each). Following "pure" ingestion, ethchlorvynol concentrations greater than 19 mg/L were usually associated with dysarthria, mydriasis, nystagmus, and tachycardia. When concentrations exceeded 38 mg/L, coma, areflexia, hypotension, and respiratory depression were generally noted as well. All patients recovered with supportive care alone.

Adult↗
PubMedDate not supplied

Nonresponsiveness of the metastatic human lung carcinoma MV522 xenograft to conventional anticancer agents.

The human lung carcinoma cell line MV522 was previously noted to produce extensive metastasis to the lungs, spleen and lymph nodes after subcutaneous transplantation into athymic nude mice. Animals eventually succumb to these metastases, and not primary tumor growth. The ability to produce extensive metastasis after a simple subcutaneous injection in 100% of animals (> 100 tested to date) would be an advantage when screening compounds for anticancer activity. To validate the utility of this xenograft model for testing anticancer agents, we tested the ability of 10 anticancer drugs to either inhibit primary tumor growth and/or prolong life span of MV522-bearing animals. Among the 10 antitumor conventional agents, only mitomycin C and taxol demonstrated primary tumor growth inhibition. Mitomycin C produced a mild increase in median life span of 41% to 63%, while taxol had inconsistent effects. The metastatic MV522 carcinoma model appears to reflect clinical resistance of primary non-small cell lung cancer to conventional chemotherapeutic agents and should be useful for testing new anti-cancer drugs.

Animals↗
PubMedDate not supplied

In vitro and in vivo studies on the anticancer activity of dehydroilludin M.

Six first-generation illudin analogs were tested for antitumor activity using in vitro cytotoxicity and in vivo xenograft models. One analog, dehydroilludin M, inhibited xenograft growth and prolonged life span of tumor bearing animals, when administered IP or IV, whereas the parent Illudin S compound was ineffective. The efficacy of dehydroilludin M in the MV522 lung carcinoma model exceeded that of 9 known anticancer drugs, and equaled that of mitomycin C. Dehydroilludin M retained the in vitro relative selective cytotoxicity for carcinomas and myeloid leukemia cell lines noted with the parent illudin compounds. In vitro cytotoxicity data predicted response of xenografts. Dehydroilludin M also retained the in vitro activity of the parent compounds against different multidrug resistant mdr cell lines.

Analysis of Variance↗