Oxidation of sulfhydryl groups to disulfides by sulfoxides.
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Biomedical subjects
Publications and source records attributed to M Friedman.
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The preparation of cast films of ethylcellulose containing caffeine and salicylic acid is described. These films exhibit timed release of drugs. Release rates were found to agree with both the classical first-order equation (log drug retained against time) and diffusion-controlled release models, as exemplified by Higuchi's equations (drug release linearly related to square root of time). Mathematical analysis of the data shows that the release behavior actually conforms with the diffusion-controlled model. Literature results, reported as first order, for the release of cetylpyridinium chloride and benzalkonium chloride from polyamide films were analyzed similarly and shown to be diffusion controlled. Recommendations are made for presentation and routine treatment of drug release data to avoid ambiguity and provide useful biopharmaceutical information.
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Plasma norepinephrine (NE) and epinephrine (E) were assayed in 15 men prone to develop coronary heart disease (type-A behavior pattern) and in 15 coronary-disease-resistant men (type-B behavior pattern) under resting, noncompetitive conditions and also immediately before, during, and after participation in a nonphysical competitive struggle. The average concentration of catecholamines was virtually the same in both groups under resting conditions. Under competitive conditions the NE concentration of the coronary-susceptible group rose an average of 30%, while that of the resistant group remained essentially unchanged. E concentration remained unchanged in both groups.
The electron spin resonances (ESR) of several native and modified melanins have been determined. Melanins isolated from black wool and synthesized from 3,4-dihydroxyl-L-phenylalanine (L-DOPA) and tyrosine all show similar ESR signals. Modification of the isolated melanins by treatment with reducing agents causes some lightening in color and slight changes in the ESR spectra. Lithium and liquid ammonia (Birch) reduction applied to melanins from wool and L-DOPA gave very different results, as reflected by ESR spectra, but in both cases the changes were much greater than those produced by other treatments. In general, reductive treatments in nonaqueous media in the presence of metals increase the free radical content and line width, whereas treatment in aqueous media resulted in decreased free radical content. These observations are consistent with a melanin pigment which is an irregular polymer and has unpaired electrons localized on different but similar monomer units.
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Hydrolysis rates of N-acetyl dehydroalanine methyl ester (methyl 2-acetamidoacrylate) and related model compounds were measured in aqueous, organic and mixed aqueous media. Adding dimethylsulfoxide (DMSO) to water, retarded hydrolysis of the ester by a factor of 2 to 500, depending on the pH of the medium and concentration of DMSO. Ethanol also slowed hydrolysis, but the effect was not so pronounced. Related studies show that the acetamido group C-N bond of sodium 2-acetamido-acrylate is hydrolyzed only about 1/130 as fast as the ester group C-O bond. Aqueous dimethyl sulfoxide should by a useful medium for synthesis of peptide, amino acid and protein derivatives of N-acetyl dehydroalanine methyl ester.
Ethly vinyl sulfone (EVS) alkylates xi-amino groups of lysine side chains and imidazole groups of histidine residues in proteins. Amino acid analysis of hydrolyzates of EVS-treated polylysine shows that lysine forms two derivatives, presumably xi-N-(ethylsulfonylethyl)lysine and xi, xi, N,N-bis(ethylsulfonylethyl)lysine that are eluted as well-resolved peaks on the (long basic) physiological column of our amino acid analyzer at about 118 and 60 min, respectively. Peaks with identical elution times were also observed after EVS-treatment of BSA and wool. The postulated histidine derivative, presumably N3-im-(ethylsulfonylethyl)histidine is also eluted as a well-resolved peak on the same column at about 90 min. A peak with an identical elution time was observed in a hydrolyzate of EVS-treated polyhistidine. The described alkylation has potential utility for modifying proteins.
Permeability constants of salicylic acid, caffeine and benzoic acid have been measured at 37 degrees for heterogeneous films of ethyl cellulose containing up to 50% PEG 4000, the latter component undergoing leaching out. For the first two compounds, steady state constants were independent of film thickness and solute concentration but increased linearly and sharply with PEG content and were reproducible. The films were impermeable to NaOH and permeation rates were independent of receiver compartment pH. Solubility coefficients and diffusion coefficients of the substances in the films were measured using sorption and/or time lag methods and were low as compared with polyethylene films. High solubility seemed to be associated with the presence of a free activated hydrogen, shown by sorption studies on other substances. From the evidence, it appeared that mass transfer was controlled by the solubility diffusion process in the ethyl cellulose of the membranes with all three substances. Enhancement of permeability by PEG thus seemed due to increased porosity, equivalent to reduction in the effective thickness of the matrix, which nevertheless retained its barrier properties. Enhancement coefficients calculated from the slopes of PEG concentration plots may be useful for predicting the increased mass transfer of drugs through such membranes and could enable the porosity and thickness factors to be balanced against each other for formulation of coated products.
Ten children with severe asthma, who had been well controlled on maintenance betamethasone valerate aerosol for an average of 11 months, were given placebo aerosols without their knowledge. The period of placebo substitution was campared with one 28-day period of betamethasone valerate therapy beforehand, and two 28-day periods afterwards. Symptoms were increased during the placebo period, and patients did not return to their previous well-controlled state until the second month after reinstitution of therapy. Changes in the means of twice-daily peak expiratory flow readings (PEFR) followed the same pattern as changes in symptoms. The exacerbation of asthma which occurred during placebo treatment was accompanied by a widening in the diurnal variation between morning and evening PEFR. In comparison with the previous period, morning PEFR fell by a greater amount than evening PEFR. Standardized running tests suggest an increase in exercise-induced bronchoconstriction and in the Exercise Lability Index when the child was receiving only placebo treatment as compared with betamethasone valerate treatment. The trial provided further evidence of the efficacy of betamethasone valerate aerosol in the prophylatic therapy of severe childhood asthma. As 2 of these children were able to discontinue long-term therapy it is unlikely that this drug causes dependency.
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Some of the possible mechanisms responsible for the hypocholesterolemic effect of glucagon were investigated. Glucagon was found to inhibit the intestinal absorption of cholesterol. In addition, it was found to either hasten the rate of egress of lipoprotein cholesterol from the blood into the liver or to retard the rate of re-entry of cholesterol from the liver into the blood. The data do not distinguish between these two possibilities, which indeed may occur simultaneously.
The initial appearance and continuous development of a coronary plaque depends on a combination of hemodynamic trauma, deposition of excess cholesterol, and accretion and incorporation of thrombogenic elements as well as fully formed mural thrombi. Plaques become life-threatening when rupture of their intimal surface due to internal necrosis and calcification leads to acute thrombosis and/or intramural hemorrhage. Although infarcts can and do occur in the absence of acute thrombi, the latter are caused not by the occurrence of infarcts, but almost always by plaque rupture. Following the occurrence of and survival from an acute occlusive coronary thrombosis, canalization of the thrombus frequently takes place, leading to the formation of a "luminal collateral vascularization." The vessels making up such complexes are prone in turn to hemorrhage and thrombosis.
Experience with 70 patients having osteogenic sarcomas treated between 1968 and 1973 demonstrated the importance of persistence in the management of the disease of these patients. Resection for pulmonary metastases in one or both lungs, often on more than one occasion, will salvage a number of these patients, thus improving the cure rate. Adriamycin has proved an effective palliative agent and a useful adjuvant to surgical therapy. Although the cure rate of tumors arising distal to the knee is much higher than that of more proximally situated tumors, resection of osteogenic sarcomas of the distal part of the femur does not require removal of the entire femur when care is taken to resect well above the site of the apparent tumor. Some osteogenic sarcomas are sensitive to adequate dosages of radiation therapy, but the exact role of this method is yet to be determined. No definite beneficial result could be attributed to any of a variety of modalities of immune stimulation therapy.
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