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Biomedical subjects

A Cerami

Publications and source records attributed to A Cerami.

At least 307 records · Page 17Linked to original sources
PubMed1980

Modification of hemoglobin by ninhydrin.

The Strecker degradation reaction was evaluated as a means of modifying hemoglobin in vitro, utilizing ninhydrin as a model compound. Ninhydrin led to modification of hemoglobin (when incubated with hemoglobin or red cells) at physiologic temperature and pH. Isoelectric focusing documented the formation of new hemoglobin bands, all with decreased (more negative) isoelectric points that hemoglobin A. Both alpha and beta chains were modified to an equal degree, although electrophoretic studies documented two modified species of alpha-chains and three modified species of beta-chains. Amino acid analysis of modified hemolysate following NaB3H4 reduction revealed peaks that coeluted with deaminated valine, epsilon-deaminated lysine, and a product with the guanidino group of arginine. The oxygen affinity of hemoglobin increased following its incubation with increasing concentrations of ninhydrin. These studies suggest that ninhydrin is representative of a class of carbonyl compounds that could be utilized to specifically modify that structure and function of hemoglobin variants.

Chemical Phenomena↗
PubMed1979

A glucose-controlled insulin-delivery system: semisynthetic insulin bound to lectin.

A stable, biologically active glycosylated insulin derivative that is complementary to the major combining site of concanavalin A has been synthesized. Hormone release is proportional to the quantity of glucose present. Glucose regulation of exogenous insulin delivery could have important applications in the therapy of diabetes mellitus.

Blood Glucose↗
PubMed1979

Nonenzymatic glycosylation, sulfhydryl oxidation, and aggregation of lens proteins in experimental sugar cataracts.

The formation of sugar-cataracts has been hypothesized to involve the nonenzymatic glycosylation, sulfhydryl oxidation, and aggregation of lens proteins. Cataractous lenses of diabetic and galactosemic rats were analyzed for glycosylated lysine residues in crystallins. A five- and a ten-fold increase in glycosylated lysine residues was measured in galactose and diabetic cataracts, respectively. The modification was predominant in the insoluble fraction of the lens homogenate. The proteins were further examined for the presence of disulfide bonds and high molecular weight aggregates. After careful disruption of the lens in a nitrogen environment, a cloudy solution was obtained from cataractous lenses whereas a clear solution was obtained from normal lenses. The absorbance at 550 nm of the solution of both the galactosemic and the diabetic cataracts could be decreased by approximately 50% with the addition of dithioerythritol (50 mM). The presence of high molecular weight aggregates was ascertained by sucrose gradient centrifugation and gel filtration chromatography. The proteins were heterogenous in size and showed a mol wt range of 36 to greater than 176 million daltons. Treatment with dithioerythritol induced a marked decrease in the amount of high molecular weight proteins. These data suggest that sugar cataracts of experimental animals have, in common with human cataracts, the presence of high molecular weight aggregates which are in part linked by disulfide bonds.

Alloxan↗
PubMed1979

Neurotoxicity of sodium cyanate. New pathological and ultrastructural observations in Maccaca nemestrina.

The effects of sodium cyanate (NaNCO) on the nervous system of Maccaca nemestrina were studied at 2, 4, and 6 months of administration of the drug. The two groups injected with daily doses of 35 and 25 mg/kg/day of Na-cyanate developed a predominantly demyelinating lesion in the pyramidal tracts of the spinal cord. No neuronal changes were observed in the motor cortex, basal ganglia, midbrain, medulla or anterior horn cells of the spinal cord. There was no evidence of peripheral neuropathy. A comparison between the cyanate induced neuropathy in the rat and in the primate was drawn. Ultrastructurally, both species developed a demyelinating process of central or peripheral myelin characterized by vacuolation of the myelin sheath, removal of myelin debris by macrophages and re-myelination. There was little evidence of axoplasmic damage except for an occasional distended fiber containing abundant dense bodies and whorls of neurofilaments. Oligodendrocytes and Schwann cells were electron microscopically intact and participated actively in remyelination. Maccacas maintained at 15 mg/day and sham animals remained normal clinically and anatomically. The predominantly myelinotoxic effect of cyanate is similar to that produced by other myelinotoxic agents and is attributed to a selective modification of myelin proteins by carbamylation.

Animals↗
PubMed1979

Role of nonenzymatic glycosylation in the development of the sequelae of diabetes mellitus.

The increased level of the glycosylated hemoglobin (hemoglobin A1c) in the diabetic patient has proved to be an interesting clue to understanding the biochemical basis of the sequelae of diabetes. This minor hemoglobin, which arises as nonenzymatic postsynthetic addition of glucose to hemoglobin A, acts as an indicator molecule for the glucose environment over a 3-5-wk period prior to measurement. Reasoning that a similar glycosylation reaction could be occurring with other body proteins, we have studied the ocular lens. The lens, like the erythrocyte, is not dependent on insulin for glucose concentration in the extracellular milieu that would be elevated in the diabetic state. These studies have revealed that a high glucose in vivo or an increased glucose or glucose-6-phosphate concentration in vitro leads to the glycosylation of epsilon-amino groups of lysine residues in bovine and rat lens crystallins. This glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfide crosslinks result in the formation of high molecular weight aggregates and an opalescence of the crystallin solutions.

Animals↗
PubMed1979

Rhodotorulic acid--investigation of its potential as an iron-chelating drug.

The use of rhodotorulic acid (RA) as an iron-chelating drug was suggested by experiments in hypertransfused rats in which urinary and fecal iron excretion were significantly enhanced in response to RA. The toxicity of the drug appears to be minimal at a parenteral dose less than 250 mg/kg. An increased excretion of zinc was the only notable side effect of the drug at the doses used. When administered i.v. to humans, RA was only 16% more effective than desferrioxamine (DF). Pharmacokinetic studies showed that RA persisted in the bloodstream of dogs 6 times longer than desferrioxamine after an intravenous injection. Accordingly RA was evaluated as a potential repository drug. While animal experiments were encouraging, human subjects experienced a painful local reaction to RA administered either i.m. or s.c. as a suspension in physiological saline. Accordingly it appears that RA is best looked at as a second line drug, unless a means can be found to obviate local inflammatory reactions.

Adult↗
PubMed1979

Chelation therapy in beta-thalassemia major: a one-year double blind study of 2,3-dihydroxybenzoic acid.

A year-long double-blind study of 2,3-dihydroxybenzoic acid (2,3-DHB) given orally at a dose of 25 mg/kg four times per day was undertaken in 15 patients with beta-thalassemia major. 2,3-DHB and placebo (mannitol) were tolerated to an equal degree and there were no signs of drug toxicity at the end of 1 year. Efficacy in terms of retardation of iron accumulation could be documented using serial liver biopsies, serum ferritin determinations, or clinical laboratory assessment. Serum iron values increased, as did the iron binding capacity, in the group receiving 2,3-DHB. The increase in iron binding capacity was due to drug interference with the method of determination. Because of the greater efficacy of slow infusions of desferrioxamine in chelating iron when administered slowly, the clinic has shifted its emphasis toward further evaluation of that compound. Nevertheless, in view of the minimal toxicity of 2,3-DHB, further work appears warranted to define its role in the treatment of iron-overload.

Administration, Oral↗
PubMed1978

An approach to the development of new drugs for African trypanosomiasis.

The inability of the bloodstream form of Trypanosoma brucei brucei to decompose hydrogen peroxide forms the basis of our attempt to develop new pharmacological agents to kill these organisms. Approximately 1-3% of the oxygen consumed by these parasites appears in the form of hydrogen peroxide. Our previous observation that free radical initiators such as heme and hematoporphyrin D proved to be trypanocidal in vitro and in vivo, respectively, prompted this investigation into the mechanism of action of this class of compounds to enhance their therapeutic efficacy. The locus of H2O2 production within the trypanosome was examined using cell-free homogenates. Experiments described herein suggest that H2O2 is formed by the alpha-glycerol phosphate dehydrogenase in an adventitious manner, and that no enzymatic means of disposing of this potentially toxic compound are present with the organisms. Naphthoquinones were found to substantially increase the rate of both oxygen consumption and H2O2 production by trypanosomal mitochondrial preparations. Presumably, the naphthoquinones are acting as coenzyme Q analogues. The addition of sublytic concentrations of both naphthoquinones and heme leads to a synergistic lysis of the organisms in vitro. Another approach to increasing the susceptibility of T. b. brucei to free radical damage involved reduction of the intracellular concentration of glutathione. This was accomplished through the use of trypanocidal arsenicals. Melarsenoxide and heme acted synergistically in vitro, an effect which was further enhanced via addition of a naphthoquinone. Moreover, hematoporphyrin D and tryparsamide were shown to have a synergistic effect in T. b. brucei-infected mice.

Animals↗
PubMed1978

Diabetic cataract formation: potential role of glycosylation of lens crystallins.

A high glucose concentration in vivo or an increased glucose of glucose 6-phosphate concentration in vitro has been found to lead to the glycosylation of epsilon-amino groups of lysine residues in bovine and rat lens crystallins. In vitro, this glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfide crosslinks result in the formation of high molecular weight aggregates and an opalescence in the crystallin solutions. The addition of reducing agents prevents as well as reverses the formation of high molecular weight aggregates and the opalescence of the crystallins. These phenomena suggest a new interpretation of previous results on cataract formation and a new approach for development of drugs to prevent cataracts.

Animals↗
PubMed1978

Immunologic characterization and quantification of haemoglobin A1c.

Sheep antiserum developed against the human glycohaemoglobin, Hb A1c, distinguishes this fraction from the major component Hb A0. Partial cross reactivity is observed with Hb A1a and Hb A1b, as well as with analogous glycohaemoglobins from mouse and dog haemolysates. The reactivity of the haemoglobins with this specific antiserum is abolished by the reduction of the keto group of the sugar ligand. The immunological specificity displayed provides the basis of a quantitative assay for Hb A1c, suitable for studies of clinical and experimental diabetes.

Animals↗
PubMed1978

The development of new iron-chelating drugs. II.

For the past several years, we have searched for an orally effective iron-chelating drug and report here on several compounds which warrant further investigations based on their ability to promote iron excretion in the hypertransfused rat. Administrered orally, 2,3-dihydroxybenzyolglycine induced both urinary and fecal iron excretion, suggesting that a conjugate of 2,3-dihydroxybenzoic acid may be more efficacious than the parent compound. Tropolone, although rather toxic, stimulated fecal excretion of iron when given p.o. at low doses. Evaluation of less toxic derivatives of tropolone appears to be justifiable. L-Histidine may also be of use in chelatin therapy. Fecal iron excretion is significantly increased in response to oral doses of this essential amino acid. Lastly, cholylhydroxamic acid proved to be the most efficacious oral agent examined thus far. A marked increase in fecal iron excretion results from its administration.

Animals↗
PubMed1978

Mechanism of iron chelation in the hypertransfused rat: definition of two alternative pathways of iron mobilization.

The mechanism of action of two recently identified iron-chelating drugs, RA and CHA, was compared with that of two well-known chelating agents, DF and DTPA, in hypertransfused rats labeled with selective parenchymal and RE cell radioiron probes. The existence of two alternative pathways for the in vivo chelation of iron has been indicated by the present findings. The first of these pathways involves the extracellular chelation of RE cell iron and its subsequent excretion in the urine. The second pathway is concerned with the intracellular binding of hepatic parenchymal cell iron and its subsequent excretion in the bile. Iron chelation by DTPA is restricted to the first pathway, whereas iron chelation by CHA is confined to the second pathway. DF and RA have a dual effect and are able to enhance the urinary excretion of RE cell iron as well as the biliary excretion of hepatic parenchymal iron. Hypertransfused rats are a simple and useful experimental model for the study of iron mobilization by chelating agents of potential clinical usefulness. However, further studies are required to show whether the pathways of iron chelation identified in rats may represent the mechanism of iron chelation in patients with transfusional iron overload.

Animals↗