Studies on monocomponent insulin. IV. Subcutaneous absorption of insulin from preparations with protracted action.
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Absorption↗
Biomedical subjects
T Kasama
Publications and source records attributed to T Kasama.
Determination of purity and identification of animal sources of insulin in various insulin preparations.
Prolonged administration of insulin leads to the formation of insulin-binding antibodies due to contaminant peptides and the animal source of the insulin. It follows that quantitation and identification of these factors are of significant importance in pharmaceutical insulin preparations. The assay and test procedures stipulated in the current pharmacopoeia of various countries, nevertheless, cannot determine either of these effects. In the present study, the content of impurities in insulin preparations was measured by polyacrylamide gel disc electrophoresis and the animal source of insulin identified by amino acid analysis. Assays of 17 commercial insulin preparations by these techniques revealed diversity in purity and animal sources of insulin. The present results suggest potential usefulness of these assay methods and advisability of their adoption not only by the manufacturers but also by the official pharmacopoeia as well.
Amino Acids↗
Stereochemical course of enoyl reduction catalyzed by fatty acid synthetase. Stereochemistry of hydrogen incorporation from reduced pyridine nucleotide.
The stereochemical course of the enoyl reduction catalyzed by fatty acid synthetase was investigated using the enzymes from rat liver and Brevibacterium ammoniagenes. Deuterium-labeled fatty acids were synthesized by incubating the synthetases with either 4R-[4-2H1]- or 4S-[4-2H1]NADPH. The deuterium-labeled fatty acids thus produced were subjected to the action of a stereospecific enzyme, acyl-CoA oxidase. The deuterium-labeled fatty acids and 2,3-dehydroacyl thioesters, the products of acyl-CoA oxidase, were methylated and analyed for deuterium content by gas chromatography-mass spectrometry. These experiments provided information to determine the configuration at the C-3 position of fatty acids formed by fatty acid synthetases. The results suggested that the stereochemistry of hydrogen (as hydride) incorporation from reduced pyridine nucleotides during enoyl reduction was different between rat liver and B. ammoniagenes synthetases: the enoyl reduction of rat liver enzyme involved the re-attack of hydride and that of B. ammoniagenes enzyme involved the si-attack of hydride.
Acyl Coenzyme A↗
Identification of sources of hydrogen atoms in fatty acids synthesized using deuterated water and stereospecifically deuterium labelled NADPH by gas chromatographic mass spectrometric analysis.
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Alcohol Oxidoreductases↗
Stereochemical studies of hydrogen incorporation from nucleotides with fatty acid synthetase from Brevibacterium ammoniagenes.
The biosynthesis of fatty acids from malonyl-CoA and acetyl-CoA was investigated with an enzyme preparation which was purified 100-fold from Brevibacterium ammoniagenes. Fatty acids synthesized in the presence of D2O and stereospecifically deuterated NADPH and NADH were isolated and analyzed by mass chromatography to examine the localization of deuterium in the molecule. The following results were obtained: 1) HB hydrogen of NADPH was used for beta-ketoacyl reductase. 2) HB hydrogen of NADH was used for enoyl reductase. 3) Hydrogen atoms from water were found on the even-numbered methylene carbon atoms (2-hydrogen atoms per carbon atom) and some were also found on the odd-numbered methylene carbon. 4) Hydrogen atoms from NADPH were found on odd-numbered methylene carbon atoms (1-hydrogen per carbon). 5) Hydrogen atoms from NADH were also found on the odd-numbered methylene carbon atoms, but the number of incorporated hydrogen atoms was less than expected. The exchange of HB hydrogen of NADH with water catalyzed by enoyl reductase was suspected. 6) The exchange of methylene hydrogen atoms of malonyl-CoA with proton of water was suggested by 13C NMR analysis.
Brevibacterium↗
Stereochemical studies of hydrogen incorporation from nucleotides with fatty acid synthetase from Brevibacterium ammoniagenes.
The biosynthesis of fatty acids from malonyl-CoA and acetyl-CoA was investigated with an enzyme preparation which was purified 100-fold from Brevibacterium ammoniagenes. Fatty acids synthesized in the presence of D2O and stereospecifically deuterated NADPH and NADH were isolated and analyzed by mass chromatography to examine the localization of deuterium in the molecule. The following results were obtained: 1) HB hydrogen of NADPH was used for beta-ketoacyl reductase. 2) HB hydrogen of NADH was used for enoyl reductase. 3) Hydrogen atoms from water were found on the even-numbered methylene carbon atoms (2-hydrogen atoms per carbon atom) and some were also found on the odd-numbered methylene carbon atoms. 4) Hydrogen atoms from NADPH was found on the odd-numbered methylene carbon atoms (1 hydrogen per carbon). 5) Hydrogen atoms from NADH was also found on the odd-numbered methylene carbon atoms, but the number of incorporated hydrogen atoms was less than expected. The exchange of HB hydrogen of NADH with water catalyzed by enoyl reductase was suspected. 6) The exchange of methylene hydrogen atoms of malonyl-CoA with protons of water was suggested by 13C NMR analysis.
Acetyl Coenzyme A↗
Origin of hydrogen atoms in the fatty acids synthesized with yeast fatty acid synthetase.
The mechanism of hydrogen incorporation into fatty acids was investigated with an enzyme preparation from baker's yeast. Fatty acids synthesized from malonyl-CoA and acetyl-CoA in the presence of D2O or stereospecifically deuterium-labeled NADPH were isolated and analyzed by mass chromatography to examine the localization of deuterium atoms in the molecule. The following results were obtained: 1. Hydrogen atoms from water were found on the even-numbered methylene carbon atoms (2-hydrogen atoms per carbon atom). The second hydrogen atom was incorporated as the result of hydrogen exchange phenomenon between the methylene group of malonyl CoA and water. 2. HB hydrogen of NADPH was used for beta-ketoacyl reductase. 3. HB hydrogen of NADPH was also used for enoyl reductase. 4. Hydrogen atoms from HB position of NADPH were found on the odd-numbered methylene carbon atoms (2-hydrogen atoms per carbon atom).
Deuterium↗
Modulation of granuloma formation in vitro by endogenous mediators.
We have reported previously that in vitro granulomas are inducible by culturing murine spleen cells in the presence of artificial microparticles, dextran beads, and that macrophages and macrophage-derived cytokines (monokines) including interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play a critical role in the initiation of bead-induced granulomas in vitro. To investigate regulatory mechanisms of granuloma formation, we examined the modulatory effects of various mediators such as IL-1, TNF-alpha, interferon-gamma (IFN-gamma), IL-4, IL-6, transforming growth factor-beta (TGF-beta), dexamethasone and prostaglandin E2 (PGE2) on the development of lesions, because these mediators are known to play a pivotal role in inflammatory responses. The lesions were suppressed by the addition of dexamethasone, PGE2 or certain T cell-derived lymphokines such as IL-4 and IFN-gamma. These results suggest that suppressive signals are different from granulomatogenic cytokines including IL-1 and TNF-alpha and that granulomas are regulated by multi-factor dependent mechanisms.
Animals↗
Suppression of pulmonary hypersensitivity granulomas in mice by superoxide dismutase.
Pulmonary hypersensitivity granulomas were induced in immunized mice by the intratracheal injection of antigen-coupled agarose beads. Foreign body lung granulomas were induced in mice by the intratracheal injection of dextran beads. Both lesions developed within 1 day, reached peak intensity within 3 days, and gradually declined in size thereafter. Hypersensitivity granulomas were much larger than foreign body lesions. The lung extracts prepared from mice with hypersensitivity lung granulomas, but not foreign body lesions, contained high levels of superoxide dismutase (SOD) and thiobarbiturate-reactive substances including lipid peroxides. SOD activity and levels of thiobarbiturate-reactive substances in the extracts correlated with sizes of hypersensitive lesions. Hypersensitivity granulomas, but not foreign body lesions, were inhibited by the administration of recombinant human SOD (rh-SOD). Thiobarbiturate-reactive substances were decreased in the lung extracts of mice bearing hypersensitivity granulomas injected with rh-SOD. These results suggest that reactive oxygen intermediates such as superoxide anion may play an important role in the development of hypersensitivity granulomas and that rh-SOD is capable of inhibiting the lesions by its antioxidant action.
Acetylglucosaminidase↗
Long-term effects of bezafibrate on in vivo VLDL-triglyceride production in the rat.
Long-term effects of bezafibrate on in vivo production of VLDL-triglyceride were studied in the rat. Bezafibrate given at a daily dose of 30 mg/kg body weight for 14 days produced a decrease not only in triglyceride by 51% but in cholesterol by 28% and phospholipid by 18%. Despite a marked reduction in plasma triglyceride concentrations, there was no significant change in the rate of VLDL-triglyceride secretion from the liver into the circulation between bezafibrate-treated and control animals (1113 +/- 58 and 1234 +/- 63 micrograms/min, respectively). In addition, bezafibrate produced no change in lipid composition in VLDL. These results suggest that bezafibrate enhances triglyceride removal from the circulation, which leads to reduction in plasma triglyceride.
Animals↗
Recommendation for strict control of plasma triglyceride in diabetic subjects.
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Cholesterol↗
Suppression of thrombin formation during hemodialysis with triglyceride.
Effect of blood-air contact in the venous line air-trap chamber on blood clotting was studied. Fourteen chronic hemodialysis patients (six men, eight women; mean age, 49 years) with elevation of thrombin-antithrombin III were studied. To prevent blood-air contact, triglyceride (NOF-005) was floated over the blood in the chamber. Control hemodialysis was performed for 4 weeks and hemodialysis using NOF-005 followed for the next 4 weeks. Clot formation in the circuit was examined after each hemodialysis and clotting factors including thrombin-antithrombin III, FXII Antigen, vWF Antigen, PF4 and beta-thromboglobulin were measured before and after the last hemodialysis of each control and NOF-005 hemodialysis. Clotting in the chamber was improved when NOF-005 was used. Thrombin-antithrombin III increase during hemodialysis was suppressed to about 30% of control values by using NOF-005. blood-air contact seems to promote thrombin generation and accelerate clot formation.
Adult↗