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Biomedical subjects

I H Hall

Publications and source records attributed to I H Hall.

At least 145 records · Page 8Linked to original sources
PubMed1985

Hypolipidemic activity of antiepileptic 5-phenylhydantoins in mice.

Administration (20 mg/kg i.p.) of antiepileptic 5-phenylhydantoins phenytoin, ethotoin, mephenytoin, and selected metabolites to mice over a period of 16 days produced lower serum concentrations of cholesterol and triglycerides with most of the compounds studied. Several compounds were more effective hypolipidemic agents than clofibrate at 150 mg/kg per day. Several N-alkylated derivatives of the most active compound, 5-ethyl-5-phenylhydantoin, a metabolite of mephenytoin, displayed activities equal to those of the underivatized compound. These in vivo studies suggest that antiepileptic phenylhydantoins, when used in chronic therapy in man, could possibly act as hypolipidemic agents.

Animals↗
PubMed1985

Antitumor agents 68: effects of a series of helenalin derivatives on P-388 lymphocytic leukemia nucleic acid and protein synthesis.

A series of analogues related to helenalin demonstrated moderate capability for inhibiting the growth of murine P-388 lymphocytic leukemia cells in vivo and in vitro. The growth inhibition correlated with suppression of both DNA and protein synthesis in P-388 cells. The inhibition of protein synthesis occurred at a relatively low concentration and appeared to occur at the level of initiation. The suppression of DNA synthesis in P-388 cells correlated positively with inhibition of inosine 5'-monophosphate dehydrogenase activity. Although nuclear and alpha DNA polymerase activities were suppressed by certain analogues, the inhibition of the polymerases did not correlate positively with DNA synthesis inhibition and, furthermore, the magnitude of suppression of DNA polymerase activity did not appear to be sufficient to account for the observed suppression of DNA synthesis in P-388 cells.

Animals↗
PubMed1985

Antineoplastic activity of a series of boron analogues of alpha-amino acids.

A series of amine cyanoboranes, amine carboxyboranes, and boron analogues of alpha-amino acids have been investigated for antineoplastic activity against the growth of Ehrlich ascites cells. Additional studies demonstrated that the boron analogues inhibited DNA and RNA synthesis at 300 microM. The suppression of DNA synthesis of Ehrlich ascites cells correlated with the reduction of DNA polymerase, 5-phosphoribosyl-1-pyrophosphate amidotransferase, and dihydrofolate reductase activities afforded by the boron compounds. These derivatives did not suppress protein synthesis, thymidylate synthetase, or thymidine monophosphate kinase activities as previously reported for some boron antineoplastic agents.

Amino Acids↗
PubMed1985

Hypolipidemic activity of 6-amino-2-mercapto-5-methyl-pyrimidine-4-carboxylic acid and related derivatives in rodents.

6-Amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid proved to be a potent hypolipidemic agent in rodents at the low dose of 20 mg/kg/d. The agent effectively reduced the liver enzyme activities required for the synthesis of triglycerides and cholesterol. Lower lipid levels in tissue were observed in mice but not in rats. Preliminary studies indicate that the agent accelerated the excretion of cholesterol and its metabolites from the body. The agents lowered the low-density lipoprotein (LDL) cholesterol content and raised the high-density lipoprotein (HDL) cholesterol content. These changes in lipoprotein cholesterol content suggest that the agent may be helpful in protecting against coronary disease. The agent is more effective than the commercially available agent, i.e., clofibrate at 150 mg/kg/d.

Animals↗
PubMed1985

Hypolipidemic activity of the surfactants aminimides, and their effects on lipid metabolism of rodents.

A series of short chain fatty acid derivatives of aminimides were shown to possess hypolipidemic activity in rats and mice. Most of the agents tested lowered both serum cholesterol and triglyceride levels by at least 30% in mice and were effective in hyperlipidemic induced mice. 1,1-Dimethyl-1-(2-hydroxypropyl)-amine mersitimide lowered serum cholesterol levels 41% and serum triglyceride levels 56% at 20 mg/kg/day I.P. after 16 days. The same agent was active orally when administered to rats with a 38% reduction in serum cholesterol and a 52% reduction in serum triglycerides after 14 days. The agents inhibited liver acetyl CoA synthetase, ATP dependent citrate lyase and phosphatidate phosphohydrolase activities in vitro and in vivo. Reduction of cholesterol, triglycerides, neutral lipids and phospholipid levels were noted in the livers of mice treated for 16 days. In rat studies, cholesterol, triglyceride and phospholipid levels were reduced in liver, small intestine and the feces after two weeks' dosing. The cholesterol content was reduced in the very low density lipoprotein (VLDL) and low density lipoprotein (LDL) fractions but elevated in the high density lipoproteins (HDL). Triglyceride levels were lowered in the VLDL, and neutral lipid levels were reduced in the chylomicron and VLDL fractions.

ATP Citrate (pro-S)-Lyase↗
PubMed1985

Hypolipidemic activity of indan-1,3-dione derivatives in rodents.

A series of 2-substituted indan-1,3-dione derivatives, including alkyl (C-1-C-5), mono- and disubstituted phenyl, and other 2-aryl derivatives, were tested for hypolipidemic activity of CF1 male mice at 20 mg/kg per day. These derivatives reduced both serum cholesterol and triglycerides after 16 days of administration intraperitoneally. 2-(4-Methoxyphenyl)indan-1,3-dione was one of the more active compounds with 41% reduction of serum cholesterol and 58% reduction of serum triglyceride levels on day 16. This activity was confirmed in the rat after oral administration. 2-(2-Methylphenyl)- and 2-(4-chlorophenyl)indan-1,3-dione were effective in reducing serum triglyceride levels 58% and 53%, respectively, in mice. Serum cholesterol on day 16 was effectively reduced 46% by 2-(2,4-dimethylphenyl)indan-1,3-dione. The indan-1,3-dione derivatives were more effective than clofibrate in lowering lipid levels in mice. A more detailed study on the effects of 2-(4-methoxyphenyl)indan-1,3-dione demonstrated that key enzymes in the de novo synthesis of lipids were inhibited by the drug lowering tissue levels of lipids but raising those in the feces. The alterations in lipid content of rat lipoprotein fractions by the drug appeared favorable.

Animals↗
PubMed1985

Comparison of the hypolipidemic activity of cyclic vs. acyclic imides.

Two series of nitrogen-substituted cyclic and acyclic imides were examined for hypolipidemic activity in mice after dosing for 16 days at a dose of 20 mg/kg per day. The hypolipidemic activity of the unsubstituted, N-butyl, N-3-oxobutyl, and N-2-carboxyethyl derivatives of diacetimide and succinimide were compared as well as the unsubstituted and N-substituted dibenzimide and diphenimide. It was shown that an imide functionality incorporated into a ring was not necessary for hypocholesterolemic activity. Good hypocholesterolemic activity was observed in both series of acyclic and cyclic imides. However, a cyclic imido structure was a necessary requirement for good hypotriglyceridemic activity. A decrease in hypotriglyceridemic activity was noted when comparing the cyclic imides to their respective acyclic congeners.

Animals↗
PubMed1984

Indirect inactivation of rabbit reticulocyte initiation factor eIF-2 by helenalin and bis(helenalinyl) malonate.

Helenalin and bis(helenalinyl) malonate, sesquiterpene lactones that react primarily with exposed sulfhydryl groups, were shown to be equally effective inhibitors of endogenous protein synthesis in rabbit reticulocyte lysates. By use of partially fractionated systems, it was possible to show that helenalin preferentially inhibited the conversion of the ternary initiation complex to the 48S preinitiation complex. Previous experiments have shown that this preferential inhibition is due to selective inactivation of eIF-3 [Williams, W. L., Chaney, S. G., Willingham, W., Considine, R. T., Hall, I. H., & Lee, K.-H. (1983) Biochim. Biophys. Acta 740, 152-162]. Bis(helenalinyl) malonate was much less active as an inhibitor of 48S complex formation than helenalin and clearly did not possess sufficient activity in that assay to explain its effectiveness as a protein synthesis inhibitor in whole lysates. Kinetic studies also showed a clear difference between the mechanism of action of these two drugs. Bis(helenalinyl) malonate inactivated protein synthesis in reticulocyte lysates only after a lag of 10 min, and the inhibition of protein synthesis could be completely reversed by the addition of 5 mM cAMP. Helenalin showed more complex kinetics. While full inhibition only occurred after a lag of 10-15 min, a partial inhibition was observed from very early times. cAMP at 5 mM was only partially able to reverse inhibition by helenalin. Phosphorylation studies showed that both helenalin and bis(helenalinyl) malonate were equally effective at activating eIF-2 alpha kinase and indirectly causing phosphorylation of eIF-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Antineoplastic activity of tetrakis-mu-(trimethylamine-boranecarboxylato)-bis (trimethylamine-carboxyborane)dicopper (II) in Ehrlich ascites carcinoma.

A binuclear copper(II) complex derived from trimethylamine carboxyborane [tetrakis-mu-(trimethylamine-boranecarboxylato)-bis-(trimethyla mine- carboxyborane)dicopper(II)] was shown to have antineoplastic activity in the Ehrlich ascites carcinoma screen. Metabolic studies demonstrated that the compound suppressed DNA and protein syntheses. The inhibition of DNA synthesis appeared to be due to reduction of the DNA polymerase activity and the regulatory enzymes of de novo purine synthesis. Preliminary data suggest that the compound is an initiation inhibitor of protein synthesis in Ehrlich ascites cells.

Animals↗
PubMed1984

Synthesis and evaluation of the antitumor properties of esters of 2-furoic acid and 2-furylacrylic acid.

A series of activated and nonactivated esters of 2-furoic and 2-furylacrylic acids were synthesized and examined for antineoplastic activity in the Ehrlich ascites carcinoma screen at 20 mg/kg/d. 2-Furoic acid and 2-furylacrylic acid demonstrated potent activity, as did the methyl and cyanomethyl esters of each series. The vinyl ester of 2-furoic acid possessed antineoplastic activity. However, the ethyl and D,L-tetrahydropyranyl esters of each series were inactive in the tumor screen.

Animals↗
PubMed1984

Structure-activity studies on antihyperlipidemic N-benzoylsulfamates, N-benzylsulfamates, and benzylsulfonamides.

A series of aryl substituted N-benzoyl- and N-benzylsulfamic acid sodium salts and benzylsulfonamide sodium salts have been prepared and examined for antihyperlipidemic activity in male CF1 mice at a dose level of 20 mg/kg/d ip for 16 d. These substances were also subjected to toxicological evaluation and chemical stability studies. In general, both series of sulfamates and sulfonamides significantly lowered serum cholesterol and triglyceride levels in mice. The compounds were nonmutagenic, showed no acute toxicity or impaired liver or kidney function in male mice, and were chemically stable both as the monohydrates and in aqueous solution over a pH range of 3.5-7.4. While both series of sulfamates and sulfonamides lowered serum cholesterol and triglyceride levels, the sulfamates were relatively more potent with regard to decreasing cholesterol levels, while the sulfonamides were more effective in lowering serum triglyceride levels in mice.

Animals↗
PubMed1984

Antihyperlipidemic activity of o-chlorobenzylsulfonamide in rodents.

o-Chlorobenzylsulfonamide was observed to be a potent hypolipidemic agent in rodents, reducing serum cholesterol levels 71% and triglyceride levels 49% at 60 mg/kg/d. The agent was effective both in normal and hyperlipidemic mice and was active both orally and intraperitoneally. o-Chlorobenzylsulfonamide significantly inhibited phosphatidate phosphohydrolase activity and marginally inhibited sn-glycerol-3-phosphate acyl transferase activity both in vitro and in vivo. The lowering of serum cholesterol levels appeared to be correlated with the accelerated excretion of cholesterol via the bile into the feces, with a marginal reduction of cholesterol absorption from the intestine. Reduced concentrations of lipids, e.g., cholesterol, triglycerides, and neutral lipids, were observed in the liver, small intestine, and blood lipoprotein fractions of rats.

Absorption↗
PubMed1984

Hypolipidemic activity of 4-phenyl-5,5-dicarbethoxy-2-pyrrolidinone in rodents.

A series of pyrrolidinones have been reported to possess hypolipidemic activity in mice. The most active agent, 4-phenyl-5-5-dicarbethoxy-2-pyrrolidinone, effectively lowered both serum cholesterol and triglyceride levels at 20-30 mg/kg/d. The agent suppressed liver mitochondrial citrate exchange, phosphatidate phosphohydrolase, and sn-glycerol-3-phosphate acyl transferase activities. Lipid content of the liver, small intestine, and serum lipoprotein fractions was reduced by drug treatment, but lipid levels increased in the bile and fecal samples, suggesting the drug accelerated lipid excretion. The mode of action of the pyrrolidinone appears similar to that of the cyclic imides.

Animals↗
PubMed1984

Hypolipidemic activity of 3-N-(1',8'-Naphthalimido)propionic acid in rodents.

3-N-(1',8'-Naphthalimido)propionic acid was synthesized and shown to effectively lower both serum cholesterol and triglyceride levels in rats and mice. In hyperlipidemic mice, serum lipid levels were lowered significantly, approaching normal levels of cholesterol and below normal levels of triglyceride. The serum lipid levels were reduced due to accelerated clearance of cholesterol via the biliary route as well as a lowering of available acetyl CoA in the cytoplasm for liver de novo cholesterol and triglyceride syntheses. The liver regulatory enzyme of fatty acid and triglyceride syntheses were depressed by drug treatment. Significant reduction of liver lipids as well as the lipid content of the lipoprotein fractions were observed. The agent possessed a safe therapeutic index when used as a hypolipidemic agent.

Animals↗
PubMed1984

Hypolipidemic activity of tetrakis-mu-(trimethylamine-boranecarboxylato)-bis(trimethylamin e- carboxyborane)-dicopper(II) in rodents and its effect on lipid metabolism.

A binuclear copper(II) complex was shown to have potent hypolipidemic activity in rats and mice at low doses, i.e., 2.5-10 mg/kg/d. The agent moderately lowered liver ATP-dependent citrate lyase, acetyl CoA synthetase, and phosphatidate phosphohydrolase activities in vivo. The appetite of the animal was reduced by drug treatment, and orally administered cholesterol absorption from the intestine was markedly lowered. Higher lipid levels were found in the chyme and the feces, indicating accelerated excretion of lipids by the drug, probably via the biliary route. Organs, e.g., liver and small intestine, as well as serum lipoprotein levels, demonstrated lower lipid content after drug administration. Thus, this chemical class of agents may have potential as a hypolipidemic agent in humans.

Animals↗
PubMed1984

Hypolipidemic activity of phthalimide derivatives V: Reduced and hydrolytic products of simple cyclic imides.

A series of cyclic imides and related compounds have previously been shown to possess hypolipidemic activity at the low dose level of 20 mg/kg/d. Hydrolytic and reduced products of the cyclic imides were synthesized and examined to discern if possible metabolic products were the active chemical species of these hypolipidemic agents. Phthalimide proved to be the most active cyclic imide tested. Unfortunately, the new products did not, in general, improve hypolipidemic activity in rodents. The exceptions were piperidine which demonstrated improved hypotriglyceridemic activity, and 3,4,5,6-dibenzohomopiperidin-2-one, which demonstrated improved hypocholesterolemic activity compared to phthalimide.

Animals↗
PubMed1984

Biological activity of the hypolipidemic agent, N2-n-butylindazolone.

Previously, a series of N-substituted indazolone derivatives proved to be effective hypolipidemic agents in rodents. The most effective agent, N2-n-butylindazolone, at 20 mg/kg/d was shown to suppress the levels of cytoplasm acetyl coenzyme A required for cholesterol and fatty acid synthesis as well as sn-glycerol-3-phosphate acyl transferase and phosphatidate phosphohydrolase activities. Lipid content of the liver, small intestine, and serum lipoprotein fractions was lowered, whereas lipid content was increased in fecal excretions by drug treatment for 14 d. The absorption of orally administered cholesterol from the intestine was severely reduced after drug administration. The mode of action of N2-n-butylindazolone appears to be similar to cyclic imides possessing hypolipidemic activity.

Animals↗