Biomedical subjects

I H Hall

Publications and source records attributed to I H Hall.

At least 91 records · Page 5Linked to original sources

PubMed1992

The effects of cyclic imides on lipoprotein receptor binding and degradation of rat and human cells and effects on regulatory enzymes of lipid metabolism.

A series of cyclic imides, which possess a bulkier N-ring structure than phthalimide and saccharin, were shown to suppress LDL receptor binding, internalization and degradation of isolated rat hepatocytes, foam cells, human fibroblasts and mouse macrophages. The HDL receptor binding and internalization was accelerated in hepatocytes but not in other tissue types. In general, the HDL receptor activity and degradation was reduced by the cyclic imides. The in vivo studies with selected cyclic imides supported this finding in that 125I-LDL was not cleared from serum as rapidly as the control after 14 days of treatment, whereas 125I-HDL was cleared more rapidly by treated rats. The tissue uptake of 125I-LDL amd 125I-HDL was generally reduced in the treated rat tissues after 14 days dosing. These agents did not suppress HMG-CoA reductase activity in any of the tissue cell lines. A correlation existed between lower LDL receptor activity and stimulated HMG-CoA reductase activity in cells. The cyclic imides suppressed the activities of acyl-CoA cholesterol-acyltransferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced tissue lipoprotein lipase. Neutral cholesterol ester hydrolase activity and protein synthesis were markedly stimulated by the cyclic imides in the aorta foam cells, but not the other cell types.

Animals↗

PubMed1992

The effects on lipid metabolism of 4-phenyl-5,5-dicarbethoxy-2-pyrrolidenone in Sprague Dawley rats.

4-Phenyl-5,5-dicarbethoxy-2-pyrrolidenone [XIV] treatment in Sprague Dawley rats caused significant reduction of serum cholesterol and triglyceride levels with reduction of VLDL and LDL cholesterol levels. The compound significantly reduced regulatory enzyme activities, e.g. ATP dependent citrate lyase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, cholesterol-7-alpha-hydroxylase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase. In tissue cultured cells, the compound suppressed LDL receptor activity and degradation, and elevated HDL receptor activity and HDL degradation. Rat bile cholesterol and phospholipids were elevated; however, overall bile acids were reduced. In situ loop studies suggest that the agent interfered with interhepatic reabsorption of cholesterol and cholic acids. At the therapeutic dose of compound XIV, no deleterious effects were demonstrated in mice.

Animals↗

PubMed1992

Effects of isoxazolidine or triazolidine on rat serum lipids in vivo and LDL and HDL binding and degradation in human and rodent cultured cells in vitro.

2-(3,4,5-Trimethoxybenzoyl)-4,4-diethyl-3,5-isoxazolidione (TDI) and 1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione (APTD) are two chemically related derivatives which have demonstrated potent hypolipidemic activity in mice at 20 mg/kg/day I.P. for 16 days. The purpose of this study is to correlate in vivo effects of TDI and APTD on rat serum lipoprotein lipids and apoprotein levels as well as plasma clearance and tissue uptake with effects of the agents on tissue cultured cells' LDL and HDL receptor binding, internalization and degradation. This study also correlates in vivo effects of TDI and APTD with endogenous enzyme activities regulated by these high affinity receptors. In rats at 20 mg/kg/day orally serum cholesterol, triglyceride, and VLDL-cholesterol levels were effectively reduced while HDL cholesterol levels were significantly elevated with both agents. These compounds in human hepatocytes lowered LDL receptor binding and degradation, whereas HDL receptor binding and degradation were elevated in human hepatocytes, rat small intestinal epithelium cells, human BG fibroblasts, rat aorta cells and mouse macrophages. These drugs inhibited HMG CoA reductase and sn-glycerol-3-phosphate acyl transferase activities, findings consistent with the observed in vivo reductions in serum cholesterol and triglyceride levels. Both drugs reduced activity of acyl CoA:cholesterol acyl transferase and accelerated activity of neutral cholesterol hydrolase in liver and aorta cells. This modulation by the drugs should reduce disposition of cholesterol esters in these tissues especially aorta wall; this effect was indeed observed in vivo. In the presence of TDI and APTD, HDL uptake of intracellular cholesterol from fibroblasts was accelerated. This was consistent with results from in vivo rat studies showing that HDL clearance was faster after treatment while clearance of LDL slowed. Tissue uptake of HDL and LDL after drug treatment was reduced for the major organs; however the liver accumulation was elevated. The accelerated uptake in the liver was probably due to the observed higher levels of Apo-E and Apo-AI in HDL after drug treatment. Increased excretion of cholesterol from the liver to the bile after drug treatment indicated that the reserve cholesterol transport system by HDL was accelerated by the agents in vivo.

Animals↗

PubMed1992

The synthesis and anti-neoplastic activity of N2-isobutyryl-2'-deoxyguanosine-N7-cyanoborane derivatives.

N2-Isobutyryl-2'-deoxyguanosine-N7-cyanoborane derivatives were observed to be potent antineoplastic agents and to be active against a number of human tissue culture tumor cells, e.g. Tmolt3 leukemia, HeLa-S3 uterine carcinoma. Selective agents were active against colon adenocarcinoma, osteosarcoma and glioma growth. These agents preferentially inhibited both DNA and RNA synthesis of L1210 cells. De novo synthesis of purines was significantly inhibited at the regulatory sites of PRPP amido transferase and IMP dehydrogenase. Other sites of inhibition were thymidylate synthetase, OMP decarboxylase and thymidine kinases. The agents also significantly reduced deoxyribonucleotide levels and caused DNA strand scission.

Animals↗

PubMed1992

The cytotoxicity of helenalin, its mono and difunctional esters, and related sesquiterpene lactones in murine and human tumor cells.

Naturally occurring sesquiterpene lactones and their semisynthetic derivatives, such as the O = C-C = CH-bearing helenalin and its esters, have been shown to demonstrate potent cytotoxicity against the growth of murine L1210 lymphoid leukemia and human Tmolt3 leukemia, colon adenocarcinoma, HeLaS3, lung bronchogenic, KB, osteosarcoma, and glioma cells. The modes of action of helenalin in L1210 cells are the inhibition of DNA, RNA, and protein syntheses. This study confirms that thiol bearing enzymes of nucleic acid metabolism were significantly inhibited, e.g. DNA polymerase alpha, IMP hydrogenase, and ribonucleoside reductase. The addition of GSH to the reaction medium demonstrated total recovery of L1210 ribonucleoside reductase activity. Helenalin reduced cellular GSH levels in L1210 cells. Helenalin also reduced all four pool levels of d(NTP)s which would account for part of the observed inhibition of DNA synthesis. Reductions in the ribonucleotide pool levels were also generally evident after drug treatment. Thus, the sesquiterpene lactones appear to have more than one mode of action in L1210 cells. All of the modes of actions of helenalin are feasible mechanisms to lower nucleic acid synthesis and cause cell death of the L1210 leukemia cells.

Animals↗

PubMed1991

In vivo and in vitro effects of helenalin on mouse hepatic microsomal cytochrome P450.

Helenalin, a natural plant product with significant antitumor activities, decreased male BDF1 mouse hepatic microsomal cytochrome P450 contents in vivo and in vitro. A single i.p. dose of 25 mg helenalin/kg body weight significantly (P less than 0.05) decreased microsomal cytochrome P450 contents and inhibited cytochrome P450-dependent mixed-function oxidase activities within 1-2 hr post-exposure. Helenalin (1.0 mM) decreased microsomal cytochrome P450 contents in vitro by 11% in the absence of NADPH and by 32% in the presence of NADPH. These in vitro and in vivo decreases in cytochrome P450 were accompanied by comparable decreases in total microsomal heme contents. Helenalin (1.0 mM) increased mouse hepatic microsomal oxygen consumption and NADPH utilization by 3.2 and 5.4 nmol/min/mg protein respectively. Helenalin (1.0 mM) significantly (P less than 0.05) increased microsomal lipid peroxidation in vitro, and this helenalin-induced increase in lipid peroxidation was inhibited completely by the addition of 0.05 mM EDTA. However, microsomal cytochrome P450 contents were equally affected by helenalin in the presence or absence of EDTA, suggesting that lipid peroxidation did not contribute to the helenalin-induced decrease in cytochrome P450. The addition of 0.05 mM hemin to microsomes treated in vitro with 1.0 mM helenalin resulted in a 58% recovery of cytochrome P450 contents. This ability of hemin to reconstitute cytochrome P450 in helenalin-treated microsomes suggests that helenalin produced a selective loss of heme from the cytochrome P450 holoprotein, and that the resulting cytochrome P450 apoprotein remained intact after helenalin treatment. The increased loss of microsomal cytochrome P450 produced by helenalin in the presence of NADPH suggests that a helenalin metabolite may be responsible for heme loss and the in vitro destruction of cytochrome P450.

Animals↗

PubMed1991

Synthesis and hypolipidemic activity of amine-carboxyboranes, and their amides and esters in rodents.

A series of amine carboxyboranes including their amides and esters were synthesized and shown to have potent hypolipidemic activity in rodents at 20 mg/kg/day. Ethylamine carboxyborane, di-n-propylamine-carboxyborane, trimethylamine-carbomethoxyborane, n-butylamine carbomethoxyborane, methylamine-N-ethyl carbamoylborane and trimethylamine-N-n-octyl carbamoylborane were the most potent derivatives demonstrating hypocholesterolemic and hypotriglycemic activities in rats orally at 20 mg/kg/day. These derivatives lowered tissue lipids, e.g. cholesterol, in the rat liver, small intestine and aorta. The fecal lipids were elevated. Furthermore, the agents lowered cholesterol and triglycerides in the serum VLDL and LDL fractions but caused elevations in the HDL fraction after 14 days. The agents inhibited hepatic enzymatic activities of rate limiting steps involved in lipid metabolism, e.g. ATP dependent citrate lyase, sn-glycerol-3-phosphate acyltransferase and phosphatidylate phosphohydrolase.

Amides↗

PubMed1991

Acute toxicity of amine-boranes and related derivatives in mice.

Three boron derivatives, i.e. trimethylamine-carbomethoxyborane, tetrakis-mu-(trimethylamine-boranecarboxylato)-bis(trimethylamine- carboxyborane)-dicopper(II), and N,N-dimethyl-n-octadecylamine borane were evaluated for acute toxicity in male mice, at 1, 2 or 5 x their therapeutic dose in rodents for pharmacological activity. Based on organ weights, clinical chemistry, hematopoietic parameters and tissue morphology, the trimethylamine-carbomethoxyborane was shown to be free of toxicity. The dicopper(II) complex and N,N-dimethyl-n-octadecylamine borane demonstrated slight toxicity with marginal disturbance in hepatic and kidney morphology. The dicopper(II) complex may cause marginal myocardial damage and the N,N-dimethyl-n-octadecylamine borane caused elevations in cholic acid. All three derivatives demonstrated reductions in hematocrit.

Animals↗

PubMed1991

Synthesis and antineoplastic activity of some cyano-, carboxy-, carbomethoxy-, and carbamoylborane adducts of heterocyclic amines.

Boron analogues of piperidine, piperazine, morpholine, and imidazole proved to be cytotoxic against the growth of murine and human tissue culture cells. Significant activity was demonstrated for single-cell suspensions of L1210 lymphoid leukemia, Tmolt3 lymphoblastic leukemia, and HeLa-S3 cervical carcinoma. Trimethylamine-imidazole carbonyldihydroborane 17 demonstrated activity against solid tumor growth of human colorectal adenocarcinoma, KB nasopharynx, and osteosarcoma. In addition, 4-methylpiperidine-carbomethoxyborane 12, 2-methylimidazole-3-cyanoborane 16, and 1-methylimidazole-3-(N-ethylcarbamoyl)borane 19 were active against the KB nasopharynx growth. Piperidine-cyanoborane 2, piperidine-carboxyborane 4, and 1-methylimidazole-3-(N-ethylcarbamoyl)borane 19 were effective in reducing the growth of osteosarcoma cells. The imidazole derivatives 13-19, as well as 4-methylpiperidine-carboxyborane 11 and carbomethoxyborane 12, demonstrated good activity against lung bronchogenic and glioma growth. In the in vivo studies, N-methylmorpholine-carboxyborane 7,4-phenylpiperidine-carboxyborane 9, 4-phenylpiperidine-carbomethoxyborane 10, 4-methylpiperidine-carboxyborane 11, imidazole cyanoborane 14, and 1-methylimidazole-3-carbomethoxyborane 18 demonstrated the best activity against Lewis Lung growth and P388 lymphocytic leukemia growth in mice. Mode of action studies in L1210 leukemia cells demonstrated that piperidine-carboxyborane 4 and N-methylmorpholine-carboxyborane 7 inhibited DNA synthesis, purine synthesis at PRPP amido transferase and IMP dehydrogenase sites, and thymidine kinase and thymidine diphosphate kinase activities, while lowering d(NTP) pool levels. Also, DNA strand scission was evident after incubation with these drugs.

Amines↗

PubMed1991

The hypolipidemic activity of heterocyclic amine boranes in rodents.

Heterocyclic amine boranes were observed to be potent hypolipidemic agents in rodents at 8 mg/kg per day lowering both serum cholesterol and triglyceride levels. These agents were also effective in lowering tissue lipids. Rat serum lipoprotein cholesterol levels were reduced in the low density lipoprotein (LDL) and very low density lipoprotein (VLDL) fractions and elevated in the high density lipoprotein (HDL) fraction after 14 days. The modes of action of the agents appear to accelerate excretion of lipids in the bile and the suppression of the activities of key hepatic regulatory enzymes of lipids synthesis.

Animals↗

PubMed1991

Disposition of an antineoplastic sesquiterpene lactone, [3H]-plenolin, in BDF1 mice.

The pharmacokinetics of a radiolabelled analog of helenalin, [3H]-plenolin ([3H]-11,13-dihydrohelenalin), was determined in BDF1 mice following intravenous, intraperitoneal, and oral administration. A two-compartment pharmacokinetic model predicted that the maximum terminal (beta) half-life of [3H]-plenolin was 57.3 hours. Urinary excretion accounted for 40.3% to 64.4% of the administered radioactivity, while fecal excretion accounted for 9.3% to 39.7%. The fecal excretion data also suggested that [3H]-plenolin was secreted in the bile. Following intraperitoneal administration of [3H]-plenolin, no radioactivity was sequestered in the major organs. However, radioactivity was sustained in the carcass and skin for 24 days. [3H]-Plenolin was rapidly taken up by murine tumor cells and human fibroblasts. The drug did not significantly associate with DNA, RNA, or protein of P388 leukemia or human fibroblast cells.

Animals↗

PubMed1991

DNA interaction with metal complexes and salts of substituted boranes and hydroborates in murine and human tumor cell lines.

A series of metal complexes and sodium salts of substituted boranes and hydroborates was shown to have cytotoxicity in murine and human tumor screens. Most of these agents were active against the growth of L-1210, Tmolt3 and Hela-S3. Selected agents demonstrated activity against the growth of monolayer human cell lines derived from solid tumors. Interestingly, many of the compounds demonstrated even lower ED50 values in the solid tumor than the L-1210 leukemic screen. Four compounds, Cu2(m-CH3)3NBH2CO2)4.2(CH3)NBH2COOH (I), [Fe3O((CH3)3NBH2CO2)6(CH3OH)3]NO3.CH3CN (II), cis-[Co(en)2((CH3)3N.BH2CO2)2]Cl.2.5 H2O.0.5 CH3OH (V), and Na(CH3)3NBH2CO2.0.25 CH3OH (IX) were shown preferentially to inhibit DNA synthesis of L-1210 cells with only moderate inhibition of RNA and protein synthesis. In preliminary studies these agents effectively inhibited the activities of regulatory enzymes involved in the purine pathway and nucleoside kinases resulting in the suppression of d(NTP) pool levels. The boron derivatives also caused L-1210 DNA strand scission. These drugs may act together to inhibit DNA synthesis and induce cytotoxicity.

Animals↗

PubMed1991

Disposition of the hypolipidaemic agent, 6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid, in Sprague-Dawley rats.

The disposition of [2-14C]6-amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid has been determined in rats following intravenous and oral administration. A two-compartment pharmacokinetic model fitted to the blood and urinary data predicted its maximum terminal (beta) half-life to be 38 h. Urinary and faecal excretion accounted for approximately 30 and 8% of the administered radioactivity, respectively. The parent compound accounted for 88% of the urine radioactivity after oral administration. In a tissue distribution study, the largest percentages of radioactivity were found in the skin and carcass; by 24 h, all other organs contained less than 1% of the administered radioactivity. The drug was highly water soluble, not extensively bound to plasma proteins, nor taken up by red blood cells. The drug uptake by human fibroblasts or rat aorta cells appeared to be by passive diffusion.

Administration, Oral↗

PubMed1991

Hypolipidemic activity of some hydropolyborate salts in rodents.

A series of hydropolyborate salts were observed to possess hypolipidemic activity in rodents. Tetramethylammonium octahydrotriborate, tetramethylammonium hexahydrohexaborate, tetramethylammonium dodecahydrododecaborate and triethyl-ammonium dodecahydrododecaborate proved to be very effective in lowering serum cholesterol and triglyceride levels in CF1 mice, i.p. and Sprague Dawley rats, orally. Tissue lipids were reduced by these agents e.g. liver cholesterol, and triglyceride and small intestine mucosa cholesterol levels. [3H] Cholesterol distribution studies confirm that steroid levels are lower in most major tissues. The rat serum lipoprotein lipid content was altered by drug treatment, with cholesterol and triglyceride being reduced in the VLDL and cholesterol being reduced in the LDL. HDL cholesterol levels were elevated by drug treatment. The fecal lipids were increased with select derivatives. The enzyme activities involved in de novo synthesis of hepatic lipids were affected by the hydropolyborate salts including cytoplasmic ATP-dependent citrate lyase, acetyl CoA synthetase, acyl CoA cholesterol acyl transferase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase.

Animals↗

PubMed1991

Hypolipidemic activity of aliphatic dicarboxylic acids in rodents.

Small molecular weight aliphatic dicarboxylic acids, i.e. dimethylmalonic acid, diethylmalonic acid and maleic acid, afford greater than 35% reduction in serum cholesterol and triglycerides levels in CF1 mice at 20 mg/kg/day, i.p. Furthermore, these agents lowered greater than 40% serum cholesterol levels in rat after oral administration at 20 mg/kg/day. Dimethylmalonic and diethylmalonic acids lowered rat serum triglyceride levels by at least 23%. Rat tissue lipids, e.g. liver, small intestinal mucosa and aorta wall, were reduced in concentration and fecal lipids were elevated by dimethyl- and diethylmalonic acids. Rat serum lipoproteins after 14 days of treatment demonstrated reduction of VLDL and LDL cholesterol levels with elevated HDL cholesterol levels by dimethylmalonic and maleic acids. The agents also inhibited de novo hepatic enzyme activities, specifically mitochondrial citrate exchange, acetyl-CoA synthetase, ATP-dependent citrate lyase, acyl-CoA:cholesterol acyltransferase, cholesterol-7 alpha-hydroxyase, sn-glycerol-3-phosphate acyltransferase and phosphatidate phosphohydrolase, which would result in the reduction of de novo synthesis of fatty acids, cholesterol and triglycerides.

Animals↗

PubMed1991

The cytotoxicity of amine-cyanoboranes, amine-cyanoalkylboranes and aminomethyl-phosphonate cyanoborane adducts against the growth of murine and human tissue culture cells.

The amine-cyanoboranes, the amine-cyanoalkylboranes and the aminomethyl-phosphonate-N-cyanoborane adducts proved to be active antineoplastic agents. These compounds were more effective against single cell cultured cell growth rather than solid tumors. The following amine-cyanoboranes, (CH3)2(C18H37)NBH2CN (5), (CH3)2NHBH[CH(CH3)2]CN (7) and (CH3)3NB(CN)2.CH3 (10), were the most active in vivo and in vitro. A related phosphine-cyanoborane was also very active in both in vivo and in vitro model screens. Of the amino-methyl-phosphonate-N-cyanoborane adducts, (CH3O)2.P(O)CH2N(C2H5)2BH2CN (13) proved to be the most active. The amine-cyanoalkylboranes had the poorest in vivo activity; the in vitro cytotoxicity, however, was similar to that of other cyanoboranes.

Amines↗

PubMed1990

Hypolipidemic activity in rodents of phenobarbital and related derivatives.

A series of 5-alkyl-5-phenylbarbituric acid analogues were shown to be potent hypolipidemic agents in rats and mice at 20 mg/kg/day. This dose is lower than that required for hypolipidemic activity for clofibrate and nicotinic acid derivatives in rodents and man. These new derivatives reduced both serum cholesterol and triglyceride levels in rodents by either the oral or intraperitoneal route of administration. Previous studies have demonstrated that similar heterocyclic compounds, i.e. cyclic imides, glutarimides and hydantoins are potent hypolipidemic agents in rodents. The barbituric acid derivatives probably interfered with de novo synthesis of cholesterol and fatty acids in the early steps since the agents inhibit the activities of ATP-dependent citrate lyase and acetyl-CoA synthetase. Triglyceride synthesis may be blocked since the agents inhibited the rate limiting enzyme, sn-glycerol-3-phosphate-acyl-transferase. Rat tissue lipids especially cholesterol and triglycerides were reduced after 14 days treatment. Fecal lipids were increased in cholesterol and phospholipid content by selected compounds. The rat serum lipoprotein after 14 days drug administration showed reduced VLDL-cholesterol and HDL-triglyceride contents. The modulation of the lipid content of the serum lipoproteins by the barbituric acids suggest that these agents may be helpful in treating clinical hyperlipidemic disease states.

Animals↗

PubMed1990

Inhibition of DNA synthesis in P388 lymphocytic leukemia cells of BDF1 mice by cis-diamminedichloroplatinum(II) and its derivatives.

cis-Diamminedichloroplatinum(II) (cisplatin; cDDP) derivatives were found to afford T/C% values greater than 200 against the growth of P388 lymphocytic leukemia cells in vivo. The parent compound, cDDP, preferentially inhibited DNA synthesis. The RNA synthesis was elevated, whereas protein synthesis was unaffected after two or three daily ip doses. Radiolabeled drug studies demonstrated cellular uptake and binding of cDDP derivatives to the DNA molecule. cis-Diamminedichloroplatinum(II) (cDDP) treatment resulted in DNA strand scission after a single dose, but caused cross-linking of DNA strands after two or three ip doses. There was an accumulation of deoxynucleoside triphosphates [d(NTP)s] on day 2 and 3, indicating that incorporation of nucleotides into the DNA strand had been blocked. Thymidine kinase, thymidine monophosphate kinase, carbamoyl phosphate synthetase, and aspartate transcarbamoylase activities were inhibited in vivo after three doses of cDDP at 1.5 mg/kg/day. However, only the inhibition of a cytoplasmic preparation of DNA polymerase alpha by cDDP appeared to be directly related to the inhibition of DNA synthesis and the accumulation of d(NTP) pool levels. Thus, the primary target for cDDP appears to be DNA itself, although direct inhibition of DNA polymerase alpha may play a minor role in the inhibition of DNA replication by cDDP.

Animals↗