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Biomedical subjects

C E Day

Publications and source records attributed to C E Day.

At least 37 records · Page 2Linked to original sources
PubMed1990

Anti-atherosclerotic activity of colestipol hydrochloride in SEA quail.

Young, male, SEA (Susceptible to Experimental Atherosclerosis) Japanese quail (Coturnix coturnix japonica) were fed an atherogenic diet consisting of yellow corn meal and soybean meal supplemented with 2% cholesterol and 1% cholic acid. A control group of ten animals was fed the atherogenic diet for eight weeks, and another group was fed the same diet containing 2% colestipol hydrochloride for the same length of time. At the end of the treatment period serum and arterial total cholesterols were measured and extent of macroscopic atherosclerotic lesions assessed. Colestipol hydrochloride treatment significantly reduced both serum and arterial total cholesterol levels by 50 and 59%, respectively. Grossly visible atherosclerosis was significantly reduced by 64%. These data further demonstrate that male SEA quail are an appropriate and relevant small animal model for examining the cardiovascular effects of bile acid sequestrants.

Animals↗
PubMed1990

Comparison of hypocholesterolemic activities of the bile acid sequestrants cholestyramine and colestipol hydrochloride in cholesterol fed SEA quail.

The pharmacopolymer bile acid sequestrants cholestyramine and colestipol hydrochloride were mixed with a diet supplemented with 0.5% cholesterol at levels of 0.25%, 0.5%, and 1.0% for cholestyramine and 0.5% and 1.0% for colestipol and fed to young, male, SEA (Susceptible to Experimental Atherosclerosis) Japanese quail (Coturnix coturnix japonica) for a period of seven days. After treatment blood was obtained by venipuncture from non-fasted animals and analyzed for serum total cholesterol concentration. Cholestyramine significantly reduced total cholesterol concentrations at all doses in a dose dependent manner. Colestipol significantly reduced total cholesterol only at the 1.0% dose. Based on these observations, cholestyramine is significantly more potent for reducing serum cholesterol in hypercholesterolemic male SEA quail than is colestipol hydrochloride.

Animals↗
PubMed1989

Hypocholesterolemic activity of colestipol hydrochloride in SEA quail.

Male SEA (Susceptible to Experimental Atherosclerosis) quail were fed a semi-purified diet containing 0.5% cholesterol for a period of one week. Colestipol hydrochloride was mixed with the diet at levels of 0.5% and 1.0%. In control animals total serum cholesterol increased from a basal level of 241 mg/dl to 820 mg/dl after one week on the cholesterol supplemented diet. At 0.5% colestipol hydrochloride treated animals experienced a change in serum cholesterol from 223 mg/dl to 528 mg/dl after one week of cholesterol feeding. Colestipol hydrochloride at 1.0% in the diet completely prevented any increase in serum cholesterol in response to the hypercholesterolemic diet. Total serum cholesterols in this treatment group were 258 and 222 mg/dl initially and after the one week treatment, respectively. These data demonstrate that the bile acid sequestrant colestipol hydrochloride clearly prevents the hypercholesterolemia produced by feeding male SEA quail a cholesterol supplemented diet. Based on this activity cholesterol fed SEA quail may be a convenient and practical model for the preclinical evaluation of new cholesterol lowering drugs which act via a mechanism of bile acid sequestration.

Animals↗
PubMed1988

Molecular basis for the defective expression of the mouse Ew17 beta gene.

Four of the eleven independent H-2 haplotypes of inbred mouse strains and approximately 15% of wild mouse chromosomes 17 fail to express the E alpha E beta class II histocompatibility (Ia) Ag. These E- haplotypes are defective in the expression of the E alpha and/or the E beta chain. None of the E beta defects has previously been described at the molecular level. In this study, we report the molecular basis for the defective expression of the E beta gene from the w17 haplotype of the H-2 congenic strain B10.CAS2, derived from wild Mus musculus castaneus. Comparison of the Ew17 beta genomic sequence to those of the functional Eb beta and Ed beta genes reveals a single base insertion in the RNA donor splice site of the first intron. By DNA shuffling, we have corrected the single base mutation, and we show by FACS analysis and 2-D PAGE of immunoprecipitates that the corrected Ew17 beta is expressed in L cells when co-transfected with an Ed alpha gene. Conversely, an Eb beta gene construct containing the mutant RNA splice site from Ew17 beta is not expressed. We conclude that the single base insertion in the first RNA splice donor site is the sole molecular defect in the Ew17 beta gene.

Amino Acid Sequence↗
PubMed1985

Evaluation of timefurone, a new anti-atherosclerotic drug, for its effects on lipoprotein cholesterol in male cynomolgus monkeys fed an atherogenic diet for 18 months.

Forty male cynomolgus monkeys were fed a nutritionally complete diet containing butter and 0.5% cholesterol for 18 months to ensure development of atherosclerosis. Timefurone was administered daily at 10 mg/kg/day. Lipoprotein cholesterol parameters were measured every 4 weeks and clinical chemistries were done at approximately 8-week intervals. Low density lipoprotein cholesterol [LDL-C] was significantly reduced 24-45% at all time periods and total-C was lowered 17-23% at weeks 12, 16, and 24-40 in the timefurone group. Very low density lipoprotein cholesterol [VLDL-C] was increased 68-156% from weeks 40-78 and triglycerides [TG] were significantly elevated 52-220% on weeks 4-16, 24, 28, and 36-78 by timefurone. Timefurone caused small but significant changes in several clinical chemistry parameters including: creatinine, total bilirubin, albumin, glucose, serum glutamic-oxalacetic transaminase, and serum glutamic-pyruvic transaminase during the test. Significant reductions in arterial cholesterol were observed in thoracic aorta (-24%) and carotid arteries (-29%) in treated monkeys when compared to placebo. Arterial cholesterol in treated monkeys was positively correlated to LDL-C (R = 0.54, p less than or equal to 0.05). Timefurone, therefore, appears to have a significant beneficial effect against the development of atherosclerosis in cholesterol-fed male monkeys and possesses excellent potential for clinical experimentation.

Animals↗
PubMed1985

Evaluation of timefurone, a new anti-atherosclerotic drug, for its effects on lipoprotein cholesterol in male SEA Japanese quail and rats.

Timefurone was evaluated in several animal models for cholesterol-lowering and anti-atherosclerotic activity. In normal male rats, a dose-response study with timefurone (3, 10, 30, 50 and 100 mg/kg/day) was conducted for 7 days. Significant activity was observed only at 50 and 100 mg/kg/day, where very low and low density lipoprotein cholesterol [(VLDL + LDL)-C] and total-C levels were reduced (mean 27 and 20%). High density lipoprotein cholesterol (HDL-C) was lowered 24% by the high timefurone dose. Timefurone (10, 20, 50 and 100 mg/kg/day in the diet) was then examined in normocholesterolemic SEA japanese quail. beta-lipoprotein cholesterol (VLDL + LDL)-C was reduced at all doses (mean 58%), while alpha-lipoprotein cholesterol (HDL-C) was elevated by all doses of timefurone (mean 45%). Male weanling rats made moderately hypercholesterolemic represented a 3rd phase of timefurone (2.5, 5, 10, 20, 50, 100 mg/kg/day) testing. After 4 days of drug treatment, marked hypocholesterolemic activity was observed for (VLDL + LDL)-C (mean decrease 49%) and total-C (mean 33%). HDL-C levels were increased with 10 and 100 mg/kg/day doses. Timefurone (25 and 100 mg/kg/day in the diet) also caused a significant reduction in atherosclerotic development in hypercholesterolemic SEA japanese quail. Atherosclerotic involvement (determined by visual assessment of plaque), arterial weight, and arterial cholesterol (total and mg/g artery) were clearly lowered by both doses of timefurone. There was no evidence of significant drug toxicity in any of these experiments. On the basis of these data, timefurone has excellent therapeutic potential and additional study of the drug's hypocholesterolemic and anti-atherosclerotic properties appears warranted.

Animals↗
PubMed1985

Hypocholesterolemic effect of khellin and khelloside in female cynomolgus monkeys.

Khellin and khelloside (khellol glucoside) were examined in female cynomolgus monkeys to substantiate their ability to favorably modify serum lipoprotein cholesterol. Clinical chemistry parameters were also measured to obtain information indicative of possible drug toxicity. Both drugs were evaluated in two week multiple-dose studies and after a single oral dose. After two weeks at 20 mg/kg per day, khellin and khelloside significantly lowered low density lipoprotein cholesterol (LDL-C) by 87% and 73%, high density lipoprotein cholesterol (HDL-C) by 41% and 23%, and total-C by 55% and 44%, respectively. Very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) were not changed. No apparent toxicity was observed as clinical chemistry parameters and body weights were not different compared to control values. Similar results were observed with lower doses of khellin and khelloside. Khellin at 5 mg/kg per day reduced LDL-C by 50%, HDL-C by 15%, and total-C by 30%, while khellol glucoside at 10 mg/kg per day lowered LDL-C by 46%, HDL-C by 20%, and total-C by 31%. Neither drug produced significant changes in VLDL-C, TG, body weights, or clinical chemistry variables. A 2 mg/kg per day dose of khellin also had no observable effect in this study. Single oral doses (20 mg/kg) of khellin and khelloside caused modulation of LDL-C (-32% and -30%) and total-C (-18% and -15%). Visual observation of the monkeys during this study revealed that khellin caused emesis in 9/9 animals, while khelloside and control had no emetic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Comparative effects of khellin and timefurone on serum parameters in normal male cynomolgus monkeys.

Timefurone and khellin (10 mg/kg/day, gavage, 14 days) significantly lowered low density lipoprotein cholesterol, high density lipoprotein cholesterol, and total cholesterol. Khellin-induced changes were significantly greater than those induced by timefurone. Neither drug altered body weights or clinical chemistry parameters. Monkeys treated with khellin, however, exhibited elevated levels of very low density lipoprotein cholesterol and marked emesis, while no changes were observed with timefurone. On the basis of these data, timefurone has a better therapeutic ratio and further study with this promising drug appears warranted.

Animals↗
PubMed1983

The gene encoding the Ia antigen-associated invariant chain (Ii) is not linked to the H-2 complex.

The invariant (Ii) chain of murine Ia antigens is associated with the intracellular but not the cell-surface forms of the A alpha:A beta and E alpha:E beta Ia complexes. Due to its unique subcellular localization, Ii has been postulated to play a part in the assembly or intracellular transport of the Ia alpha:beta complexes, which function in immune recognition. A more general role for Ii in the transport of other cell proteins has also been suggested. Because of the unusual subunit composition of Ia antigens and because the synthesis of alpha, beta and Ii chains is coordinately regulated, it was of interest to determine whether, like the alpha and beta chains, Ii is encoded by a gene in the I region of the H-2 histocompatibility complex. We report here the use of an Ii chain polymorphism present in Mus spretus to demonstrate that the gene for Ii is not linked to the H-2 complex. Thus, intracellular Ia antigens consist of the products of two linked genes and one unlinked gene.

Animals↗
PubMed1983

Comparison of clofibrate and ethyl-5-(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate induced changes in serum lipoprotein cholesterol and hepatic peroxisome proliferation in the normal rat.

Clofibrate and ethyl-5(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate (HMP), at 0.1 and 0.25% in the diet, were evaluated in normal rats. Effects on serum lipoprotein cholesterol, liver cholesterol and peroxisome proliferation changes were compared. Both doses of HMP significantly lowered high density lipoprotein cholesterol (HDL-C) and total cholesterol (mean 22% and 18%). The distribution of cholesterol in the lipoproteins was altered (p less than 0.05) and liver weights were increased 18% by the 0.25 dose of HMP. Clofibrate treatment increased (p less than 0.01) the combination of very low and low density lipoprotein cholesterol (VLDL + LDL-C) by 42% at the 0.1% dose and lowered HDL-C by 28% at the 0.25% dose; total-C was not changed from control values. Both levels of clofibrate shifted the distribution of lipoprotein cholesterol, increased liver weights (mean 69%) and reduced liver cholesterol (mean 33%). Image analysis of peroxisome changes showed that both doses of HMP and clofibrate increased peroxisome numbers (mean 71% vs 218%), with activity of HMP significantly lower than clofibrate. Measurement of carnitine acetyltransferase (CAT) activity (nmCoASH released/mg protein/minute) showed no significant increases in liver samples from HMP-treated rats, while clofibrate induced large increases in CAT activity, which were significant compared to control and HMP values. While having chemical structural similarity to clofibrate, HMP appears to cause comparable hypocholesterolemic activity without comparable levels of hepatomegaly and peroxisome proliferation.

Animals↗
PubMed1982

Mapping of the genes of some components of the electron transport chain (complex I) on the X chromosome of mammals.

This paper describes genetic mapping studies with several respiration-deficient mutants of Chinese hamster fibroblasts which have a defect in complex I of the electron transport chain (NADH-coenzyme Q reductase). The mutations associated with two different complementation groups map on the X chromosome. In two cases (G14 and G20) karyotypic and isozyme analyses in hybrids have shown that a gene(s) on the mouse X chromosome complements the mutation(s) in the hamster cell mutant(s). A cosegregation analysis in hybrid cells has shown the corresponding genes to be linked to the HPRT genes (hamster-mouse hybrids of G14, and hamster-hamster hybrids for G14 and G20). By the same method the defective gene in a third mutant (G4) was also shown to be X-linked. A mutation representing a third complementation group (G11) was shown to be on an autosomal gene. These results provide an explanation for our observation that cells with recessive mutations in complementation groups I and II can be selected at relatively high frequencies.

Animals↗
PubMed1981

The mechanism of action of the hypocholesterolemic drug p-(1-adamantyloxy)-aniline.

The effect of p-(1-adamantyloxy)-aniline (AOA) on the biliary secretion of cholesterol, bile salts, and phospholipids was studied in hypercholesterolemic rats. A second study was conducted using hypercholesterolemic rats with 14C-labeled cholesterol pools for the purpose of determining the effects of AOA on cholesterol metabolism. Treatment with AOA (100 mg/kg, orally) daily for 1 week resulted in the increased secretion of biliary cholesterol, but did not affect the secretion of bile salts or phospholipids. This treatment also resulted in an increase in the fecal excretion of 14C-labeled neutral and acidic sterols, and in reductions of both the total radioactivity in the liver and liver cholesterol. The data presented support the conclusion that the hypocholesterolemic action of AOA is due to the increased secretion of cholesterol into the bile and to the increased fecal excretion of cholesterol and bile salts.

Adamantane↗
PubMed1979

Hypobetalipoproteinemic agents. 2. Compounds related to 4-(1-adamantyloxy)aniline.

While the previously used displacement reaction of sodim 1-adamantyl oxide on 4-fluoronitrobenzene was applicable to the preparation of 4-(1-adamantyloxy)aniline and several related compounds, certain derivatives were not easily accessible by this route. Thus the recently reported ortho alkylation of anilines and the dicyclohexylcarbodiimide-promoted coupling of 1-adamantanol with phenols were useful in the preparation of aromatic-substituted derivatives. Furthermore, addition of phenylmagnesium bromide to 1-cyanoadamantane provided entry to the 4-(1-adamantylmethyl)aniline series. 4-(1-Adamantyloxy)aniline (3) is herein reported to be a more potent hypobetalipoproteinemic agent than the previously reported bicyclooctyloxy analogue. Replacement of the oxygen atom of 3 with sulfur (74) or methylene (62), but not nitrogen (71), results in active compounds. In the oxygen series derived from 3, the widest scope of substitution on nitrogen resulting in activity is found. The N-ethoxycarbonyl (5), acetyl (6), methyl (12), ethyl (13), N-methyl-N-(2-hydroxyethyl) (19), N-methyl-N-formyl (22), N,N-dimethyl (26), pyrrolidine (14), and piperidine (15) derivatives are active. Aromatic ring substitution also provided the active 3-chloro (44b), 2-fluoro (41b, 42, and 43), and 2-methylthiomethyl (48) compounds. Thus these active compounds are identified for further development as hypobetalipoproteinemic agents.

Adamantane↗
PubMed1979

Animal models for an integrated approach to the pharmacologic control of atherosclerosis.

A system of animal models potentially useful for the discovery and evaluation of new effective antiatherosclerotic agents is described. The models consist of a series of lipoprotein and atherosclerosis assays in rats, SEA Japanese quail and cynomolgus monkeys. SEA quail are particularly useful for detecting compounds that inhibit arterial cholesterol deposition. The use of this integrated system of models is illustrated with data on clofibrate, adamantyloxyaniline (a hypobetalipoproteinemic agent), and o,p'-DDD. Male SEA quail appear to be a quite satisfactory model for testing the effects of large numbers of compounds on atherosclerosis and are available in limited numbers to all qualified investigators in the field of atherosclerosis research for evaluation in their laboratories.

Adamantane↗
PubMed1978

Selected animal models for systematic antiatherosclerotic drug development.

We have developed an integrated system for antiatherosclerosis drug development utilizing rats, SEA quail, and cynomolgus monkeys as animal models. In general, the way the system is presently functioning is that thousands of compounds per year are randomly screened for hypobeta- or hyperalphalipoproteinemic activity in rats, and hundreds of compounds per year are screened in SEA quail for antiatherosclerotic and hypocholesterolaric activity. A few selected compounds that have activity in both rats and quail are then tested for lipoprotein modifying activity in cynomolgus monkeys. Nontoxic compounds having very good lipoprotein modifying activity in the monkey will then be recommended for clinical trials in man. We do not anticipate that this battery of testing will guarantee activity in man, but are hoping that it will at least increase the probability for finding a truly effective antiatherosclerotic drug to control the human disease.

Animals↗