Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.     

Chemoprevention of rat prostate carcinogenesis by 9-cis-retinoic acid

A chemoprevention study was conducted to evaluate the activity of 9-cis-retinoic acid (9-cis-RA) as an inhibitor of prostate carcinogenesis in male Wistar-Unilever (HsdCpb:Wu) rats. After pretreatment with a sequential regimen of cyproterone acetate (50 mg/kg/day for 21 days) and testosterone propionate (100 mg/kg/day for 3 days), groups of 40 rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU; 30 mg/kg body weight). Beginning 2 weeks after carcinogen administration, rats received chronic exposure to testosterone administered in s.c. implanted silastic capsules. The study was terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. Continuous dietary administration of 9-cis-RA at 100 mg/kg diet or 50 mg/kg diet beginning 1 week before MNU administration reduced cancer incidence in the dorsolateral + anterior prostate from 65% in dietary controls to 18 and 20%, respectively (P < 0.001 for both comparisons). Similarly, these dose levels of 9-cis-RA reduced the incidence of cancer in all accessory sex glands from 79% in dietary controls to 48 and 33% (P < 0.01 for both comparisons), respectively. Chronic dietary administration of 9-cis-RA induced no gross or organ-specific toxicity in any animal and did not suppress group mean body weight gain. The potent anticarcinogenic activity of 9-cis-RA in the rat prostate, when considered with its apparent lack of toxicity in rodents, suggests that this and other ligands for the retinoid X receptor merit consideration for evaluation in clinical prostate cancer chemoprevention trials.     

Different degrees of moderate iron deficiency modulate lipid metabolism of rats

Severe iron deficiency affects lipid metabolism. To investigate whether moderate iron depletion also alters lipid variables-including lipid levels in serum and liver, hepatic lipogenesis, and fatty acid composition indicative of an impaired desaturation-we carried out experiments with rats fed 9, 13, and 18 mg iron/kg diet over a total of 5 wk. The study also included three pair-fed control groups and an ad libitum control group, fed with 50 mg iron/kg diet. The iron-depleted rats were classified as iron-deficient on the basis of reduced serum iron, hemoglobin concentration, and hematocrit. All moderately iron-deficient rats had significantly lower cholesterol concentrations in liver and serum lipoproteins than their pair-fed controls. Rats with the lowest dietary iron supply had higher concentrations of hepatic phosphatidylcholine (PC) and phosphatidylethanolamine (PE), lower activities of glucose-6-phosphate dehydrogenase, malic enzyme and fatty acid synthase, and higher triacylglycerol concentrations in serum lipoproteins than the corresponding pair-fed control rats. Moderate iron deficiency also depressed the serum phospholipid level. Moreover, several consistent significant differences in fatty acid composition of hepatic PC and PE occurred within moderate iron deficiency, which indicate impaired desaturation by delta-9 and delta-6 desaturases of saturated and essential fatty acids. We conclude that lipid variables, including cholesterol in liver and serum lipoproteins as well as fatty acid desaturation, reflect the gradations of iron status best and can be used as an indicator of the degree of moderate iron deficiency.     

Treatment of A2-B2 prostatic cancer: results of a hormonoradiotherapy combination in the PSA era

The effect of the dose of oyster mushroom in the diet (1.0, 2.5, and 5.0%) and of the period of application (8, 16, 28, and 52 wk) on cholesterol accumulation in blood and body organs was studied in weanling male Wistar rats fed a diet containing 0.3% cholesterol. Reduction of cholesterol in serum and body organs was found to be dependent on the amount of dietary oyster mushroom administered. A negative correlation between the mushroom dose and cholesterol level was found after 8 and 28 wk of feeding (r=-0.9821 and -0.9803, respectively; P < 0.02 for both cases). The dose of 1% oyster mushroom did not affect cholesterol levels in serum or body organs. A significant reduction of cholesterol levels was observed in serum (31-46%) and liver (25-30%) at a dose of 5% of oyster mushroom for all periods. Reduced cholesterol content in very low-density lipoproteins (VLDL) was also observed at this level. The highest dose of oyster mushroom induced a decrease in conjugated diene levels in erythrocytes and an increase in the levels of reduced glutathione in the liver and stimulated the activities of catalase and glutathione peroxidase in the liver in the final period of the experiment.     

Platelet-activating factor and the vascular effects of zymosan in rats

Platelet-activating factor (PAF; 2.5 micrograms/kg) injected in the tail vein of anaesthetized rats increased the vascular permeability of the duodenum, paws, skin and muscles, as measured by the extravasation of 125I-labelled albumin. It did not affect the permeability of the lungs or the presence of labelled albumin in the liver and spleen. The effects of PAF were dose dependently inhibited by WEB 2086 (ID50: 1.39 to 2.09 mg/kg) and SM-12502 (ID50: 7.17 to 8.36 mg/kg). Zymosan, an activator of the alternative complement pathway (10 or 16 mg/kg), induced protein extravasation in the lungs, duodenum, paws and skin, and the accumulation of labelled albumin in the liver. The effects of zymosan on the duodenum and liver were dose dependently inhibited by WEB-2086 and SM-12502. Both PAF antagonists increased the effects of zymosan in the paws but they did not affect protein extravasation in the lungs. The hypotensive effect of PAF (0.5 micrograms/kg) was inhibited by WEB 2086 (ID50: 1.21 mg/kg) and SM-12502 (ID50: 13.4 mg/kg). Both PAF antagonists reduced the hypotensive effects of zymosan (4 or 16 mg/kg) with a similar relative inhibitory potency. PAF is the major mediator involved in the hypotensive effect of zymosan but plays only a minor role in the permeability-enhancing effect of zymosan, mostly in the splanchnic area.     

Potent inhibitors of acyl-CoA:cholesterol acyltransferase. 2. Structure-activity relationships of novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amides

Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized compounds, N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives showed potent ACAT inhibitory activity. The synthesis and structure-activity relationships of these compounds are described. A methyl group at position 6 of the 2,3-dihydrobenzofuran moiety was important for potent ACAT inhibitory activity. In the series of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl) amides, lipophilicity of the acyl moiety was necessary for the potent ACAT inhibitory activity. The highly lipophilic acid amides N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2- dimethyldodecanamide (10) and 6-(4-chlorophenoxy)-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-y l)-2,2-dimethyloctanamide (50) showed potent activity. Introduction of a dimethylamino group at position 5 of the 2,3-dihydrobenzofuran moiety resulted in highly potent activity. The most potent compound, N-[5-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl ]-2,2-dimethyldodecanamide (13, TEI-6620), showed highly potent ACAT inhibitory activity (rabbit small intestine IC50 = 0.020 microM, rabbit liver IC50 = 0.009 microM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50 = 0.030 microM), extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (Cmax = 2.68 microg/mL at 1 h, 10 mg/kg po).     

PNU 157706, a novel dual type I and II 5alpha-reductase inhibitor

PNU 157706 is a novel dual inhibitor of 5alpha-reductase (5alpha-R), the enzyme responsible for the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5alpha-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5alpha-R type I and II isozymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isozyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting reduction of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, respectively). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate weight in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate weight, the ED50 values being 0.12 and 1.9 mg/kg/day, respectively. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5alpha-R with a very marked antiprostatic effect in the rat.     

Transcriptional activation of the human c-myc gene by simian virus 40 large T antigen without binding to p53 and RB proteins in the transient expression system

Male adult Wistar rats were randomly divided into four groups in a 2 x 2 factorial design and were fed diets containing cooked-stored polished rice (CSPR), with and without 0.7 g/100 g of Nebacitin [bacitracinneomycin sulfate (2:1, wt/wt)] and with and without 1 g cholesterol/100 g diet. The CSPR diet contained 1.87 g resistant starch/100 g. After 4 wk, arterial blood and liver were collected. Feces were collected during the last 7 d. Rats fed the diet with Nebacitin and cholesterol had higher serum total cholesterol than the rats fed diets without cholesterol. Serum triglyceride concentration was greater in rats fed Nebacitin, regardless of dietary cholesterol concentration. Rats fed the diet with Nebacitin and cholesterol had higher serum LDL cholesterol concentration and liver total cholesterol concentration than rats fed the other three diets. Rats fed the CSPR diet with Nebacitin both with and without cholesterol had a higher fecal resistant starch concentration and excretion and lower serum short-chain fatty acid concentration than rats fed the diets without Nabacitin. Hepatic cholesterol concentration was greater in rats fed Nebacitin only when the diet also contained cholesterol. Therefore, dietary Nebacitin alters lipid metabolism in rats, and some effects are most pronounced in those also fed cholesterol.     

Possible modulatory effect of browned yam flour diet on chemically-induced toxicity in the rat

The possible modulatory effect of browned yam flour, a local dietary staple in south western Nigeria, on the toxicity of 7,12-dimethylbenzanthracene (DMBA), 3-methylcholanthrene (3-MC), carbon tetrachloride (CCl4) and bromobenzene (BrB) in rats was investigated. Feeding rats with 25% browned yam flour 2 wk before treatment with 65 mg/kg DMBA (single dose) and 5 mg/kg 3-MC and continued for 3 wk significantly decreased the reduction in final body weight or weight gain and organ weights caused by the two compounds. Similarly, the diet decreased the reduction in body weight or weight gain and the increase in relative liver weight mediated by oral treatment with 0.5 ml CCl4/kg and 2.5 mmol BrB/kg body weight. Incorporation of 25% browned yam flour into rat diet significantly reduced the DMBA-mediated decrease in haemoglobin content, packed cell volume, red blood cell count and white blood cell count by 7, 5, 20 and 10%, respectively; while the diet reduced the 3-MC-mediated decrease in these parameters by 15, 28, 9 and 17%, respectively. The same diet elicited 23, 45, 13 and 33% decreases in CCl4 mediated reduction in these parameters and 23, 18, 16 and 29% in the case of BrB. Browned yam flour diet caused 10, 14 (P < 0.001) and 4% (P < 0.05) reductions in the DMBA-mediated increase in serum aspartate aminotransferase, alanine aminotransferase and serum alkaline phosphatase, respectively; and 32, 31 (P < 0.05) and 13% (P < 0.001) in the case of the 3-MC-mediated increase. Also, the diet reduced CCl4-mediated increase in the activities of these by 40, 34 and 31%, respectively and by 23, 30 and 29% following BrB treatment. These results suggest that browned yam flour diet could possibly be a modulator of chemically induced toxicity.     

The effects of selenium deficiency, dietary selenium, and vitamin E supplementation on the oxidative status of pig liver

The aim of this work was to determine the effect of selenium (Se) deficiency on the porcine liver oxidative stability and to investigate Se content and oxidative status in porcine liver after dietary supplementation with vitamin E (vit E), sodium selenite, and selenized yeast. Experimental animals were fed a basal corn meal, low in Se and vit E, for a 4-week depletion period before being given the experimental diets containing different levels of Se and/or vit E for 5 months. Dietary treatments were the basal diet with no additions (control); the basal diet supplemented with 25 mg of vit E/kg of feed (group I); basal diet + 0.3 mg selenite-Se/kg (group II); basal diet + 0.3 mg selenized yeast-Se/kg (group III); basal diet + 0.1 mg selenite-Se + 10 mg vit E/kg (group IV); and basal diet + 0.3 mg selenite-Se + 25 mg vit E/kg (group V). The Se content in pig liver samples was 33 to 192% lower in the control group than in all the other groups. Dietary Se from selenized yeast had a more pronounced effect on Se level than dietary sodium selenite. The highest Se content was found in liver samples from the Se + vit E supplemented group (group V). All the dietary supplementation schemes significantly improved the oxidative status of porcine liver compared with the control group samples. The best results were obtained by simultaneous dietary supplementation with Se + vit E (groups IV and V) > group III > group II > group I.     

Effects of spinach leaf protein concentrate on the serum cholesterol and amino acid concentrations in rats fed a cholesterol-free diet

The effects of spinach leaf protein concentrate (SPPC) on serum and liver lipid concentrations and on serum free amino acid concentrations were examined in rats fed a cholesterol-free diet containing 2 and 10% fats. The serum total cholesterol, triacylglycerol and phospholipid concentrations in the rats fed an SPPC diet containing 2% corn oil were significantly lower than those of the rats fed a corresponding casein diet. When 10% corn oil or lard was used, the serum cholesterol-lowering effect of the SPPC became insignificant, but the serum and liver triacylglycerol concentrations were kept at significantly lower levels. Both the amounts of fecal neutral steroids and bile acids were significantly higher in the rats fed the SPPC than those of the casein-fed rats. The concentrations of serum threonine, serine, glutamine, glycine, cystine, and isoleucine were significantly higher in the rats fed the SPPC diet containing 2% corn oil compared with those of the control rats, but when the dietary fat was raised to 10%, only glycine showed a higher serum concentration. These results indicate that the SPPC has a stronger cholesterol-lowering effect at a lower dietary fat level, 2%, and the activity is partly due to the inhibition of intestinal absorption of cholesterol and bile acid, and partly due to an increase in the concentration of some of the serum amino acids.     

Hypocholesterolemic action of Lactobacillus acidophilus ATCC 43121 and calcium in swine with hypercholesterolemia induced by diet

Thirty-three Yorkshire barrows (92 kg), fed a high cholesterol diet for 14 d had mean concentrations of serum cholesterol of 294.6 +/- 7.8 mg/dl. Starting on d 15 and for an additional 15 d, crystalline cholesterol was removed from the diet and pigs were assigned to one of four treatments: including two levels of calcium (0.7% and 1.4%) with and without added viable Lactobacillus acidophilus ATCC 43121 (2.5 x 10(11) cells per feeding). Serum cholesterol levels decreased, as expected, for all groups. However, the declines were initiated sooner for the groups receiving L. acidophilus. and those receiving the high level of calcium than for the respective control groups. When averaged over days, pigs fed L. acidophilus had 11.8% lower total cholesterol than pigs fed a diet without L. acidophilus. Similarly, pigs fed 1.4% calcium had a significantly lower total cholesterol than pigs fed 0.7% calcium. The effects were greater on low density lipoprotein cholesterol than on high density lipoprotein cholesterol. In addition, during the overall 15-d experimental period, serum bile acids were reduced 23.9% by dietary L. acidophilus and by 21.4% by 1.4% dietary calcium compared with those of their controls. Total bile acid concentration was positively correlated with total cholesterol concentration for pigs fed L. acidophilus or 1.4% calcium. These data suggest that both L. acidophilus and calcium can enhance the reduction of serum cholesterol in pigs that had been fed a high cholesterol diet, probably through alteration in the enterohepatic circulation of bile acids.     

A comparison of the abilities of chlorpromazine and molindone to interact adversely with guanethidine

Chlorpromazine and molindone were tested for their abilities to impair conditioned avoidance behavior of rats. Chlorpromazine was effective within the dose range of 0.3 to 7.0 mg/kg (ID50approximately 2.0 mg/kg); molindone was effective within the range of 0.3 to 5.0 mg/kg (ID50 approximately 0.6 mg/kg). Behaviorally relevant doses of chlorpromazine and molindone were then tested for their effects on blood pressure and on adrenergic mechanisms. When given intravenously to anesthetized, hypertensive animals, both drugs (1.0 mg/kg) produced significant but transient vasodepression. When given intraperitoneally to anesthetized or to conscious hypertensive rats, the drugs did not produce significant effects on blood pressure. Both drugs (1.0 mg/kg) blocked responses to an alpha agonist (methoxamine), but chlorpromazine was significantly more potent than molindone. In addition, chlorpromazine produced a dose-dependent (1.0-10.0 mg/kg) inhibition of 3H-l-norepinephrine uptake into heart, but molindone at the same doses produced no inhibition of uptake. In related experiments, it was found that guanethidine (50 mg/kg) was an effective agent for lowering blood pressure of hypertensive rats. When chlorpromazine (3-10 mg/kg) was administered concomitantly with guanethidine, the blood pressure lowering properties of guanethidine were diminished or abolished. When molindone (1-10 mg/kg) was administered concomitantly with guanethidine, there was no loss of blood pressure control. It is concluded that molindone is an important drug, because it is an antipsychotic agent that does not interact adversely with guanethidine.     

Effects of different levels of dietary iron on pregnancy superimposed upon growth in the rat

The effects of feeding four levels of dietary iron, 10, 50, 250 and 1.250 mg/kg were studied during pregnancy in growing and adult rats. Hematological measurements, plasma iron and total iron binding capacity, and iron content in liver, spleen and tibia were compared relative to pregnancy, diet and growth. Iron content in fetuses and fetal livers were compared relative to diet and growth of the dams. All parameters were lowest in rats fed the 10 mg Fe/kg diet. The highest level of iron fed, 1,250 mg/kg, resulted in increased iron content in liver, spleen and tibia of all treatment groups but did not alter hematological values or fetal iron content. Pregnant rats fed any of the four levels of iron had significantly lower Hb, Ht, total and storage iron concentration and ferritin and hemosiderin iron in liver than nonpregnant rats fed the same levels. The level of dietary iron needed by growing pregnant rats for maximal iron content in fetuses and fetal livers was between 50 and 250 mg Fe/kg which was fivefold that needed to obtain maximal hemoglobin concentration in dams. However, adult pregnant rats only needed between 10 to 50 mg Fe/kg for both maximal iron stores in fetal tissues and maximal hemoglobin concentration.     

Cancer of the breast: Interrelations betwpen the primary tumor and the axillary and internal mammary nodes

Effect of fluorescent products from the reaction of malonaldehyde with dipalmitoyl phosphatidylethanolamine on the content of lipids in plasma and liver of rats was examined, and the results are as follows: Growth of rats was suppressed by daily intraperitoneal administration of fluorescent products (10 or 50 mg/kg) for 7 days. Levels of triglycerides and total cholesterol in the plasma tended to decrease but that of phospholipids increased significantly by the administration of fluorescent products in a dose of 50 mg/kg/day. On the other hand, content of triglycerides in liver decreased by about 26% at a dose of 10 mg/kg and 23% at a dose of 50 mg/kg. Total cholesterol and phospholipids showed a slight diminution. Free fatty acid content in the liver was almost constant. Thiobarbituric acid values in the plasma and liver increased significantly by treatment with the fluorescent products, especially the values at a rate of increase were higher in the plasma than in the liver. No significant changes were observed in the relative fluorescence intensity between control animals and groups treated with fluorescent products. Serum lipoprotein patterns after Agarose gel electrophoresis revealed diffuse bands in the pre-beta and beta-regions.     

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.     

Pharmacokinetics of a new reversible proton pump inhibitor, YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5-20 mg kg(-1), to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50-200 mg kg(-1), to rats, the area under the plasma concentration-time curve from time zero to 12 or 24 h (AUC(0-12 h) or AUC(0-24 h)) was proportional to the oral dose of the drug, 50-100 mg kg(-1), however, the AUC(0-24 h) value at 200 mg kg(-1) increased with less proportion to the dose increase (324, 689, and 815 microg x min mL(-1) for 50, 100, and 200 mg kg(-1), respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg(-1), respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg(-1). The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg(-1), was approximately 70% (116 versus 163 microg x min mL(-1)) of that after iv administration of the drug, 5 mg kg(-1), to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5-20 mg kg(-1), to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg(-1), to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5-20 mg kg(-1), to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC(0-10 h) values were not significantly different (96.8 versus 98.2 microg x min mL(-1)) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs.     

Effects of inhaled KAA-276, a selective histamine H1 receptor antagonist, on antigen- and histamine-induced bronchoconstriction in animals

The antiasthmatic profile of KAA-276 (1-[1-(4-fluorophenylmethyl)-1H-benzimidazole-2-yl]-5-[2-[4-(2- carboxethyl) phenyl]ethyl]-1,5-diazacyclooctane sulfate, CAS 167264-26-8), a newly synthesized histamine H1 receptor antagonist, given by inhalation as an aerosol was investigated and compared with the profiles obtained using other routes of administration. When given by inhalation, or by intravenous or oral routes, KAA-276 inhibited antigen-induced bronchoconstriction in rats with ID50 (a dose to inhibit the antigen-induced response by 50%) values of 0.054%, 1 mg/kg, and 51.2 mg/kg, respectively. KAA-276 prevented the histamine-induced wheal reaction in rats dose-dependently with ID50 values of 0.22% by inhalation, 0.18 mg/kg by the intravenous route, and 2.3 mg/kg by the oral route. To judge from these results, inhaled KAA-276, unlike intravenous or oral KAA-276, had no inhibitory effect on the histamine-induced wheal reaction at a dose (0.054%) that is effective against the antigen-induced airway asthmatic response. Inhaled KAA-276 suppressed antigen-induced bronchoconstriction in actively sensitized guinea pigs, and histamine-induced bronchoconstriction in monkeys. These results suggest that inhalation of KAA-276 would benefit patients with bronchial asthma without inducing unwanted systemic effects.     

The relative effect of dietary fats and carbohydrates on lipid metabolism in the albino rat

This study is concerned with the effect of two carbohydrates, cane-sugar and corn starch, at four different levels in the presence of two dietary fats, on the serum and the tissue lipids (cholesterol, phospholipid and fatty acid patterns). Keeping the dietary fats (coconut safflower seed oil) at 20% level, diets containing (a) startch (54%) + cane sugar (0%), (b) starch (44%) + cane sugar 10%), (c) starch (10%) + cane sugar (44%) and (d) only cane sugar (54%) were administered to rats for 8 weeks. The lipid levels were determined at the end of the feeding period. The beneficial effect of the unsaturated fat in lowering the serum cholesterol level is nullified by an excess of cane sugar in the diet. In liver, there is an increase of 40-50% of cholesterol, as the cane sugar level in the diet is raised, irrespective of the type of dietary fat. The fatty acid pattern of the serum and tissue lipids is influenced by dietary fats as well as carbohydrates.     

Dietary components modify the ability of garlic to suppress 7,12-dimethylbenz(a)anthracene-induced mammary DNA adducts

Various dietary components were evaluated as factors influencing garlic's ability to depress rat mammary cell DNA adducts resulting from 7,12-dimethylbenz(a)anthracene (DMBA) treatment. Diets with or without garlic powder (20 g/kg) were provided for 2 wk before DMBA treatment (25 mg/kg body weight). Rats fed diets containing 36 g casein/100 g diet had 31% fewer (P < 0.05) mammary cell DNA adducts than those fed 12 g/100 g. Garlic supplementation significantly (P < 0.05) reduced DNA adducts in rats fed either 12 or 36 g casein/100 g by 35 and 32% respectively. In the absence of dietary garlic, DNA adducts were 23% lower (P < 0.05) in rats provided a diet containing supplemental L-methionine at 0.9 g/100 g than at 0.3 g/100 g. However, adduct inhibition by garlic supplementation was greater in rats fed the lower (P < 0.05) amount of methionine (54 vs. 26% inhibition). Adduct levels in rats fed diets with 20 g corn oil/100 g were twice those occurring in rats fed 5 g/100 g (P < 0.05), regardless of adjustment for energy density. Garlic supplementation prevented the increase in DNA adducts caused by increasing dietary corn oil. Combining dietary supplements of garlic, selenite (0.5 mg/kg diet) and retinyl acetate (328 mg/kg diet) inhibited the occurrence of DNA adducts to a greater degree than when each was supplied individually. These studies demonstrate that while dietary garlic can reduce DNA adduct formation in mammary tissue caused by DMBA, this protection is influenced by several dietary components.