A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis.

AIM: To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice. METHODS: The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined. RESULTS: Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in ß-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the ß2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice. CONCLUSION: BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.

Vitamin D and health-related quality of life in a community sample of older Canadians.

PURPOSE: To assess how vitamin D status is associated with health-related quality of life (HRQOL) among older residents of Canada. DESIGN: We analysed baseline data of 1,493 Canadians aged 50 years and over in Alberta on HRQOL (EQ-5D-5L) and serum 25-hydroxyvitamin D (25(OH)D) as a measure of vitamin D status. We applied multivariable regression methods to examine the association between vitamin D status and each of the five dimensions and the summary index of the EQ-5D-5L. RESULTS: Participants with higher serum 25(OH)D levels were significantly less likely to report problems with mobility, usual activities, and depression and anxiety. Specifically, age- and gender-adjusted odds ratios for reporting problems with mobility, usual activities, and depression and anxiety were 0.58 (95 % confidence interval 0.44-0.78), 0.67 (0.50-0.89), and 0.67 (0.51-0.88) per 100 nmol/L increase in 25(OH)D, respectively. No significant associations were observed for problems with self-care and with pain and discomfort. HRQOL scores combining the responses of each of the five dimensions increased significantly with increasing serum 25(OH)D levels. CONCLUSIONS: This is the first study to reveal the importance of vitamin D for the five dimensions of HRQOL in a community-based sample. The observed associations of vitamin D and HRQOL call for intervention studies to strengthen the evidence of the potential benefits of vitamin D supplementation for HRQOL among older adults.

Vitamin D status of Canadians employed in northern latitudes.

BACKGROUND: Vitamin D deficiency and insufficiency are prevalent worldwide, but relatively few studies have examined vitamin D status in working populations. AIMS: To assess the prevalence of vitamin D deficiency and insufficiency in Canadian workers and investigate risk factors in this population. METHODS: A cross-sectional study using data from a health programme enrolling workers mostly from Northern Alberta, Canada. As part of the programme, volunteers were invited to complete a lifestyle questionnaire. Blood was taken to determine plasma 25-hydroxyvitamin D (25(OH)D) levels. Logistic and linear regressions were used to investigate the relationships between individual characteristics and vitamin D status. RESULTS: Between October 2007 and December 2012, 6101 eligible workers enrolled in the health programme. The prevalence of vitamin D deficiency (plasma 25(OH)D, levels <27.5 nmol/l) and insufficiency (<37.5 nmol/l) were 3 and 8%, respectively. Male employees were significantly more likely to be vitamin D deficient and insufficient than females. Residing at a more northern latitude increased the likelihood of vitamin D deficiency and insufficiency. Age, assessments made in summer, better general health and physical activity and use of vitamin D supplementation were all related to lower likelihood of deficiency and insufficiency. CONCLUSIONS: Vitamin D deficiency and insufficiency are a concern in this sample of Canadian workers. Vitamin D supplementation is recommended to reduce the prevalence of deficiency and insufficiency in this group.

A common environmental pollutant, 4-nonylphenol, promotes allergic lung inflammation in a murine model of asthma.

BACKGROUND: Exposure to environmental hormones, such as alkylphenols, has been suggested to be associated with the development of asthma, but the mechanism of action remains unclear. OBJECTIVE: This study examined the effect of 4-nonylphenol (NP), one of the most important alkylphenols, on conventional dendritic cells (cDCs) and adaptive T-cell responses. It also explored the role of aryl hydrocarbon receptor (AhR) in NP's effect. METHODS: NP-conditioned bone marrow-derived DCs (BM-DCs) and splenic CD11c(+) cDCs were assessed regarding function in a murine model under conditions relevant to route and level of exposure in humans. RESULTS: Our results showed that splenic cDCs from NP-exposed mice have potent Th2-skewing ability and secrete increased levels of IL-6 and TNF-α, but not IL-10 and IL-12, at baseline and after stimulation with LPS. Further, bone marrow-derived DCs were cultured in the presence of NP and showed similar cytokine pattern and influenced the antigen-specific T cells secreting significantly less IFN-γ. Importantly, NP-exposed mice developed more severe OVA-induced allergic lung inflammation compared with control group. Interestingly, in a congenic strain of mice carrying low-affinity, ligand-binding mutant AhR (AhR(d) ), NP's effect on DC functions and lung inflammation was not observed in vitro and in vivo. CONCLUSION: These results suggested that NP may disturb physiologic function of DCs through, in part, AhR-dependent mechanisms, supporting the importance of NP exposure on the regulation of DC functions and allergic inflammation.

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors.

OBJECTIVE: Fatty acid oxidation has been implicated in amelioration of obesity by burning off excessive accumulated lipid. BPR697, a peripheral cannabinoid receptor 1 (CB1) antagonist, elevated fat oxidation without added energy expenditure. Its impact on food intake, body weight changes and metabolic alterations were examined in rats fed standard chow and in diet-induced obesity (DIO) mice. MATERIALS AND METHODS: CB1 agonist-induced hypothermia and analgesia responses were measured to examine the brain activity of BPR697. The acute effects of BPR697 on food intake, body weight change and post-absorptive metabolic profiles were investigated in rats. Energy utilization with BPR697 was examined by indirect calorimetry. Chronic treatment of DIO mice was used to evaluate the long-term effects of BPR697. RESULTS: Distribution of BPR697 was significantly biased in favor of the periphery instead of the brain, as shown by its low brain/plasma concentration ratio and confirmed by the negative response of BPR697 in CB1 agonist-induced hypothermia and analgesia. When administered to rats at 20 mg kg(-1), BPR697 showed a unique spectrum of effects with significant weight loss without altered food intake. Furthermore, BPR697 increased serum levels of free fatty acids and ketone bodies and reduced hepatic lipid accumulation with preservation of liver glycogen in postprandial rats. Indirect calorimetric profiling of BPR697 revealed a similar trend, shifting whole-body energy catabolism toward fat oxidation, but without elevated energy expenditure. In DIO mice with chronic treatment, animals treated with BPR697 at 20 mg kg(-1) resisted weight gain and showed a reduction of high-fat-induced cardiometabolic abnormalities such as hyperglycemia, abdominal fat and liver steatosis. CONCLUSION: The induction of fatty acid oxidation without concomitant elevation of energy expenditure by the peripheral CB1 antagonist BPR697 is sufficient to cause substantial weight loss in chow-fed rats. In the presence of high-dietary fat intake, BPR697 resists weight gain and alleviates obesity-related cardiometabolic risk factors.

BPR1J-097, a novel FLT3 kinase inhibitor, exerts potent inhibitory activity against AML.

BACKGROUND: Activating mutations of Fms-like tyrosine kinase 3 (FLT3) constitute a major driver in the pathogenesis of acute myeloid leukaemia (AML). Hence, pharmacological inhibitors of FLT3 are of therapeutic interest for AML. METHODS: The effects of inhibition of FLT3 activity by a novel potent FLT3 inhibitor, BPR1J-097, were investigated using in vitro and in vivo assays. RESULTS: The 50% inhibitory concentration (IC(50)) of BPR1J-097 required to inhibit FLT3 kinase activity ranged from 1 to 10 nM, and the 50% growth inhibition concentrations (GC(50)s) were 21±7 and 46±14 nM for MOLM-13 and MV4-11 cells, respectively. BPR1J-097 inhibited FLT3/signal transducer and activator of transcription 5 phosphorylation and triggered apoptosis in FLT3-driven AML cells. BPR1J-097 also showed favourable pharmacokinetic property and pronounced dose-dependent tumour growth inhibition and regression in FLT3-driven AML murine xenograft models. CONCLUSION: These results indicate that BPR1J-097 is a novel small molecule FLT-3 inhibitor with promising in vivo anti-tumour activities and suggest that BPR1J-097 may be further developed in preclinical and clinical studies as therapeutics in AML treatments.

High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists.

Dyslipidemia, a major risk factor for cardiovascular disease, may be directly linked to diabetic hyperglycemia and insulin resistance. An appropriate dyslipidemic animal model that has diabetes would provide an important tool for research on the treatment of diabetic dyslipidemia. Ten days of high fat feeding in golden Syrian hamsters resulted in a significant increase in insulin resistance and baseline serum lipid levels accompanied by a pronounced dyslipidemia. Thirteen days of treatment with fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) selective agonist, produced a dose-dependent decrease in serum lipid levels. The pattern observed was characterized by lowered very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) and raised high-density lipoprotein (HDL) cholesterol in a fashion similar to that seen in man. Diabetic conditions were also significantly improved by fenofibrate with a normalization of impaired glucose tolerance and an improvement of insulin sensitivity during an oral glucose tolerance test. These data suggest that fenofibrate may correct not only the dyslipidemia but also the insulin resistance caused by a high fat diet, and the high fat fed hamster may be a good animal model for research on the treatment of diabetic dyslipidemia with PPARalpha selective agonists.

ApoE(-/-) mice develop atherosclerosis in the absence of complement component C5.

Previous studies have suggested that the terminal complex of complement may contribute to the pathogenesis of atherosclerosis. C5b-9 complexes colocalize with the extracellular lipid in the aortic intima of hypercholesterolemic rabbits, and C6-deficient rabbits develop less atherosclerosis than controls. To test the role of complement in atherosclerosis in a different animal model, C5 deficient (C5def) mice were cross-bred with atherosclerosis susceptible apoE(-/-) mice, generating mice deficient in both apoE and C5 and control apoE(-/-) mice. Progeny were typed for C5 titer and serum cholesterol levels. Both male and female mice were fed a high fat diet from weaning until 22 weeks of age. At that time there were no significant differences in plasma cholesterol or triglycerides between apoE(-/-) control and apoE(-/-)/C5def groups. Morphometric analysis of the aortic root lesions gave mean (+/-SEM) lesion areas for male apoE(-/-) and apoE(-/-)/C5def mice of 468,176 +/- 21,982 and 375,182 +/- 53,089 microm(2), respectively (n = 10 each, P value = 0.123). In female apoE(-/-) mice (n = 5), the mean lesion area was 591,981 +/- 53,242 microm(2), compared to 618,578 +/- 83,457 microm(2) for female apoE(-/-)/C5def mice (n = 10) (P value = 0.835). Thus neither male nor female mice showed a significant change in lesion area when C5 was not present. In contrast to the case in the hypercholesterolemic rabbit, activation of the terminal complex of complement does not play a major role in the development of atherosclerosis in apoE(-/-) mice.

Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering.

Inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, such as simvastatin, lower circulating cholesterol levels and prevent myocardial infarction. Several studies have shown an unexpected effect of HMG-CoA reductase inhibitors on inflammation. Here, we confirm that simvastatin is anti-inflammatory by using a classic model of inflammation: carrageenan-induced foot pad edema. Simvastatin administered orally to mice 1 hour before carrageenan injection significantly reduced the extent of edema. Simvastatin was comparable to indomethacin in this model. To determine whether the anti-inflammatory activity of simvastatin might affect atherogenesis, simvastatin was tested in mice deficient in apoE. Mice were dosed daily for 6 weeks with simvastatin (100 mg/kg body wt). Simvastatin did not alter plasma lipids. Atherosclerosis was quantified through the measurement of aortic cholesterol content. Aortas from control mice (n=20) contained 56+/-4 nmol total cholesterol/mg wet wt tissue, 38+/-2 nmol free cholesterol/mg, and 17+/-2 nmol cholesteryl ester/mg. Simvastatin (n=22) significantly (P<0.02) decreased these 3 parameters by 23%, 19%, and 34%, respectively. Histology of the atherosclerotic lesions showed that simvastatin did not dramatically alter lesion morphology. These data support the hypothesis that simvastatin has antiatherosclerotic activity beyond its plasma cholesterol-lowering activity.

PPARalpha agonists reduce 11beta-hydroxysteroid dehydrogenase type 1 in the liver.

11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol-cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11betaHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11betaHSD1 expression and activity after chronic treatment of wild-type mice with PPARalpha agonists, while 11betaHSD1 in the livers of PPARalpha knockout mice, or in mice treated for only 7 h with PPARalpha agonists, was unaltered. Our results are the first to show PPARalpha agonists can affect glucocorticoid metabolism in the liver by altering 11betaHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARalpha agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.

Deficiency in inducible nitric oxide synthase results in reduced atherosclerosis in apolipoprotein E-deficient mice.

Inducible NO synthase (iNOS) present in human atherosclerotic plaques could contribute to the inflammatory process of plaque development. The role of iNOS in atherosclerosis was tested directly by evaluating the development of lesions in atherosclerosis-susceptible apolipoprotein E (apoE)-/- mice that were also deficient in iNOS. ApoE-/- and iNOS-/- mice were cross-bred to produce apoE-/-/iNOS-/- mice and apoE-/-/iNOS+/+ controls. Males and females were placed on a high fat diet at the time of weaning, and atherosclerosis was evaluated at two time points by different methods. The deficiency in iNOS had no effect on plasma cholesterol, triglyceride, or nitrate levels. Morphometric measurement of lesion area in the aortic root at 16 wk showed a 30-50% reduction in apoE-/-/iNOS-/- mice compared with apoE-/-/iNOS+/+ mice. Although the size of the lesions in apoE-/-/iNOS-/- mice was reduced, the lesions maintained a ratio of fibrotic:foam cell-rich:necrotic areas that was similar to controls. Biochemical measurements of aortic cholesterol in additional groups of mice at 22 wk revealed significant 45-70% reductions in both male and female apoE-/-/iNOS-/- mice compared with control mice. The results indicate that iNOS contributes to the size of atherosclerotic lesions in apoE-deficient mice, perhaps through a direct effect at the site of the lesion.

Intestinal absorption of cholesterol is mediated by a saturable, inhibitable transporter.

Although the mechanism by which dietary cholesterol is absorbed from the intestine is poorly understood, it is generally accepted that cholesterol is absorbed from bile acid micelles in the jejunum. Once inside the enterocytes, cholesterol is esterified by the action of acyl-coenzyme A:cholesterol acyltransferase (ACAT), assembled into chylomicrons, and secreted into the lymph. In this work, mechanistic aspects of cholesterol absorption were probed using compounds that block cholesterol absorption in hamsters. Sterol glycoside cholesterol absorption inhibitors, exemplified by L-166,143, (3 beta, 5 alpha,25R)-3-[(4", 6"-bis[2-fluoro-phenylcarbamoyl]-B-D-cellobiosyl)oxy]-spirostan -11-on e, potently blocked absorption of radioactive cholesterol, and the potencies of several analogs correlated with their ability to lower plasma cholesterol. Each molecule of L-166,143 blocked the uptake of 500 molecules of cholesterol, rendering it unlikely that the inhibitor interacts directly with the cholesterol or bile acid. Radiolabeled L-166,143 bound to the mucosa and binding was blocked by active, but not inactive, cholesterol absorption inhibitors. Subtle changes in the structure of sterol glycosides yielded large changes in their ability to block both cholesterol absorption and binding of radiolabeled L-166,143. Large species-to-species variation in potency was also observed. These lines of evidence support the interpretation that dietary cholesterol is absorbed via a specific transporter found in the intestinal mucosa.

A target for cholesterol absorption inhibitors in the enterocyte brush border membrane.

Uptake of cholesterol by the intestinal absorptive epithelium can be selectively blocked by specific small molecules, like the sterol glycoside, L-166,143. Furthermore, (3)H-labeled L-166,143 administered orally to hamsters binds specifically to the intestinal mucosa, suggesting the existence of a cholesterol transporter. Using autoradiography, the binding site of (3)H-L-166,143 in the hamster small intestine was localized to the very apical aspect of the absorptive epithelial cells. Label was competed by non-radioactive L-166,143 and two structurally distinct cholesterol absorption inhibitors, suggesting a common site of action for these compounds. L-166,143 blocked uptake of (3)H-cholesterol into enterocytes in vivo, as demonstrated by autoradiography, suggesting that it inhibits a very early step of cholesterol absorption, incorporation into the brush border membrane. This conclusion was confirmed by studies in which intestinal brush borders were isolated from hamsters dosed with (3)H-cholesterol in the presence or absence of L-166,143. Uptake of (3)H-cholesterol into the membranes was substantially inhibited by the compound. In contrast, an inhibitor of acyl CoA:cholesterol acyltransferase, did not affect uptake of (3)H-cholesterol into the brush border membranes. These results strongly support the existence of a specific transporter that facilitates the movement of cholesterol from bile acid micelles into the brush border membranes of enterocytes.

Infectious agents are not necessary for murine atherogenesis.

Recent work has revealed correlations between bacterial or viral infections and atherosclerotic disease. One particular bacterium, Chlamydia pneumoniae, has been observed at high frequency in human atherosclerotic lesions, prompting the hypothesis that infectious agents may be necessary for the initiation or progression of atherosclerosis. To determine if responses to gram-negative bacteria are necessary for atherogenesis, we first bred atherosclerosis-prone apolipoprotein (apo) E(-/)- (deficient) mice with animals incapable of responding to bacterial lipopolysaccharide. Atherogenesis was unaffected in doubly deficient animals. We further tested the role of infectious agents by creating a colony of germ-free apo E(-/)- mice. These animals are free of all microbial agents (bacterial, viral, and fungal). Atherosclerosis in germ-free animals was not measurably different from that in animals raised with ambient levels of microbial challenge. These studies show that infection is not necessary for murine atherosclerosis and that, unlike peptic ulcer, Koch's postulates cannot be fulfilled for any infectious agent in atherosclerosis.

A fluorescent cholesterol analog traces cholesterol absorption in hamsters and is esterified in vivo and in vitro.

The fluorescent cholesterol analog 22-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3beta-ol (fluoresterol) was characterized as a tool for exploring the biochemistry and cell biology of intestinal cholesterol absorption. Hamsters absorbed fluoresterol in a concentration- and time-dependent manner, with an efficiency of about 15-30% that of cholesterol. Fluoresterol absorption was blocked by compounds known to inhibit cholesterol absorption, implying that fluoresterol interacts with those elements of the normal pathway for cholesterol absorption on which the inhibitors act. Confocal microscopy of small intestinal tissue demonstrated that fluoresterol was taken up by absorptive epithelial cells and packaged into lipoprotein particles, suggesting a normal route of intracellular trafficking. Uptake of fluoresterol was confirmed by biochemical analysis of intestinal tissue, and a comparison of [(3)H] cholesterol and fluoresterol content in the mucosa suggested that fluoresterol moved through the enterocytes more rapidly than did cholesterol. This interpretation was supported by measurements of fluoresterol esterification in the mucosa. Four hours after hamsters were given fluoresterol and [(3)H]cholesterol orally, 44% of the fluoresterol in the intestinal mucosa was esterified, compared to 8% of the [(3)H]cholesterol. Caco-2 cells took up 2- to 5-fold more [(3)H]cholesterol than fluoresterol from bile acid micelles, and esterified 21-24% of the fluoresterol but only 1-4% of the [(3)H]cholesterol. Thus fluoresterol apparently interacts with the proteins required for cholesterol uptake, trafficking, and processing in the small intestine.

Hepatic responses to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase: a comparison of atorvastatin and simvastatin.

We have compared the cellular responses to simvastatin (Simva) and atorvastatin (Atorva), two potent HMG-CoA reductase inhibitors. The two drugs exhibited similar IC50's for inhibition of either rat or human reductase, and single oral dosing in rats showed the compounds to be nearly equipotent at inhibiting hepatic cholesterol synthesis. Treatment of rats with Simva or Atorva in the feed for four days yielded comparable inductions of hepatic reductase activity and reductase protein. For example, 0.05% Simva induced reductase activity 27.3 +/- 9.1 fold and 0.05% Atorva induced activity 26.9 +/- 4.7 fold. This adaptive response was also studied in HepG2 cells, a human hepatoblastoma line, cultured for 24 h in delipidated serum and then for an additional 24 h with Simva or Atorva. Over a broad range (10 nM-10 microM), both drugs caused similar inductions of reductase activity, reductase protein, and reductase mRNA. Under all conditions, the drugs induced similar changes in the ratio of mRNA/protein suggesting that Simva and Atorva have similar effects on both transcriptional and post-transcriptional regulatory machinery. Moreover, reductase in cells treated with Simva or Atorva for 22 h responded similarly to subsequent challenge with 25-hydroxycholesterol. Finally, we measured the ability of the two reductase inhibitors to reduce ApoB secretion by HepG2 cells. Simva and Atorva at 0.5 microM inhibited ApoB secretion nearly identically, 38% and 42% respectively. We conclude that these two drugs induce similar adaptive responses in cells and that their actions are qualitatively and mechanistically identical. Human studies have shown that plasma is cleared of Atorva much more slowly than it is of Simva. The large pharmacokinetic difference in man, rather than some difference in mechanism, is the most likely explanation for the finding that the equipotent dose ratio for cholesterol lowering in humans of Simva to Atorva is about 2/1.

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 9. The synthesis and biological evaluation of novel simvastatin analogs.

Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro. Oral activity of these compounds was determined in an acute rat model and a three-week study in cholestyramine-primed dogs. Compounds were identified that possessed in vitro and in vivo activity comparable to that of simvastatin.

Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N'-diphenyl-phenylenediamine.

The oxidative modification of low density lipoprotein (LDL) may play an important role in atherosclerosis. We found that the antioxidant N,N'-diphenyl-1,4-phenylenediamine (DPPD) inhibits in vitro LDL oxidation at concentrations much lower than other reported antioxidants. To test whether DPPD could prevent atherosclerosis, New Zealand White rabbits were fed either a diet containing 0.5% cholesterol and 10% corn oil (control group) or the same diet also containing 1% DPPD (DPPD-fed group) for 10 wk. Plasma total cholesterol levels were not different between the two groups, but DPPD feeding increased the levels of triglyceride (73%, P = 0.007) and HDL cholesterol (26%, P = 0.045). Lipoproteins from DPPD-fed rabbits contained DPPD and were much more resistant to oxidation than control lipoproteins. After 10 wk, the DPPD-fed animals had less severe atherosclerosis than did the control animals: thoracic aorta lesion area was decreased by 71% (P = 0.0007), and aortic cholesterol content was decreased by 51% (P = 0.007). Although DPPD cannot be given to humans because it is a mutagen, our results indicate that orally active antioxidants can have antiatherosclerotic activity. This strongly supports the theory that oxidized LDL plays an important role in the pathogenesis of atherosclerosis.

3-Hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors. 7. Modification of the hexahydronaphthalene moiety of simvastatin: 5-oxygenated and 5-oxa derivatives.

Modification of the hexahydronaphthalene ring 5-position in simvastatin 2a via oxygenation and oxa replacement afforded two series of derivatives which were evaluated in vitro for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acutely in vivo for oral effectiveness as inhibitors of cholesterogenesis in the rat. Of the compounds selected for further biological evaluation, the 6 beta-methyl-5-oxa 10 and 5 alpha-hydroxy 16 derivatives of 3,4,4a,5-tetrahydro 2a, as well as, the 6 beta-epimer 14 of 16 proved orally active as hypocholesterolemic agents in cholestyramine-primed dogs. Subsequent acute oral metabolism studies in dogs demonstrated that compounds 14 and 16 evoke lower peak plasma drug activity and area-under-the-curve values than does compound 10 and led to the selection of 14 and 16 for toxicological evaluation.

Effect of weight-bearing on healing of cortical defects in the canine tibia.

UNLABELLED: It has been generally accepted that mechanical stimulation is an important factor in the promotion of formation of bone. Fracture-healing consists of periosteal bridging of the fracture, which achieves stability, and proliferation of endosteal bone to fill the defects between the ends of the bone. To evaluate the effect of weight-bearing on bone-healing, an operatively created defect in the tibial cortex was chosen as an experimental model. In one set of dogs (Group 1), a bilateral defect in the tibial cortex was created and weight-bearing was permitted on one tibia but not on the opposite one. In Group 2, a bilateral defect in the tibial cortex was made and weight-bearing was allowed on both tibiae. A third group of dogs of similar age (Group 3) had no tibial defects. Quantitative histomorphometry was used to measure formation and porosity of bone. Weight-bearing was measured with both static and dynamic techniques. Significantly less woven bone formed in the defects in the non-weight-bearing tibiae than in the weight-bearing tibiae. This appeared to be due to a disuse response in the underloaded tibiae, in which less bone formed, rather than to the formation of more bone in the weight-bearing tibiae. The data suggest that weight-bearing is a permissive factor, not a stimulus, for formation of woven bone in a tibial defect. CLINICAL RELEVANCE: This animal model supports the concept that lack of weight-bearing decreases the amount of woven bone that is formed in a healing tibial defect. The results of this study indicate that weight-bearing increases the formation of bone in fracture-healing.(ABSTRACT TRUNCATED AT 250 WORDS)