Novel antidiabetic and hypolipidemic agents. 5. Hydroxyl versus benzyloxy containing chroman derivatives.

Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.     

Risk factors in dental implant failure

The goal of this study was to assess risk factors for dental implant failure. Eighty-three implants were placed in thirty patients who were followed for three years using digital subtraction radiography. The following putative risk factors for implant failure were employed in the model: age, sex, implant length, implant position, implant surface coating, smoking habit, and presence of infection. Implant failure was defined as progressive bone loss compromising the implant. We found that the presence of infection (P < 0.001) and absence of HA coating (P < 0.001) were the primary factors associated with early implant failure.     

Risk factors for retinopathy in diabetes mellitus in Kelantan, Malaysia

Few attempts have been made to determine the risk factors for diabetic retinopathy which is a major cause of visual impairment and blindness. One hundred and forty patients of diabetes mellitus were studied to determine the prevalence and types of retinopathy, and its relation to various risk factors. Nearly half (48.6%) of the patients suffered from retinopathy. The significant associated risk factors were long duration of diabetes, proteinuria and elevated serum creatinine level. However, there was no significant association between the prevalence of retinopathy and high levels of serum cholesterol, C-peptide levels, associated hypertension, and glycaemic control of diabetes mellitus. An effective screening programme for detection of retinopathy in the patients of diabetes as a regular practice is encouraged.     

Effect of chronic tobacco-betel-lime "quid" chewing on human salivary secretions

Salivary flow rates by mechanical stimulation with forced spitting method and by chemical stimulation with 10% citric acid were determined in 25 healthy adult subjects with a history of chronic tobacco-betel-lime "quid" chewing and in 25 healthy control adults with no history of chewing. The chewers secreted more saliva as compared to nonchewers on chemical, but not on mechanical stimulation. The salivary amylase, potassium, and sodium levels were lower in chewers, but the reductions of the first two components only were significant. These reductions were thought to be due to increased salivary flow with its dilutional effect. There was no difference between the two groups with respect to salivary pH. The salivary flow rates by either method had significant positive correlation with the duration of chewing, but not with the amount of tobacco chewed. Salivary potassium was inversely correlated with the amount of tobacco chewed. It was concluded that chronic tobacco-betel-lime quid chewing induces excessive secretion of more watery saliva leading to a concomitant decrease in enzyme and electrolyte content. One or more of the following factors were considered to be operating in causing increased salivary flow in chewers effect of nicotine or tobacco on other constituents of the quid, chronic salivary gland hyperplasia, or chronic hypertrophy of the muscles of mastication.     

Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans

In this critical review, I would like to provide a brief outline of the morphology, biochemical composition, distribution, and functions of peroxisomes. The induction of peroxisome proliferation and peroxisome-associated enzymes in the rodent liver by two classes of chemicals (hypolipidemic drugs and the industrial plasticizers) will be considered. The role of peroxisomes in lipid metabolism will be discussed. Carcinogenicity studies in rats and mice with these peroxisome proliferators will be evaluated critically. Careful consideration will be given to the hypothesis that "potent hepatic peroxisome proliferators as a class are carcinogenic." The possible mechanism(s) by which peroxisome proliferators induce liver tumors will be outlined. Particular attention will be paid to the possible role of peroxisome proliferation-mediated radical toxicity and generation of endogenous initiators of carcinogenesis.     

Effect of retinoids on the induction of colon cancer in F344 rats by N-methyl-N-nitrosourea or by 1,2-dimethyihydrazine

The possible modifying effect of synthetic and natural retinoidson the incidence of colon cancer in rats induced by 2 intrarectaldoses of 2.5 mg of N-methyl-N-nitrosourea (MNU) given once aweek for 2 successive weeks or a single 150 mg/kg body weightdose of 1,2-dime-thylhydrazine (DMH), s.c. was investigated.Emphasis was on the effect of the development of early tumorsas visualized by endoscopy. With the retinoids N-ethyl-retinamide,N-2-hydroxyethylretinamide, N-(4-hydro- xyphenyl)-all-trans-retinamide(RAHA), and retinyl acetate (RA) administered orally after thecarcinogens, significant differences in early developing tumorswere not found. At histopathological examination of the tumorsthe RAHA + DMH group had significantly fewer adenomas per animal.The percentage of adenoma bearing rats was significantly lowerin groups receiving RAHA + DMH or RA + DMH. However, food consumptionwas lower in rats consuming either RAHA or RA. Retinyl palmitate(RP) and RAHA was administered intrarectally to MNU-inducedrats either before or after the carcinogen. When administeredbefore MNU, RP caused a significant increase in the percentageof tumor bearing animals and the average number of tumors peranimal as visualized endos copically. At histopathological examination,all retinoid groups except RAHA given after the carcinogen,produced significantly more adenomas per animal and a significantlygreater adenoma incidence than did the control groups. Thus,in two systems, the oral administration of retinoids did notclearly inhibit the early or later stages of colon tumor development.Inirarectal infusion of two retinoids had no effect on colonicmor phology but at histopathological examination of later stagetumors there was an enhanced adenoma response.     

Effect of unsaturated fats and cholesterol on serum and fecal lipids. A study of healthy middle-aged men.

Modification of the Western diet, with an intake of 2,500 kcal per day and a decrease in cholesterol and fat intake to 33 per cent of calories with a P:S of 0.40, failed to alter serum lipids significantly. Evidence suggested that increasing the daily intake of cholesterol resulted in deposition in the body tissues. However, when the fatty acid composition and the P:S ratio of dietary fat were adjusted, lower serum lipids and a compensatory increase in fecal sterols occurred when cholesterol was added to the diet. Changes in serum lipoproteins in the subjects fed a "prudent" or a common diet indicate an increase in the proportion of HDL-cholesterol which may be beneficial in reducing coronary heart disease. Evidence suggests that, in absence of caloric excess, lowering of serum lipids and increased removal of fecal sterols is possible on a prudent diet without major modification of the customary foods, but that a high P:S ratio is required.     

A modified geometric factor approach to internal gamma ray dosimetry.

In internal gamma-ray dosimetry, the conventional geometric factor approach, where the "effective absorption coefficient" is taken as 0 or 0-028 cm-1, irrespective of source energy, leads to significant errors especially in the low energy region. An ettempt has been made in this paper to modify the approach to increase the accuracy of calculation and to extend its usefulness to low energies while retaining its inherent simplicity. The modification consists in replacing the effective absorption coefficient by the attenuation coefficients appropriate to the source energies and taking into account the effects due to multiple scattering by using point source build-up factor. The method has been applied for the particular case of dosimetry of a sphere. Comparison of the results obtained by this method with those got from Monte Carlo computations indicates excellent agreement at higher energies and a departure of around 15 per cent only at lower energies (as against a variation of 400 per cent when conventional geometric factor approach is used).     

Induction of liver tumors by aflatoxin B1 in the tree shrew (Tupaia glis), a nonhuman primate.

The epidemiological studies suggest that aflatoxins, the toxic metabolites of the ubiquitous mold Aspergillus flavus, may play a significant role in the evolution of hepatocellular carcinoma in man in certain geographic areas of the world. To ascertain their carcinogenicity in nonhuman primates, we have administered highly purified aflatoxin B1, intermittently in the diet at 2 ppm, to 10 female and 8 male tree shrews. The tree shrew (Tupaia glis) is a nonhuman primate occurring throughout Southeast Asia which can be reared easily in captivity. Of 12 animals that survived, 6 of 6 female (100%) and 3 of 6 male (50%) tree shrews developed hepatocellular carcinomas between 74 and 172 weeks after the beginning of the experiment. None of the 8 control animals developed liver cancers. The estimated total amount of aflatoxin B1 consumed by these animals ranged from 24 to 66 mg. The development of liver tumors did not follow a specific pattern; considerable variation in hepatocellular responses to aflatoxin B1 was noted in these animals. In 2 tree shrews, the liver tumors were associated with severe post necrotic scarring; in the other 7 tumor-bearing livers, only mild to moderate portal fibrosis was encountered. This individual variation in hepatocellular response and in the amount of aflatoxin B1 required to induce hepatocellular carcinomas is attributed to inherent differences in the susceptibility within a given species of outbred animals and suggests extreme caution in proposing the "permissible" or "safe" levels of contamination of carcinogens in the food-stuffs.