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Many structurally unrelated hypolipidemic agents and certain phthalate-ester plasticizers induce hepatomegaly and proliferation of peroxisomes in liver parenchymal cells of rodents, but there is relatively limited evidence regarding the ability of such compounds to induce peroxisome proliferation in the livers of nonrodent species including man. The present study was designed to determine if DL-040 (4-(((1,3-benzodioxol)-5-yl)methyl)amino-benzoic acid), a newly developed hypolipidemic agent, induces peroxisome proliferation in the liver of adult rhesus monkeys. Feeding of DL-040 (300 mg/kg body wt for 1 week; and 400 mg/kg body wt for 10 weeks) caused a significant increase in peroxisome population as determined by ultrastructural and morphometric analyses. The DL-040-induced peroxisome proliferation was accompanied by increases in the levels of catalase, carnitine acetyltransferase and the peroxisomal fatty acid beta-oxidation system. As expected, DL-040 caused a significant reduction of serum cholesterol and low density lipoprotein content. These data suggest that hepatic peroxisome proliferation is inducible in nonhuman primates at dose levels that exceed therapeutic levels.

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The antineoplastic drug hexamethylmelamine (HMM) was evaluated for effects on reproduction and postnatal development in the rat and on embryonal and fetal development in the rat and rabbit. Daily po treatment of male rats for 62 days with doses of 0, 10, 20, or 40 mg/kg/day resulted in testicular atrophy, reduced fertility, and a possible dominant lethal mutagenic effect at the higher two dose levels. Alterations in morphology and function of the beta cells of the pancreatic islets were observed after treatment of males for more than 28 days with 20 or 40 mg/kg/day. The same dose levels administered to female rats for 14 days prior to breeding and through Day 13 or 20 of gestation had no adverse effects on fertility, but the highest dose was embryocidal and postnatal survival was decreased at both the 20- and 40-mg/kg/day dose levels. Similar effects on postnatal survival were observed when the drug was administered by gavage to rats during the last week of gestation and throughout the lactation period. Treatment of pregnant rats throughout organogenesis (Days 6 to 15) or for 4-day intervals during organogenesis (Days 6 to 9, 9 to 12, or 12 to 15) with po doses ranging from 20 to 80 mg/kg/day resulted in decreased body weight gain and food consumption, an increased resorption rate in dams receiving 80 mg/kg/day on Days 6 to 9, and decreased fetal weights at all dose levels and most treatment intervals. The incidence of minor skeletal defects was increased among litters of HMM-treated groups. Major fetal malformations were limited in number but were considered treatment related. Treatment of pregnant rabbits po on Days 6 to 18 of gestation with doses of 0, 20, 40, or 60 mg/kg/day did not result in an embryocidal or teratogenic effect. Treatment with 60 mg/kg/day did, however, result in decreased kit weights, indicating a mild embryo-fetotoxic effect.

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The effects of hexamethylmelamine (HMM) on morphology and function of the endocrine pancreas were investigated following the induction of a diabetic-like syndrome in a reproduction study in rats. Doses of 0, 20, 40, or 80 mg/kg/day were administered once daily, by gavage, to groups of 10 male and 10 female Sprague-Dawley rats for up to 77 days. Signs of toxicity were observed at all treatment levels and were of such severity at 80 mg/kg/day that this group was terminated after 8 days of treatment. Measurement of serum glucose levels revealed a dose- and time-related hyperglycemia in rats from the 20- and 40-mg/kg/day groups with levels exceeding 700 mg/dl in some rats after 77 days of treatment. Reversal of the hyperglycemia after discontinuing treatment with HMM occurred in some rats receiving 20 mg/kg/day, whereas the effects of higher doses were still present following a 2-month recovery period. Microscopically, there were hydropic degeneration of renal tubular epithelium and vacuolation of pancreatic beta cells. Ultrastructurally, vesiculation of the Golgi-smooth membrane reticular complex and a marked reduction in the number of insulin granules were observed. It appeared that HMM exerted a disruptive effect on the production of insulin at or prior to the level of the Golgi complex. The severity and time course of morphologic changes and hyperglycemia were dependent on dose and duration of treatment.

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The effects on rat liver of probucol (250 or 500 mg/kg/24 h), clofibrate (250 mg/kg/24 h) and fenofibrate (100 mg/kg/24 h) were compared after 28 days' treatment. Th bodyweight of animals treated with probucol 250 mg/kg/24 h has increased, as compared with a control group of untreated animals. The increase in liver weight and live weight/bodyweight ratio was greater in rats treated with clofibrate or fenofibrate than in rats treated with probucol. Cholesterol and triglyceride plasma levels were lower in clofibrate-treated animals. There were no changes in SGOT and SGPT in any of the three groups. Alkaline phosphatases were increased only in rats treated with clofibrate (these enzymes were not assayed in rats which received fenofibrate). Electron microscope study of liver sections showed the following changes in clofibrate--and fenofibrate-treated rats as compared with the control group: increase in smooth-surfaced endoplasmic reticulum, ribosome detachment, slight glycogen depletion and increase in the number of peroxysomes. In the probucol-treated group, apart from an occasional increase in smooth-surfaced endoplasmic reticulum, liver cells were identical with those of the control group; in particular, there was no increase in the number of peroxysomes.

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Probucol [4,4'-(isopropylidenedithio)bis(2,6-di-tert-butylphenol)], a hypocholesterolemic agent, was given orally to male and female rhesus monkeys at 0, 60, 125, 250, and 500 mg/kg . d for more than 8 yr without adverse effect. Of 40 monkeys on test, 14 were killed for interim studies (wk 81 and 102), 21 were maintained for more than 8 yr, and 5 were submitted for necropsy for conditions unrelated to treatment. Monitored parameters included growth rate, demeanor, hematology, clinical chemistries, urinalyses, ophthalmoscopy, organ weights, and gross, histopathologic, and electron microscopic evaluations. Bone marrow smears at the conclusion of the test revealed no differences between control and treated animals. Electron microscopy of liver specimens from monkeys treated for 8 yr revealed comparable hepatocellular ultrastructure in control and treated monkeys. Probucol was given orally at 0, 100, 500, and 1000 mg/kg to Sprague-Dawley rats during appropriate time intervals to evaluate effects on fertility and postnatal development. The same dose levels were given during organogenesis, or in some cases prior to breeding and throughout organogenesis, to Sprague-Dawley rats and New Zealand white rabbits. No adverse effects on fertility or postnatal development were observed in rats, and no evidence of teratogenicity was observed in either species. The results indicate that probucol does not affect reproduction of rats, lacks teratogenic potential in the species studied, and is nontoxic to subhuman primates treated for more than 8 yr.

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Experimental findings are reported for two similarly conducted studies. One was designed to compared rat liver cell ultrastructure during and after 91 d of dosing with probucol, a hypocholesterolemic agent, and clofibrate, a hypolipidemic drug known to elicit marked alteration of rat hepatocellular morphology. The second was designed to similarly assess male rats after 28 d of treatment with the hypolipidemic agent fenofibrate. Diet mixes for these studies were prepared to attain dosage levels of approximately 500 mg/kg . d for probucol, 250 mg/kg . d for clofibrate, and 100 mg/kg . d for fenofibrate. Control rats were given untreated basal ration. Weekly adjustments in dietary concentrations were made in accordance with group mean food consumption and body weight changes. Probucol and clofibrate treatments produced statistically significant reductions in mean serum cholesterol levels of both sexes after 28 and 91 d of dosing. Only male rats were given fenofibrate, and they exhibited statistically significant cholesterol reductions after 28 d. Clofibrate and fenofibrate administration resulted in marked increases in liver weight/body weight ratios. Probucol had no statistically significant effects on liver weight/body weight ratios after 28 and 91 consecutive days of treatment. Light microscopy of liver sections stained with hematoxylin and eosin revealed an abnormal amount of cytoplasmic granularity within hepatocytes from rats given clofibrate and fenofibrate. The granules were identified by electron microscopy and cytochemistry as enlarged, proliferated peroxisomes--a known rat hepatocellular response to treatment with many hypolipidemic drugs. In addition, ultrastructural cytochemistry suggested reduced amounts of catalase in individual peroxisomes after clofibrate and fenofibrate dosing. Liver tissue from rats given probucol showed no abnormal cytoplasmic granularity and, ultrastructurally, no peroxisomal changes. Liver tissues from probucol-treated rats revealed features similar to those encountered in tissues from untreated control animals. It was concluded that the hypocholesterolemic response elicited by probucol treatment does not involve significant changes in rat liver cell morphology.

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The antitumor drugs adriamycin and daunomycin were evaluated for effects on embryonal and fetal development in the rat and rabbit. Doses of adriamycin ranging from 1-2 mg/kg/day or daunomycin ranging from 1-4 mg/kg/day were administered ip to pregnant rats on days 6-15, 6-9, 9-12 or 12-15 of gestation. Both drugs were teratogenic in the rat, particularly when administered on days 6-15 or 6-9 of gestation. Relatively few anomalies resulted from treatment on days 9-12 or 12-15. On a mg/kg basis, adriamycin was the more potent teratogen, producing major anomalies at doses as low as 1.25 mg/kg. Similar anomalies, but at a lower incidence, were produced by daunomycin at dose levels of 4 mg/kg. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophgeal fistula, hypoplasia of the urinary bladder and various cardiovascular anomalies. Neither drug was teratogenic when given iv to rabbits at doses up to and including 0.6 mg/kg/day on days 6-18 of gestation, but a high incidence of abortion occurred in rabbits treated with adriamycin.

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Probucol was effective in lowering serum total cholesterol in mice at dietary livels as low as 0.0075%. It was also effective after a single 100 mg/kg I.V. dose in mice. The incorporation of acetate-(14)C into liver lipids of rats and mice was not significantly affected by probucol, although the results, especially in mice, make it impossible to rule out such an effect. Cholesterol absorption was estimated in rats using a dual isotope technique. The observed reductions were not statistically significant. Several liver enzyme activities were determined after probucol treatment in rats, and a significant elevation (32%) was observed in only one, glutamic dehydrogenase. Serum cholesterol was lowered markedly in cholesterol-fed cynomolgus monkeys by probucol. There was no effect on the excretion of neutral steroids and the observed increase in fecal bile acids after drug treatment could not be confirmed statistically.

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A relatively simple procedure was devised to obtain blood pressures in rhesus monkeys. This procedure utilized a polygraph, pulse transducer, pressure transducer, blood pressure mixer unit, and pediatric sphygmomanometer cuff. Previous attempts to auscultate the Korotkoff sounds by use of a sphygmomanometer cuff and stethoscope were unsuccessful. Blood pressure can be obtained by cannulation of the femoral artery, but repeated puncture may cause serious trauma to the arterial wall. This procedure was developed and used in our laboratory to obtain repeated blood pressures over a 90-da period. Results from using the cuff and polygraph have been shown to correlate favorably with cannulation of the femoral artery.

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