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2′-β-Fluoro-2′,3′-dideoxyadenosine (F-ddA), an acid-stable, pu-rine dideoxynucleoside with anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily × 1 (2.5–250 mg/kg); daily × 5 (125, 250 mg/kg), and BID × 1 (250 mg/kg)] as well as one oral schedule [BID × 1 (500 mg/kg)] using 8- to 12-week-old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddl and ddI, the respective deaminated catabolites of F-ddA and ddA, were essentially nontoxic in this study (iv, 250 mg/kg, daily × 1 and daily × 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily × 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily × 5) than when administered only once, suggesting that rat cardiotoxicity is related to C, rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with iv F-ddA administration when the F-ddA plasma concentration approaches 300 μM, 30–50 times the anticipated therapeutic level in humans. [ABSTRACT FROM PUBLISHER]

Dose Related Induction of the Drug Metabolizing Enzymes of Rat Liver by Cilobamine. LEESON, G. A., SHAATH, Z. A., BIEDENBACH, S. A., YARRINGTON, J. T., AND OKERHOLM, R. A. (1984). . 4, 261–269. Cilobamine, an antidepressant, was investigated for its influence on the hepatic drug metabolizing enzymes (DME) of male Charles River CD rats. Cilobamine doses (3, 10, 30, 100, and 300 mg/kg po, as free base) were compared to sodium phenobarbital (PB) doses (3, 10, 30, 100, and 200 mg/kg po, as free acid). Compounds were given daily for 4 days and all tests were done on Day 5. Ethylmorphine -demethylase, aniline hydroxylase, microsomal cytochrome -450 content, relative liver weight, and recoverable microsomal protein were quantitated. The results indicated that cilobamine was an inducer of the DME but not as potent as PB. Cilobamine did not exert any inductive responses at 3 mg/kg. At 10 and 30 mg/kg some but not all test systems were increased. However, at 100 and 300 mg/kg all were increased. PB increased all systems at all doses studied. Electron micrographs of livers of rats given 100 mg/kg of cilobamine or PB revealed hypertrophy of the smooth endoplasmic reticulum. The time course of induction in rats given 100 mg/kg po showed that responses in the cilobamine rats peaked after the second dose and plateaued with later doses. Responses in PB rats increased markedly after one dose and showed a continual increase with later doses. Induction of the DME was also demonstrated in female rats. [ABSTRACT FROM PUBLISHER]

Comparative Toxicity of the Hematinic MDL 80,478 — Effects on the Liver and Adrenal Cortex of the Dog, Rat and Monkey. Yarrington, J. T., Huffman, K.W., Leeson, G.A., Sprinkle, D.J., Loudy, D.E., Hampton, C., Wright, G.J. and Gibson, J.P. (1983). . 3:86-94. The ferrocene hematinic MDL 80,478 was administered orally at dosages ranging from 0 to 500 mg/kg/day to dogs (2 weeks), monkeys (6 weeks), and rats (6 weeks). Rats given 500 mg/kg/day had distended abdomens due to enlarged livers while the high-dose (250 mg/kg/day) dogs and monkeys demonstrated the following signs: emesis, depression, ataxia, anorexia and a high number of deaths. Increase in serum total bilirubin, alkaline phosphatase, and glutamic-pyruvic transaminase, indicators of hepatocellular injury, were detected in these high-dose dogs and monkeys prior to their deaths. Necropsy examination revealed yellowish discoloration of the abdominal fat of the rat and enlarged yellow livers of all three species. In the rat, increasing the dose of 25 to 250 mg/kg/day resulted in significantly (P < 0.05) elevated levels of plasma MDL 80, 478 following longterm administration. At the highest dosage for each test animal drug-related microscopic lesions occurred in the livers as diffuse, Prussian blue positive, brown pigmentation (rats), fatty degeneration (dogs), and centrolobular necrosis (monkeys) and the adrenals with focal to diffuse cortical vacuolar degeneration (all three species). Ultrastructural evaluation of rat tissue demonstrated iron storage and hypertrophy of smooth endoplasmic reticulum (SER) of the liver and mild vacuolar degeneration of the mitochondria and lipid droplet accumulation of the adrenal cortex. In addition to increased SER, the parent compound caused in the liver of the rat increased hepatic activity of ethylmorphine N-demethylase and aniline hydroxylase with no change in cytochrome P-450 or microsomal protein, findings suggestive of mild drug-related induction of the monoxygenase system. [ABSTRACT FROM PUBLISHER]

The adrenal gland is one of the most common endocrine organs affected by chemically induced lesions. In the adrenal cortex, lesions are more frequent in the zona fasciculata and reticularis than in the zona glomerulosa. The adrenal cortex produces steroid hormones with a 17-carbon nucleus following a series of hydroxylation reactions that occur in the mitochondria and endoplasmic reticulum. Toxic agents for the adrenal cortex include short-chain aliphatic compounds, lipidosis inducers, amphiphilic compounds, natural and synthetic steroids, and chemicals that affect hydroxylation. Morphologic evaluation of cortical lesions provides insight into the sites of inhibition of steroidogenesis. The adrenal cortex response to injury is varied. Degeneration (vacuolar and granular), necrosis, and hemorrhage are common findings of acute injury. In contrast, chronic reparative processes are typically atrophy, fibrosis, and nodular hyperplasia. Chemically induced proliferative lesions are uncommon in the adrenal cortex. The adrenal medulla contains chromaffin cells (that produce epinephrine, norepinephrine, chromogranin, and neuropeptides) and ganglion cells. Proliferative lesions of the medulla are common in the rat and include diffuse or nodular hyperplasia and benign and malignant pheochromocytoma. Mechanisms of chromaffin cell proliferation in rats include excess growth hormone or prolactin, stimulation of cholinergic nerves, and diet-induced hypercalcemia. There often are species specificity and age dependence in the development of chemically induced adrenal lesions that should be considered when interpreting toxicity data.

Vigabatrin (Sabril) is a gamma-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fornix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

Nine male and nine female Beagle dogs were divided into three groups and administered orally 0, 15, or 30 mg/kg/day of the antidepressant compound MDL 19,660(5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3H-1,2,4-triazole-3-t hione) for 3 months to determine the long-term effects on hemopoietic cells. Compared to a control platelet range of 353,000-452,000/microliters, a thrombocytopenia reached lowest mean levels of 135,000/microliters in the 15 mg/kg/day dogs after 2 weeks and 81,000/microliters in the 30 mg/kg/day dogs after 1 week. Subsequently, platelet numbers progressively increased and by the end of the study averaged 222,000/microliters and 203,000/microliters in dogs administered 15 and 30 mg/kg/day. Ultrastructural study of the platelet increase in the 30 mg/kg/day dogs revealed more smaller discoid platelets but no change in percentage platelets with vacuolar degeneration. Histologically, megakaryocyte hyperplasia was present in the sternal marrows and spleens of treated dogs. These observations suggest that increased thrombopoiesis rather than reduced destruction was involved in this partial recovery of platelet numbers during continuous treatment. Concurrently, cyclic formation of reticulocytes and Heinz bodies occurred in dogs given 30 mg/kg/day of MDL 19,660. These dogs had slightly lower erythrocyte counts, hemoglobin levels, and hematocrits in association with hemosiderosis (spleen, liver), extramedullary hematopoiesis (spleen), and bone marrow hypercellularity. These findings indicate that both destructive and regenerative processes followed MDL 19,660-induced Heinz body formation.

Two-week oral administration of MDL-19,660, a triazole antidepressant compound, resulted in a dose-related thrombocytopenia in rats given 40-360 mg/kg/d and dogs treated with 5-50 mg/kg/d. Consumptive loss of platelets was not apparent since splenomegaly, hemorrhage, microscopic thrombi or prolonged coagulation times (prothrombin and activated partial thromboplastin) were not observed. Platelet production did not appear to be impaired since megakaryocytes in the bone marrow of treated animals were similar in number or slightly increased compared to control animals. Although the pathogenesis of this thrombocytopenia is presently unknown, intravascular destruction by immune mechanisms or direct drug-related effects seems most likely.

After 2 days of dosing, platelet counts progressively declined in dogs treated orally with 30 mg/kg/day of the antidepressant compound MDL 19,660 for 8 days. Accompanying the decrease in platelet counts was an increase in both large and vacuolated degenerating platelets. Upon cessation of dosing, the platelet counts returned to levels equal to or exceeding predosing levels within 4-7 days. Co-administration with aspirin, a known antiaggregating agent, had no protective effect on the drug-induced thrombocytopenia. In vitro testing of normal canine platelets in the presence of MDL 19,660 further revealed that spontaneous aggregation did not occur and that ADP-induced aggregation was inhibited. Drug-related platelet loss was also not prevented by the co-administration of prednisone, a steroid with immunosuppressive effects and inhibitory properties against reticuloendothelial cell phagocytosis of platelets. The results of the present investigation indicate that MDL 19,660 may produce in the dog a reversible thrombocytopenia in the form of vacuolar degeneration and subsequent destruction of the platelet by means other than aggregation or steroid-responsive mechanisms.

The GABA-transaminase inhibitor, vigabatrin, has been shown to have a rather low degree of acute toxicity in several animal species. Oral administration of the drug at 1,000 mg/kg/day for 2-4 weeks caused decreased food consumption and weight loss with resultant prostration and death in both rats and dogs. Dosages of 200 mg/kg/day were tolerated for a year without clinical signs in dogs, although rats suffered reduced weight gains and convulsions after 3-4 months when given the drug in the diet. The convulsions continued to occur frequently throughout the one-yr study, but abated 3-4 months after cessation of treatment. The only consistent histopathologic evidence of toxicity in rats and dogs has been the finding of intramyelinic edema (microvacuolation) in the brain, most notably in certain areas of white matter (cerebellum, reticular formation and optic tract in rats and columns of fornix and optic tract in dogs). No lesions were found in the spinal cord or peripheral nervous system. It took several weeks for the microvacuolation to develop, even at high dosages, but it did not continue to progress thereafter, even though a slight effect was noted at dosages as low as 30-50 mg/kg/day after one yr of treatment. The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn. No residual effects were observed in dogs, whereas rats exhibited swollen axons and microscopic mineralized bodies in the cerebellum. Monkeys exhibited no adverse clinical effects except for occasional loose stools at 300 mg/kg/day. After 16 months of oral treatment at 300 mg/kg/day any suggestion of intramyelinic edema was considered to be equivocal, and there was no evidence of any effect in the 50 or 100 mg/kg/day monkeys after 6 yr of treatment. Higher doses caused chronic diarrhea, thus limiting the dosage in this species. Vigabatrin was shown to be well absorbed in rat, dog and man, whereas dose-limited absorption occurred in the monkey. Metabolism is practically nil in all 4 species and the primary elimination pathway is by glomerular filtration. Because vigabatrin is an irreversible inhibitor of GABA-transaminase and the enzyme has a slow turnover rate, plasma levels of the drug are not indicative of its pharmacologic activity. For this reason cerebrospinal fluid levels of GABA and vigabatrin were evaluated, with considerable species differences being noted. The significance of these differences in relation to the differences in toxic response is discussed.

Subacute (2 week) oral or intravenous administration of DL-alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), caused diarrhea and frequent emesis as early as 4 to 5 days in dogs (dose greater than or equal to 200 mg/kg/day). Diarrhea also occurred in monkeys after 1 week of treatment with an intravenous dose of 1000 mg/kg/day. Especially evident in the treated dogs with diarrhea were fluid loss, hemoconcentration, and decreased serum sodium and chloride which were findings totally reversible about 2 weeks after cessation of dosing. As a result of treatment with the highest intravenous dosage (1000 mg/kg/day), villous atrophy of the mucosa was observed by light and scanning electron microscopy in the canine small intestine. Transmission electron microscopy demonstrated that the most significant alterations of the canine intestinal tract involved the microvilli of epithelial cells which became shorter and were frequently less numerous or absent along focal areas of the plasma membrane. Intestinal mucosal levels of putrescine, especially in the duodenum and jejunum, were decreased as demonstrated in the monkeys following intravenous treatment with 100, 300, or 1000 mg/kg/day of DFMO. The results of this investigation are consistent with the hypothesis that the inhibition of ODC activity and subsequent altered polyamine metabolism may lead to delayed maturation of the intestinal epithelial cells and the impaired development of their microvilli, causing fluid loss due to reduced absorptive surface area.

The administration of 4 mg/kg/day of dichloromethane diphosphonate (Cl2MDP) subcutaneously to pregnant cows fed a low-calcium diet significantly reduced bone resorption as indicated by microradiographic evaluation of endosteal surfaces of cross sections of ribs. Plasma parathyroid hormone levels were similar between Cl2MDP-treated and control cows prepartum, during EDTA infusions, and near parturition. Ultrastructurally, chief cells of the parathyroid glands of both groups of cows were in the active stage of the secretory cycle. The chronically stimulated chief cell from cows administered Cl2MDP had a large cytoplasmic area containing many lipofuscin granules and lysosomal bodies and a few secretory granules near the large Golgi apparatus or aligned along the plasma membrane. Uptake of calcium 45 by the duodenal mucosa incubated in vitro was greater in Cl2MDP-treated cows compared to control cows. The administration of Cl2MDP significantly reduced rapidly mobilization calcium reserves. Following an intravenous EDTA infusion and the spontaneous calcium drain associated with parturition and the beginning of lactation, Cl2MDP-treated cows developed severe hypocalcemia. The rapid mobilization of calcium reserves in cows administered Cl2MDP prepartum was impaired mainly because of diminished resorption of bone despite adequate parathyroid hormone secretion in response to severe postpartal or EDTA-induced hypocalcemia.

The antibacterial drug alpha-(1,4-dioxido-3-methylquinoxalin-2-yl) N-methylnitrone (DMNM) given at a dose of 22.5 mg/kg bid to four dogs for 14 days caused diminished adrenal cortical reserves as determined by decreased plasma cortisol (three dogs) and lower aldosterone levels (four dogs) following the intravenous infusion of ACTH. A dose of 100 mg/kg/day of DMNM administered to rats for 31 or 35 days resulted in significant decreases in blood glucose. Histologically, the adrenal glands of both species treated with DMNM for a maximum period of 21 days (dogs) and 35 days (rats) had widespread granular and vacuolar degeneration of the cortex. This degeneration in treated rats began in the zona reticularis and inner regions of the zona fasciculata and eventually involved the entire cortex including the zona glomerulosa. As a result of treatment, significant ultrastructural alterations within cells of the rat and canine adrenal cortex consisted of degeneration of the mitochondria and an increase in the numbers and lipolysis of lipid droplets. The ultrastructure of the zona reticularis and fasciculata was most severely affected.

The long term (70 days) effects of administering ethane-1-hydroxy-1,1-diphosphonate (EHDP) (4 mg. per kg. per day) on parathyroid function was investigated in pregnant cows fed a low calcium diet. Serum calcium and phosphorus were significantly lower at parturition and postpartum in EHDP-treated cows compared to pregnant control cows fed the low calcium diet. Plasma immunoreactive parathyroid hormone levels were similar prepartum, at parturition, and postpartum in cows administered EHDP and control cows. Immediately available calcium reserves were greater preparation in control cows than in cows receiving EHDP as indicated by a more rapid rate of return of serum calcium toward normal levels following ethylenediaminetetraacetic acid (EDTA)-induced hypocalcemia approximately 10 days prepartum. EHDP-treated cows responded to the hypocalcemic challenge with similar changes in plasma immunoreactive parathyroid hormone levels as in control cows; however, urinary hydroxyproline excretion increased at certain intervals only in control cows. Ultrastructurally, chief cells in parathyroid glands of both groups of cows were in an active stage of the secretory cycle with well developed organelles concerned with hormonela synthesis. Chief cells in cows administered EHDP were degranulated and contained fewer secretory granules in response to the hypocalcemia than those in control cows. Chief cells in EHDP-treated cows often had prominent perinuclear accumulations of microfilaments, scattered vacuolated mitochondria, and lysosomal bodies in the cytoplasm. Thyroid C-cells were densely granulated and thyroid calcitonin content was similar in both groups of cows. The principal defect in calcium homeostasis of EHDP-treated cows appeared to be an impairment both in bone calcium mobilization and bone matrix catabolism in response to the secretion of parathyroid hormone. In vitro uptake of 45Ca by duodenal mucosa and urinary excretion of cyclic adenosine monophosphate were similar in both groups of cows. The ability of the parathyroid glands to synthesize and secrete parathyroid hormone in response to hypocalcemia induced either by EDTA or associated with parturition was not impaired by the administration of EHDP.

The antibacterial drug alpha- (1,4-dioxido-3-methylquinoxalin-2-yl)-N-methylnitrone (DMNM) given at a dose of 22.5 mg/kg/bid to 4 dogs for 14 days caused diminished adrenal cortical reserves as determined by decreased plasma corticol (3 dogs) and lower aldosterone levels (4 dogs) following the intravenous infusion of ACTH. A dose of 100 mg/kg/day of DMNM administered to rats for 31 or 35 days resulted in significant decreases in blood glucose. Histologically, the adrenal glands of both species treated with DMNM for a maximum period of 21 days (dogs) and 35 days (rats) had widespread granular and vacuolar degeneration of the cortex. The degeneration, as demonstrated in treated rats, began in the zona reticularis and inner regions of the zona fasciculata and eventually involved the entire cortex including the zona glomerulosa. As a result of treatment, significant ultrastructural alterations within cells of the rat and canine adrenal cortex consisted of degeneration of the mitochondria and an increase in the numbers and lipolysis of lipid droplets. The ultrastructure of the zona reticularis and fasciculata was most severely affected.

The earliest ultrastructural lesions involving smooth muscle of duck duodenum and gizzard produced by a vitamin E-selenium deficiency were a degereration of sarcoplasmic reticulum and mitochondria. Lysosomes were not observed during these earliest alterations of deficient smooth muscle. Lipid droplets and mineral deposits were present in more severely degernerating smooth muscle that was being infiltrated by heterophils. In areas of necrotic smooth muscle, myoblasts were forming while macrophages, fibroblasts, and an occasional syncytial giant cell contained lipid droplets and surrounded coalesced mineral crystals. Endothelial cells of capillaries and stromal connective tissue were less severely affected with lesions developing after the earliest signs of smooth muscle degeneration. Neuroaxonal degeneration of nonmyelinated nerve fibers was not observed until after most of the smooth muscle had undergone either degeneration or necrosis. A possible explanation for the pathogenesis of the smooth muscle necrosis is discussed in light of the ultrastructural findings.

The antibacterial compound alpha-(1,4-dioxido-3-methylquinoxalin-2-yl)-N-methylnitrone (DMNM), which was administered for a maximum period of 90 days, was given orally at 0, 7.5, 15.0 or 22.5 mg/kg/day for dogs; 0, 15, 50 or 100 mg/kg/day for rats; and 35 mg/kg/day for monkeys. Reduced food consumption and weight gain, depression, debility, and deaths occurred starting at doses (mg/kg/day) of 15 in dogs, 35 in monkeys and 50 in rats. Frequent emesis and occasional black, tarry feces were also observed in most treated dogs. Necropsy examinations revealed small, pale adrenal glands in rats given a dose of 50 mg/kg/day and gastrointestinal hemorrhage in dogs administered 15.0 or 22.5 mg/kg/day of DMNM. Microscopically, vacuolar degeneration of the canine, monkey and rat adrenal cortex was seen at all dosages and appeared to progress from the zona reticularis to the zona glomerulosa. In rats treated with 50 mg/kg/day of the drug chronic lesions of adrenal cortical fibrosis, atrophy, and nodular hyperplasia were also detected. The only other significant microscopic lesions consisted of mild testicular atrophy and occasional gastric erosions in dogs treated with 7.5 mg/kg/day of DMNM.

Cows fed a balanced diet with the required amounts of calcium and phosphorus developed acute hypocalcemia and hypophosphatemia shortly after parturition, even in the presence of the a responsive parathyroid gland, when bone resorption was selectively inhibited by the prepartal administration of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP). When serum total and ionized calcium levels declined below 6.0 and 1.0 mg/100 ml, respectively, cows developed clinical signs similar to naturally occurring parturient paresis. The plasma immunoreactive parathroid hormone levels were similar prepartum, at parturition, and 1 day postpartum in cows administered EHDP as in control cows. Parathyroid chief cells were predominately in the actively synthesizing phase of the secretory cycle with a prominent Golgi apparatus and lamellar arrays of rough endoplasmic reticulum. Many chief cells were degranulated of mature secretory gransules. Calcitonin activity in thyroid extracts, determined by bioassay, and the numbers of secretory granules in thyroid C-cells were similar in both groups of cows. EDTA infusion after 60 days of the experiment demonstrated that the immediately available calcium reserves were reduced in EHDP-treated cows. The serum calcium remained significantly lower and did not return to preinfusion levels by 24 hours. Serum calcium in control cows returned to within the normal range by 6 hours after EDTA infusion. The urinary excretion of hydroxyproline was consistently reduced prepartum and following EDTA infusion in cows receiving EHDP. The experimental induction of parturient of parturient hypocalcemia by the prepartal administration of EHDP provides a valuable model for studies to investigate the mechanisms in bone responsible for the development of severe hypocalcemia that occurs in response to the increased calcium demand imposed by parturition and the initiation of lactation.

Hypercalcemia, normo- or hypophosphatemia, and increased urinary calcium clearance were observed in 8 dogs with malignant disease consisting of lymphosarcoma (n = 4), lymphogenous leukemia with bone involvement (n = 2), or carcinoma arising in the perianal region (n = 2). Parathyroid glands from these dogs had a normal or atrophic microscopic appearance. Ultrastructurally, the chief cells of the parathyroid glands had small cytoplasmic areas devoid of secretory granules and containing few organelles associated with hormonal synthesis, which is indicative of an inactive phase of the secretory cycle. In relationship to total serum calcium, serum canine immunoreactive parathyroid hormone was moderately increased in 3 dogs whose parathyroid glands had morphologic characteristics of inactivity. As a result of prolonged hypercalcemia, the thyroid glands contained prominent areas of parafollicular cell hyperplasia. The ultrastructure of a typical hyperplastic parafollicular cells was characterized by a large cytoplasmic area filled with numerous secretory granules and moderate numbers of organelles associated with hormonal synthesis. The results of this study indicate that some nonendocrine malignant neoplasms of dogs may be capable of secreting a hypercalcemia substance immunologically indistinguishable from parathyroid hormone. In the absence of neoplastic involvement of bone, the canine disease has many similarities to pseudohyperparathyroidism.

The hypolipidemic drug RMI 14,514 (5-tetradecyloxy-2-furoic acid) has an oral LD50 of over 5000 mg/kg in rats. In a chronic toxicity study (6 months drug diet) doses of 30, 100, or 300 mg/kg/day produced no obvious signs of toxicity or abnormal clinical pathology parameters, other than prominent growth retardation at 300 mg/kg, which was somewhat alleviated when the dose was reduced to 200 mg/kg after 6 weeks. Hepatic change in the form of mild lipid accumulation was noted histopathologically after 6 months of treatment at 100 or 300 mg/kg/day, but was not present at 3 months or after 4 weeks off drug. The administration of RMI 14,514 in the diet to pregnant rats at 30, 100, or 150 mg/kg/day on Days 7 thru 21 of pregnancy (day 1 = day sperm detected) did not induce any teratogenic effects. When rats were exposed to the drug from implantation thru sexual maturity (126 days of age) at the same dosage, it produced no adverse developmental or behavioral effects, except for slight reduction in weight gain from birth to sexual maturity at 150 mg/kg/day. The drug caused reductions in plasma cholesterol and total fatty acids, but no distinct changes in various tissue lipids, except in the erythrocyte where fatty acids and phospholipids were reduced. These differences did not affect membrane integrity of the erythrocyte as far as osmotic or mechanical fragility tests could determine. The drug, which bears a structural resemblance to long-chain fatty acids, was incorporated into tissue lipids in detectable amounts, but tended to disappear from tissues at a rate similar to that of expected lipid turnover after treatment was stopped.