Rapid induction of hyperplasia in vitro in rat bladder explants by elevated sodium ion concentrations and alkaline pH.

The effects of alkaline pH and elevated sodium concentrations in culture medium on rat bladder explants for 1, 2, and 3 weeks were investigated by continuous BrdU labeling and histopathology. Increasing the sodium chloride concentration of normal medium by 50 or 100 mM caused slight urothelial hyperplasia with statistically significant increases in labeling in week 2 (50 mM) and at all time points with 100 mM NaCl. Cytotoxicity was seen in the high salt group. Increasing the pH from 7.2 to 7.8 and 8.2 also caused a slight hyperplastic response with significant increases in labeling and cytotoxicity at pH 8.2. However, bladder explants treated at pH 7.8 or 8.2 with excess sodium concentrations of 50 to 100 mM had a more marked hyperplastic response with evidence of cytotoxicity as well. There were significant increases in the labeling index (6.4- to 15.0-fold relative to control) after 1 week, with the maximum response at 100 mM sodium/pH 8.2. These results suggest that alkaline pH and elevated sodium concentration have a direct mitogenic effect on rat urothelial cells with some cytotoxicity-induced regenerative cell proliferation as well. These in vitro results in an organ culture system are in agreement with in vivo studies that have shown an important role for elevated urinary cation concentrations and pH in the stimulation of DNA synthesis, induction of hyperplasia, and tumor promotion in rat bladder epithelium.

Developmental neurotoxicity evaluation of acrylamide in Sprague-Dawley rats.

Based on the literature to-date, the potential of acrylamide (ACRL) to cause developmental neurotoxicity in laboratory animals has not been assessed. We examined this potential in Sprague-Dawley rats using a study design similar to that proposed by the USEPA. Dosages of 0 (deionized water), 5, 10, 15, or 20 mg/kg/day were administered at 5 ml/kg by oral gavage from gestational day 6 to lactational day 10 to groups of 12 mated females each. Females were allowed to deliver and the offspring were evaluated for survival, growth, development, behavior, and histological changes to brain, spinal cord, and peripheral nerve. Behavioral assessments consisted of open-field motor activity, auditory startle habituation, and passive avoidance tests during both the preweaning and adult periods (1 animal/sex/litter). All F0 and F1 animals in the 20 mg/kg/day group were euthanized early in the lactation period due to high pup mortality. Significantly increased pup mortality was also present in the 15 mg/kg/day group. There were dose-related decreases in average F0 maternal body weight gains during the dosing period in the 10, 15, and 20 mg/kg/day groups, and characteristic hindlimb splaying was observed in dams of the two highest dosage groups. Pup body weight proved to be the most sensitive indicator of developmental toxicity. Dose-related decrease in preweaning average weights were observed at all dose levels, although only transiently in the 5 mg/kg/day group. Average weight gain during the postweaning period was significantly decreased only in males of the 15 mg/kg/day group. Significant decreases in average horizontal motor activity and auditory startle response were observed only in weanlings of the 15 mg/kg/day group. The only behavioral effect in F1 adult animals was a decrease in auditory startle response in females of the 15 mg/kg/day group. There were no effects in the passive avoidance test or in the histological examination of the nervous system of preweaning pup or adult animals. Based on these results, the NOAEL (No Observed Adverse Effect Level) for developmental toxicity is less than 5 mg/kg/day, the NOAEL for maternal toxicity is 5 mg/kg/day, and that for developmental neurotoxicity is 10 mg/kg/day. Thus behavioral changes in the offspring were observed only at a dose which was also maternally toxic. These results suggest that acrylamide may be a selective developmental toxicant but not a selective developmental neurotoxicant, because a conventional measure of offspring toxicity (i.e., pup body weight) was affected at a dosage lower than that which produced maternal effects or offspring behavioral effects.

Qualitative and quantitative evaluation of prostatic histomorphology in rats following chronic treatment with finasteride, a 5-alpha reductase inhibitor.

OBJECTIVE: To determine any potential direct and/or indirect effects of elevated intraprostatic T levels on the prostates of rats chronically (1-2 years) exposed to high doses (160 mg/kg/day) of finasteride, a selective inhibitor of 5-alpha reductase. METHODS: Sprague-Dawley male rats were administered daily finasteride by oral gavage. Prostates from all rats were weighed, fixed in 10% neutral buffered formalin, and processed for light microscopic examination. The volume fractions of the prostatic glandular and stromal compartments were quantitated by morphometric analysis. RESULTS: Administration of finasteride at doses of 20, 40, and 80 mg/kg/day for one year resulted in a significant (P < or = 0.05) decrease in prostatic weight; prostatic atrophy was evident by light microscopy. Morphometric analysis of the prostate showed that chronic finasteride administration resulted in a significant (P < or = 0.001) decrease in the absolute volume of both glandular (-65.2%) and stromal (-57.1%) compartments of the prostate. Furthermore, the total number of epithelial and stromal cells per gland were significantly (P < or = 0.002) decreased in finasteride-treated rats compared with vehicle controls; the magnitude of mean decrease was 69.8 percent and 50.6 percent of controls in epithelial and stromal cells, respectively. In addition, prostates from all two hundred fifty rats in a two-year study were qualitatively evaluated by light microscopy. Administration of finasteride at doses ranging from 2.5 mg/kg/day to 160 mg/kg/day for two years did not result in an increase over the background incidence of prostatic focal hyperplasia or adenoma. No malignant tumors of the prostate were seen in any of the groups. CONCLUSIONS: These studies have demonstrated that the expected pharmacologic effects of finasteride on the prostate are maintained following chronic treatment and that there was no evidence of a direct and/or an indirect effect of elevated intraprostatic T on prostatic morphology in rats.

Effects of chronic oral administration of a selective 5 alpha-reductase inhibitor, finasteride, on the dog prostate.

Young mature dogs received finasteride, a selective 5 alpha-reductase inhibitor, orally at 0, 5, 15, and 45 mg/kg/day for 27 or 53 weeks. The effect of finasteride administration on prostatic size and morphology was evaluated macroscopically and microscopically. Changes in glandular and fibromuscular compartments were quantitated by a point counting method on trichrome-stained sections. Finasteride administration induced a decrease of mean prostatic weights and epithelial atrophy in all treated groups. No changes in testicular weights and morphology were observed. The greatest prostatic shrinkage was obtained in the group receiving 45 mg/kg/day for 53 weeks; compared to placebo controls, the percent decreases in absolute volumes occupied by epithelium, lumens, fibrovascular stroma, and smooth muscle were 88, 97, 51 and 72, respectively. These results clearly demonstrate that prostatic shrinkage following finasteride administration results from a decrease in both glandular and fibromuscular compartments.

Renal papillary cytoplasmic granularity and potassium depletion induced by carbonic anhydrase inhibitors in rats.

Renal papillary cytoplasmic granularity (RPCG) induced by carbonic anhydrase inhibitors (CAIs) in rats is characterized by the accumulation of dense secondary lysosomes in epithelial, endothelial, and interstitial cells and may be related to drug-induced potassium depletion. Female Sprague-Dawley rats were given the CAI, acetazolamide, by gavage. Half were supplemented with 1% potassium chloride in the drinking water. Two treated groups were allowed to recover for 1 or 2 mo. Potassium supplementation inhibited RPCG by 80% but produced little amelioration of the mild 13% decrease in serum potassium induced by 200 mg/kg/day acetazolamide for 28 days. Acetazolamide-induced RPCG is reversible because 1- and 2-mo recovery periods decreased the incidence by 75% and 80%, respectively. The results support the hypothesis that RPCG is related to potassium depletion secondary to carbonic anhydrase inhibition. Because supplementation of potassium chloride had little effect on serum potassium, these data suggest that depletion of renal medullary potassium content is important in the pathogenesis of RPCG as previously suggested by others. Other types of diuretics that produce hypokalemia as a side effect may not deplete medullary potassium since RPCG has not been reported in humans or animals given these drugs.

Urothelial hyperplasia induced by carbonic anhydrase inhibitors (CAIs) in animals and its relationship to urinary Na and pH.

Investigations of MK-0927 and acetazolamide, both carbonic anhydrase inhibitors (CAIs), showed that urothelial hyperplasia develops in rats and mice, but not in rabbits, dogs, or monkeys. Rats given MK-0927 orally had a rapid onset of the change which regresses often completely despite continued treatment. Increased urinary pH and Na excretion, pharmacologic effects of CAIs, tended to be correlated with lesions. Rats given MK-0927 orally and fed either a 5% potassium phosphate meal or a 5% ammonium chloride meal had reduced urinary pH and/or urinary Na excretion and a reduced incidence of urothelial hyperplasia. Rats given MK-0927 orally and fed a low Na diet had very low urinary Na and essentially no urothelial hyperplasia. It was concluded that a clear relation exists between increased urinary Na excretion and pH, and urothelial hyperplasia induced by CAIs. These results in rats confirm the importance of increased Na and pH as stimuli for the development of urothelial hyperplasia.

An examination of lifestyle and adjustment in three community residential alternatives.

Lifestyle normalization, community integration, adjustment, social support, and personal satisfaction were examined for 133 adults with mild and moderate retardation living in small group homes, supervised apartments, and with their natural families. Results of questionnaires and structured interviews with care providers showed that the residence settings supported quite different lifestyles with respect to independence, lifestyle normalization, and integration. Persons in supervised apartments achieved the most normative lifestyles with greater personal independence and community integration while reporting levels of lifestyle satisfaction and personal well-being similar to that of persons living with their own families. Results also showed that social integration, that is, participation in activities with peers without disabilities, was extremely limited for all participants, even those living in natural families. The study exemplifies the use of a residential typology to investigate the relationship of environmental factors to community adjustment. It also exemplifies the use of multiple perspectives and multiple measures to evaluate quality of life in community living alternatives.

Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat.

Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phenobarbital (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of 125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Corneal toxicity studies in rabbits and dogs with hydroxyethyl cellulose and benzalkonium chloride.

Hydroxyethyl cellulose (HEC) is used as a viscosity-enhancing agent in ophthalmic formulations to prolong corneal contact time and increase intraocular drug levels. Benzalkonium chloride (BAK) is the preservative most frequently used in ophthalmic formulations. Corneal epithelial changes were seen by slit lamp and light microscopic examination in rabbits but not dogs after multiple instillations of an ophthalmic vehicle containing 0.01% BAK and 0.5% HEC. Microscopically, there was sloughing of superficial epithelial cells and a slight loss of polarity of the basal cells. Formulations with 0.01% BAK and HEC, at concentrations between 0.3 and 0.8%; caused these changes but not with BAK or HEC alone. It was concluded that hydroxyethyl cellulose increased the viscosity and prolonged the contact time of BAK with cornea resulting in corneal epithelial damage in the rabbit. Physiological and anatomical features of the rabbit combined with the increased contact time were concluded to favor these changes in this species. The results confirm that the rabbit is a sensitive and unique species in studies of ocular toxicity of drugs.

Drug-induced changes in dogs after long term application of a beta-blocker.

Ocular irritation studies are important in the safety evaluation of ocular formulations. There are many reports on acute ocular irritation studies, but almost nothing about prolonged ocular instillation of ophthalmic formulations. This report discusses the predominantly lymphocytic infiltrates seen in the limbus corneae and eyelids of dogs treated with 1 and 2% solutions of L-653,328, an ocular hypotensive beta-adrenoceptor antagonist, for up to 53 weeks. The number of animals affected and severity of the lesions increased with time and concentration. A minimal effect was seen microscopically with the 2% solution as early as 14 weeks. Rabbits treated similarly for 14 weeks had no such changes. The first and only clinical sign in dogs was diffuse pinkness of the bulbar conjunctiva seen from Drug Week 22 onwards. Although not seen with similar molecular structures, given the equivocal results in sensitization studies and the long time required for the development of change, delayed contact hypersensitivity was suspected as the cause of the ocular infiltrates. Simple chronic irritation was not ruled out, however. These findings suggest that delayed contact hypersensitivity in dogs may be a phenomenon not limited to skin, but may also involve the eye after repeated ocular instillation.

Prostatic effects induced in dogs by chronic or acute oral administration of 5 alpha-reductase inhibitors.

A series of 4-azasteroidal 5 alpha-reductase inhibitors was tested in dogs to determine the effect of chronic (35-44 day) oral administration on prostate size and histology and acute oral administration on prostatic concentrations of testosterone (T) and dihydrotestosterone (DHT). The extent to which the results of the two tests were correlated was also studied in order to see whether the acute test could be used to predict activity in the chronic test. Six delta 1 analogs of the potent 5 alpha-reductase inhibitor, 4-MA (17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5 alpha-androstan-3-one) were uniformly active at low dosage levels (less than or equal to 3 mg/kg) in both types of assay whereas several C1-C2 saturated analogs exhibited little activity in the chronic test. The nature of the side chain and whether there was a methyl or a proton at 4-N did not dramatically influence the activity of delta 1 compounds. There was a broad general agreement between the results of the two kinds of test in that if a compound acutely decreased the prostatic concentration of DHT it was likely to reduce prostate size and alter prostatic histology when given on a chronic basis.

Spontaneous lipomatous tumors in the kidney of the Crl:CD(SD)BR rat.

Primary tumors of the rat kidney are uncommon (0.05%) and are most often seen in older rats. Nephroblastoma is the most commonly diagnosed tumor, but benign and malignant tumors of epithelial cell and mesenchymal cell origin occur. Lipomatous tumors are occasionally seen, especially in aged rats, and are controversial lesions. They have been variously classified in the literature in lipomas, liposarcomas, and lipomatous hamartomas. In my experience, the range of diagnoses has also included post-inflammatory change and lipidosis. The lipomatous tumors are the focus of discussion for the purpose of defining criteria for the various diagnostic categories. The implications of these diagnostic categories for safety assessment are also discussed.

Development, implementation, and findings of a continuing client satisfaction survey.

Development of a client-satisfaction survey is described and details are given for sampling clients and iterating survey mailings on a monthly basis. Consent rates, response rates, confidentiality concerns, and costs are discussed on the basis of one year of data collection experience. Analyses revealed a general satisfaction factor and problem severity factor for both active and terminated clients. A factor of improvement was found for active clients. The utility of continuous monitoring of client satisfaction is discussed.

Effect of a new 5 alpha-reductase inhibitor on size, histologic characteristics, and androgen concentrations of the canine prostate.

Mature male beagles were used in studies designed to determine the effect of the steroidal 5 alpha-reductase inhibitor 17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5 alpha-androstan-3-one (4-MA) on size, histology, and androgen concentration of the prostate. Subcutaneous administration of 3 or 15 mg/kg/day for 43 days caused a sharp decline in prostate volume. flattening of prostatic epithelial cells, vacuolization of the cytoplasm and pycnosis of the nuclei. Whereas serum testosterone levels remained normal in dogs injected with 3 mg/kg/day, they were lower in those that received 15 mg/kg/day. Concentration of both testosterone and 5 alpha-dihydrotestosterone were reduced in the prostates of dogs that had received either 3 or 15 mg/kg/day of 4-MA. The 15 mg/kg/day level also appeared to adversely affect spermatogenesis. In a 43-day study, 4-MA given orally once each day at levels of 0.1, 0.3, or 1 mg/kg failed to cause a significant decrease in prostate volume. However, daily divided oral doses totaling 1 or 3 mg/kg were given in a 42-day test and both treatment levels produced significant reductions in prostate size.

Reintegrating institutionalized mental retardates in the community: A descriptive survey.

Communities are giving relatively little attention to the problem of reintegrating institutionalized mental retardates into their home communities. Findings indicate that 25 percent of a group of institutionalized retardates may be capable of being reintegrated into community living. These retardates appear to be brighter, have been institutionalized a shorter period of time, and are in more consistent contact with their homes than those considered terminal cases. The data suggest that many retardates possess a variety of skills valuable to community adjustment, but that the lack of adequate community services may prohibit their leaving the institution.