Comparative study of potential for bisphosphonates to damage gastric mucosa of rats.

Bisphosphonates have generally few clinical adverse effects, the most common being gastrointestinal disturbances. It is generally believed that bisphosphonates with a primary amine are more irritating to the gastrointestinal tract than those without a primary amine. The objective of this study was to compare the gastric irritation potential of an amino bisphosphonate (alendronate) to that of two nonamino bisphosphonates (risedronate and etidronate) in a rat model at pharmacologically equivalent and clinically relevant doses. The doses used were 1, 5, 10, and 30 mg/kg/day for alendronate and risedronate and 40, 200, 400, and 1200 mg/kg/day for etidronate. These doses represent 5-150 times the recommended clinical dose. The drugs were given orally, daily by gavage for four weeks. The gastric irritation potential was assessed by gross and microscopic evaluation of multiple sections of the stomach. This study showed that, at pharmacologically equivalent doses, the gastric irritation potential for alendronate is no greater than that for etidronate or risedronate.

Leydig cell hyperplasia and adenomas in mice treated with finasteride, a 5 alpha-reductase inhibitor: a possible mechanism.

Finasteride is a selective inhibitor of the enzyme 5 alpha-reductase which is responsible for the conversion of testosterone (T) to dihydrotestosterone (DHT). Finasteride is indicated for the treatment of benign prostatic hyperplasia in man (approximately 0.1 mg/kg/day). The effect of long-term treatment was studied in mice given high doses (2.5, 25, and 250 mg/kg/day) of finasteride for 83 weeks. In finasteride-treated mice, increased incidences of testicular Leydig cell hyperplasia (52% compared to 24% in control group) at doses equal to or greater than 25 mg/kg/day and Leydig cell adenomas (32% compared to 0.5% in control group) at 250 mg/kg/day were observed. There were no drug-related effects on the seminiferous tubules. Since luteinizing hormone (LH) is a trophic hormone for Leydig cells, short-term studies (5 to 14 weeks) were done to investigate the relationship between Leydig cell hyperplasia and serum LH levels in finasteride-treated mice. In these studies, there was a positive correlation between the drug-related increased incidence of Leydig cell hyperplasia and a statistically significant (p < or = 0.05) increase in serum LH levels in finasteride-treated (250 mg/kg/day) mice. Furthermore, studies in castrated male mice showed that the suppression of serum LH levels by T is reversible by inhibition of conversion of T to DHT with finasteride (250 mg/kg/day), supporting the hypothesis that DHT is involved in the regulation of LH release in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

[Chemical safety (III)--its prospects in Poland]. / Bezpieczenstwo chemiczne (III)--perspektywy w Polsce.

The paper discusses principles of the chemical safety system to be introduced in Poland. It is thought that the system should be based on a doctrine comprising theoretical considerations, definitions of concepts and scope of activity. Moreover, the organizational and legal background of the future system was also considered. According to the main principle of the chemical safety system, any activity, involving the use of chemicals gives rise to a risk of adverse health and environmental effects. The numerical value that can be assigned to such risk ranges between 0 and 1. Thus an essential activity related to chemical safety seems to be the determination of a socially acceptable risk. Chemical safety has been defined as an environmental state where the chemical substances of different origin pose either no risk of adverse health and environmental effects or the risk whose level is socially acceptable. The chemical safety system aims at limiting or preventing the risk arising from the use of chemicals. It is suggested that the activities of the future system should be supervised by the National Coordinating Committee for Chemical Safety which would stimulate both the research work on risk assessment and management as well as other activities pertaining to chemical safety.

Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors.

Simvastatin, a hydroxy-methylglutaryl-coenzyme A reductase inhibitor intended for use as a hypocholesterolemic agent, has undergone a thorough preclinical toxicology evaluation. This review describes preclinical toxicology findings associated with simvastatin administration in animals and provides the rationale for our conclusion that these changes are not indicative of potential human toxicity. Although it was not surprising to find that a potent inhibitor of this key biochemical pathway produces toxicity at high dosages in animals, none of the observed changes poses a significant risk to humans at clinical dosages. Many of the toxicities produced by high dosage levels of simvastatin in animals are directly related to the drug's biochemical mechanism of action and are the result of a profound, sustained inhibition of the target enzyme that is not anticipated at clinical dosages. Furthermore, several of the simvastatin-induced changes are species-specific responses to this agent and are not relevant to human risk assessment. Of the treatment-related changes reported for simvastatin, the development of cataracts in dogs has received considerable attention. The available data demonstrate a wide margin of safety in terms of dosage levels required to elicit this response as well as the plasma concentrations associated with the development of these ocular lesions. The data suggest that the development of lenticular opacities at clinical doses of simvastatin is highly improbable. Overall, simvastatin is highly improbable. Overall, simvastatin was well-tolerated by animals in preclinical toxicology studies, and no findings contraindicating its use in humans were identified.

[Chemical safety (II)--Methodologic and practical problems]. / Bezpieczenstwo chemiczne (II)--Zagadnienia metodyczne i utylitarne.

Main components of the problem of chemical safety, their role and aims as well as their mutual relations are presented. Need to create a register of chemical compounds and necessity to set up an information centre which would help functioning the whole system are justified. Risk assessment is believed to be the main aspect of cognitive activities aimed at determining the probability of occurrence of harmful consequences of exposure. Risk assessment is a set of complex legal, organizational and administrative undertakings supposed to reduce the hazards resulting from exposure to chemicals. Necessity to calculate costs and benefits coming from the undertaking and need to analyse social perception of risk which is important for preventive action are justified. What is stressed is the significance of a widespread education aimed at forming attitudes towards chemical hazards.

Famotidine: an appraisal of its mode of action and safety.

Famotidine is a potent histamine (H2)-receptor antagonist that binds to the H2 receptor in a competitive reversible manner as shown by in vivo, in vitro, and clinical studies. Famotidine has shown no evidence of carcinogenicity, mutagenicity, or teratogenicity in extensive and adequately designed safety assessment studies. The drug produces neither prolonged anacidity nor doses its use result in significant elevations of serum gastrin levels beyond those seen with other available H2-receptor antagonists when used as recommended for the treatment of ulcer disease. Taken together, these data demonstrate no undue or disproportionate risk to the use of famotidine.

Famotidine: summary of preclinical safety assessment.

Extensive preclinical safety studies with famotidine were performed or sponsored by Yamanouchi Phamaceutical Co, Ltd, Tokyo, Japan, and Merck, Sharp & Dohme Research Laboratories, West Point, Pennsylvania, USA. These studies were performed in dogs, rats, mice and rabbits, receiving oral and intravenous administration of the compound. Minimal toxicologic effects (after acute, subacute, or chronic administration) have been observed even at extremely high dosage levels (4,000 mg/kg/day) and for extended periods of administration (2,000 mg/kg/day for 105 weeks). No evidence of teratogenic, mutagenic, or carcinogenic effects or alterations of reproductive function have been seen. Based on these data, there are no contraindications for administration of this compound to humans.

Predictive value of surveillance skin cultures in total-parenteral-nutrition-related infection.

To assess the importance of skin flora in the pathogenesis of infection complicating total parenteral nutrition and the predictive value of positive skin cultures for the development of infection 54 patients, who received 59 courses of total parenteral nutrition, were followed up. Three times per week, at the time of dressing and line changes, the skin at the site of insertion of the cannula was swabbed for culture. Results of skin cultures were compared with results of semiquantitative culture of the proximal intravascular portion of the cannula. Infected patients were defined as those having cannula cultures with greater than or equal to 15 colonies or those with primary septicaemia. 21 of 59 courses (36%) were associated with positive skin cultures; 14 of these 21 courses were associated with cannula infection, 2 with bacteraemia or fungaemia, and 12 with local infection. 38 of 59 (64%) courses had sterile skin cultures; in none of these 38 patients did infection develop (p less than 0.001). Skin colonisation was associated with otherwise unexplained fever (11 of 21 with positive skin culture versus 5 of 38 with negative skin culture, p less than 0.001), inflammation at the insertion site (13 of 21 versus 10 of 38, p less than 0.05), and violations of line protocol (11 of 21 versus 10 of 38, p less than 0.05). The absence of any organism on the skin had a negative predictive value of 98%, whereas the presence of an organism on the skin had a positive predictive value of 61%. Skin culture thus seems able to identify which patients receiving parenteral nutrition are at high risk of infection.

Total parenteral nutrition-related infections. Prospective epidemiologic study using semiquantitative methods.

Studies of total parenteral nutrition-related infection have incorrectly relied on positive results on culture of the cannula tip to confirm the source. We undertook a prospective study of total parenteral nutrition-related infections in adult patients by obtaining blood from all total parenteral nutrition lines for pour-plate culture twice weekly and culturing intravascular line segments by the technique of Maki. Twelve of 100 courses of total parenteral nutrition (12 percent) in 69 patients resulted in infections--five (5.0 percent) had sepsis, and seven (7.0 percent) had local infection. In five of these 12, pour-plate culture gave positive results (five of 38 pour plates) with counts of 8 colony-forming units per ml (cfu/ml) for Candida tropicalis, and 25 to more than 1,000 for bacterial isolates. In nine of 12, culture of the intravascular line segment gave positive results with more than 50 cfu/ml. Pathogens isolated from intravascular line segments included Staphylococcus epidermidis (three cases), Candida species (three cases), Staphylococcus aureus (two cases), Serratia marcescens (one case) and mixed bacterial pathogens (one case). In contrast, pour-plate culture gave positive results in only seven of 88 uninfected (control) courses (318 pour plates), and culture of intravascular line segments gave positive results in two of 65 uninfected courses (p less than 0.001). No differences existed among patients with and without infection with regard to age, underlying disease, surgery, systemic antibiotic usage, or the presence of other infections. The duration of total parenteral nutrition was longer in courses without infection than in courses with infection (14.7 +/- 9.4 days versus 11.0 +/- 4.0 days; p less than 0.02). In six of 12 courses with infection, the line had been violated compared with 22 of 88 courses without infection (p less than 0.001). T-connectors for the centra administration of intralipid were associatd with infection (p less than 0.02). The value of routine pour-plate culture was illustrated in three courses in which the positive pour-plate culture results antedated positive blood culture results or line removal.

Porcine Hemophilus parahemolyticus pneumonia in Saskatchewan. I. Natural occurrence and findings.

An outbreak of fibrinous pleuropneumonia was observed in October 1971 in Saskatchewan on a farm of 900 feeder pigs. Morbidity and mortality were low. Pathologic-anatomic findings included fibrinous pleuritis, pulmonary vascular thrombosis and necrotizing fibrinous pneumonia. Hemophilus parahemolyticus was isolated from the lungs of affected animals. In addition pulmonary lesions were found which suggested an adenovirus infection. It was speculated that the viral infection possibly predisposed the pigs to the Hemophilus infection. The H. parahemolyticus isolate was sensitive to common antibiotics.