The urinary tract plays an important role in removing wastes and extra water in non-human primates and often demonstrates test article-related findings in nonclinical safety assessment studies. Furthermore, the urinary tract also displays multiple background findings, many of which are specific to non-human primates. This chapter discusses renal anatomy and the normal urinary system histology in non-human primates, particularly the features that are relevant to nonclinical safety assessment studies. The chapter also includes sections on common congenital, degenerative, inflammatory, miscellaneous and infectious diseases in the non-human primate urinary tract. The chapter concludes with a discussion of common toxicologic findings in the non-human primate urinary tract.

The extent of DNA damage and cellular proliferation induced in rat kidneys by single doses of the diabetogenic alkylating agent streptozotocin (STZ) and the time course of repair of that damage were evaluated using an in vivo alkaline elution assay for DNA strand breaks and a bromodeoxyuridine (BrdUrd) labeling assay for cell replication. Male Sprague-Dawley rats were given iv injections of 0.25 to 60 mg/kg STZ and kidneys were harvested 3 hr later for alkaline elution. A dose of 2.5 mg/kg STZ was the lowest dose to induce detectable DNA strand breaks and extensive damage was produced by the commonly used diabetogenic dose of 60 mg/kg. To characterize the repair of the drug-induced DNA damage, kidneys were harvested from a 60 mg/kg group of animals 3 hr to 27 days after dosing. BrdUrd-labeled kidney sections were also evaluated to assess any cellular proliferative response associated with STZ administration. Significant DNA damage was detected up to 14 days after dosing with return to near background levels by 20 days. Similarly, treatment with 60 mg/kg STZ was associated with increases in BrdUrd labeling indices 4 and 9 days after treatment with resolution by 27 days. These results indicate that the cellular and molecular repair responses to a single diabetogenic dose of STZ are prolonged, requiring up to 3 weeks to complete. Thus, to avoid potential additive or synergistic effects on STZ-induced nephrotoxicity and/or genotoxicity, a delay in the start of experimental therapies in this model (other than insulin) should be considered.

Nocardiosis arose in seven of 191 liver transplant patients (3.7%) over a period of 3.5 years. Four patients had only pulmonary lesions while three had disseminated disease. Nocardia asteroides was isolated from three patients following bronchoscopy, percutaneous aspirate of a pulmonary lesion in one patients, and from the skin from the aspirates in three patients. Delay in diagnosis in two cases was due to negative microscopy; in one, the diagnosis was made only after repeated bronchoscopy. Of the seven patients, three (43%) died. In two of these, nocardiosis was considered to have directly contributed to death. Co-existent bacterial and viral infections were present in all patients who died. In vitro susceptibility of the organism to co-trimoxazole was variable and did not necessarily reflect clinical efficacy. In one patient, a good clinical response was achieved with co-trimoxazole despite apparently reduced in vitro susceptibility.

British Journal of Clinical PharmacologyVolume 4, Issue S1 p. 19S-29S Free Access Pharmacology and toxicology of diflunisal. CA Stone, CA StoneSearch for more papers by this authorCG Van Arman, CG Van ArmanSearch for more papers by this authorVJ Lotti, VJ LottiSearch for more papers by this authorDH Minsker, DH MinskerSearch for more papers by this authorEA Risley, EA RisleySearch for more papers by this authorWJ Bagdon, WJ BagdonSearch for more papers by this authorDL Bokelman, DL BokelmanSearch for more papers by this authorRD Jensen, RD JensenSearch for more papers by this authorB Mendlowski, B MendlowskiSearch for more papers by this authorCL Tate, CL TateSearch for more papers by this authorHM Peck, HM PeckSearch for more papers by this authorRE Zwickley, RE ZwickleySearch for more papers by this authorSE McKinney, SE McKinneySearch for more papers by this author CA Stone, CA StoneSearch for more papers by this authorCG Van Arman, CG Van ArmanSearch for more papers by this authorVJ Lotti, VJ LottiSearch for more papers by this authorDH Minsker, DH MinskerSearch for more papers by this authorEA Risley, EA RisleySearch for more papers by this authorWJ Bagdon, WJ BagdonSearch for more papers by this authorDL Bokelman, DL BokelmanSearch for more papers by this authorRD Jensen, RD JensenSearch for more papers by this authorB Mendlowski, B MendlowskiSearch for more papers by this authorCL Tate, CL TateSearch for more papers by this authorHM Peck, HM PeckSearch for more papers by this authorRE Zwickley, RE ZwickleySearch for more papers by this authorSE McKinney, SE McKinneySearch for more papers by this author First published: February 1977 https://doi.org/10.1111/j.1365-2125.1977.tb04510.xCitations: 58AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References BRODIE, D.A. & CHASE, B.J. (1967). Role of gastric acid in aspirin-induced gastric irritation in the rat. Gastroenterology, 53, 604– 610. BRODIE, D.A., COOK, P.G., BAUER, B.J. & DAGLE, G.E. (1970). Indomethacin-induced intestinal lesions in the rat. Toxic, appl. Pharmac., 17, 615– 624. CHIRIGOS, M.A. & UDENFRIEND, S. (1959). A simple fluorometric procedure for determining salicylic acid in biologic tissues. J. Lab. clin. Med., 54, 769– 772. DUGGAN, D.E., HOOKE, K.F., NOLL, R.M. & KWAN, K.C. (1975). Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem. Pharmac., 25, 1749– 1754. FERREIRA, S.H. & VANE, J.R. (1974). New aspects of the mode of action of non-steroidal anti-inflammatory drugs. A. Rev. Pharmac., 14, 57– 73. GOLDENTHAL, E.I. (1971). A compilation of LD50 values in newborn and adult animals. Toxic appl. Pharmac., 18, 185– 207. LITCHFIELD, J.T. & WILCOXON, F. (1949). A simplified method of evaluating dose-effect experiments. J. Pharmac., 96, 99– 113. MAJERUS, P.W. & STANFORD, N. (1977). Comparative effects of aspirin and diflunisal on prostaglandin synthetase from human platelets and sheep seminal vesicles. Br. J. clin. Pharmac., 4, 15S– 18S. MINSKER, D.H., JORDAN, P.T., KLING, P., MACMILLAN, A., HUCKER, H.B. & TOCCO, D.J. (1976). The effect of halofenate or halofenate-free acid on human, rat and guinea pig platelet aggregation. Thromb. Haemost., 35, 358– 363. PECK, H.M., MATTIS, P.A., STONIER, P.F. & ZWICKEY, R.E. (1967). Toxicology, Drug Information Bulletin 1, 32– 47. RANDALL, L.A. & SELITTO, J.J. (1957). A method for measurement of analgesic activity on inflamed tissue. Arch. Int. Pharmacodyn., 111, 409– 419. SIBINGA, SMIT C. TH. (1977) Effect of diflunisal on platelet function and blood coagulation. Br. J. clin. Pharmac., 4, 37S– 38S. STONE, C.A., VAN ARMAN, C.G., PECK, H.M., MINSKER, D.H. & HAM, E.A. (1974). Pharmacological and toxicological actions of prostaglandin synthetase inhibitors: Potential role of prostaglandin synthetase blockade. In Prostaglandin Synthetase Inhibitors, ed. H.J. Robinson & J.R. VANE ( Raven: New York, 79– 90). TEMPERO, K.F., CIRILLO, V.J. & STEELMAN, S.L. (1977). Diflunisal: A review of the pharmacokinetic and pharmacodynamic properties, drug interactions and special tolerability studies in humans. Br. J. clin. Pharmac. 4, 31S– 36S. TOCCO, D.J., BREAULT, G.O., ZACCHEI, A.G., STEELMAN, S.L. & PERRIER, C.V. (1975). Physiological disposition and metabolism of 5-(2′, 4′-difluorophenyl) salicylic acid, a new salicylate. Drug Metab. Dispos. 3, 453– 466. VAN ARMAN, C.G. & CARLSON, R.P. (1970). The two distinct phases of inflammatory response in the dog's knee joint. In Bradykinin and Related Kinins: Cardiovascular, Biochemical and Neural Actions ( Plenum: New York, 525– 533). VAN ARMAN, C.G., RISLEY, E.A. & LOTTI, V.J. (in press). Diflunisal, an aspirin-like analgesic and anti-inflammatory drug. Fedn Proc. (abstr.). VAN ARMAN, C.G., BEGANY, A.J., MILLER, L.M. & PLESS, H.H. (1965). Some details of the inflammations caused by yeast and by carrageenan. .J. Pharmac. 150, 328– 334. VIN WINZUM, C. & RODDA, B. (1977). Diflunisal: Efficacy in postoperative pain. Br. J. clin. Pharmac., 4, 39S– 43S. WEIL, G.S. (1952). Tables for convenient calculation of median-effect dose (LD50-ED50) and instructions in their use. Biometrics, 8, 249– 263. WINTER, C.A. & FLATAKER, L. (1965). Reaction thresholds to pressure in edematous hindpaws of rats and responses to analgesic drugs. J. Pharmac.s 150, 165– 171. WINTER, C.A. & NUSS, G.W. (1966). Treatment of adjuvant arthritis in rats with anti-inflammatory drugs. Arthritis and Rheumatism, 9, 394– 404. WINTER, C.A., RISLEY, E.A. & NUSS, G.W. (1962). Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc exp. Biol. Med., 111, 544– 547. ZWICKEY, R.E., PECK, H.M., BAGDON, W.J., BOKELMAN, D.L., BROWN, W.R., HITE, M., JENSEN, R.D., MATTIS, P.A., MENDLOWSKI, R., PORTER, C.C., TATE, C.L. & STONE, C.A. (1974). Preclinical toxicological studies of carbidopa and combinations of carbidopa and levodopa. Toxic, appl. Pharmac. 29, 181– 195. Citing Literature Volume4, IssueS1February 1977Pages 19S-29S ReferencesRelatedInformation

Laboratory experiments were conducted to study temperature dependence of soil-water diffusivity and specific water capacity coefficients. Duplicate determinations of soil-water diffusivity, as a function of water content, were made at constant temperatures of 15, 25, and 35 °C on the same sample of Dundee silt loam. Diffusivity was determined by a one-step pressure-plate outflow method. Specific water capacity was computed from the slope of desorption curves obtained during the diffusivity measurements over the pressure head range of 0 to −0.66 bar. In general, diffusivity as a function of water content increased with increase in temperature. However, the effect of temperature was not large and probably can be neglected at normal field temperatures. Near saturation, it is difficult to interpret the thermal influence, for diffusivity approaches infinity and becomes indeterminate at saturation. Variations in soil-water diffusivity in low-swelling soils due to thermal effects can be explained on the basis of temperature dependence of surface tension and viscosity ratio.