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Biomedical subjects

K N Khan

Publications and source records attributed to K N Khan.

42 records · Page 3Linked to original sources
PubMedDate not supplied

Clinical pathologic changes in two marmosets with wasting syndrome.

Two sexually mature marmosets (Callithrix jacchus) showing clinical signs similar to those seen in wasting marmoset syndrome (weight loss, decreased muscle mass, and alopecia) were evaluated for clinical and anatomic pathologic changes. The most prominent clinical pathologic alterations included macrocytic normochromic anemia, hypoproteinemia, hypoalbuminemia, elevated serum aspartate aminotransferase and alkaline phosphatase levels, and previously unreported changes of thrombocytosis. The principal gross and histopathologic finding was chronic colitis, which appeared to be the most important contributing factor to the development of wasting syndrome in these marmosets.

Animals↗
PubMedDate not supplied

Toxicity of subacute intravenous manganese chloride administration in beagle dogs.

Manganese (Mn), a naturally occurring essential trace element, is currently being used as a metal complex for pharmaceutical and magnetic resonance imaging agents. Despite its popularity in these practices, minimal attention has focused on possible toxicity of released free Mn ions, which could occur if these agents decomplexed. There is especially limited information available regarding acute toxicity of Mn in dogs. In this study, we performed an in-depth evaluation of acute toxicologic potential of manganese chloride (MnCl2) when administered as a 4-hr/day intravenous infusion to male beagle dogs. The dose of MnCl2 used (16 mg/kg/day) was equivalent to approximately 3-5 times the daily dose of Mn typically administered in some of the Mn-complexed agents. All routine toxicologic endpoints were evaluated, including cardiovascular parameters. This dosing regimen resulted in the death or moribund sacrifice of all the animals within 4 days of initiation of treatment. Clinical evidence of toxicity included loss of appetite, reduction in blood pressure with reflex tachycardia, and a marked increase in liver enzymes, beginning with the first dose and increasing in severity with successive doses. Gross and histopathologic evaluations confirmed severe hepatotoxicity, which was characterized by massive hepatocellular necrosis, periportal hemorrhages, and mild biliary epithelial hyperplasia. These results indicate that acute treatment of beagle dogs with MnCl2 causes severe hepatotoxicity and hypotension with reflex tachycardia and suggest that dogs are very sensitive to toxic effects of Mn.

Animals↗
PubMedDate not supplied

Effect of papillotoxic agents on expression of cyclooxygenase isoforms in the rat kidney.

Inhibition of renal vasodilatory prostaglandins (PGs) and secondary ischemia due to inhibition of cyclooxygenase (COX) activity has been suggested as a possible mechanism for development of analgesic-related renal papillary necrosis (RPN) in rats. Recently, it has been shown that COX exists in two related but unique isoforms, COX-1 and COX-2. It is unclear what potential roles these isoforms play in the maintenance of blood flow in the renal papilla or genesis of RPN. We evaluated the effect of 2 papillotoxic agents, including a nonsteroidal anti-inflammatory drug, indomethacin, and a chemical agent, 2-bromoethanamine hydrobromide (2-BEA), on COX-1 and COX-2 in the renal papilla as a means of assessing what changes occur in the expression of these isoforms during the development of RPN. Female Wistar rats approximately 10-17 wk old were treated with either indomethacin (75 mg/kg, single dose, or 10 mg/kg/day for 5 days) or 2-BEA (100 mg/kg/day for 4 days) to create lesions of RPN. In this study, a single 75-mg/kg dose of indomethacin did not cause light microscopic changes of RPN. However, RPN was observed in animals administered indomethacin at 10 mg/kg/day for 1 wk or 2-BEA for 5 days. The immunohistochemical analyses of kidneys showed that both COX-1 and COX-2 were present in the renal papilla of control rats. In animals treated with indomethacin (75 mg/kg), a slight to moderate decrease in both isoforms was observed in essentially normal renal papillary cells within 2 hr, that was followed by an increase in COX-2 immunoreactivity in the renal papilla, macula densa, and thick ascending limbs (both 10- and 75-mg/kg animals). This COX-2 immunoreactivity was greatest in animals with concomitant indomethacin-induced gastrointestinal injury, suggesting a possible role of inflammatory cytokines in COX-2 induction. No changes in the expression of COX isoforms in the intact papilla occurred as a result of 2-BEA; however, cells undergoing degeneration and necrosis lost immunoreactivity to both COX isoforms. The possible mechanism that leads to an initial decrease in COX immunoreactivity in indomethacin-treated animals is not known; however, a reversible ultrastructural change in the papillary cells cannot be ruled out. This decrease in COX isoforms in the renal papilla may contribute to the development of RPN through the loss of vasodilatory PGs.

Animals↗
PubMedDate not supplied

Interspecies differences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal antiinflammatory drug-related nephrotoxicity.

Cyclooxygenase (COX) exists in 2 related but unique isoforms: one is constitutive (COX-1) and functions in normal cell physiology, and the other is inducible (COX-2) and is expressed in response to inflammatory stimuli. Nonsteroidal antiinflammatory drugs (NSAIDs) cause renal toxicity following inhibition of renal cyclooxygenases. Humans and animals exhibit differences in susceptibility to NSAID-related renal toxicity, which may be associated with differences in expression of 1 or both isoforms of COX in the kidney. In this study, we evaluated COX-1 and COX-2 expression in the kidneys of mixed-breed dogs, Sprague-Dawley rats, cynomolgus monkeys, and humans. In addition, the effect of volume depletion on renal COX expression was investigated in rats, dogs, and monkeys. COX expression was evaluated using 1 or more of the following procedures: reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. We demonstrated that both COX isoforms are expressed in the kidneys of all species examined, with differences in the localization and level of basal expression. COX-1 is expressed at high levels in the collecting ducts and renal vasculature of all species and in a small number of papillary interstitial cells in rats, monkeys, and humans. Basal levels of COX-2 are present in the maculae densa, thick ascending limbs, and papillary interstitial cells in rats and dogs and in glomerular podocytes and small blood vessels in monkeys and humans. COX-2 expression is markedly increased in volume-depleted rats and dogs but not monkeys. These results indicate that significant interspecies differences exist in the presence and distribution of COX isoforms, which may help explain the difference in species susceptibility to NSAID-related renal toxicity.

Adult↗