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Articles by A Khanna
Total Records ( 3 ) for A Khanna
  A Fura , A Khanna , V Vyas , B Koplowitz , S. Y Chang , C Caporuscio , D. W Boulton , L. J Christopher , K. D Chadwick , L. G Hamann , W. G Humphreys and M. Kirby
 

Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50–75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml/min/kg) than in dogs (9.3 ml/min/kg) and monkeys (14.5 ml/min/kg) and was predicted to be low to moderate in humans. The plasma elimination half-life was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The volume of distribution values observed in rats, dogs, and monkeys (1.3–5.2 l/kg) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (≤30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged pharmacodynamic properties relative to its plasma pharmacokinetic profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4.

  A Fura , A Khanna , V Vyas , B Koplowitz , S. Y Chang , C Caporuscio , D. W Boulton , L. J Christopher , K. D Chadwick , L. G Hamann , W. G Humphreys and M. Kirby
 

Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50–75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml/min/kg) than in dogs (9.3 ml/min/kg) and monkeys (14.5 ml/min/kg) and was predicted to be low to moderate in humans. The plasma elimination half-life was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The volume of distribution values observed in rats, dogs, and monkeys (1.3–5.2 l/kg) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (≤30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged pharmacodynamic properties relative to its plasma pharmacokinetic profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4.

  A Khanna , C Bockelman , A Hemmes , M. R Junttila , J. P Wiksten , M Lundin , S Junnila , D. J Murphy , G. I Evan , C Haglund , J Westermarck and A. Ristimaki
  Background

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that stabilizes the c-Myc (MYC) protein. However, the clinical relevance of CIP2A to human cancers had not been demonstrated, but the mechanism of its regulation and its clinical role in cancer were completely unknown.

Methods

Tissue microarrays consisting of 223 gastric adenocarcinoma specimens were evaluated for the presence of CIP2A using immunohistochemistry, and the association of CIP2A expression with survival was assessed using Kaplan–Meier analysis. The effects of MYC and CIP2A on each other's expression and on cell proliferation were investigated in several gastric cancer cell lines using small interfering RNAs to CIP2A and MYC and immunoblotting. To further evaluate the role of MYC in CIP2A regulation, an inhibitor of MYC dimerization, 10058-F4, and an inducible MycER model were used.

Results

Expression of CIP2A protein was associated with reduced overall survival for gastric cancer patients with tumors 5 cm or smaller, with a 10-year overall survival in the CIP2A-immunopositive group of 8.1% as compared with 37.6% in the CIP2A-negative group (difference = 29.5%, 95% confidence interval = 12.5% to 46.5%, P = .001). In gastric cancer cell lines, CIP2A depletion led to decreased proliferation and anchorage-independent growth of the cells, as well as to reduced stability and expression of MYC protein. Interestingly, MYC depletion led to reduced expression of CIP2A mRNA and protein. Moreover, experiments with an MYC inhibitor and activator suggested that MYC directly promotes CIP2A gene expression. Finally, CIP2A and MYC immunopositivities were associated in gastric cancer specimens (P = .021).

Conclusions

CIP2A immunopositivity is a predictor of survival for some subgroups of gastric cancer patients. CIP2A and MYC appear to be regulated in a positive feedback loop, wherein they promote each other's expression and gastric cancer cell proliferation.

 
 
 
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