Background: Enhanced thrombin generation has been found in patients with peripheral arterial obstructive disease (PAOD). The objective of this study is to investigate the effect of thrombin inhibition in PAOD patients. Methods: Argatroban (20 mg/day) was infused intravenously over 2 hours for 14-68 days in 27 patients with chronic PAOD of the lower extremities. Plasma thrombin-antithrombin III complex (TAT) levels and clinical signs were assessed. Results: TAT levels before argatroban therapy were significantly higher in the PAOD patients than in age- and gender-matched controls. In the PAOD patients, TAT levels increased stepwise in the presence of rest pain classified as Fontain III and IV. To assess the effect of thrombin inhibition, we divided the patients into a high-TAT group (pretreatment TAT level >/=5 ng/ml, n = 12) and a low-TAT group (pretreatment TAT level <5 ng/ml, n = 15). In the high-TAT group, TAT levels were suppressed in 8 of 12 patients after the administration of argatroban, along with improvement of their clinical symptoms and a decrease in the size of ischemic skin ulcers, indicating that argatroban clearly inhibited thrombin generation in vivo. Even in the low-TAT group, argatroban improved the clinical signs and symptoms, and also reduced the size of ischemic skin ulcers although TAT levels remained within the low range (<5 ng/ml) in 13 of the 15 patients, indicating that PAOD signs and/or symptoms may be related to small amounts of thrombin generated locally at the sites of atherothrombotic stenotic lesion. Conclusions: These results suggest that thrombin generation was enhanced in PAOD and that the amount was related to disease severity. Thrombin inhibition by argatroban may break this vicious cycle and lead to clinical improvement in PAOD.

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acute cellular rejection (ACR), antibody-mediated rejection (AMR), and infections remains challenging. 1 Risk factors for poor clinical prognosis or difficulties for their management by healthcare practitioners for patients necessitate alternative immunosuppression strategies. 1 Induction T riple immunosuppressive therapy including calcineurin inhibitors (CNIs), mycophenolate mofetil (MMF), and steroids, has substantially improved outcomes for heart transplant (HTx) recipients. Nevertheless, the management of CNI-related nephrotoxicity, fatal

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Similar concentration-time curves for tacrolimus were obtained in the expresser and non-expresser groups by dose adjustment based on therapeutic drug monitoring. These results demonstrate the importance of the CYP3A5 genotype in tacrolimus dose optimization based on therapeutic drug monitoring after heart transplantation.

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