4-bromo-6-(3-(4-chlorophenyl)propoxy)-5-(3-pyridylmethylamino)-3(2h)-pyridazinone-hydrochloride and Intermittent-Claudication

Treadmill testing is frequently used to assess the functional capacity of patients with claudication, but the optimal application of treadmill testing in the setting of multicenter clinical trials remains uncertain. The current study used data from a recent clinical trial of the drug NM-702, which employed three baseline assessments of peak walking time (PWT) using a graded treadmill. These data were used to describe the different methods of defining the baseline peak treadmill performance with respect to reproducibility, stability over time and detection of treatment effect. A series of baseline definitions (first test only, last test only, highest PWT of the three tests, arithmetic mean of the three tests, mean of the first two tests, median of the three tests and a reproducibility-based criterion) were used to calculate the population (n = 386) variability in baseline testing, the placebo response over the 24 weeks of treatment, and the effect size of NM-702. Placebo responses and NM-702 effect sizes were not substantively affected by the method used to calculate baseline PWT. Changes in PWT on placebo were less than 25% for all methods of baseline quantitation. No method yielded an NM-702 effect size quantitatively greater than that obtained using only the first baseline test in the analysis for either PWT or claudication onset time. The graded treadmill test quantifies PWT with high reproducibility and stability over time. These characteristics may obviate the need for multiple treadmill tests, potentially saving study costs and improving patient acceptance of trial participation.

Topics: Exercise Test; Humans; Intermittent Claudication; Leg; Phosphodiesterase Inhibitors; Pyridazines; Randomized Controlled Trials as Topic; Reproducibility of Results; Walking

The current study tested the hypothesis that NM-702 improves treadmill exercise performance in peripheral arterial disease patients with claudication-limited exercise performance.. Patients with claudication experience significant disability, owing to their exercise limitation. Therapeutic options to improve exercise performance in these patients are limited. NM-702 is a novel drug that inhibits phosphodiesterase as well as thromboxane A2 synthase.. This study was a randomized, multi-center, placebo-controlled, double-blind trial. Patients were randomized to receive 24 weeks of twice-daily treatment with either placebo (intent to treat population, n = 130), 4 mg NM-702 (n = 126), or 8 mg NM-702 (n = 130).. After 24 weeks of treatment, 8 mg NM-702 was associated with a statistically significant increased peak walking time on a graded treadmill as compared with placebo (p = 0.004). Peak walking time after 24 weeks was increased by 17.1 +/- 49.0% in the placebo arm, 22.1 +/- 60.1% in the 4-mg NM-702 arm, and 28.1 +/- 50.5% in the 8-mg NM-702 arm. NM-702 at the 8-mg dose for 24 weeks was associated with statistically significant improvements in the treadmill claudication onset time as compared with placebo. In addition, as compared with placebo, NM-702 improved the physical component and physical functioning scores of the Medical Outcomes Study 36-Item Short Form and the walking distance and stair climbing domains of the Walking Impairment Questionnaire. NM-702 was generally well tolerated, but adverse events typical of vasodilators were common.. NM-702 used for 24 weeks by patients with claudication was associated with improvements in laboratory- and ambulatory-based exercise performance.

Topics: Aged; Aged, 80 and over; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Humans; Intermittent Claudication; Male; Middle Aged; Peripheral Vascular Diseases; Phosphodiesterase Inhibitors; Pyridazines

NT-702 (parogrelil hydrochloride, NM-702), 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-[(pyridin-3-ylmethyl)amino]pyridazin-3(2H)-one hydrochloride, a novel phosphodiesterase (PDE) inhibitor synthesized as a potent vasodilatory and antiplatelet agent, is being developed for the treatment of intermittent claudication (IC) in patients with peripheral arterial disease. We assessed the efficacy of NT-702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo. NT-702 selectively inhibited PDE3 (IC(50)=0.179 and 0.260 nM for PDE3A and 3B) more potently than cilostazol (IC(50)=231 and 237 nM for PDE3A and 3B) among recombinant human PDE1 to PDE6. NT-702 inhibited in vitro human platelet aggregation induced by various agonists (IC(50)=11 to 67 nM) and phenylephrine-induced rat aortic contraction (IC(50)=24 nM). Corresponding results for cilostazol were 4.1 to 17 microM and 1.0 microM, respectively. NT-702 (3 mg/kg or more) significantly inhibited ex vivo rat platelet aggregation after a single oral dose. For cilostazol, 300 mg/kg was effective. In a rat femoral artery ligation model, NT-702 at 5 and 10 mg/kg repeated oral doses twice a day (BID) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2.5 mg/kg and more. Cilostazol also improved the walking distance and surface temperature at 300 mg/kg BID but significant difference was only observed for surface temperature on day 8. These results suggest that NT-702 can be expected to have therapeutic advantage for IC.

Topics: Animals; Body Temperature; Cilostazol; Hindlimb; Humans; Intermittent Claudication; Male; Phosphodiesterase Inhibitors; Platelet Aggregation; Pyridazines; Rats; Rats, Wistar; Tetrazoles; Vasodilation; Walking