Testing for nonlinearity in nonstationary time series: A network-based surrogate data test.

The classical surrogate data tests, which are used to differentiate linear noise processes from nonlinear processes, are not suitable for nonstationary time series. In this paper, we propose a surrogate data test that can be applied on both stationary time series as well as nonstationary time series with short-term fluctuations. The method is based on the idea of constructing a network from the time series, employing a generalized symbolic dynamics method introduced in this work, and using any one of the several easily computable network parameters as discriminating statistics. The construction of the network is designed to remove the long-term trends in the data automatically. The network-based test statistics pick up only the short-term variations, unlike the discriminating statistics of the traditional methods, which are influenced by nonstationary trends in the data. The method is tested on several systems generated by linear or nonlinear processes and with deterministic or stochastic trends, and in all cases it is found to be able to differentiate between linear stochastic processes and nonlinear processes quite accurately, especially in cases where the common methods would lead to false rejections of the null hypothesis due to nonstationarity being interpreted as nonlinearity. The method is also found to be robust to the presence of experimental or dynamical noise of a moderate level in an otherwise nonlinear system.

Synthesis and evaluation of dual antiplatelet activity of bispidine derivatives of N-substituted pyroglutamic acids.

N-aralkylpyroglutamides of substituted bispidine were prepared and evaluated for their ability to inhibit collagen induced platelet aggregation, both in vivo and in vitro. Some compounds showed high anti-platelet efficacy (in vitro) of which six inhibited both collagen as well as U46619 induced platelet aggregation with concentration dependent anti-platelet efficacy through dual mechanism. In particular, the compound 4j offered significant protection against collagen epinephrine induced pulmonary thromboembolism as well as ferric chloride induced arterial thrombosis, without affecting bleeding tendency in mice. Therefore, the present study suggests that the compound 4j displays a remarkable antithrombotic efficacy much better than aspirin and clopidogrel.

Pharmacokinetics and tissue distribution study of novel potent antiplatelet agent S007-867 in mice using HPLC-MS/MS.

1. S007-867 is a novel antiplatelet agent that shows promising in vitro and in vivo efficacy. For further development and better pharmacological elucidation, we characterized pharmacokinetics and tissue distribution of S007-867 in a mouse model. 2. A sensitive, selective and robust LC-MS/MS method was developed and validated in the mouse plasma and tissue for quantification of S007-867. The chromatographic separation was performed on Waters Symmetry Shield C18 column (150 × 4.6 mm, 5 µm) using methanol and ammonium acetate buffer. 3. S007-867 was rapidly absorbed and distributed to various tissues. Following single oral administration of S007-867 in the mouse, the concentration was in the order of C intestine > C liver > C kidney > C heart > C spleen > C lungs > C brain. Tissue to plasma area under the plasma curve ratio suggested that the maximum amount of drug was found in the intestine and liver. Half life of S007-867 was found longer in the heart (8.08 h), spleen (∼ 7.94 h) and kidney (∼ 15.41 h) as compared with other tissues. 4. The preclinical pharmacokinetics and tissue distribution data obtained using this LC-MS/MS method are expected to assist the future clinical investigations of S007-867 as a promising antiplatelet agent.

Synthesis and identification of chiral aminomethylpiperidine carboxamides as inhibitor of collagen induced platelet activation.

A series of chiral lactam carboxamides of aminomethylpiperidine were synthesized and investigated for the collagen induced in vitro anti-platelet efficacy and collagen plus epinephrine induced in vivo pulmonary thromboembolism. The compound 31a (30 µM/kg) displayed a remarkable antithrombotic efficacy (60% protection) which was sustained for more than 24 h and points to its excellent bioavailability. The compounds 31a (IC50 = 6.6 µM) and 32a (IC50 = 37 µM), as well as their racemic mixture 28i (IC50 = 16 µM) significantly inhibited collagen-induced human platelet aggregation in vitro. Compound 34c displayed dual mechanism of action against both collagen (IC50 = 3.3 µM) and U46619 (IC50 = 2.7 µM) induced platelet aggregation. The pharmacokinetic study of 31a indicated very faster absorption, prolonged and constant systemic exposure and thereby exhibiting better therapeutic response.