3 Removal of NH4Cl caused a transient decrease in intracellular pH followed by a marked increase in tension. 4 Both contraction and intracellular Ca21 mobilization induced by acidic pH0 were markedly inhibited by removal of extracellular Ca2", verapamil and adenosine, whereas these were not affected by tetrodotoxin or Gd3 +, a stretch-activated cation channel blocker. Furthermore, cromakalim (a K+ channel opener) inhibited acidic pH.-induced contraction (APIC).5 Acidic pH0 induced a depolarization of cultured smooth muscle cells from SHR aorta. 6 Blood pressure elevated with increasing age of WKY and SHR accompanied by an increase in APIC. Feeding WKY with N0-nitro-L-arginine, an inhibitor of nitric oxide synthases caused a marked elevation of their blood pressure followed by an increase in APIC. 7 These results suggest that APIC is caused by Ca2" influx mediated through the activation of voltagesensitive Ca2+ channels mainly due to acidic pH.-induced depolarization of the plasma membrane of smooth muscle cells. It is also suggested that APIC is strengthened by the elevation of blood pressure.

Abstract. Consensus practices and regulatory guidance for liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) assays of small molecules are more aligned globally than for any of the other bioanalytical techniques addressed by the Global Bioanalysis Consortium. The three Global Bioanalysis Consortium Harmonization Teams provide recommendations and best practices for areas not yet addressed fully by guidances and consensus for small molecule bioanalysis. Recommendations from all three teams are combined in this report for chromatographic run quality, validation, and sample analysis run acceptance.

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ONO-2952 was safe and well tolerated in these early clinical studies investigating safety, tolerability, and pharmacokinetic properties of single and multiple doses. ONO-2952 systemic exposure increased in a less than dose-proportional manner under fasted conditions and in a slightly greater than dose-proportional manner under fed conditions. These results support the progression of ONO-2952 to further studies in humans. SAD study: ClinicalTials.gov identifier: NCT01364441. MAD study: ClinicalTrials.gov identifier: NCT01489345.