Nociceptin Is a Chemorepellent in \u3ci\u3eTetrahymena thermophila\u3c/i\u3e

Tetrahymena thermophila are free-living, ciliated, eukaryotic organisms that respond to stimuli by moving toward chemoattractants and avoiding chemorepellents. Chemoattractant responses involve faster ciliary beating, which propels the organisms forward more rapidly. Chemorepellent signaling involves ciliary reversal, which disrupts forward swimming, and causes the organism to jerk back and forth, swim in small circles, or spin in an attempt to get away from the repellent. Many food sources, such as proteins, are chemoattractants for Tetrahymena, while a variety of compounds are repellents. Repellents in nature are thought to come from the secretions of predators, or from ruptured organisms, which may serve as “danger” signals. Several hormones involved in human pain signaling have been shown to be chemorepellents in Tetrahymena, including substance P, ACTH, PACAP, VIP, and nociceptin. We have been studying the response of Tetrahymena to nociceptin, using pharmacological inhibitors in order to elucidate components of the nociceptin signaling pathway. We have found that G-protein inhibitors and a number of mammalian tyrosine kinase inhibitors have no effect on nociceptin avoidance. However, the tyrosine kinase inhibitor, genistein, inhibits avoidance to nociceptin, likely by an unrelated mechanism. Nociceptin avoidance is also inhibited by the calcium chelator, EGTA, and partially inhibited by the ER calcium ATPase inhibitor, thapsigargin. Whole cell electrophysiology experiments in a calcium-containing buffer show that addition of 50 μM nociceptin to the buffer causes a sustained depolarization of approximately 30 mV. This depolarization is nearly eliminated in the presence of EGTA, further supporting the hypothesis that calcium is involved in nociceptin signaling. J-113397, an inhibitor of the human nociceptin receptor, also inhibits nociceptin avoidance in Tetrahymena, though other nociceptin antagonists we tested had no effect on avoidance. Further experimentation on this organism will give a more complete picture of the signaling pathway, as well as allowing greater comparison between nociceptin avoidance in Tetrahymena and nociceptin signaling in vertebrates

Nociceptin Signals Through Calcium in \u3ci\u3eTetrahymena thermophila\u3c/i\u3e

Tetrahymena thermophila are free-living, ciliated, eukaryotic organisms that respond to stimuli by moving toward chemoattractants and avoiding chemorepellents. Chemoattractant responses involve faster ciliary beating, which propels the organisms forward more rapidly. Chemorepellents signaling involves ciliary reversal, which disrupts forward swimming, and causes the organisms to jerk back and forth, swim in small circles, or spin in an attempt to get away from the repellent. Many food sources, such as proteins, are chemoattractants for these organisms, while a variety of compounds are repellents. Repellents in nature are thought to come from the secretions of predators, or from ruptured organisms, which may serve as danger signals. Interestingly, several hormones involved in human pain signaling have been shown to be chemorepellents in Tetrahymena, including substance P, ACTH, PACAP, VIP, and nociceptin. Recently, we have been studying Tetrahymena response to nociceptin, using pharmacological inhibitors in order to elucidate components of the nociceptin signaling pathway. We have found that G-protein inhibitors and a number of mammalian tyrosine kinase inhibitors have no effect on nociceptin avoidance. However, the tyrosine kinase inhibitor, genistein, inhibits avoidance to nociceptin. Nociceptin avoidance is also inhibited by the calcium chelator, EGTA, which implicates calcium in the avoidance response. Electrophysiology studies done in a calcium-containing buffer show that 50 μM nociceptin causes a sustained depolarization of approximately 30 mV, further supporting the hypothesis that calcium is involved in nociceptin signaling. J-113397, an inhibitor of the human nociceptin receptor, also inhibits nociceptin avoidance in Tetrahymena. We are currently working to determine whether other inhibitors of the human nociceptin receptor have any effect on Tetrahymena, in order to get a more complete picture of the signaling pathway

Pharmacokinetics and safety of a single dose of telavancin in pediatric subjects 2-17 years of age.

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics