doxapram LD50 of 85 mg/kg in mice). Acutely, almitrine is generally well tolerated and safe in humans. Not surprisingly, increased awareness of breathing and breathlessness are ZD1839 manufacturer the most common side-effects following almitrine administration ( Marsac, 1986 and Naeije

et al., 1981). Other side effects included headache, fatigue, insomnia, malaise, flushing, sweating, and postural dizziness ( Naeije et al., 1981 and Sergysels et al., 1980). Gastro-intestinal side effects included nausea, abdominal discomfort, and diarrhea ( MacLeod et al., 1983). There are minimal changes in cardiovascular parameters except for a mild increase in pulmonary artery pressure ( Gluskowski et al., 1984, Gluskowski et al., 1985 and MacNee et al., 1986). Almitrine is less tolerated when administered chronically. Multi-year trials observed that patients receiving almitrine exhibited significant weight loss

(>15%) that appeared to be anorectic ATM Kinase Inhibitor in nature (Ansquer, 1985, Ansquer et al., 1985 and Gherardi et al., 1989). The most significant and consistent side effect of chronic (more than 3 months) almitrine administration is peripheral neuropathy (Allen, 1988, Allen and Prowse, 1989, Bouche et al., 1989, Gherardi et al., 1989 and Suggett et al., 1985). Further examination revealed that these patients showed axonal degradation and a decrease in the density of large myelinated fibers. Mechanistic studies in animals identified the detriazinyl metabolite,

4,4′-fluorobenzhydrylpiperazine, the major almitrine metabolite formed in humans, as the probable cause of the evoked neuropathy (Yamanaka et al., 1997). Thus, the use of almitrine is no longer Thalidomide recommended and is withdrawn or in regulatory review in many countries. There have been only a few new therapeutic agents developed that focus on respiratory control and even fewer have been approved for clinical use during the previous decades. One issue has been poor translation of pre-clinical efficacy into humans, as has occurred with the 5-HT1A and 5-HT4 receptors agonists, buspirone and mosapride (Lotsch et al., 2005 and Oertel et al., 2007). This may be more about the targets selected and not related to the use of rodents as models for drug-induced respiratory depression, given the initial success and translatability of the AMPAkines and GAL-021 (see below). The paucity of the new molecule entities in respiratory modulation has resulted in the route to and benchmarks for registering new therapeutic products to be absent, outdated, or limited to single pharmacological mechanism action. Thus, the methods for determining an early clinical Proof-of-Concept trial, including the selection of meaningful endpoints, will need to be developed for each potential indication that has strong negative predictive value balanced by good positive predictive value for the therapeutic utility of potential agents.