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Aims: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. Methods: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine >= 0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. Results: Of the 7306 patients that were enrolled, VIN occurred in 14.2% of them (1035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio 0.701, 95% confidence interval 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM < 7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations >= 20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. Conclusions: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

Aims: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. Methods: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine >= 0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. Results: Of the 7306 patients that were enrolled, VIN occurred in 14.2% of them (1035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio 0.701, 95% confidence interval 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM < 7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations >= 20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. Conclusions: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

Aims: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. Methods: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine >= 0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. Results: Of the 7306 patients that were enrolled, VIN occurred in 14.2% of them (1035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio 0.701, 95% confidence interval 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM < 7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations >= 20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. Conclusions: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

Aims: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. Methods: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine >= 0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. Results: Of the 7306 patients that were enrolled, VIN occurred in 14.2% of them (1035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio 0.701, 95% confidence interval 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM < 7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations >= 20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. Conclusions: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

OBJECTIVES:To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. DESIGN:Parallel-arm, randomized, double-blinded, placebo-controlled trial. SETTING:Academic medical center in La Jolla, California. PATIENTS:Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. INTERVENTIONS:Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. MEASUREMENTS AND MAIN RESULTS:Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively. CONCLUSIONS:Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

OBJECTIVES:To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. DESIGN:Parallel-arm, randomized, double-blinded, placebo-controlled trial. SETTING:Academic medical center in La Jolla, California. PATIENTS:Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. INTERVENTIONS:Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. MEASUREMENTS AND MAIN RESULTS:Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively. CONCLUSIONS:Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

The primary outcome measure of the on-road driving test is the Standard Deviation of Lateral Position. However, other outcome measures, such as lapses and excursions out-of-lane, also need to be considered as they may be related to crash risk. The aim of this study was to determine the direction of lapses and excursions out-of-lane (i.e. towards/into the adjacent traffic lane or towards/into the road shoulder). In total, data from 240 driving tests were re-analysed, and 628 lapses and 401 excursions out-of-lane were identified. The analyses revealed that lapses were made equally frequently over left (49.4%) and over right (43.3%). In contrast, excursions out-of-lane were almost exclusively directed over right into the (safer) road shoulder (97.3%). These findings suggest that drivers are unaware of having lapses, whereas excursions out-of-lane are events where the driver is aware of loss of vehicle control.

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon's use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders.

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon's use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders.

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon's use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders.

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon's use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders.

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon's use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders.

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.

Due to inconsistency among reports on the therapeutic efficacy of melatonin, attention has been focused on the development of more potent melatonin analogues with prolonged effects. Melatonergic drugs, ramelteon and agomelatine have been effective in treating either sleep disorders or sleep disturbances associated with depressive disorders. MT1 and MT2 melatonergic receptor agonist, ramelteon, was found effective in increasing total sleep time and sleep efficiency, and in reducing sleep latency in patients with insomnia. No reduction in its efficacy was found even after 6-12 months of continuous use. The mechanism of sleep promoting action of ramelteon is entirely different from that of conventional hypnotics that are in use today. Ramelteon's use is not associated with any adverse effects even after six months to one year after its continuous usage. Another melatonergic drug, agomelatine, has also been found effective in improving sleep efficiency and quality, and this action of agomelatine is suggested to be one of the major mechanism by which agomelatine ameliorates depressive symptoms in patients with major depressive disorders and bipolar disorders.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonin receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands has been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonin receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands has been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonin receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands has been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation.

Fifteen epidemiologic studies have associated hypnotic drugs with excess mortality, especially excess cancer deaths. Until recently, insufficient controlled trials were available to demonstrate whether hypnotics actually cause cancer. The U.S. Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone, and ramelteon. Since zolpidem was used as a comparison drug in zaleplon trials, some zolpidem data were also available. Incident cancers occurring during randomized hypnotics administration or placebo administration were tabulated. Combining controlled trials for the 4 drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. Restudy of on-line FDA files led to somewhat altered counts of incident cancers, which are currently being checked against an FDA case review. FDA files revealed that all 4 of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Combining these new randomizing trials provided equivocally- significant data that new hypnotics cause cancer. Together with the epidemiologic data and laboratory studies, the available evidence signals that new hypnotics may increase cancer risk. Due to limitations in available data, further review of case files for these trials and confirmatory research is needed.

Fifteen epidemiologic studies have associated hypnotic drugs with excess mortality, especially excess cancer deaths. Until recently, insufficient controlled trials were available to demonstrate whether hypnotics actually cause cancer. The U.S. Food and Drug Administration (FDA) Approval History and Documents were accessed for zaleplon, eszopiclone, and ramelteon. Since zolpidem was used as a comparison drug in zaleplon trials, some zolpidem data were also available. Incident cancers occurring during randomized hypnotics administration or placebo administration were tabulated. Combining controlled trials for the 4 drugs, there were 6190 participants given hypnotics and 2535 given placebo in parallel. Restudy of on-line FDA files led to somewhat altered counts of incident cancers, which are currently being checked against an FDA case review. FDA files revealed that all 4 of the new hypnotics were associated with cancers in rodents. Three had been shown to be clastogenic. Combining these new randomizing trials provided equivocally- significant data that new hypnotics cause cancer. Together with the epidemiologic data and laboratory studies, the available evidence signals that new hypnotics may increase cancer risk. Due to limitations in available data, further review of case files for these trials and confirmatory research is needed.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonim receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands have been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation. © 2007 Bentham Science Publishers Ltd.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonim receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands have been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation. © 2007 Bentham Science Publishers Ltd.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonim receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands have been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation. © 2007 Bentham Science Publishers Ltd.