The absolute bioavailability of oral melatonin.
ABSTRACT The absolute bioavailability of oral melatonin tablets was studied in 12 normal healthy volunteers. Subjects were administered, in a randomized crossover fashion, melatonin 2 mg intravenously and 2 and 4 mg orally. Blood was sampled over approximately eight (estimated) half-lives. Both the 2 and the 4 mg oral dosages showed an absolute bioavailability of approximately 15%. No difference in serum half-life was seen in any of the study phases. Oral melatonin tablets in dosages of 2 and 4 mg show poor absolute bioavailability, either due to poor oral absorption, large first-pass metabolism, or a combination of both. Further studies examining larger doses, in an attempt to saturate first-pass metabolism if it occurs, may be warranted.
Article: Melatonergic drugs in development[Show abstract] [Hide abstract]
ABSTRACT: Melatonin (N-acetyl-5-methoxytryptamine) is widely known as "the darkness hormone". It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.Clinical Pharmacology: Advances and Applications 09/2014; 6:127-37. DOI:10.2147/CPAA.S36600
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ABSTRACT: We have demonstrated that mitochondrial oxidative damage and PKCδ overexpression contribute to methamphetamine-induced dopaminergic degeneration. Although it is recognized that antioxidant melatonin is effective in preventing neurotoxicity induced by methamphetamine, its precise mechanism remains elusive. C57BL/6J wild type mice exhibited a similar degree of dopaminergic deficit when methamphetamine was administered during light and dark phases. Furthermore, dopaminergic neuroprotection by genetic inhibition of PKCδ during the light phase was comparable to that during the dark phase. Thus, we have focused on the light phase in order to examine whether melatonin modulates PKCδ-mediated neurotoxic signaling after multiple high doses of methamphetamine. To enhance the bioavailability of melatonin, we applied liposomal melatonin. Treatment with methamphetamine resulted in hyperthermia, mitochondrial translocation of PKCδ, oxidative damage (mitochondria > cytosol), mitochondrial dysfunction, pro-apoptotic changes, ultrastructural mitochondrial degeneration, dopaminergic degeneration, and behavioral impairment in wild type mice. Treatment with liposomal melatonin resulted in a dose-dependent attenuation against degenerative changes induced by methamphetamine in wild type mice. Attenuation by liposomal melatonin might be comparable to that by genetic inhibition (using PKCδ(-/-) mice or PKCδ antisense oligonucleotide). However, liposomal melatonin did not show any additional protective effects on the attenuation by genetic inhibition of PKCδ. Our results suggest that the circadian cycle cannot be a key factor in modulating methamphetamine toxicity under the current experimental condition, and that PKCδ is one of the critical target genes for melatonin-mediated protective effects against mitochondrial burdens (dysfunction), oxidative stress, pro-apoptosis, and dopaminergic degeneration induced by methamphetamine.This article is protected by copyright. All rights reserved.Journal of Pineal Research 11/2014; 58(1). DOI:10.1111/jpi.12195 · 7.81 Impact Factor
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ABSTRACT: To investigate whether melatonin administered intraoperatively reduced pain following laparoscopic cholecystectomy. Randomized, placebo-controlled, double-blinded study. Two surgical departments in Copenhagen. 44 women between 18 and 70years of age, who were surgical candidates for laparoscopic cholecystectomy. Patients were anesthetized by a standard protocol and received a standard multimodal postoperative analgesic regimen. Patients undergoing surgery were admitted on the day of surgery and were discharged the day after surgery. Ten mg of intravenous (IV) melatonin or placebo were administered at the time of surgical incision. Pain was assessed by a set of questionnaires documenting "pain at rest" using a visual analog scale (VAS). The use of rescue medication was recorded. Sleep quality and general well-being were measured on separate VAS scales. Sleepiness was assessed by the Karolinska Sleepiness Scale. Forty-four patients were included and randomized to the study. Three patients did not complete the study. No differences in VAS pain scores, sleep quality, general well-being, or sleepiness were found between the two groups in the postoperative period. The use of postoperative rescue medication did not differ between the groups. The use of 10mg of IV melatonin administered during laparoscopic cholecystectomy did not affect postoperative pain or use of analgesic medication. Copyright © 2014 Elsevier Inc. All rights reserved.Journal of Clinical Anesthesia 11/2014; 26(7):545-50. DOI:10.1016/j.jclinane.2014.03.008 · 1.21 Impact Factor