Melatonin for pre-medication in children: a systematic review.

BACKGROUND: Melatonin's effectiveness as an anxiolytic medication has been confirmed in adults; however, its efficacy in a paediatric population is unclear. A number of small studies have assessed its use in children as a pre-operative anxiolytic, with conflicting results. METHODS: We undertook a systematic review of pre-operative melatonin use in children. Four databases (MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Web of Science), and ' ClinicalTrials.gov ' were searched for ongoing and completed clinical trials of relevance. Citation tracking reference lists and relevant articles were also accessed. The review was unrestricted by comparator or outcomes. Eleven studies were judged eligible for inclusion. There were high levels of heterogeneity in melatonin administration (in terms of dose and timing). Variable outcomes were reported and included: anxiety; anaesthetic success; analgesia; sedation; post-operative recovery; and safety. Outcomes were not always assessed with the same measures. RESULTS: Evidence to support melatonin's anxiolytic properties in this setting is conflicting. Melatonin was associated with reduced sedative effects, post-operative excitement and improved emergence behaviour, compared to comparator drugs. One study reported the benefit of melatonin use on sleep disturbance at two weeks post-surgery. No adverse safety events were identified to be significantly associated with melatonin, affirming its excellent safety profile. CONCLUSION: Despite potential advantages, including improved emergence behaviour, based on current evidence we cannot confirm whether melatonin is non-inferior to current "usual care" pre-medications. Further consideration of melatonin as an anxiolytic pre-medication in paediatric surgery is needed.

Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays.

The protozoan parasite Leishmania causes leishmaniasis; a spectrum of diseases of which there are an estimated 1 million new cases each year. Current treatments are toxic, expensive, difficult to administer, and resistance to them is emerging. New therapeutics are urgently needed, however, screening the infective amastigote form of the parasite is challenging. Only certain species can be differentiated into axenic amastigotes, and compound activity against these does not always correlate with efficacy against the parasite in its intracellular niche. Methods used to assess compound efficacy on intracellular amastigotes often rely on microscopy-based assays. These are laborious, require specialist equipment and can only determine parasite burden, not parasite viability. We have addressed this clear need in the anti-leishmanial drug discovery process by producing a transgenic L. mexicana cell line that expresses the luciferase NanoLuc-PEST. We tested the sensitivity and versatility of this transgenic strain, in comparison with strains expressing NanoLuc and the red-shifted firefly luciferase. We then compared the NanoLuc-PEST luciferase to the current methods in both axenic and intramacrophage amastigotes following treatment with a supralethal dose of Amphotericin B. NanoLuc-PEST was a more dynamic indicator of cell viability due to its high turnover rate and high signal:background ratio. This, coupled with its sensitivity in the intramacrophage assay, led us to validate the NanoLuc-PEST expressing cell line using the MMV Pathogen Box in a two-step process: i) identify hits against axenic amastigotes, ii) screen these hits using our bioluminescence-based intramacrophage assay. The data obtained from this highlights the potential of compounds active against M. tuberculosis to be re-purposed for use against Leishmania. Our transgenic L. mexicana cell line is therefore a highly sensitive and dynamic system suitable for Leishmania drug discovery in axenic and intramacrophage amastigote models.