Long term melatonin treatment is safe in children with Down syndrome

1. Introduction

Statistical analysis:

Data were subjected to statistical analysis using the statistical software program Prism (GraphPad, Prism, 6.01). Means and the standard error of the mean (±SEM) n = 25 for each variable were estimated. Differences between means of different groups were evaluated using one-way ANOVA.

1. Results

Age and body mass index in Down syndrome children during six months of treatment with I mg/day melatonin and after withdrawal terminating the treatment after 18 months.

Table (1): Age and body mass index in Down syndrome children during six months of treatment with melatonin.

The treatment of DS children with 1mg/day melatonin showed values of liver function parameters (Glutamic pyruvic Transaminase (GPT), glutamic oxalacetic transaminase (GOT), albumin, total protein levels) within the normal ranges of normal children (Table 2). The withdrawal of melatonin did not affect liver function parameters after 18 months of withdrawal.

Table 2: Prevalence of GPT, GOT, albumin and total protein (U/L) &(mg/dL) levels in serum of DS children during six months of treatment.

The present study also assayed kidney function parameters including uric acid, creatinine and urea in children with Down syndrome compared with normal range of healthy children. The data showed normal value of kidney function in DS children during treatment with melatonin as compared to normal children (Table 3). The withdrawal of melatonin did not affect kidney function parameters.

The treatment of DS children with 1mg/day melatonin showed values of cholesterol and triglycerides in serum within the normal ranges of normal children (Table 2). The withdrawal of melatonin did not affect these parameters after 18 months of withdrawal.

Table (3): Levels of uric acid, creatinine and urea (mg/dL) in serum of DS children during six months of treatment with melatonin.

Table (4): Levels of cholesterol and triglyceride (mg/dL) in serum of DS children during six months of treatment.

Many clinical trials give an evidence that exogenous melatonin has protective effects in avoidance of cell damage in body circumstances, such as sepsis, chronic metabolic disease, asphyxia, inflammation, and lung cancer (Eghbal et al., 2016). The level of melatonin in children with DS is extremely reduced when compared to age-matched controls, resulting in increased reactive species and oxidative risk in their organs (Uberos et al., 2010), (Vacca et al., 2019).

Studies of melatonin treatment for children with developmental disabilities provide mounting evidence of its efficacy and safety. Melatonin is commonly recommended to treat sleep problems in children with developmental disabilities (Schwichtenberg and Malow, 2015). However, few studies document the efficacy and safety of melatonin in Down syndrome children. Children with Down syndrome often have a weakened immune system, and as a result are especially vulnerable to infection. By middle age, they appear to be years older than their chronological age, and they are prone to develop some of the diseases associated with aging, such as osteoporosis and premature senile dementia. 

Melatonin can be safe and effective in treating pediatric sleep disturbances including both sleep disorders and the sleep disorders associated with various neurological conditions(Esposito et al., 2019). It is also reported that patients with nonalcoholic steatohepatitis (NASH) were administered melatonin at a dose of 10 mg for 3 months. The follow-up after 3 months revealed the decrease in the level of liver enzymes. Similarly, Cichoz-Lach et al used the same regime and they also found the decreased level of liver enzymes and triglycerides and proinflammatory cytokines (Cichoz-Lach et al., 2010) . In another study a single melatonin dose of 50–100 mg/ was injected for the regulation of inflammatory and metabolic disorders (Cardinali and Hardeland, 2017). The same high doses of melatonin were administered preoperative single dose of melatonin in patients undergoing major liver resection and showed good tolerability. This positive impact on the postoperative condition was demonstrated by faster drop in GOT and GPT compared to placebo (Schemmer et al., 2008),(Nickkholgh et al., 2011),(Chojnacki et al., 2017). Statins are medications for regulating lipid metabolism and taken chronically and therefore hepatoprotective factors should be used on long-term basis and should be free of side effects. Recent report confirm that melatonin satisfies such conditions and displayed a significant hepatoprotective effect in patients treated with statins (Nickkholgh et al., 2011).

Accumulating evidence has suggested that individuals with chronic kidney disease (CKD) or on dialysis exhibit altered circadian rhythms of melatonin levels in the blood, and the production of melatonin is decreased with the progression of CKD to end-stage renal disease (ESRD)(Nicholl et al., 2014). In numerous experimental animal models of CKD and clinical settings, the effects of melatonin have been obvious on the improvement of renal function and lowering of blood pressure, accompanied by the normalization of circadian rhythms (Rahman et al., 2019). The present data confirm these studies and showed an insignificant effect on liver and kidney function in children with Down syndrome. The current study demonstrated values with normal ranges of the specific parameters of liver and kidney functions. The safety of long term intake of melatonin is attributed to the pleiotropic effects of melatonin comprising the consequences of numerous complementary interconnecting mechanisms, including the reduction of oxidative stress, inflammation and fibrosis. The present results also demonstrated an insignificant effect of melatonin administration on cholesterol and triglycerides in Down syndrome children compared and showed values with normal ranges. However, triglycerides showed lower values than DS patients even after withdrawal of melatonin treatment.

In conclusion, the daily administration with melatonin for six months is safe on liver and kidney functions and the levels of cholesterol, triglycerides.