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http:// ijp.mums.ac.ir Original Article (Pages: 6413-6419)

Evaluation of Hydrochloride Effects on in Children with ; A Randomized Clinical Trial Seyed Alinaghi Kazemi1, Maedeh Khosravi Yekta2, Ramazan Fallah3, Diana Noemi Diaz4, *Kambiz Eftekhari512

1Professor of Pediatric, Pediatric Department, Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran. 2Assistant of Pediatric, Pediatric Department, Mousavi Hospital, Zanjan University of Medical Science, Zanjan, Iran. 3Biostatistics, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. 4Assistant Professor of Pediatric Surgery, Surgery Department, Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran. 5Assistant Professor of Pediatric Gastroenterology, Pediatric Department, Bahrami Children’s Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Abstract Background: Cyproheptadine hydrochloride is an antihistaminic . stimulation is one of its secondary effects that can be of advantage in some diseases. In this study we investigated the effect of Cyproheptadine hydrochloride on weight gain in underweight children with anorexia at age group 2 to10 years old. Materials and Methods: In this randomized clinical trial, we selected 2-10 year-old underweight children with anorexia who referred to Ayatollah Mousavi Hospital in Zanjan (Iran), during 2015. One hundred and thirty-six children were allocated at random in two groups. The Cyproheptadine - treated children group were given the drug orally; 0.1 mg/kg/dose three times per day for 8 weeks, while patients in placebo group received placebo with the same dose. After two months, weight gain was compared with the previous values in both groups. Results: In this study, 86 patients (63.2%) were female. The average increase in weight in the cyproheptadine - treated group was significantly higher than in the placebo group (1.08 ± 0.67 kg and 0.22 ± 0.46 kg, respectively) (p=0.005). The average increase height in the Cyproheptadine -treated group was significantly higher than in the placebo group (1.60 ± 0.97 cm, and 0.86 ± 0.85 cm, respectively) (p=0.005). According to the parents of both groups, anorexia in the Cyproheptadine - treated group improved in 100%, and in the placebo group in 52.7%. This difference was statistically significant (p=0.005). No any side effects of Cyproheptadine hydrochloride were observed. Conclusion: According to the finding of our study, there were no serious side effects of Cyproheptadine hydrochloride. Therefore considering the acceptable safety of Cyproheptadine hydrochloride for inducing growth in underweight children, we propose its administration with the aforementioned dose. Key Words: Anorexia, Children, Cyproheptadine hydrochloride, Weight gain.

*Please cite this article as: Kazemi SA, Khosravi Yekta M, Fallah R, Noemi Diaz D, Eftekhari K. Evaluation of Cyproheptadine Hydrochloride Effects on Weight Gain in Underweight Children with Anorexia; A Randomized Clinical Trial. Int J Pediatr 2017; 5(12): 6413-19. DOI: 10.22038/ijp.2017.25604.2179

*Corresponding Author: Kambiz Eftekhari, MD, Mailing Address: Pediatric department, Bahrami Children’s Hospital, Tehran, Iran. Fax: +982177568809 Email: [email protected] Received date Aug.23, 2016; Accepted date: Sep.12, 2017

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1- INTRODUCTION demonstrated that is not a safe drug, with Cyproheptadine hydrochloride is an serious side effects including edema, drug, antagonist of histamine thromboembolic events and sudden deaths and serotonin (1). The drug was approved (11). Other of the drug is the by Food and Drug Administration (FDA) suppression of the adrenal axis, impaired for the treatment of allergic rhinitis, glucose regulation, mood disorders, allergic conjunctivitis, urticaria, hyperlipidemia and testicular damage (1, dermatographism and mild angioedema in 10). Therefore Cyproheptadine children (1, 2). Clinicians used hydrochloride is safer (8, 12- 14) and more Cyproheptadine hydrochloride in some effective than to treat diseases due to its effects on appetite in patients undergoing stimulation. Some studies described (10, 11). unexplained weight gain after ingestion of There is limited knowledge on the Cyproheptadine hydrochloride (3, 4). mechanisms of action of Cyproheptadine There is no objective method for assessing hydrochloride and its side effects. appetite in children yet (2). The cause of Rerksuppaphol et al. investigated the effect anorexia is probably multifactorial (2). of this drug in children with malnutrition. There is a lot of difference between Theirs results showed that weight gain in appetite and weight gain among the the group treated with Cyproheptadine general population (2, 3). However, it can hydrochloride was significantly higher be assumed that increased appetite causes than in the control group. No significant weight gain (2). Stimulation of appetite is difference was observed between the one way to deal with anorexia (2). Several groups in terms of fat percentage. Some articles depict that consumption of side effects were rarely observed, like mild Cyproheptadine hydrochloride as an drowsiness, nausea, diarrhea, abdominal appetite stimulator was useful for patients pain and headache but serious side effects were not reported and the drug was well with asthma, failure to thrive (FTT), short stature, anorexia nervosa, tolerated (15). and some types of cancers (1, 4-7). The Iranian study reported a significant Usually these types of have effect of Cyproheptadine hydrochloride in not serious or life-threatening side effects. children with malnutrition aged 24 to 64 The most important side effect of them is months during 4 weeks treatment. In this transient drowsiness (4, 8). study the average weight gain in children The results on treatment of anorexia with treated with the drug compared to placebo was 0.60 and 0.11 kg respectively (16). Cyproheptadine hydrochloride in patients with acquired immune deficiency Anorexia and growth disturbance are the syndrome (AIDS) and asthma were common problems in children that referred different (9). Among the used to to the pediatric gastroenterology clinic. treat anorexia in underweight children is Most appetite in children have Megestrol acetate (MA), , serious side effects (1, 10). Therefore, we and Cyproheptadine aimed to investigate the effect of hydrochloride (9, 10). Most studies were Cyproheptadine hydrochloride on weight done on Megestrol acetate, showed a gain with low side effects (8, 12-14). The positive effect on weight gain, increasing purpose of our study was to evaluate the appetite and fat mass (10). In 1993 effect of Cyproheptadine hydrochloride on Megestrol Acetate was approved for treat weight gain in underweight children with cachexia, loss of appetite or unexplained anorexia (below the 50th percentile) aged weight loss. However, it was

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2-10 years compared with the control appetite in the study was done by asking group in Zanjan city, Iran. their parents.

2- MATERIALS AND METHODS 2-4. Intervention 2-1. Study design and population The Sample size was one hundred and This study is a double blind cross over thirty-six patients for both groups. Written randomized clinical trial. Children from 2 informed consent was taken from parents to 10 years old participated in 2015. They to participate in the study. The had been brought to the pediatric demographic data and results of the study gastroenterology clinic of Ayatollah were collected and a questionnaire was Mousavi Hospital in Zanjan (Iran) because prepared. The sample size was calculated of anorexia and underweight (under 50th according to following formula: percentile). Anorexia was considered as 2   2 2 Z   Z1   1   2  valuable when accompanied by a weight 1 n   2  = 68 less than 50% and only parents’ complaint d 2 did not have enough. = 4 (the variance of the children’s 2-2. Inclusion and Exclusion criteria weight without any intervention), Inclusion criteria included: children aged = 9 (the variance of the children’s 2-10- year-old with anorexia and weight with intervention), underweight (below the 50th percentile), without a justifiable condition for proper α = 0.05, β = 0.2, d = 1.5 (the difference of growth retardation, including underlying mean weight in two groups). gastrointestinal, cardiovascular, The patients were allocated by using a respiratory, endocrine and metabolic, simple randomized method in two groups neurological or renal diseases. Exclusion (68 patients in each group). The first group criteria include: Children that were not was Cyproheptadine - treated who taking Cyproheptadine hydrochloride received oral Cyproheptadine completely and regularly were withdrawn hydrochloride (named Trustorix from the study; if adverse drug reactions manufactured by Tadbir Kalaye Jam, Iran occurred; if used another [Tekaje]) during 8 weeks with a dose of interacting with Cyproheptadine, and 0.1 mg/kg (Equal to 0.25 cc/kg) 3 times a identification of underlying organic day. The second group was the placebo disease. and received placebo with a dose of 0.25 cc/kg 3 times a day. 2-3. Measuring tools and measurement Dietary recommendations were given to all Questionnaires were completed with the patients, including the use of high-protein cooperation of parents, which included and home-made foods avoiding snacks and demographic information (age, gender, industrial drinks. Weight, height and developmental status, positive findings in appetite condition in each child were physical examination). The weight was measured at the end of each month, measured using a digital column scale compared with their initial values and with (Seca 769, made in Germany) with an up the values obtained in the placebo group. to 100 grams sensitivity and height After that, questionnaires that include measured using a wall-mounted metal weight, height, and appetite status before height gauge, according to scientific and after the study were filled. Parents principles. The assessment of children’s were informed about the side effects of

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Cyproheptadine hydrochloride such as placebo group were 15.2 ± 5.7 and 18.9 ± drowsiness, nausea, diarrhea, abdominal 6.6, respectively. The mean and standard pain and headache and they were asked to deviation (SD) of primary height in the contact the researcher if any of these Cyproheptadine -treated group and placebo effects appeared. group were 113.8 ± 17.3 and 100.9 ± 17.3, respectively. The mean age, primary 2-5. Data analysis weight and height of children (Table.1) Data were analyzed by SPSS software were statistically different in the two (version 22.0). The descriptive results groups (p <0.05). were expressed as frequency, percentage, In the study, according to Table.2, the mean and standard deviation. The results mean and standard deviation (SD) of the were analyzed used with chi-square tests children’s weight difference in the and variances analysis of covariance Cyproheptadine -treated group were 1.08 (ANCOVA). The normality of the data and 0.67 kg, respectively and in the was obtained using the Kolmogorov- placebo group 0.22 and 0.46 kg, Smirnov test. The P values less than 0.05 respectively. By controlling the age of were considered statistically significant. children with using of covariance analysis (age of children was not match in two 2-6. Ethical consideration groups), this difference was statistically The study was approved by the ethics significant (p <0.05). committee of Zanjan University of The mean and standard deviation of the Medical Sciences on 2014 with Number children’s height difference in the ZUMS.REC.1392.192. Registry code in a Cyproheptadine -treated group were 1.60 clinical trial registry center (IRCT) is and 0.97cm, respectively and in the IRCT.2014101318971N3. placebo group were 0.86 and 0.85cm, respectively. By controlling the age of 3- RESULTS children using covariance analysis, this In this study participated 136 children difference was statistically significant aged 2-10 years old. Of these, 86 patients (p <0.05). At the end of the study (two (63.2%) were female. Forty-four (51.2%) months later), anorexia in the girls and 24 (48.0%) boys were in the Cyproheptadine -treated group improved intervention group. The groups were in 100%, and in the placebo group in matched in gender and did not have a 52.7%. This difference was statistically significant statistical difference (p = significant (p <0.05). 0.722). All patients were followed up until According to the table, mean weight the end of the study and none of them was difference with normal appetite and SD excluded from the study. were 1.14 and 0.80 kg respectively. The The mean and standard deviation (SD) of mean weight variation in the age in the Cyproheptadine -treated and Cyproheptadine -treated group was greater placebo groups were 4.7 ± 2.7 and 6.7 ± than in the placebo group. This difference 2.7 years, respectively. The mean and was statistically significant (p=0.005). No standard deviation (SD) of primary weight any side effects of Cyproheptadine in the Cyproheptadine -treated group and hydrochloride were observed.

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Table-1: Comparison of mean age, primary weight and height of children in two groups Variables Groups Number Mean Standard Deviation P-value Age Cyproheptadine 68 4.7 2.7 > 0.05 Placebo 68 6.7 2.7 Primary weight Cyproheptadine 68 15.2 7.5 0.001 Placebo 68 18.9 6.6 Primary height Cyproheptadine 68 100.9 17.9 > 0.05 Placebo 68 113.8 17.3

Table-2: Comparison of children’s weight and height difference in two groups with age control (covariance analysis). Variables Groups Number mean Standard Deviation P-value Weight difference Cyproheptadine 68 1.08 0.69 > 0.05 Placebo 68 0.22 0.46 Height difference Cyproheptadine 68 1.60 0.97 > 0.05 Placebo 68 0.86 0.85

4- DISCUSSION Rerksuppaphol treated 37 underweight The aim of this study was to evaluate children aged 6-15 years old randomly the effect of Cyproheptadine hydrochloride with Cyproheptadine hydrochloride for 8 on weight gain in underweight children weeks (15). In this study, definitive weight with anorexia (below the 50th percentile) gain in the case group was coincident with aged 2-10 years. The study was followed our results (1.25 and 0.65 kg, respectively). But weight gain was slightly up for 2 months after the intervention. In the study, children in the Cyproheptadine - higher than our study. This difference can treated group showed significant weight be attributed to differences in age range and height gain compared to the placebo and race of participants. On the other hand, group. Both groups were matched in terms their sample size was lower than ours. of gender but not matched in terms of age. Homnick et al. performed a study on 16 The confounding factor was removed children with Cystic fibrosis (CF) (4). using analysis of covariance. Similar to Patients receiving Cyproheptadine our study, Najib, found that Body Mass hydrochloride had significantly higher Index (BMI) was significantly higher in weight gain than the other group (3.45 kg Cyproheptadine -treated group than vs. 1.1 kg). Of course the dose of placebo group after 8 weeks of treatment Cyproheptadine hydrochloride was 4 mg at (16). The average weight gain was 0.60 kg, 4 times a day and the results of weight which is lower than our results (1.80 kg). gain were evaluated after 12 weeks. They Our sample size is larger than their, 136 did not record any side effect. We decided and 77 people, respectively. On the other to be more conservative. Couluris et al. hand, the age range of children in our investigated the effect of Megestrol acetate study was wider than Najib’s et al., as they and Cyproheptadine hydrochloride in 66 studied only children 24 to 64 months. children with cachexia due to Also due to the double-blind study the chemotherapy (1). They showed that results were being less influenced by Cyproheptadine hydrochloride was safer confounding factors. Rerksuppaphola and and more effective than Megestrol acetate

Int J Pediatr, Vol.5, N.12, Serial No.48, Dec. 2017 6417 Cyproheptadine Effects on Weight Gain to gain weight in these children. Megestrol in appropriate dose for children under 50th acetate had some side effects such as percentile with anorexia. decreased level of and hyperlipidemia. Compared with her study, 6- CONFLICT OF INTEREST our sample size was higher. Marchand and The Authors had no conflict of interest. colleagues compared the therapeutic effect The study had no funding source and only of Cyproheptadine hydrochloride with was supported by Vice-Chancellor's Office Megestrol acetate, demonstrating that for Research at Zanjan University of Cyproheptadine hydrochloride is safe and Medical Sciences, Zanjan, Iran. had little side effects (17). This finding was consistent with our study. They 7- ACKNOWLEDGMENT studied malnourished CF patients (17). The average weight gain in the case group We thank to the children and their parents and control group was 3.05 kg and 0.3 kg, who volunteered their time and respectively. The patients benefited from information. Also we appreciate the Megestrol acetate treatment, gained weight cooperation of vice chancellor for research and improved the results of the respiratory of Zanjan University of medical sciences. tests. Unfortunately some side effects appeared, such as adrenal suppression, 8- REFERENCES glucose intolerance and diabetes mellitus 1. Couluris M, Mayer JL, Freyer DR, Sandler E, Xu P, Krischer JP. The effect of Since few researchers have evaluated the Cyproheptadine hydrochloride hydrochloride effect of Cyproheptadine hydrochloride on (periactin) and megestrol acetate (megace) on weight gain in children without underlying weight in children with cancer/treatment- disease, no additional references are related cachexia. J Pediatr Hematol Oncol available to compare with the results of 2008; 30: 791-97. present study. Most of these studies have 2. Chinuck R, Dewar J, Baldwin DR, been done on underweight children with an Hendron E. Appetite stimulants for people underlying disease. The strength of this with cystic fibrosis. Cochrane Database Syst study is the novelty of the idea. It can be Rev. 2014 Jul 27(7): 1-48. CD008190. doi: concluded that the use of Cyproheptadine 10.1002/14651858 hydrochloride for appetite stimulation 3. Saeidi M, Vakili R, Khakshour A, produces significant increase in weight and Taghizade Moghaddam H, Kiani MA, Zarif B, height in children and have less side et al. Iron and multivitamin supplements in effects. children and its association with growth rate. 4-1. Limitations of the study International Journal of Pediatrics. 2013; 1(1):13-17. From the limitations of the study, which is 4. Homnick DN, Homnick BD, Reeves one of its weaknesses were did not AJ, Marks JH, Pimentel RS, Bonnema SK. evaluate some factors such as duration of Cyproheptadine hydrochloride is an effective weight loss and previous treatments to appetite in cystic fibrosis. Pediatr improve growth. Pulmonol 2004; 38: 129-34.

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