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Formulation, stability testing, and analytical characterization of melatonin-based preparation for clinical trial

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      Abstract

      A new institutional clinical trial assessed the improvement of sleep disorders in 40 children with autism treated by immediate-release melatonin formulation in different regimens (0.5 mg, 2 mg, and 6 mg daily) for one month. The objectives of present study were to (i) prepare low-dose melatonin hard capsules for pediatric use controlled by two complementary methods and (ii) carry out a stability study in order to determine a use-by-date. Validation of preparation process was claimed as ascertained by mass uniformity of hard capsules. Multicomponent analysis by attenuated total reflectance Fourier transformed infrared (ATR-FTIR) of melatonin/microcrystalline cellulose mixture allowed to identify and quantify relative content of active pharmaceutical ingredients and excipients. Absolute melatonin content analysis by high performance liquid chromatography in 0.5 mg and 6 mg melatonin capsules was 93.6%±4.1% and 98.7%±6.9% of theoretical value, respectively. Forced degradation study showed a good separation of melatonin and its degradation products. The capability of the method was 15, confirming a risk of false negative <0.01%. Stability test and dissolution test were compliant over 18 months of storage with European Pharmacopoeia. Preparation of melatonin hard capsules was completed manually and melatonin in hard capsules was stable for 18 months, in spite of low doses of active ingredient. ATR-FTIR offers a real alternative to HPLC for quality control of high-dose melatonin hard capsules before the release of clinical batches.

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      Global Prevalence of Autism and Other Pervasive Developmental Disorders

      We provide a systematic review of epidemiological surveys of autistic disorder and pervasive developmental disorders (PDDs) worldwide. A secondary aim was to consider the possible impact of geographic, cultural/ethnic, and socioeconomic factors on prevalence estimates and on clinical presentation of PDD. Based on the evidence reviewed, the median of prevalence estimates of autism spectrum disorders was 62/10 000. While existing estimates are variable, the evidence reviewed does not support differences in PDD prevalence by geographic region nor of a strong impact of ethnic/cultural or socioeconomic factors. However, power to detect such effects is seriously limited in existing data sets, particularly in low-income countries. While it is clear that prevalence estimates have increased over time and these vary in different neighboring and distant regions, these findings most likely represent broadening of the diagnostic concets, diagnostic switching from other developmental disabilities to PDD, service availability, and awareness of autistic spectrum disorders in both the lay and professional public. The lack of evidence from the majority of the world's population suggests a critical need for further research and capacity building in low- and middle-income countries. Autism Res 2012, 5: 160–179. © 2012 International Society for Autism Research, Wiley Periodicals, Inc.
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        Validation of high-performance liquid chromatography methods for pharmaceutical analysis. Understanding the differences and similarities between validation requirements of the US Food and Drug Administration, the US Pharmacopeia and the International Conference on Harmonization.

         G. A. Shabir (2003)
        One of the most critical factors in developing pharmaceutical drug substances and drug products today is ensuring that the HPLC analytical test methods that are used to analyze the products generate meaningful data. The US Food and Drug Administration (FDA) and United States Pharmacopeia (USP) have each recognized the importance of this to the drug development process and have separately increased validation requirements in recent years. A third source, the International Conference on Harmonization (ICH), has added requirements that, when combined with the previous two sources, have led to three different sets of validation requirements leaving the industry in a state of confusion. This paper is written to clear up the confusion over the validation requirements that are presented by each of these three sources.
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          Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis.

          Clock gene anomalies have been suggested as causative factors in autism. We screened eleven clock/clock-related genes in a predominantly high-functioning Autism Genetic Resource Exchange sample of strictly diagnosed autistic disorder progeny and their parents (110 trios) for association of clock gene variants with autistic disorder. We found significant association (P<0.05) for two single-nucleotide polymorphisms in per1 and two in npas2. Analysis of all possible combinations of two-marker haplotypes for each gene showed that in npas2 40 out of the 136 possible two-marker combinations were significant at the P<0.05 level, with the best result between markers rs1811399 and rs2117714, P=0.001. Haplotype analysis within per1 gave a single significant result: a global P=0.027 for the markers rs2253820-rs885747. No two-marker haplotype was significant in any of the other genes, despite the large number of tests performed. Our findings support the hypothesis that these epistatic clock genes may be involved in the etiology of autistic disorder. Problems in sleep, memory and timing are all characteristics of autistic disorder and aspects of sleep, memory and timing are each clock-gene-regulated in other species. We identify how our findings may be relevant to theories of autism that focus on the amygdala, cerebellum, memory and temporal deficits. We outline possible implications of these findings for developmental models of autism involving temporal synchrony/social timing.
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            Author and article information

            Affiliations
            [a ]Service pharmaceutique, Plateforme FRIPHARM, Groupement Hospitalier Edouard Herriot, 5 Place d′Arsonval, F-69437 Lyon Cedex 03, France
            [b ]Laboratoire de Recherche et Développement de Pharmacie Galénique Industrielle, Plateforme FRIPHARM, Faculté de Pharmacie, Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique – UMR 5305, Université Claude Bernard Lyon 1, 8 Avenue Rockefeller, F-69373 Lyon Cedex 08, France
            Author notes
            [* ]Correspondence to: Service pharmaceutique, Plateforme FRIPHARM, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437 Lyon Cedex 03, France. fabrice.pirot@ 123456chu-lyon.fr
            Contributors
            Journal
            J Pharm Anal
            J Pharm Anal
            Journal of Pharmaceutical Analysis
            Xi'an Jiaotong University
            2095-1779
            2214-0883
            06 April 2017
            August 2017
            06 April 2017
            : 7
            : 4
            : 237-243
            5790709 S2095-1779(17)30046-1 10.1016/j.jpha.2017.04.001
            © 2017 Xi'an Jiaotong University. Production and hosting by Elsevier B.V.

            This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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