PMID- 30796634 OWN - NLM STAT- MEDLINE DCOM- 20200702 LR - 20210109 IS - 1179-1934 (Electronic) IS - 1172-7047 (Linking) VI - 33 IP - 3 DP - 2019 Mar TI - Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis. PG - 239-250 LID - 10.1007/s40263-019-00606-6 [doi] AB - BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder classified into four types based on the age of onset of the disease. Early onset is correlated with a higher mortality rate, mainly due to respiratory complications. Valproic acid (VPA) is a histone deacetylase (HDAC) inhibitor that has shown positive results on SMA both in experimental and cohort studies. OBJECTIVES: This systematic review and meta-analysis aimed to investigate the efficacy and safety of VPA in patients with SMA. METHODS: Eleven databases were systematically searched on 30 May 2017 for clinical trials that reported the efficacy and safety of VPA in SMA patients. The primary outcome was the efficacy of VPA in terms of gross motor function and expression of both full-length spinal motor neuron (SMN) gene (FL-SMN) and exon 7-lacking SMN. The secondary outcome was the safety of VPA in terms of reported adverse effects. The protocol was registered at PROSPERO (CRD42017067203). RESULTS: Five of the ten included studies were used in the meta-analysis (n = 126). The overall effect estimate, comparing pre- and post-VPA treatment, regardless of carnitine co-administration and design of the studies, showed significant improvement in gross motor function (standard mean difference [SMD] = 0.302, 95% confidence interval [CI] 0.048-0.556, P = 0.02) using the Hammersmith Functional Motor Scale (HFMS), Modified Hammersmith Functional Motor Scale (MHFMS), and MHFMS-Extend, with no significant heterogeneity. Similarly, in non-randomized controlled studies, the results indicated that there was a significant improvement detected (SMD = 0.335, 95% CI 0.041-0.628, P = 0.025), with no significant heterogeneity. Meanwhile, our results suggest that there was no significant improvement in treatment with co-administered carnitine (SMD = 0.28, 95% CI - 0.02 to 0.581, P = 0.067). No significant differences were found between pre- and post-VPA treatment co-administered with carnitine, in terms of the change in FL-SMN and exon 7-lacking SMN. Qualitative synthesis showed that other motor functions were not improved, while respiratory function test results were contradictory. Regarding the safety of the treatment, a double-blind, randomized, placebo-controlled trial reported no statistically significant differences for adverse events (AEs) between groups. Moreover, most of the included studies reported no serious AEs related to VPA use, although weight gain, gastrointestinal symptoms and respiratory symptoms were notable problems. CONCLUSIONS: Our study suggests that VPA treatment results in an improvement in gross motor functions for SMA patients, but not in other assessments of motor function or, possibly, in respiratory function. Furthermore, VPA appears to be a relatively safe drug, although treatment may be associated with a wide range of AEs (including body weight increase, fatigue, fever, flu-like symptoms, irritability, and pain). Double-blind, randomized, controlled trials are required to confirm these findings. FAU - Elshafay, Abdelrahman AU - Elshafay A AUID- ORCID: 0000-0002-6562-6341 AD - Faculty of Medicine, Al-Azhar University, Cairo, 11884, Egypt. FAU - Hieu, Truong Hong AU - Hieu TH AUID- ORCID: 0000-0002-6846-8369 AD - Faculty of Medicine, University of Medicine of Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam. FAU - Doheim, Mohamed Fahmy AU - Doheim MF AUID- ORCID: 0000-0001-8279-5078 AD - Faculty of Medicine, Alexandria University, Alexandria, 21544, Egypt. FAU - Kassem, Mahmoud Attia Mohamed AU - Kassem MAM AD - The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA. FAU - ELdoadoa, Mohammed Fathi AU - ELdoadoa MF AD - Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt. FAU - Holloway, Sarah Keturah AU - Holloway SK AD - University of North Texas, Denton, TX, 76205, USA. FAU - Abo-Elghar, Heba AU - Abo-Elghar H AD - Faculty of Medicine, Menofia University, Menofia, 32512, Egypt. FAU - Hirayama, Kenji AU - Hirayama K AUID- ORCID: 0000-0001-9467-1777 AD - Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, and Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. FAU - Huy, Nguyen Tien AU - Huy NT AUID- ORCID: 0000-0002-9543-9440 AD - Evidence Based Medicine Research Group, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam. nguyentienhuy@tdtu.edu.vn. AD - Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, 70000, Vietnam. nguyentienhuy@tdtu.edu.vn. AD - Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, 852-8523, Japan. nguyentienhuy@tdtu.edu.vn. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review PL - New Zealand TA - CNS Drugs JT - CNS drugs JID - 9431220 RN - 0 (SMN1 protein, human) RN - 0 (SMN2 protein, human) RN - 0 (Survival of Motor Neuron 1 Protein) RN - 0 (Survival of Motor Neuron 2 Protein) RN - 614OI1Z5WI (Valproic Acid) SB - IM MH - Gene Expression/drug effects MH - Humans MH - Motor Activity/*drug effects/genetics MH - Motor Neurons/drug effects/metabolism MH - Muscular Atrophy, Spinal/*drug therapy/genetics MH - Respiration/drug effects/genetics MH - Survival of Motor Neuron 1 Protein/genetics MH - Survival of Motor Neuron 2 Protein/genetics MH - Treatment Outcome MH - Valproic Acid/administration & dosage/adverse effects/*therapeutic use EDAT- 2019/02/24 06:00 MHDA- 2020/07/03 06:00 CRDT- 2019/02/24 06:00 PHST- 2019/02/24 06:00 [pubmed] PHST- 2020/07/03 06:00 [medline] PHST- 2019/02/24 06:00 [entrez] AID - 10.1007/s40263-019-00606-6 [pii] AID - 10.1007/s40263-019-00606-6 [doi] PST - ppublish SO - CNS Drugs. 2019 Mar;33(3):239-250. doi: 10.1007/s40263-019-00606-6.