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An investigation on the effects of carbamazepine and sodium valproate on neuromuscular transmission.
Ay, H, Ethemoğlu, Ö
Acta neurologica Belgica. 2020;(3):545-548
Abstract
The aim of this study was to investigate the effects of sodium valproate (SV) and carbamazepine (CBZ) on neuromuscular transmission using single-fibre electromyography (SFEMG) in patients with epilepsy. We performed SFEMG during the voluntary contraction of extensor digitorum communis muscle. 30 epileptic patients taking SV, 25 epileptic patients taking CBZ, and 25 age-matched healthy volunteers were included in the study. Mean jitter values (MCD) of subjects taking SV and CBZ were compared with normal controls. MCD values of subjects taking SV and CBZ were statistically significantly higher than those of control group. Review of the correlation between disease duration and MCD values of patients showed that MCD values were increased with the prolonged use of drugs, and thus, indicated a positive relationship between these two parameters. These results suggest that both SV and CBZ reduce neuromuscular transmission in patients without a neuromuscular junction disease.
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Clinical features of benign epilepsy of childhood with centrotemporal spikes in chinese children.
Liu, MJ, Su, XJ, Md, XS, Wu, GF, Zhang, YQ, Gao, L, Wang, W, Liao, JX, Wang, H, Mai, JN, et al
Medicine. 2017;(4):e5623
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This multicenter clinical trial was conducted to examine current practice of benign epilepsy with centrotemporal spikes and especially address the question that in what circumstances 1 antiepileptic drug (AED) should be preferred.Twenty-five medical centers participate in this clinical trial. The general information, clinical information, and treatment status were collected under the guidance of clinicians and then analyzed. Difference between different treatment groups was compared, and usefulness of the most commonly used AEDs was evaluated.A total of 1817 subjects were collected. The average age of the subject was 8.81 years. The average age of onset is 6.85 years (1-14 years). Male-to-female ratio is 1.13:1. A total of 62.9% of the patients are receiving monotherapies, and 10.6% are receiving multidrug therapy. Both age and course of disease of treated rolandic epilepsy (RE) patients are significantly different from those of untreated patients. Bilateral findings on electroencephalography (EEG) are less seen in patients with monotherapy compared with patients with multidrug therapy. Except for 25.4% patients not taking any AEDs, oxcarbazepine (OXC), sodium valproate (VPA), and levetiracetam (LEV) are the most commonly used 3 AEDs. VPA and LEV are commonly used in add-on therapy. OXC and LEV are more effective as monotherapy than VPA.Age of onset of Chinese RE patients is 6.85 years. Bilateral findings on EEG could be a risk factor to require multidrug therapy. In Chinese patients, OXC, VPA, and LEV are most commonly used AEDs as monotherapy and OXC and LEV are more effective than VPA.
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A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin.
Nilubol, N, Merkel, R, Yang, L, Patel, D, Reynolds, JC, Sadowski, SM, Neychev, V, Kebebew, E
Clinical endocrinology. 2017;(1):128-133
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OBJECTIVE Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium-iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine-negative thyroid cancer. DESIGN An open-label Simon two-stage phase II trial. PATIENTS AND MEASUREMENTS Valproic acid was administered orally, and doses were adjusted to maintain serum trough levels between 50 and 100 mg/l for 10 weeks, followed by injections of recombinant human thyroid-stimulating hormone and a radioiodine uptake scan. Anatomical imaging studies were performed at week 16 to assess tumour response and radioiodine therapy in patients with increased radioiodine uptake. RESULTS Thirteen patients with a median age of 66 years (50-78 years) were enrolled and evaluated. Seven patients had papillary thyroid cancer (PTC), two had follicular variant PTC, two had follicular thyroid cancer, and two had Hürthle cell carcinoma. None of the 10 patients who completed the 10-week treatment had increased radioiodine uptake at their tumour sites. Three patients were taken off the study prior to the 10-week radioiodine uptake scan: one with grade-3 hepatic toxicity, one with disease progression and one for noncompliance. Four of 13 patients had decreased stimulated serum thyroglobulin with VA treatment. None of the patients had complete or partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST), and six patients had disease progression. CONCLUSIONS Valproic acid does not increase radioiodine uptake and does not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin.
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Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study.
Salpekar, JA, Joshi, PT, Axelson, DA, Reinblatt, SP, Yenokyan, G, Sanyal, A, Walkup, JT, Vitiello, B, Luby, JL, Wagner, KD, et al
Journal of the American Academy of Child and Adolescent Psychiatry. 2015;(12):999-1007.e4
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OBJECTIVE To assess the efficacy of mood-stabilizing medications for depression and suicidality in pediatric bipolar disorder. METHOD The Treatment of Early Age Mania (TEAM) study is a multicenter, prospective, randomized, masked comparison of divalproex sodium (VAL), lithium carbonate (LI), and risperidone (RISP) in an 8-week parallel clinical trial. A total of 279 children and adolescents with DSM-IV diagnoses of bipolar I disorder, mixed or manic, aged 6 to 15 years were enrolled. The primary outcome measure was improvement on the Clinical Global Impression scale for depression (CGI-BP-I-D). Secondary outcome measures included the Children's Depression Rating Scale (CDRS-R) and suicidality status. Statistics included longitudinal analysis of outcomes using generalized linear mixed models with random intercept both for the complete data set and by using last observation carried forward. RESULTS CGI-BP-I-D ratings were better in the RISP group (60.7%) as compared to the LI (42.2%; p = .03) or VAL (35.0%; p = .003) groups from baseline to the end of the study. CDRS scores in all treatment groups improved equally by study end. In week 1, scores were lower with RISP compared to VAL (mean = 4.72, 95% CI = 2.67, 6.78), and compared to LI (mean = 3.63, 95% CI = 1.51, 5.74), although group differences were not present by the end of the study. Suicidality was infrequent, and there was no overall effect of treatment on suicidality ratings. CONCLUSION Depressive symptoms, present in the acutely manic or mixed phase of pediatric bipolar disorder, improved with all 3 medications, though RISP appeared to yield more rapid improvement than LI or VAL and was superior using a global categorical outcome. Clinical trial registration information-Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents (TEAM); http://clinicaltrials.gov; NCT00057681.
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Valproate sodium enhances body weight gain in patients with childhood epilepsy: a pathogenic mechanisms and open-label clinical trial of behavior therapy.
Kanemura, H, Sano, F, Maeda, Y, Sugita, K, Aihara, M
Seizure. 2012;(7):496-500
Abstract
OBJECTIVES Excessive weight gain associated with valproate sodium (VPA) may predispose patients with epilepsy to other health problems such as insulin resistance. The purpose of this study was to examine the changes in body weight and several biochemical parameters in children receiving VPA treatment. The effects of behavior therapy for epileptic children with VPA-induced weight gain are discussed. METHODS Fifteen patients newly diagnosed with epilepsy were included in the study. The following parameters were measured: body weight, body mass index (BMI), serum glucose, serum insulin, serum VPA concentration and serum free carnitine. In addition, behavior therapy was introduced at the initiation of VPA therapy, and lasted at least for 2 years. RESULTS After 6 months of follow-up, there were eight (53%) patients in whom weight gain was demonstrated. Significant increases in the serum insulin level and the insulin/glucose ratio were observed in the weight gain group (p<0.01). All patients with significant weight gain showed increased appetite. However, BMI stopped increasing with intensive behavior therapy. CONCLUSIONS These findings suggest that an increase in serum insulin and insulin/glucose levels may cause weight gain, possibly by stimulating appetite, and that weight changes seem to be reversible with intensive behavior therapy without discontinuation of VPA.
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SCN1A IVS5N+5 polymorphism and response to sodium valproate: a multicenter study.
Haerian, BS, Baum, L, Tan, HJ, Kwan, P, Raymond, AA, Saruwatari, J, Nakagawa, K, Mohamed, Z
Pharmacogenomics. 2012;(13):1477-85
Abstract
AIM: Approximately 30% of epilepsy patients do not response to antiepileptic drugs (AEDs). The functional SCN1A IVS5N+5 polymorphism may play a role in response to some AEDs. The purpose of this study was to examine this hypothesis in a cohort study of Malaysian and Hong Kong Chinese epilepsy patients on sodium valproate (VPA) monotherapy and in a meta-analysis. PATIENTS & METHODS The SCN1A IVS5N+5 polymorphism was genotyped in 583 Malaysian (84%) and Hong Kong Chinese (16%) epilepsy patients receiving VPA monotherapy. The related association studies, including the current study, were meta-analyzed by using fixed- and random-effects models under various genetic models. RESULTS A total of 277 (47.5%) and 306 (52.5%) patients were VPA nonresponsive and responsive, respectively. Unlike Chinese and Indian patients, Malay nonresponsive patients with idiopathic generalized epilepsy showed significant association, probably caused by the small sample size. CONCLUSION The cohort study and meta-analysis did not demonstrate an association between AED responsiveness and this polymorphism. Future studies with a larger sample size of Malays with idiopathic generalized epilepsy are suggested.
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Intravenous sodium valproate aborts migraine headaches rapidly.
Shahien, R, Saleh, SA, Bowirrat, A
Acta neurologica Scandinavica. 2011;(4):257-65
Abstract
OBJECTIVES This preliminary study was designed to evaluate the efficacy and safety of intravenous sodium valproate in managing severe migraine headache. DESIGN/METHODS In a preliminary prospective open-label study, we treated patients with severe migraine headache using intravenous sodium valproate, after obtaining written informed consent. Thirty-six patients, hospitalized with acute established migraine, were infused with sodium valproate. The diagnosis of migraine was based on the International Headache Society classification criteria. Severity of headache was reported on 10-point visual analog. Disability was assessed on a five-point scale. Primary and secondary endpoints were measured as sustained pain relief and symptoms improvement at 2 h, respectively. RESULTS The study participants had a mean±SD age of 35.7±9.3 years. The loading dose of sodium valproate was 900-1200 mg, and the average time to best response for headache severity was 50 min. A reduction in pain from severe or moderate to mild or no pain in 60 min was reported in 75% of patients [OR=7.187 (95% confidence intervals: 1.32-38.95)]. After treatment with sodium valproate, headache severity was significantly decreased (P<0.0001). No serious adverse events were reported. CONCLUSIONS Intravenous Sodium Valproate (iVPA) seems to be safe and rapidly effective for intractable migraine attack. Randomized, double-blinded, controlled studies are warranted.
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Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome.
Raffoux, E, Cras, A, Recher, C, Boëlle, PY, de Labarthe, A, Turlure, P, Marolleau, JP, Reman, O, Gardin, C, Victor, M, et al
Oncotarget. 2010;(1):34-42
Abstract
In this Phase 2 study, we evaluated the efficacy of combination of 5-azacitidine (AZA), valproic acid (VPA), and all-trans retinoic acid (ATRA) in patients with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Treatment consisted of six cycles of AZA and VPA for 7 days, followed by ATRA for 21 days. Sixty-five patients were enrolled (median age, 72 years; 55 AML including 13 relapsed/refractory patients, 10 MDS; 30 unfavorable karyotypes). Best responses included 14 CR and 3 PR (26%), 75% of the responders and 36% of the non-responders achieving an erythroid response. Median overall survival (OS) was 12.4 months. Untreated patients had a longer OS than relapsed/refractory patients. In patients who fulfilled the 6 planned cycles, OS did not appear to depend on CR/PR achievement, suggesting that stable disease while on-treatment would be a surrogate for survival with this approach. During therapy, early platelet response and demethylation of the FZD9, ALOX12, HPN, and CALCA genes were associated with clinical response. Finally, there was no evidence for the restoration of an ATRA-induced differentiation during therapy. Epigenetic modulation deserves prospective comparisons to conventional care in patients with high-risk AML, at least in those presenting previously untreated disease and low blast count.
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Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection.
Archin, NM, Cheema, M, Parker, D, Wiegand, A, Bosch, RJ, Coffin, JM, Eron, J, Cohen, M, Margolis, DM
PloS one. 2010;(2):e9390
Abstract
BACKGROUND Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART. METHODS Patients with plasma HIV RNA<50 c/mL added sustained-release VPA (Depakote ER) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA). RESULTS In three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (>50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA. CONCLUSIONS The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued.
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Early predisposition to osteomalacia in Indian adults on phenytoin or valproate monotherapy and effective prophylaxis by simultaneous supplementation with calcium and 25-hydroxy vitamin D at recommended daily allowance dosage: a prospective study.
Krishnamoorthy, G, Nair, R, Sundar, U, Kini, P, Shrivastava, M
Neurology India. 2010;(2):213-9
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BACKGROUND Long-term therapy with antiepileptic drugs (AED) may be associated with increased total serum alkaline phosphatase (ALP) levels and reduced serum calcium, inorganic phosphorous, and vitamin D levels. These adverse biochemical alterations have an adverse effect on bone health. OBJECTIVE To determine (a) onset of derangements in serum total ALP and its isoenzymes (liver, bone), calcium and 25-hydroxy vitamin D (25-OHD) concentrations after initiation of treatment with phenytoin or valproic acid monotherapy and (b) the effect of simultaneous supplementation with calcium and 25-OHD at recommended daily allowance (RDA) dosage, on these biochemical parameters. MATERIALS AND METHODS Study was a prospective, case-controlled study in adults. Serum biochemical parameters were estimated at baseline, 30, 60, and 90 days of starting AED treatment in the study subjects: Groups--A (only calcium supplementation) and Group B (both calcium and 25-OHD supplementation). STATISTICAL ANALYSIS Mean+/-SD, and students' paired t test (between groups A and B) unpaired students' t test (drug-wise). RESULTS At 60 days of AED therapy Group A showed a significant increase in serum total ALP (78.83+/-11.04 to 101.75 +/- 9.56 IU/l) (P < 0.001), ALP-liver isoenzyme, (41.97+/- 10.81 to 68.83 +/-7.81 IU/L) (P < 0.001), significant decrease in calcium (9.30 +/- 0.36 to 8.80 +/- 0.38 mg%) (P < 0.001), ALP-bone isoenyzme (36.84 +/- 5.01 to 32.92 +/- 6.46 IU/L) (P < 0.001), and a significant decrease in 25-OHD (25.19 +/- 5.98 to 19.76 +/- 5.35 ng/ml) (P < 0.001) at 90 days. In contrast Group B, at 60 days, showed a significant decrease in serum total ALP (81.92 +/- 19.63 to 54.77. +/- 11.53 IU/L) (P < 0.0001), ALP-liver isoenzyme (48.01. +/- 13.53 to 28.12. +/- 5.88 IU/L) (P < 0.0001), significant increase in calcium ((9.24 +/- 0.31 to 9.93 +/- 0.26 mg%) (P < 0.001) and ALP-bone isoenzyme levels (33.93 +/- 12.2 to 26.25 +/- 8.23 IU/L). In Group B, 25-OHD levels showed a significant increase at 90 days (24.36 +/- 3.42 to 31.53 +/- 327 ng/ml) (P < 0.0001). CONCLUSION Biochemical derangements in calcium metabolism involving the bone are seen by 60 days after starting AED monotherapy, indicating predisposition to development of osteomalacia in these patients. This is preventable by simultaneous oral supplementation with calcium and 25-OHD.