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Effect of sodium valproate on esophageal motility in healthy subjects and patients with gastroesophageal reflux.
Tzovaras, G, Tsiaoussis, J, Athanasakis, E, Zoras, O, Xynos, E, Chrysos, E
Scandinavian journal of gastroenterology. 2004;(6):521-6
Abstract
BACKGROUND There is experimental evidence to show that upper gastrointestinal tract motility is influenced by a GABAergic mechanism. Sodium valproate acts as a GABA agonist, and has been proven to affect the human internal anal sphincter. The aim of this study was to evaluate any possible effect of sodium valproate on esophageal motility in healthy subjects and patients with gastroesophageal reflux disease (GERD). METHODS Ten healthy volunteers (4 M, 6 F; age range: 20-61 years) and 12 patients (4 M, 8 F; age range: 25-70 years) with GERD were included in the study. Standard esophageal manometry and ambulatory 24-h esophageal pH monitoring were performed before and 5 days after oral administration of sodium valproate (400 mg four times per day). Main measurements included a) lower esophageal sphincter (LES) resting pressure and amplitude and duration of peristalsis at 5, 10 and 15 cm proximal to LES, and b) percentage of time with esophageal pH <4 and number of reflux episodes. RESULTS Sodium valproate (i) significantly increased LES resting pressure in both groups (P<0.05), without affecting either the LES postdeglutition relaxation or any of the parameters of the esophageal peristaltic activity, (ii) significantly reduced the number of reflux episodes at the postprandial period in both healthy subjects (P=0.02) and reflux patients without hiatal hernia (P=0.04) and (iii) the time percentage with esophageal pH <4 at the postprandial period in reflux patients (P=0.01). CONCLUSIONS Sodium valproate increases normal and reduced tonic activity of the human LES and reduces the number of reflux episodes in health and GERD. This action could be attributed to a central GABAergic mechanism.
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Marijuana withdrawal in humans: effects of oral THC or divalproex.
Haney, M, Hart, CL, Vosburg, SK, Nasser, J, Bennett, A, Zubaran, C, Foltin, RW
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2004;(1):158-70
Abstract
Abstinence following daily marijuana use can produce a withdrawal syndrome characterized by negative mood (eg irritability, anxiety, misery), muscle pain, chills, and decreased food intake. Two placebo-controlled, within-subject studies investigated the effects of a cannabinoid agonist, delta-9-tetrahydrocannabinol (THC: Study 1), and a mood stabilizer, divalproex (Study 2), on symptoms of marijuana withdrawal. Participants (n=7/study), who were not seeking treatment for their marijuana use, reported smoking 6-10 marijuana cigarettes/day, 6-7 days/week. Study 1 was a 15-day in-patient, 5-day outpatient, 15-day in-patient design. During the in-patient phases, participants took oral THC capsules (0, 10 mg) five times/day, 1 h prior to smoking marijuana (0.00, 3.04% THC). Active and placebo marijuana were smoked on in-patient days 1-8, while only placebo marijuana was smoked on days 9-14, that is, marijuana abstinence. Placebo THC was administered each day, except during one of the abstinence phases (days 9-14), when active THC was given. Mood, psychomotor task performance, food intake, and sleep were measured. Oral THC administered during marijuana abstinence decreased ratings of 'anxious', 'miserable', 'trouble sleeping', 'chills', and marijuana craving, and reversed large decreases in food intake as compared to placebo, while producing no intoxication. Study 2 was a 58-day, outpatient/in-patient design. Participants were maintained on each divalproex dose (0, 1500 mg/day) for 29 days each. Each maintenance condition began with a 14-day outpatient phase for medication induction or clearance and continued with a 15-day in-patient phase. Divalproex decreased marijuana craving during abstinence, yet increased ratings of 'anxious', 'irritable', 'bad effect', and 'tired.' Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marijuana condition. Thus, oral THC decreased marijuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marijuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marijuana dependence.
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Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid.
Kuendgen, A, Strupp, C, Aivado, M, Bernhardt, A, Hildebrandt, B, Haas, R, Germing, U, Gattermann, N
Blood. 2004;(5):1266-9
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Abstract
Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro. We treated 18 patients with myelodysplastic syndromes (MDS) and AML secondary to MDS (sAML/MDS) with VPA monotherapy (serum concentrations 346-693 microM [50-100 microg/mL]). Five patients received VPA and ATRA (80 mg/m(2)/d, days 1-7, every other week). Response according to international working group (IWG) criteria was observed in 8 patients (44%) on VPA monotherapy, including 1 partial remission. Median response duration was 4 months (range, 3-9 months). Four of 5 patients relapsing were treated with VPA + ATRA, 2 of them responding again. Among 5 patients receiving VPA + ATRA from the start, none responded according to IWG criteria, but 1 patient with sAML/MDS achieved a marked reduction in peripheral and marrow blasts. Thus, VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.
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Valproate, bipolar disorder and polycystic ovarian syndrome.
McIntyre, RS, Mancini, DA, McCann, S, Srinivasan, J, Kennedy, SH
Bipolar disorders. 2003;(1):28-35
Abstract
BACKGROUND Persons with bipolar disorder are often overweight and cluster risk factors for cardiovascular disease. Some antibipolar agents adversely impact upon weight and the lipid milieu. Recent data suggest that valproic acid, a commonly prescribed mood stabilizer, may be associated with polycystic ovarian syndrome (PCOS). This adverse event has not been systematically studied in bipolar disorder. METHOD Thirty-eight female subjects, aged 18-50 years, meeting DSM-IV criteria for bipolar I or II disorder, in any phase of illness were evaluated. Eighteen females received valproate (sodium valproate and valproic acid) and 20 females received lithium. Patients completed questions regarding their menstrual, reproductive and medical histories. During the follicular phase they were assessed for weight, body mass index (BMI kg/m2), and changes in the reproductive endocrine milieu that included morning estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex-hormone binding globulin (SHBG), androstenedione, dehydroepiandrosterone-sulfate (DHEAS), testosterone, free testosterone, prolactin and thyroid-stimulating hormone (TSH). The blood was also analyzed for fasting metabolic parameters which included total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin, glycosylated hemoglobin (HbA1C), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding-protein 1 (IGFBP-1), fasting blood glucose and morning leptin. RESULTS Nine (50%) of the valproate-treated females had menstrual abnormalities versus three (15%) of the lithium-treated females (p < 0.05). Valproate-treated females had significantly higher levels of follicular phase androgen concentrations than lithium-treated females (p < 0.05). Nine (50%) of females who were overweight (BMI > or = 25 kg/m2) and with a history of menstrual irregularities also exhibited laboratory evidence of hyperandrogenism (p < 0.05). Persons receiving valproate exhibited significant increases in fasting biochemical parameters suggestive of an adverse metabolic syndrome (p < 0.05). Leptin levels were significantly elevated in the valproate-treated females (p < 0.05). CONCLUSIONS In this pilot, open-label cross-sectional study, valproate-treated females exhibited higher rates of menstrual abnormalities and biochemical evidence of both hyperandrogenism and adverse metabolic parameters when compared with lithium-treated females. These preliminary data suggest that valproate may, in some predisposed females, adversely impact upon the reproductive endocrine milieu and result in aspects of the metabolic syndrome.
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A negative trial of sodium valproate in cluster headache: methodological issues.
El Amrani, M, Massiou, H, Bousser, MG
Cephalalgia : an international journal of headache. 2002;(3):205-8
Abstract
We report the result of a double-blind placebo controlled study of sodium valproate (SV) (1000-2000 mg/day) in the prophylaxis of cluster headache CH. Episodic and chronic CH were defined according to the International Headache Society classification. Ninety-six patients were included, 50 in the SV group and 46 in the placebo group. After a 7-day run-in period, patients were treated for 2 weeks. The primary efficacy criterion was the percentage of patients successfully improved, i.e having an at least 50% reduction in the average number of attacks per week between the run-in period and the last week of treatment. Whatever the type of CH, there was no difference between the two groups: 50% of subjects in the SV group and 62% in the placebo group were successfully improved (P = 0.23). This high success rate observed in the placebo group, which is likely to be due to the spontaneous remission of the episode, does not allow us to draw any valid conclusion with regard to the true efficacy of SV in the prophylaxis of CH.
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Effect of sodium valproate on somatosensory evoked potentials in juvenile myoclonic epilepsy.
Erdem, H, Yiğit, A, Culcuoğlu, A, Mutluer, N
Upsala journal of medical sciences. 2001;(3):197-203
Abstract
We analysed somatosensory evoked potentials (SEPs) in the patients with juvenile myoclonic epilepsy (JME) in order to find out if sodium valproate (VPA) affects SEP latencies and amplitudes. SEPs were studied in 23 patients with JME receiving VPA monotherapy, eight patients with JME not receiving VPA, and a control group consisting of 20 healthy subjects. The N20, P24, and N34 latencies bilaterally were significantly prolonged in the JME group receiving VPA as compared with the control group. In the untreated patients the P24, and N34 latencies bilaterally and the N20-P24 interpeak latency on the right, were significantly prolonged as compared with the control group. In addition, in the patient group without treatment, the N20-P24 amplitudes bilaterally and the P24-N34 amplitudes from left sided median nerve stimulation, were greater as compared with the control group. In the SEP latencies, no significant differences were observed between the patients treated and untreated with VPA. Regarding SEP amplitudes, in the untreated group, while the N20-P24 amplitudes from right sided median nerve stimulation were significantly enhanced, all the other amplitudes also showed increase, even insignificant, as compared with the patients treated by VPA. These findings suggest that the SEPs latencies are prolonged, and the amplitudes are enhanced in JME. The changes of the SEPs latency in JME could be due to abnormal synaptic transmission and not influenced by VPA. On the other hand, the increase of the amplitude tends to be lowered by VPA.