Development and Characterization of Hygroscopicity-Controlled Sustain Release Formulation of Divalproex Sodium.

Objectives: Divalproex sodium (DS), being a hygroscopic drug, requires low humidity during product manufacturing. This study aims to develop a hygroscopicity controlled sustained release formulation of DS that can be manufactured in relatively high humid conditions in facilities lacking dehumidifiers. Materials and Methods: This study focuses on the role of polyethylene glycol (PEG-8000) and hydroxypropyl methylcellulose (HPMC K100M) as polymers of choice to control hygroscopicity and retard release of DS using solid dispersion technique. In this study, homogeneous solid dispersions containing various ratios of PEG-8000, HPMC K100M, and DS were obtained via melt granulation technique. Fifteen different solid dispersions were prepared based on Box-Behnken experimental design created in MiniTab software. The obtained solid dispersions were separately broken down into granules and their hygroscopic properties were determined via moisture uptake studies. Granular solid dispersions were then compressed into tablets and their sustained release dissolution profiles were studied as per the United States Pharmacopoeia (USP) monograph of DS extended-release tablets. Dissolution profiles of all fifteen formulations were then analyzed in Box-Behnken experimental design under MiniTab software to determine an optimized formulation having low hygroscopic properties as well as required multipoint drug release as per USP monograph. The final optimized formulation was prepared and subjected to moisture uptake study to determine its hygroscopicity, dissolution study to determine drug release kinetics and fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) analysis to determine molecular interactions between drug and polymers. Result: Optimized final formulation yielded granular solid dispersion with 28% less hygroscopicity compared to DS and tablets with an excellent release profile in accordance with USP monograph. FTIR and DSC analysis did not show any significant interaction between DS and components of the solid dispersion. Conclusion: Optimized formulation from this study can be used to manufacture divalproex extended-release tablets inside facilities lacking dehumidifiers.

Fixed Dose Combination Tablets of Aripiprazole and Divalproex Sodium: a Pilot Pharmacokinetic Study in Human Volunteers.

A combination product of aripiprazole (antipsychotic) and divalproex sodium (mood stabilizer) was recently developed to establish their tolerability and safety in fixed dose combination (FDC). A pilot pharmacokinetic (PK) open-labeled parallel study on healthy human volunteers was carried out to assess the PK of FDC of aripiprazole/divalproex sodium in comparison with its individual components with a view to rationalize therapeutic regimen and potentially improve compliance of bipolar patients in future. A total of 24 volunteers were randomized to aripiprazole 5mg, divalproex sodium 500mg, and FDC (aripiprazole/divalproex sodium 5/500 mg) enteric-coated tablets. Peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) of aripiprazole increased, Cmax of valproic acid increased, and Tmax decreased. Half-life (t1/2) of both aripiprazole and valproic acid decreased. Area under the curve (AUC) of both aripiprazole and valproic acid increased while volume of distribution (Vd) and clearance (Cl) decreased when used in fixed combination. Increase in the AUC and decrease in the Vd of aripiprazole in the presence of valproic acid were found statistically significant while rest of the parameters were insignificant at level 0.05. Although not adequately powered, this pilot study gives an idea that FDC of aripiprazole and divalproex sodium has a PK profile comparable to its mono-component products. Thus, concomitant use of aripiprazole and valproate in FDC is possible which may prove to be a cost-effective and result-oriented substitute for conventional individual tablets to improve patients' compliance; however, further evaluation with positive control is required.

Fabrication of extended-dissolution divalproex tablets: a green solvent-free granulation technique.

Objective: Divalproex sodium (DVS) is a challenging drug owing to its hygroscopicity, bitter taste, and short in vivo half-life. This study aims to produce stable taste masked DVS once daily tablets using solvent free hot melt granulation (HMG) process.Methods: A lab scale high shear mixer granulator employing six meltable lipid binders (compritol®888 ATO, beeswax, gelucire®50/13, precirol® ATO5, stearyl alcohol, and geleol®) was used for the preparation of tablets. Quality control tests were performed on granules and tablets, and Box-Behnken's design was adopted to investigate the effect of binder concentration, impeller speed, and granulation time on the drug dissolution. Shelf and accelerated stability evaluation, taste assessment, and in vivo pharmacokinetic study were conducted on the selected batches.Results: Results revealed that DVS tablets were successfully prepared, and that the in vitro dissolution of the drug was inversely proportional to the binder concentration. Beeswax and compritol® tablets showed similar dissolution profiles to the marketed product Depakote® 500 ER tablets (F1 < 15 and F2 > 50). The selected batches showed lower moisture content (<2%) and successfully masked the bitter taste compared to uncoated tablets based on a hydrophilic matrix. The in vivo pharmacokinetic study delineated relative bioavailability values for Beeswax and Compritol® tablets of 95.6% and 118%, respectively, compared to the marketed product.Conclusion: The solvent free HMG process can be employed to formulate 24 h extended dissolution DVS tablets with masked bitter taste and high stability, and comparable or higher bioavailability than the marketed product.

Acute hyponatremia with accompanying hyperammonemia secondary to divalproex sodium: A case report.

Divalproex sodium (DVP) is an antiepileptic medication that also has mood stabilizing properties for patients with mental health disorders. Currently, there are a small number of case reports discussing the incidence of hyponatremia that occurs as an adverse effect of DVP. After completion of a thorough literature search, we present the first case report describing acute hyponatremia with accompanying hyperammonemia secondary to DVP use. This case describes a 44-year-old male patient who experienced hyponatremia with accompanying hyperammonemia following initiation of DVP for schizoaffective disorder. This case highlights the need for clinicians to consider monitoring electrolytes, in addition to liver function and platelets, with the initiation of therapy or increase in daily dosage. Given the drug's action at voltage-gated sodium channels, changes in serum sodium could be expected.

Valproic acid-induced hyperammonemia: Incidence, clinical significance, and treatment management.

INTRODUCTION: Valproic acid (VPA)-induced hyperammonemia poses several clinical challenges in psychiatric medicine. The reported incidence of this adverse effect varies widely across the literature. Furthermore, practitioners treat hyperammonemia in asymptomatic patients although studies suggest this practice is unnecessary. The purpose of this study is to evaluate if patients with VPA-induced hyperammonemia are appropriately identified for treatment based on their symptom presentation as well as determine the most efficacious treatment approach for VPA-induced hyperammonemia. METHODS: This study was completed at a community teaching hospital, and patients were retrospectively identified from June 1, 2011, to June 30, 2016, and included if they were admitted to a psychiatric unit, received at least 1 dose of VPA, and had at least 1 ammonia level drawn during admission. Hyperammonemia was defined as greater than 47 µmol/L, and symptomatic hyperammonemia was defined based on specific symptom presentation. The treatment modality was successful if the ammonia level was within normal range at discharge. RESULTS: Of the 357 patients screened, 347 patients met all inclusion criteria for analysis. The reported incidence of hyperammonemia was found to be 36% with 43.2% of those patients presenting with symptoms. Lactulose initiation was the most common treatment modality chosen (48.7%). Discontinuation of VPA was the most effective treatment (56.3% success rate). DISCUSSION: The results demonstrate that many patients with elevated ammonia levels are asymptomatic and therefore, based on findings within the literature, may not require treatment. Although lactulose was found to be the most common treatment initiated, the most effective was discontinuation of VPA.

Divalproex sodium modulates nuclear localization of ataxin-3 and prevents cellular toxicity caused by expanded ataxin-3.

BACKGROUND & AIMS: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal dominantly inherited neurodegenerative disorder and the most common form of SCA worldwide. It is caused by the expansion of a polyglutamine (polyQ) tract in the ataxin-3 protein. Nuclear localization of the affected protein is a key event in the pathology of SCA3 via affecting nuclear organization, transcriptional dysfunction, and seeding aggregations, finally causing neurodegeneration and cell death. So far, there is no effective therapy to prevent or slow the progression of SCA3. METHODS: In this study, we explored the effect of divalproex sodium as an HDACi in SCA3 cell models and explored how divalproex sodium interferes with pathogenetic processes causing SCA3. RESULTS: We found that divalproex sodium rescues the hypoacetylation levels of histone H3 and attenuates cellular cytotoxicity induced by expanded ataxin-3 partly via preventing nuclear transport of ataxin-3 (particularly heat shock-dependent). CONCLUSION: Our study provides novel insights into the mechanisms of action of divalproex sodium as a possible treatment for SCA3, beyond the known regulation of transcription.

Cognitive and behavioral outcomes among seizure-controlled children with partial epilepsy on antiepileptic drug monotherapy.

The objective of this study was to assess cognitive performance and behavioral symptoms in a sample of children diagnosed with partial epilepsy who were seizure controlled on AED monotherapy for one year. Ninety-eight seizure-controlled children on AED monotherapy were included in this study. Specific AEDs examined included topiramate, divalproex sodium, lamotrigine, levetiracetam, and oxcarbazepine. Groups did not differ on age, region of focal epilepsy, or Full-Scale IQ. Direct measures included the WISC-IV and selected tests from the DKEFS (Verbal Fluency and Trail Making Test). Parent report measures included the BRIEF and the BASC-PRS. A series of ANOVAs revealed significant differences across the AED cohorts within many domains of cognitive functioning and behavioral presentation. Children prescribed divalproex sodium or topiramate demonstrated weaker working memory and verbal fluency, when compared with children prescribed other AEDs. Additionally, parents of children prescribed topiramate reported greater executive functioning and adaptive skills deficits. The pattern of findings suggests that children prescribed divalproex sodium or topiramate generally demonstrated a higher risk of cognitive and behavioral impairments compared to the other AEDs. Future prospective studies are required in order to better understand the relationship between AED type and these outcomes to inform clinical practice.

Valproate induced hyperammonemic encephalopathy treated by haemodialysis.

Valproate (VPA)-induced hyperammonemic encephalopathy is an unusual, but serious, adverse effect of divalproex sodium (DVPX) treatment and if untreated can lead to raised intracranial pressure, seizures, coma, and eventually death. It can, however, be reversed if an early diagnosis is made. It is therefore extremely important to recognize it and discontinue DVPX treatment. Our patient developed sudden deterioration of sensorium, drowsiness, lethargy, and later severe comatose state after few days of starting DVPX with high levels of serum ammonia despite therapeutic levels of VPA and normal liver function test. He responded to hemodialysis, cerebral decongestants, and other intensive supportive measures.

Organic Bipolar Disorder: An Unusual Neuropsychiatric Sequelae following Right Frontotemporal Injury.

Psychiatric disorders are common consequences of traumatic brain injury (TBI). But organic bipolar disorder is a rare entity when compared with other disorders. Here, we report this 49 year old patient with bipolar affective disorder following traumatic brain injury, its presentation and management. Though the pathophysiology of this disorder involves the interaction of factors that precede trauma (eg, genetic vulnerability and previous psychiatric history), factors that pertain to the traumatic injury itself (eg, type, extent, and location of brain damage), in our patient it showed an atypical presentation.

Release property study on the novel divalproex sodium enteric-coated capsules.

In the present study, a novel divalproex sodium (DS) enteric-coated capsule was prepared, and high performance liquid chromatography (HPLC) assay method for DS was developed. Their uniformity, release curve and release characteristics in different solvents were examined. The release studies were performed using marketed sample as a reference and data were analyzed in terms of cumulative release amounts as a function of time. It was demonstrated by the results that assay developed was specific, rapid and reliable, which can be used to determine DS in vitro accurately, and our developed samples were similar to reference preparation in in vitro release characteristics. The release characteristics of different batches of samples were quite similar to each other, and the total release percents of DS from enteric-coated capsule were within 0-10% in HCl, and reached close to 100% in phosphate buffer. Similarity factors (f 2) of three batches between two preparations were all higher than 50. The developed enteric-coated capsule may be a promising alternative dosage form for treatment of related diseases.

The Use of Antiepileptics in Migraine Prophylaxis.

BACKGROUND: Migraine is a chronic debilitating disorder. Selected antiepileptic drugs (AEDs) are proposed as preventives for migraine. Clinical efficacy and side effects of these AEDs are discussed. SUMMARY OF REVIEW: The American Academy of Neurology and the American Society of Headache classify topiramate (TPM) and divalproex sodium (DVPX) as Level-A medications and recommend offering them to patients for migraine prophylaxis. Their mechanism(s) of actions remains not entirely known. Their recognized action as sodium channel blockers may affect the neural component of migraine pain. TPM or DVPX can be considered an obvious choice for those patients with a concomitant seizure disorder. Care must be taken to plan their treatment with their psychiatrist if a mood disorder is present. DVPX tends not to be prescribed as first/second choice due to its potential for weight gain and hepatotoxicity. TPM is generally first choice, but bears severe contraindications. Both medications require education on teratogenesis in childbearing women. Consideration of gabapentin, acetazolamide, leviteracetam, zonisamide, and carbamazipine may be given later as empiric options and in selected patients. Patients must be made aware that there is insufficient scientific support for their use in migraine. CONCLUSIONS: Available AEDs to prophylactically treat migraine are few but of robust clinical efficacy. Special care needs to be exerted with respect to their side effects. Future research is needed for a better understanding of their mechanisms of action in migraine. Such research has the potential of providing some insight into the pathophysiology of migraine.

Development of fixed dose combination tablets of aripiprazole plus divalproex sodium and their simultaneous determination using HPLC-UV.

A vast majority of psychiatric patients are effectively treated with combination of drugs to improve efficacy and adherence, but due to limited research and development in fixed dose combination (FDC) in psychiatry, these products are not commonly available. The aim of this study is to prepare cost effective FDC tablets containing aripiprazole and divalproex sodium. Two batches of fixed dose combination tablets, FDC1 and FDC2, were successfully prepared using wet granulation technique. Furthermore, aripiprazole tablets A1 and A2 and divalproex tablets D1 were also formulated as reference to compare the in vitro availability profile. An accurate and simple isocratic HPLC method was established and validated for the simultaneous quantification of aripiprazole and valproic acid in the FDC tablets. A reversed-phase C18 (250 × 4.6 mm) column in isocratic mode was used. The mobile phase consisted of acetonitrile and 0.32% KH2PO4 (60:40, v/v), flow rate was set at 1.0 mL/min and the detection was performed at 210 nm. Average percent recoveries of aripiprazole and valproic acid were 96.0 and 95.5%, respectively, meeting the official requirements. The newly developed FDC product may be used for the better therapeutic outcomes of combined use of aripiprazole and valproic acid, which may improve patient adherence.

Divalproex sodium enhances the anti-leukemic effects of imatinib in chronic myeloid leukemia cells partly through SIRT1.

Imatinib (IM) represents a breakthrough in the treatment of chronic myeloid leukemia (CML) by inhibiting the activity of Bcr-Abl tyrosine kinase. However, many patients exhibit resistance to IM in the clinic. Recent studies have indicated that sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), plays an important role in leukemogenesis. In addition, some HDAC inhibitors are being tested to determine their anti-cancer activities in clinical trials. Divalproex sodium (DVPX), a first-line treatment for epilepsy, is also a HDAC inhibitor. However, it is unclear whether the anti-leukemic effects of IM in combination with DVPX on CML cells are related to SIRT1. The aim of this study was to investigate the effects of IM in combination with DVPX on cell viability, apoptosis, and cell cycle arrest in CML cells and to explore the underlying mechanisms. It was found that DVPX enhanced IM-induced cell growth inhibition, apoptosis and cell cycle arrest in K562-S and K562-G cells. Surprisingly, the level of p-Bcr-Abl was similar in K562-S and K562-G cells. Moreover, IM combined with DVPX had no effects on the phosphorylation of Bcr-Abl and its downstream target STAT5. Further study revealed that SIRT1 expression was higher in K562-G cells compared with K562-S cells. DVPX enhanced the inhibitory effect of IM on SIRT1 expression in K562-S and K562-G cells. Furthermore, knockdown of SIRT1 promoted apoptosis of K562-G cells treated with IM and DVPX. These results indicate that DVPX may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating SIRT1 expression.

Probable Interaction Between Warfarin and Divalproex Sodium.

Objective: A potential interaction between warfarin and divalproex sodium is described. Case Summary: A 65-year-old Arabic-speaking Egyptian woman chronically anticoagulated with warfarin for atrial fibrillation and a history of stroke presented to the anticoagulation clinic with an elevated international normalized ratio (INR) of 3.2. This was an increase of 1.4 over her previous INR of 1.8 only 9 days prior. Discussion with the patient's daughter revealed the addition of divalproex sodium (a derivative of valproic acid) 250 mg twice daily to the patient's medication regimen 6 days prior. Other contributing factors that could cause an elevated INR were ruled out. The patient's total weekly dose (TWD) of warfarin was decreased from 22.5 mg to 20 mg, and the patient was instructed to return for a repeat INR in 1 week. On the day the patient was due to return for a repeat INR, she was admitted to the hospital and her INR was 2.2 on admission. Based on medication reconciliation information, the patient had decreased her warfarin TWD as instructed and had self-discontinued the divalproex sodium due to intolerable fatigue. During this time, the patient received no additional divalproex sodium. She was instructed to resume her previous TWD of warfarin of 22.5 mg on discharge and subsequently had a therapeutic INR (2.6) 11 days later. Discussion: Warfarin and divalproex sodium are commonly prescribed agents with few case reports to describe their interaction. Primary literature supports a multifactorial mechanism, including CYP450 metabolism inhibition and protein-binding displacement, both of which can result in an elevated INR. Use of the Drug Interaction Probability Scale indicated a probable interaction between warfarin and divalproex sodium. Conclusions: Patients receiving concurrent warfarin and divalproex sodium therapy should be monitored closely for changes in INR values as the combination may increase the INR and put the patient at increased risk for bleeding.