• Brain tumor
• brain-tumor related epilepsy
• epilepsy
• high-grade glioma
• levetiracetam
• valproic acid

• Humans
• Glioma/complications
• Glioma/drug therapy
• Glioma/mortality
• Levetiracetam/therapeutic use
• Valproic Acid/therapeutic use
• Valproic Acid/pharmacology
• Anticonvulsants/therapeutic use
• Anticonvulsants/pharmacology
• Brain Neoplasms/complications
• Brain Neoplasms/drug therapy
• Brain Neoplasms/mortality
• Seizures/etiology
• Seizures/drug therapy
• Epilepsy/drug therapy
• Epilepsy/etiology
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Treatment Outcome

• P50 CA221747 NCI NIH HHS

• adverse effects
• anti-convulsant
• hyperammonemia
• hyperammonemic encephalopathy
• sodium valproate

• Humans
• Epilepsy/drug therapy
• Anticonvulsants/adverse effects
• Anticonvulsants/administration & dosage
• Female
• Male
• Sex Characteristics
• Sex Factors
• Adult

• Antiseizure medications
• drug-induced liver injury
• hypersensitivity
• pediatric
• pharmacovigilance

• Child
• Female
• Humans
• Male
• Adverse Drug Reaction Reporting Systems
• Anticonvulsants/adverse effects
• Bayes Theorem
• Chemical and Drug Induced Liver Injury/epidemiology
• Chemical and Drug Induced Liver Injury/etiology
• Drug-Related Side Effects and Adverse Reactions/epidemiology
• Drug-Related Side Effects and Adverse Reactions/etiology
• Felbamate
• Lamotrigine
• Levetiracetam
• Topiramate
• Child, Preschool

• Drugs: CNS (not psychiatric)
• Healthcare improvement and patient safety
• Psychiatry (drugs and medicines)
• Safety
• Unwanted effects / adverse reactions

• Female
• Humans
• Pregnancy
• Valproic Acid/adverse effects
• Hyperammonemia/drug therapy
• Anticonvulsants/adverse effects
• Neurotoxicity Syndromes/drug therapy
• Brain Diseases/chemically induced
• Brain Diseases/drug therapy

• VHE
• encephalopathy
• paliperidone palmitate
• risperidone
• valproate

• Ammonia
• Encephalopathy
• Topiramate
• Valproic acid

• Adult
• Humans
• Valproic Acid/adverse effects
• Anticonvulsants/adverse effects
• Topiramate/adverse effects
• Hyperammonemia/chemically induced
• Ammonia/therapeutic use
• Epilepsy/drug therapy
• Risk Factors

• Humans
• Adult
• Consciousness Disorders/diagnosis
• Consciousness Disorders/therapy
• Critical Care
• Consciousness

• chemistry, clinical
• diagnosis
• education
• genetics

• Antipsychotics
• Drug side effects
• Hyperammonemia
• Valproic acid

• Ammonia
• Antiseizure medications
• Epilepsy
• Hyperammonaemia

The paucity of pediatric clinical trials has led to many medicines frequently prescribed to children without a license for use in pediatrics, resulting in an increased risk of adverse drug reactions. Pharmacovigilance databases remain, among others, a valuable tool for evaluating pediatric drug safety in the real-life setting.

We aimed to characterize pediatric adverse drug reactions reported in the Italian Pharmacovigilance database coming from the Calabria region (Southern Italy) over 10 years.

All Individual Case Safety Reports (ICSRs) concerning individuals aged under 18 years were extracted from 2010 to 2019. Duplicate and vaccine ICSRs were excluded. The remaining ICSRs were analyzed with respect to patients’ demographic data, suspected drugs, and category of adverse drug reactions across different age groups.

Among 6529 selected ICSRs, 395 pediatric ICSRs corresponding to 556 adverse drug reactions were analyzed. From 2010 to 2015, an increasing number of ICSRs were observed, but the reporting rate decreased after 2015. The highest proportion of ICSRs concerned children and adolescents. Around 52% of ICSRs involved boys: a trend observed in all age groups excluding newborns. Sixty ICSRs were serious and among them, 75% required hospitalization mainly in children and adolescents. Most of the ICSRs were issued by physicians (64.1%), followed by other healthcare professionals (22.5%) and pharmacists (9.9%). Anti-infective agents for systemic use and skin disorders were, respectively, the most frequently reported drug group and adverse drug reaction category.

This study provides an overview of adverse drug reactions reported in the pediatric population of the Calabria region and emphasizes the need for strengthening the surveillance in specific age subgroups and on given drugs in relation to their pattern of use.

The online version contains supplementary material available at 10.1007/s40264-022-01232-w.

Long-term valproic acid (VPA) administration is associated with adverse metabolic effects, including hyperammonemia and hypocarnitinemia. However, the pathogeneses of these adverse events remain unclear, and not enough reviews have been performed. The aim of this study was to conduct a meta-analysis of studies examining blood levels of ammonia and carnitine in patients treated with VPA.

We conducted database searches (PubMed, Web of Science) to identify studies examining blood levels of ammonia and carnitine in patients treated with VPA. A meta-analysis was performed to conduct pre- and post-VPA treatment comparisons, cross-sectional comparisons between groups with and without VPA use, and estimations of the standardized correlations between blood levels of ammonia, carnitine, and VPA.

According to the cross-sectional comparisons, the blood ammonia level in the VPA group was significantly higher than that in the non-VPA group. Compared to that in the non-VPA group, the blood carnitine level in the VPA group was significantly lower. In the meta-analysis of correlation coefficients, the blood VPA level was moderately correlated with blood ammonia and blood free carnitine levels in the random effects model. Furthermore, the blood ammonia level was moderately correlated with the blood free carnitine level.

Although the correlation between ammonia and free carnitine levels in blood was significant, the moderate strength of the correlation does not allow clinicians to infer free carnitine levels from the results of ammonia levels. Clinicians should measure both blood ammonia and free carnitine levels, especially in patients receiving high dosages of VPA.

• blood ammonia
• epilepsy
• lamotrigine
• risk factor

• Ammonia
• Anticonvulsants/adverse effects
• Epilepsy/chemically induced
• Epilepsy/drug therapy
• Humans
• Hyperammonemia/chemically induced
• Lamotrigine/therapeutic use
• Risk Factors
• Seizures/drug therapy
• Triazines/adverse effects
• Triazines/therapeutic use
• Valproic Acid

• adolescents
• antiepileptic drugs
• pediatric

Convulsive status epilepticus (CSE) prevention is critical for pediatric patients with epilepsy. Immediate intervention before CSE reduce severity. Despite its wide usage as an anticonvulsant, valproic acid (VPA) results in harmful side effects such as dose-dependent hepatotoxicity. Hence, reducing VPA dosage to minimize side effects while maintaining its efficacy is necessary, and transcranial photobiomodulation (tPBM) add-on therapy could facilitate this. We recently demonstrated for the first time that tPBM at a wavelength of 808 nm attenuated CSE in peripubertal rats. However, the effects of VPA with the add-on therapy of tPBM prior to seizures have not yet been explored. This study investigated whether adding tPBM to VPA exerts synergistic effect for CSE prevention in peripubertal rats.

A gallium-aluminum-arsenide laser (wavelength of 808 nm with an exposure duration of 100 s and irradiance of 1.333 W/cm² at the target) was applied transcranially 30 min after VPA injection in Sprague Dawley rats. All the rats received 90 mg/kg of pentylenetetrazole (PTZ). Except for the saline (n = 3), tPBM + saline (n = 3), and PTZ group (n = 6), all the rats received a PTZ injection 30 min after VPA injection. The rats received add-on tPBM with PTZ immediately after tPBM. In the VPA + PTZ group, the rats received low-dose (100 mg/kg, n = 6), medium-dose (200 mg/kg, n = 6), and high-dose (400 mg/kg, n = 7) VPA. In the VPA + tPBM + PTZ group, the rats received low (100 mg/kg, n = 5), medium (200 mg/kg, n = 6), and high (400 mg/kg, n = 3) doses of VPA. Seizures were evaluated according to the revised Racine’s scale in a non-blinded manner.

Adding tPBM to low-dose VPA reduced the incidence of severe status epilepticus and significantly delayed the latency to stage 2 seizures. However, adding tPBM to high-dose VPA increased the maximum seizure stage, prolonged the duration of stage 4–7 seizures, and shortened the latency to stage 6 seizures.

Adding tPBM to low-dose VPA exerted a synergistic prevention effect on PTZ-induced seizures, whereas adding tPBM to high-dose VPA offset the attenuation effect.

• Add-on therapy
• Epilepsy
• Pentylenetetrazole
• Seizures
• Status epilepticus
• Transcranial photobiomodulation
• Valproic acid

• epilepsy
• hyperammonemia
• mild cognitive impairment

• Ammonia/therapeutic use
• Anticonvulsants/adverse effects
• Cognitive Dysfunction/chemically induced
• Dementia
• Epilepsy/drug therapy
• Epilepsy/epidemiology
• Female
• Humans
• Hyperammonemia/chemically induced
• Hyperammonemia/drug therapy
• Male
• Quality of Life
• Valproic Acid/adverse effects

• Ammonium
• Complications
• Critically ill patients
• Valproate

• Glasgow score
• gene polymorphisms
• liver injury
• trough concentration
• valproic acid

Valproic acid (VPA) is widely used for the treatment of epilepsy, migraine, and a variety of psychiatric conditions. The reported incidences of hyperammonemia induced by VPA use is variable. The purpose of this study is to evaluate the incidence of VPA-induced hyperammonemia in the general adult inpatient population.

Adult patients who received at least 1 dose of VPA and derivatives between June 1, 2017 to December 31, 2017 were included. Patients were excluded if they did not have VPA administered during their inpatient stay or if they had elevated ammonia levels (>33 μmol/L) prior to initiation of VPA. Patients with a confirmed diagnosis of liver cirrhosis were also excluded. The primary endpoint was the incidence of hyperammonemia. Secondary outcomes included symptoms of hyperammonemia, diagnosis of VPA-induced hyperammonemia, and treatment of VPA-induced hyperammonemia.

A total of 162 patients were included in this study. A total of 33 (20.4%) patients were identified as having the primary outcome of hyperammonemia; 26 (16.0%) patients had symptoms of hyperammonemia, and 13 (8.0%) patients were diagnosed with VPA-induced hyperammonemia. Treatment modalities included administration of lactulose, levocarnitine, discontinuing VPA, or decreasing the VPA dose.

The administration of VPA in the general adult inpatient population resulted in a 20.4% incidence of hyperammonemia, with a lower rate of diagnosed VPA-induced hyperammonemia. Clinicians should be encouraged to obtain ammonia levels in patients receiving VPA if symptoms of altered mental status or encephalopathy develop.

• VPA
• hyperammonemia
• valproate
• valproic acid

• antiepileptic drugs
• drug utilization
• persistence
• post-stroke epilepsy
• sex differences

• Coma
• epilepsy
• metabolic disease

• MR/T033150/1 Medical Research Council

Ammonia is a normal constituent of body fluids and is found mainly through the formation of urea in the liver. Blood levels of ammonia must remain low as even slightly elevated concentrations (hyperammonemia) are toxic to the central nervous system.

To examine the relationship between the incidence of non-hepatic hype-rammonemia (NHH) and the prognosis of patients who were admitted to the intensive care unit (ICU).

This is a prospective, observational and single-center study. A total of 364 patients who were admitted to the ICU from November 2019 to February 2020 were initially enrolled. Changes in the levels of blood ammonia at the time of ICU admission and after ICU admission were continuously monitored. In addition, factors influencing the prognosis of NHH patients were analyzed.

A total of 204 patients who met the inclusion criteria were enrolled in this study, including 155 NHH patients and 44 severe-NHH patients. The incidence of NHH and severe-NHH was 75.98% and 21.57%, respectively. Patients with severe-NHH exhibited longer length of ICU stay and higher Acute Physiologic Assessment and Chronic Health Evaluation and Sequential Organ Failure Assessment scores compared to those with mild-NHH and non-NHH. Glasgow Coma Scale scores of patients with severe-NHH were than those of non-NHH patients. In addition, the mean and initial levels of ammonia in the blood might be helpful in predicting the prognosis of NHH.

High blood ammonia level is frequent among NHH patients admitted to the ICU, which is related to the clinical characteristics of patients. Furthermore, the level of blood ammonia may be helpful for prognosis prediction.

• Non-hepatic hyperammonemia
• Intestinal absorption
• Blood ammonia level
• Metabolism of amino acid
• Severe patients
• Intensive care unit

• Humans
• Hyperammonemia/diagnosis
• Hyperammonemia/epidemiology
• Incidence
• Intensive Care Units
• Prognosis
• Prospective Studies

Constipation is one of the most frequent non-motor problems in older adults. As constipation is commonly ignored by dementia patients, it is not usually reported on time. Constipation has a serious impact on the activity of daily living and quality of life in dementia patients. The relationships between constipation, demographic variables, and the nutritional status of patients with dementia remain unknown. This study aimed to assess the possible factors associated with constipation. This cross-sectional study was conducted at the Kaohsiung Chang Gung Memorial Hospital from January to November 2019. This hospital is a medical center and the main referral hospital of southern Taiwan, serving 3 million inhabitants. In total, 119 patients with dementia were evaluated using the Rome III diagnostic criteria for functional constipation. There were 30 patients with dementia included in the constipation group and 89 patients with dementia included in the no constipation group. Mini-Nutritional Assessment and 3-day diet diary records were employed. The clinical dementia rating score was used to evaluate the severity of dementia in patients of the outpatient clinic. Approximately 25.2% of dementia patients had constipation. Patients in the dementia with constipation group were older, had severer dementia, and displayed a lower water intake. After multivariable adjustment, low liquid consumption was the predictor of constipation among patients with dementia. The findings support the clinical recommendations to treat constipation with an increased liquid intake, but not exercise, in dementia patients.

• Mini-Nutritional Assessment
• constipation
• dementia
• diet diary record
• fiber
• water

• Aged
• Constipation/complications
• Constipation/epidemiology
• Cross-Sectional Studies
• Dementia/epidemiology
• Female
• Humans
• Male
• Quality of Life
• Taiwan/epidemiology

• ammonia
• cerebellum
• glutamine synthetase
• hyperammonemia
• mechanism
• prefrontal cortex
• striatum
• valproic acid

• MED-2018-3-9-F-7894 (AAB) Deanship of the Scientific Research in Northern Border University

Therapeutic drug monitoring (TDM) is recommended during valproic acid (VPA) use, and total serum concentration has been widely adopted. However, the free form of VPA is responsible for its pharmacologic and toxic effects, and the total and free concentrations are highly discordant because of VPA’s highly protein bound and saturable binding characteristics. Therefore, free VPA monitoring is increasingly advocated. Nevertheless, the correlation between free VPA concentration and associated adverse effects remains unknown.

To determine the optimal safety range of free VPA concentration in adult patients.

This prospective cohort study enrolled adult patients undergoing VPA therapy with TDM. Patient characteristics, VPA use, and adverse effects (thrombocytopenia, hyperammonemia, and hepatotoxicity) were recorded. A multivariate logistic regression model was applied to identify the predictors of adverse effects, and the receiver operating characteristic curve was applied to locate the cutoff point of free VPA concentration.

A total of 98 free serum concentrations from 51 patients were included for final analysis. In total, 31 (31.6%), 27 (27.6%), and 4 (4.1%) episodes of hyperammonemia, thrombocytopenia, and hepatotoxicity were observed, respectively. Free VPA concentration was a predicting factor for thrombocytopenia but not for hyperammonemia. A free VPA concentration of >14.67 mcg/mL had the greatest discriminating power (area under the curve = 0.77) for the occurrence of thrombocytopenia.

A free VPA serum concentration of 14.67 mcg/mL had the optimal discriminating power for the occurrence of thrombocytopenia. Ammonemia should be monitored even if free VPA concentration is within the safety range.

• carglumic acid
• hyperammonemic encephalopathy
• valproate‐induced hyperammonemia
• valproic acid

• exercise
• hyperammonemia
• skeletal muscle

• Adult
• Cresols/poisoning
• Female
• Humans
• Hyperammonemia/etiology
• Muscle, Skeletal/metabolism
• Severity of Illness Index
• Sodium Hypochlorite/poisoning
• Suicide, Attempted

• Anticonvulsants
• CNS Depressants
• Drug Side Effects-other
• Inpatient Psychiatry
• Mood Disorders-Bipolar

• drug-induced carnitine deficiency
• hyperammonemia
• valproic acid-induced hyperammonemic encephalopathy

• Aged
• Ammonia/blood
• Anticonvulsants/administration & dosage
• Anticonvulsants/adverse effects
• Biomarkers/blood
• Cardiomyopathies/chemically induced
• Carnitine/administration & dosage
• Carnitine/deficiency
• Consciousness Disorders/etiology
• Epilepsy, Generalized/drug therapy
• Female
• Humans
• Hyperammonemia/blood
• Hyperammonemia/chemically induced
• Hyperammonemia/diagnosis
• Muscular Diseases/chemically induced
• Neurotoxicity Syndromes/etiology
• Status Epilepticus/etiology
• Valproic Acid/administration & dosage
• Valproic Acid/adverse effects

• CYP2C9 expression
• CYP2C9 genotype
• Valproic acid
• epilepsy
• pediatric patients
• personalized medication
• psychiatric disorders.

• 8-OHdG
• Carnitine
• Epilepsy
• Levetiracetam
• Oxidative stress
• Valproic acid

• 8-Hydroxy-2'-Deoxyguanosine
• Anticonvulsants
• Carnitine/blood
• Child
• Deoxyguanosine/analogs & derivatives
• Deoxyguanosine/metabolism
• Epilepsy/blood
• Epilepsy/drug therapy
• Female
• Humans
• Levetiracetam/adverse effects
• Lipid Peroxidation/drug effects
• Liver/drug effects
• Liver Function Tests
• Male
• Malondialdehyde/metabolism
• Retrospective Studies
• Thiobarbituric Acid Reactive Substances/metabolism
• Valproic Acid/adverse effects

Valproic acid (VPA) is a commonly used agent in the management of seizures and psychiatric disorders. Hyperammonemia is a common complication of VPA with 27.8% of patients having elevated levels – that is unrelated to hepatotoxicity and normal transaminases. Common side effects include obesity, insulin resistance, metabolic disorder and severe forms of hepatotoxicity. Other rare and idiosyncratic reactions have been reported, one of which is presented in our case. A 27-year old patient presented with hyperammonemia and encephalopathy as a consequence of idiosyncratic VPA reaction causing drug-induced liver injury (DILI) with severely elevated transaminases. DILI is commonly overlooked when investigating encephalopathy in the setting of VPA. Physicians should consider DILI in the context of hyperammonemia and transaminitis.

• Valproic acid
• drug-induced liver injury
• hepatic encephalopathy
• hyperammonemia
• liver failure

Valproic acid (VPA) is widely used for the treatment of epilepsy, migraine, and a variety of psychiatric symptoms, including bipolar disorder, borderline personality disorder, and alcohol withdrawal. Valproate is associated with severe idiosyncratic adverse effects, the most notable being valproate-induced hyperammonemic encephalopathy (VHE). Topiramate is also a broad-spectrum anticonvulsant that is also extensively used for migraine prophylaxis, as a mood stabilizer, and for alcohol dependency. There is increased occurrence of VHE when valproate is used with other medications like phenytoin, phenobarbital, and topiramate. Our case report is on a young patient who was on valproic acid and topiramate and developed metabolic encephalopathy with hypoxic respiratory failure. We reviewed the causes and management of the hyperammonemic encephalopathy. We believe that clinicians should be aware of possible hyperammonemic encephalopathy in any patient who is taking valproic acid and presenting with impaired consciousness and cognitive decline. We also underline the importance of early recognition and high index of suspicion of encephalopathy related to hyperammonemia.

Long-term antiepileptic drug (AED) therapy is considered a risk factor of atherosclerosis. Furthermore, the duration of therapy contributes to acceleration of large-vessel atherosclerosis. Therefore, in this study, we tested the hypothesis that long-term AED therapy plays a crucial role in the pathogenesis of microangiopathy in patients with epilepsy.

We recruited 120 patients with epilepsy (age, 18–60 years) and 40 healthy controls. Optical coherence tomography (OCT) was used to measure the central macular thickness and diameters of the retinal artery and vein to evaluate atherosclerotic retinopathy; microalbumin and creatinine levels in urine were assessed to evaluate atherosclerotic nephropathy. In addition, high-sensitivity C-reactive protein (hs-CRP), lipid profiles, homocysteine, folate, uric acid, and body mass index were determined.

The ratio of urine albumin to creatine and OCT findings showed that patients with epilepsy had higher abnormal microalbuminuria and narrowing retinal vein diameters, respectively. Multiple linear regression analysis showed that increased triglyceride and hs-CRP levels might contribute to microalbuminuria. In addition, serum creatinine, duration of AED therapy, enzyme-inducing AED therapy, and duration of enzyme-inducing AED therapy were candidate risk factors for retinal vein narrowing.

Patients with epilepsy are at a higher risk for microangiopathy presented as retinopathy and nephropathy. Long-term AED therapy, particularly with enzyme-inducing AEDs; high triglyceride levels, and inflammatory processes play an important role in the development of microangiopathy in patients with epilepsy.

• antiepileptic drug therapy
• atherosclerosis
• microalbuminuria
• microangiopathy
• retinopathy

• frontal lobe epilepsy
• gait instability
• hyperammonemia
• valproate

Administration of valproic acid (VPA) is complicated with approximately 0.9% of patients developing hyperammonemia, but the pathogenesis of this adverse effect remains to be clarified. The aim of the present study was to search for mechanisms associated with VPA-induced hyperammonemia in the light of changes in serum amino acids concentrations associated with the urea cycle of schizophrenic patients.

Blood samples (10 mL) were obtained from 37 schizophrenic patients receiving VPA for the prevention of violent behaviors in the morning after overnight fast. Blood concentrations of ammonia, VPA, free carnitine, acyl-carnitine, and 40 amino acids including glutamate and citrulline were measured for each patient. Univariate and multivariate regression analyses were performed to identify amino acids or concomitantly administered drugs that were associated with variability in the blood concentrations of ammonia.

The blood ammonia level was positively correlated with the serum glutamate concentration (r = 0.44, p < 0.01) but negatively correlated with glutamine (r = −0.41, p = 0.01), citrulline (r = −0.42, p = 0.01), and glycine concentrations (r = −0.54, p < 0.01). It was also revealed that the concomitant administration of the mood stabilizers (p = 0.04) risperidone (p = 0.03) and blonanserin (p < 0.01) was positively associated with the elevation of the blood ammonia level.

We hypothisized that VPA would elevate the blood ammonia level of schizophrenic patients. The observed changes in serum amino acids are compatible with urea cycle dysfunction, possibly due to reduced carbamoyl-phosphate synthase 1 (CPS1) activity. We conclude that VPA should be prudently prescribed to schizophrenic patients, particularly those receiving mood stabilizers or certain antipsychotics.

• Antipsychotics
• CPS1
• Carnitine
• Glutamate
• Glycine
• Hyperammonemia
• Mood stabilizer
• Valproic acid

• bipolar disorder
• hyperammonemia
• reversible encephalopathy
• valproic acid

• Antimanic Agents/adverse effects
• Bipolar Disorder/blood
• Bipolar Disorder/drug therapy
• Brain Diseases/blood
• Brain Diseases/chemically induced
• Female
• Humans
• Hyperammonemia/chemically induced
• Middle Aged
• Valproic Acid/adverse effects

• Antiepileptic drug
• Craniotomy
• Encephalopathy
• Hyperammonemia
• Liver function

• Ammonia/analysis
• Breath Tests/instrumentation
• Breath Tests/methods
• Epilepsy/diagnosis
• Humans
• Lasers, Semiconductor
• Renal Insufficiency, Chronic/diagnosis

Hepatic injury is a hallmark adverse reaction to Valproate (VPA), a common used drug in the management of numerous CNS disorders, including epilepsy. DHA has a myriad of health benefits, including renal- and hepato-protective effects. Unfortunately, however, the underpinnings of such liver-pertinent VPA- and DHA-actions remain largely undefined. Accordingly, this study attempted to unveil the cellular and molecular triggers whereby VPA evokes, while DHA abates, hepatotoxicity.

We evaluated activity and/or expression of cellular markers of oxidative stress, inflammation, and apoptosis in rat liver, following treatment with VPA (500 mg/kg/day) with and without concurrent treatment with DHA (250 mg/kg/day) for two weeks.

VPA promoted hepatic oxidative stress as evidenced by enhancing activity/expression of NADPH-oxidase and its subunits, a ROS-generator, and by accumulation of lipid-peroxides. Moreover, VPA enhanced hepatic phosphorylation/activation of mitogen-activated protein kinase (MAPK), and expression of cyclooxygenase-2(COX-2), as proinflammatory signals. Besides, VPA promoted hepatocellular apoptosis, as attested by enhanced expression of cleaved caspase-9 and increased number of TUNEL-positive hepatocytes. Lastly, VPA upregulated levels of hypoxia-inducible factor-1-alpha (HIF-1α), a multifaceted modulator of hepatocytic biology, and activity of its downstream antioxidant enzyme heme-oxygenase-1(HO-1). These changes were significantly blunted by co-administration of DHA. Our findings demonstrate that VPA activated NADPH-oxidase and HIF-1α to induce oxidative-stress and hypoxia as initiators of hepatic injury. These changes were further aggravated by up-regulation of inflammatory (MAPK and COX-2) and apoptotic cascades, but could be partly lessened by HO-1 activation. Concurrent administration of DHA mitigated all VPA-induced anomalies.

• Biochemistry
• Cell biology
• Medicine
• Physiology
• Systems biology

Blood carnitine and/or acetylcarnitine deficiencies are postulated in the literature as possible causes of higher ammonia levels. The aim of this study was to investigate if the use of valproic acid, the age of the patients, or certain central nervous system pathologies can cause carnitine and/or acetylcarnitine deficiency leading to increased ammonia levels. Three groups of patients were studied: (A) epileptic under phenytoin monotherapy (n = 31); (B) with bipolar disorder under valproic acid treatment (n = 28); (C) elderly (n = 41). Plasma valproic acid and blood carnitine and acyl carnitine profiles were determined using a validated HPLC and LC-MS/MS method, respectively. Blood ammonia concentration was determined using an enzymatic automated assay. Higher ammonia levels were encountered in patients under valproic acid treatment and in the elderly. This may be due to the lower carnitine and/or acetylcarnitine found in these patients. Patients with controlled seizures had normal carnitine and acetylcarnitine levels. Further studies are necessary in order to conclude if the uncontrolled bipolar disorder could be the cause of higher carnitine and/or acetylcarnitine levels.