Inhibition of ureagenesis by valproate in rat hepatocytes. Role of <i>N</i>-acetylglutamate and acetyl-CoA

Coudé, F. X.; Grimber, G.; Parvy, P; Rabier, Daniel; Petit, Françoise

doi:10.1042/bj2160233

Cited by 56 publications

(25 citation statements)

References 34 publications

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“…The second effect is caused by the binding of VPA to coenzyme A, which is required for the formation of N-acetylglutamate, a powerful allosteric activator of carbamoyl phosphate synthetase I and critical to the regulation of nitrogen flux toward its appropriate metabolism. 15 Collectively, these actions of VPA provide the basis for the development of clinically significant hyperammonemia and offer an explanation for the palliative effect of administered L-carnitine.…”

Section: Treatmentmentioning

confidence: 99%

Valproate-associated Hyperammonemic Encephalopathy

Wadzinski¹,

Franks²,

Roane³

et al. 2007

The Journal of the American Board of Family Medicine

109

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The use of valproic acid (VPA) (also known as Depakote, Depakene, and others) frequently results in elevated plasma ammonia. In some people, hyperammonemia may be clinically significant, resulting in hyperammonemic encephalopathy, which may be severe. Valproic acid-induced hyperammonemic encephalopathy may occur in people with normal liver function, despite normal doses and serum levels of VPA. We describe 2 cases of valproic acid-induced hyperammonemic encephalopathy in patients with supratherapeutic VPA levels, although the condition has been described in people with normal VPA lev- Valproic acid (VPA) is effective in the treatment of seizure disorders, bipolar disorder, migraine headache prophylaxis, neuropathic pain, restless legs syndrome, dementia-related agitation, and social anxiety disorder, among other conditions. VPA has numerous drug interactions and toxicities; severe toxicities include hepatic damage, pancreatitis, teratogenicity, thrombocytopenia, and hyperammonemia. Here we depict 2 case reports of VPAinduced hyperammonemic encephalopathy (VHE), both occurring in patietns with no history of underlying liver disease. In one instance, the patient was able to function, but with significant cognitive limitations. In the second case, the patient was comatose. Both of the patients we describe also had supratherapeutic VPA levels, but VHE is a welldocumented potential complication of the use of VPA in the medical literature, and it may occur in people with normal VPA levels.1 Because of the wide spectrum of symptoms associated with VHE, physicians should consider hyperammonemia in the differential diagnosis of any patient taking VPA who shows changes in behavior, cognition, or orientation. Case ReportsCase 1 A 51-year-old woman was transferred from a psychiatric hospital to an emergency department to evaluate the recent deterioration in her mental status. She had been admitted to the psychiatric hospital for an exacerbation of posttraumatic stress disorder and was placed on extended-release VPA at 1,000 mg nightly. After 7 days of treatment she was no longer responsive to verbal stimuli. Her medical history was significant for migraine headaches, posttraumatic stress disorder, and major depression. Her medications included topiramate (for migraine prophylaxis), quetiapine, and VPA. In the emergency department, she was nonresponsive to verbal or painful stimuli; her vital signs were normal. Her pupils were equal at 5 mm and her ammonia level was 232 mol/L (N ϭ 10 to 47); her VPA level was 145 g/mL (N ϭ 50 to 100); and aspartate aminotransferase and alanine aminotransferase were normal at 17 IU/L and 19 IU/L, respectively. The remainder of laboratory tests, including all liver tests, were normal. For the first 24 hours, the patient remained nonresponsive; her This article was externally peer reviewed.

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Section: Treatmentmentioning

confidence: 99%

Valproate-associated Hyperammonemic Encephalopathy

Wadzinski¹,

Franks²,

Roane³

et al. 2007

The Journal of the American Board of Family Medicine

109

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“…[23,24] STP'nin de VPA metabolizmasını inhibe ederek, VPA'nın kandaki miktarını arttırdığından yukarıda bahsedilmişti. Hastanın 1 hafta süre ile yaşadığı bilinç bulanıklığı ve uyku halinin ilaçlara bağlı hiperamonyemik ensefalopati olabileceği düşünülse de bu bir hafta boyunca, hasta düzeldikten sonra ve 2 sene önce asemptomatik iken bakılan kan amonyak değerle-rinin de hafifçe yüksek (100 mmol/L civarında) olması ve ensefalopati için daha yüksek (200-300) amonyak değer-lerinin beklendiği bilgisi, ilaçlara bağlı hiperamonyemik ensefalopati tanısını tekrar gözden geçirmemize neden olmuş, ancak hastanın kliniğini açıklayabilecek başka bir neden bulunamamıştır.…”

Section: Discussionunclassified

A Case of Dravet Syndrome Who Developed Acute Reversible Encephalopathy That May Have Been Caused by Hyperamonnemia Due to Pharmacokinetic Interaction Between Valproate and Stiripentol

Atmaca¹,

Gürses²,

Marufoglu³

et al. 2012

Epilepsi

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ÖzetStiripentol (STP), Dravet sendromunda valproat (VPA) ve klobazama ek olarak kullanılmak üzere onay almış yeni bir antiepileptik ilaç (AEİ)'dir. Diğer taraftan özellikle tedaviye dirençli epilepsilerde sık görülen ani beklenmedik ölüm ("sudden unexpected death in epilepsy" SUDEP) riski Dravet sendromunda da yüksektir. Kullanmakta olduğu çeşitli AEİ'lere karşın nöbetleri devam etmekte olan, birkaç kez status epileptikus (SE) veya yapılan intravenöz diazepam sonrası 'kardiyopulmoner arest'ten geçmiş olan olgumuzda da tedaviye STP eklenmiş, tedaviye başlandıktan altı ay sonra akut geçici ensefalopati tablosu oluşmuştur. Bu tabloya STP'nin VPA ile etkileşimi sonucu ortaya çıkan hiperamonyeminin neden olabileceği üzerinde durulmuştur. Dravet sendromu, SUDEP ve STP hakkında son literatür eşliğinde tedavi seçe-nekleri ve koruyucu önlemler tartışılmıştır.Anahtar sözcükler: Dravet sendromu; hiperamonyemi; stiripentol; SUDEP; valproat. SummaryStiripentol (STP), a recent antiepileptic drug, has been approved for use in addition to valproat (VPA) and clobazam in Dravet syndrome.On the other hand, the incidence of sudden unexpected death in epilepsy (SUDEP) commonly seen in patients with intractable epilepsy, is high in patients with Dravet yndrome. In our case, who was resistant to polytherapy and had multiple cardiopulmonary arrest due to status epilepticus (SE) or intravenous diazepam; STP was used in combination with other antiepileptic drugs (AED). However, acute reversible encephalopathy developed after six months of therapy. It is argued that the condition may have been caused by hyperamonnemia due to pharmacokinetic interaction between VPA and STP. Treatment options and protective measures are discussed using recent literature on Dravet syndrome, SUDEP and STP.

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“…At the same time, the serum free carnitine level was inversely proportional to levels of lactate, pyruvate and alanine as well as blood ammonia. Since administered VPA is metabolized to its CoA derivatives, it may reduce intramitochondrial free CoA and acetyl-CoA levels, which may in turn adversely influence mitochondrial functions such as f3-oxidation (Ponchaut et al 1992; Kossak et al 1993) and ornithine cycle (Coude et al 1981(Coude et al , 1983). This metabolic alteration is probably responsible for rising blood ammonia, lactate and pyruvate levels and for inhibition of mitochondrial ATP production.…”

Section: Discussionmentioning

confidence: 99%

Alteration of Ammonia and Carnitine Levels in Short-Term Treatment with Pivalic Acid-Containing Prodrug.

Ito

Sugiyama

Kobayashi

et al. 1995

Tohoku J. Exp. Med.

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We investigated the influence on mitochondrial functions in carnitine deficiency caused by short-term treatment of cefterampivoxil (CFTM-PI) which is one of pivaloyloxymethyl-esterified antibiotics in adult volunteers and diseased children. Administration of CFTM-PI caused hypocarnitinemia in all cases, and we observed a significant elevation of blood ammonia levels compared with those after its withdrawal in diseased children. A significant negative correlation was found between the levels of serum free carnitine and blood ammonia, and a positive correlation was observed between serum carnitine and blood glutamine levels in all adult samples and samples during administration in diseased children. Our data suggest that these antibiotic medications affect the mitochondrial function even in a short-term treatment and that L-carnitine supplementation would be necessary for patients treated with CFTM-PI. carnitine deficiency; pivalic acid; hyperammonemia Carnitine, a cofactor for mitochondrial /l-oxidation of long-chain fatty acids, is essential for energy production and enhances the excretion of accumulated acyl-CoA to regulate the intramitochondrial CoA/acyl-CoA ratio. The systemic carnitine deficiency noted in various disorders can cause hypoketotic hypoglycemia, cardiomyopathy and Reye-like syndrome because functions of carnitine are insufficient.Some oral antibiotics in general use are esterified with pivaloyloxymethyl moiety in order to increase the intestinal absorption rate. This group of antibi-

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Inhibition of ureagenesis by valproate in rat hepatocytes. Role of N-acetylglutamate and acetyl-CoA

Cited by 56 publications

References 34 publications

Valproate-associated Hyperammonemic Encephalopathy

Valproate-associated Hyperammonemic Encephalopathy

A Case of Dravet Syndrome Who Developed Acute Reversible Encephalopathy That May Have Been Caused by Hyperamonnemia Due to Pharmacokinetic Interaction Between Valproate and Stiripentol

Alteration of Ammonia and Carnitine Levels in Short-Term Treatment with Pivalic Acid-Containing Prodrug.

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