Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation.

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial ß-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial ß-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.

Risk factors and outcome of hyperammonaemia in people with epilepsy.

BACKGROUND: Hyperammonaemia is a recognised complication of antiseizure treatment but risk factors leading to individual patient susceptibility and outcome remain unclear. OBJECTIVE: To identify risk factors for hyperammonaemia and investigate the impact of its management on clinical outcomes. METHODS: We carried out a retrospective observational study of adults with epilepsy who had ammonia tested over a 3-year period. Hyperammonaemia was defined as ammonia level > 35 µmol/L. Patients were classified into two groups: hyperammonaemic and non-hyperammonaemic. Association analyses and linear regression analysis were used to identify risk factors for hyperammonaemia. RESULTS: We reviewed 1002 ammonia requests in total and identified 76 people with epilepsy who had ammonia concentration measured, including 26 with repeated measurements. 59/76 (78%) were found to have hyperammonaemia. There was borderline statistical significance of hyperammonaemia being less common in patients with an established monogenic/metabolic condition than in those with structural or cryptogenic epilepsy (P = 0.05). Drug resistance, exposure to stiripentol and oxcarbazepine were identified as risk factors for hyperammonaemia. We found a dose-dependent association between valproate and hyperammonaemia (P = 0.033). Clinical symptoms were reported in 22/59 (37%) of the hyperammonaemic group. Improved clinical outcomes with concurrent decrease in ammonia concentration were seen in 60% of patients following treatment adjustment. CONCLUSIONS: Drug resistance and exposure to stiripentol, oxcarbazepine or high-dose valproate are associated with an increased risk of hyperammonaemia. Clinicians should consider symptoms related to hyperammonaemia in patients on high-dose valproate or multiple antiseizure treatments. Prompt identification of hyperammonaemia and subsequent treatment adjustments can lead to improved clinical outcomes.

The role of carnitine in maintenance dialysis therapy.

Carnitine metabolism and homeostasis is significantly altered in patients receiving maintenance dialysis. Current literature in the adult and pediatric dialysis populations suggest a high prevalence of carnitine deficiency, which may lead to erythropoietin-resistant anemia, cardiomyopathy, and muscle weakness. However, the results of pediatric dialysis studies are limited and have not provided the evidence necessary to support strong recommendations or guidelines pertaining to carnitine management. The characteristics and function of carnitine, the definition and consequences of deficiency, a brief overview of recent adult studies, and current studies on carnitine supplementation in pediatric hemodialysis (HD) and peritoneal dialysis (PD) populations are discussed in this review.

Hyperammonemia-induced impaired consciousness following mFOLFOX6 therapy in a patient with recurrent rectal cancer.

OBJECTIVES: FOLFOX is a standard chemotherapy regimen used to treat colorectal cancer. Adverse events associated with FOLFOX treatment include peripheral neuropathy and myelosuppression. This report discusses the case of a 64-year-old man with rectal cancer who developed hyperammonemia and impaired consciousness following initiation of mFOLFOX6 as a postoperative adjuvant therapy. METHODS: This case study reports on the clinical disease progression of the aforementioned patient. RESULTS: Following preoperative chemoradiotherapy, the patient underwent low anterior resection for rectal cancer. mFOLFOX6 was then initiated as postoperative adjuvant therapy. During the 5th cycle of mFOLFOX6 treatment, the patient presented with impaired consciousness and upper extremity convulsions. Blood testing revealed marked hyperammonemia (349 µg/dL (normal range: 12 - 66 µg/dL)). Imaging did not reveal any intracranial lesions that could cause impaired consciousness. The patient recovered within a day after rehydration and BCAA substitution. CONCLUSION: Although impaired consciousness is a rare adverse reaction of FOLFOX, it has a major psychological impact on the patient and his/her family. Hyperammonemia should therefore be considered a potential cause of impaired consciousness during FOLFOX therapy and should be appropriately diagnosed and treated.

Changes in the Body Composition and Nutritional Status after Long-term Rifaximin Therapy for Hyperammonemia in Japanese Patients with Hepatic Encephalopathy.

Objective Rifaximin has become available for treating hyperammonemia in patients with hepatic encephalopathy. This study analyzed the changes in the body composition and nutritional status after long-term rifaximin therapy. Methods Twenty-one patients who underwent rifaximin therapy at 1,200 mg/day for more than 24 weeks were evaluated for the changes in the controlling nutritional status (CONUT) scores for the nutritional assessment, albumin-bilirubin (ALBI) scores for the liver function assessment, and skeletal muscle index (SMI) for the body composition assessment. Results There were 17 men and 4 women, with a mean age of 67.14±8.32 years. Eleven cases had a portosystemic shunt (52.3%), and 10 had hepatocellular carcinoma (47.6%). The Child-Pugh class was A in 9 cases (42.9%), B in 9 cases (42.9%), and C in 3 cases (14.2%). The blood ammonia levels in the rifaximin group improved significantly upon rifaximin therapy, from 124.76±28.68 µg/dL at baseline to 47.00±14.43 µg/dL after 2 weeks (p<0.001) and 49.81±15.02 µg/dL after 24 weeks (p<0.001). The CONUT scores improved significantly during rifaximin therapy, from 6.47±3.25 at baseline to 3.33±2.65 after 24 weeks (p=0.0007). The ALBI scores also improved significantly from -0.39±1.89 at baseline to -2.20±0.55 after 24 weeks (p=0.0002). The SMI scores showed that the body composition had been maintained in response to rifaximin therapy (50.20±7.67 at baseline and 51.29±7.62 after 24 weeks). Conclusion Rifaximin administration for hepatic encephalopathy improved the CONUT and ALBI scores. It may have a secondary effect on the improvement in the nutritional status and hepatic reserve.

Hyperammonemia with impaired consciousness caused by continuous 5-fluorouracil infusion for colorectal cancer: A case report.

A 66-year-old woman was diagnosed with stage IVb sigmoid colon cancer. Modified FOLFOX-6 (mFOLFOX-6; levofolinate‒fluorouracil‒oxaliplatin) plus panitumumab was selected as the chemotherapeutic regimen, but she was administered a regimen without oxaliplatin (L-OHP) or bolus 5-fluorouracil (5-FU) because of her general condition and concern about adverse effects. The patient had impaired consciousness on day 3 of chemotherapy. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain showed no findings of hemorrhage, infarction, brain metastasis, and leukoencephalopathy. Except for high blood ammonia concentration (353 µg/dL), there were no other findings that could have caused her condition. Impaired consciousness due to hyperammonemia was diagnosed. We started an intravenous drip supplemented with branched chain amino acids for liver protection. Approximately 6 hours later, blood ammonia level improved to 88 µg/dL, which approached the reference value. Consciousness level improved over time, reaching a level of alertness on day 5 after starting chemotherapy. 5-FU was suspected to be the cause of impaired consciousness due to hyperammonemia, but the exact cause could not be identified because most of the previously reported cases were given L-OHP, bolus 5-FU, and other concomitant medications. In this case, since there were no other concomitant medications, it is highly probable that continuous infusion of 5-FU alone caused impaired consciousness due to hyperammonemia. This is an important case that indicates the need to monitor carefully for the occurrence of hyperammonemia when 5-FU is administered continuously; it also proposes future issues for investigation.

The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (NAFLD).

L-carnitine transports fatty acids into the mitochondria for oxidation and also buffers excess acetyl-CoA away from the mitochondria. Thus, L-carnitine may play a key role in maintaining liver function, by its effect on lipid metabolism. The importance of L-carnitine in liver health is supported by the observation that patients with primary carnitine deficiency (PCD) can present with fatty liver disease, which could be due to low levels of intrahepatic and serum levels of L-carnitine. Furthermore, studies suggest that supplementation with L-carnitine may reduce liver fat and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). L-carnitine has also been shown to improve insulin sensitivity and elevate pyruvate dehydrogenase (PDH) flux. Studies that show reduced intrahepatic fat and reduced liver enzymes after L-carnitine supplementation suggest that L-carnitine might be a promising supplement to improve or delay the progression of NAFLD.

[A Case of Disturbance of Consciousness Due to Hyperammonemia during Chemotherapy for Metastasis of Sigmoid Colon Cancer].

A 76-year-old woman had underwent 5-fluorouracil(5-FU), oxaliplatin(L-OHP)combination therapy(mFOLFOX6)as first-line chemotherapy for peritoneal recurrence after resection of sigmoid colon cancer. She showed severe general fatigue and disturbance of consciousness on the second day of the 12th course of chemotherapy. Computed tomography of the head detected no abnormal findings in the central nervous system. The laboratory results revealed a marked hyperammonemia. She was diagnosed as a disturbance of consciousness due to hyperammonemia and treated her with branched- chain amino acid solution. Then the disturbance of consciousness resolved on the following day. After changing the regimen of chemotherapy, the disturbance of consciousness was not found. Recently, it has been reported that high-dose 5-FU regimen such as mFOLFOX6 causes hyperammonemia as a rare adverse event. We should take hyperammonemia into account when disturbance of consciousness occurs during high-dose 5-FU chemotherapy.

L-carnitine supplementation as a potential therapy for suspected hyperammonaemic encephalopathy.

A 44-year-old female, with a background of cerebral palsy, epilepsy and learning disabilities, presented with multiple seizures and a persistently reduced consciousness level secondary to valproate-induced hyperammonaemic encephalopathy (plasma levels >50 µg/dl). Withdrawal of valproate and subsequent infusion of L-carnitine led to full recovery. Nonhepatic hyperammonaemia has been shown to be effectively treated by intravenous L-carnitine therapy by a series of case reports. To date, no randomised controlled trials have demonstrated this. Hyperammonaemic encephalopathy is possibly a more common presentation than expected that is currently underdiagnosed and exacerbated by valproate.

Effects of Levocarnitine on Cardiac Function and Renal Anemia in Hemodialysis Patients.

BACKGROUND: Carnitine deficiency is a common condition in hemodialysis patients. There have been numerous reports on the efficacy of levocarnitine therapy in hemodialysis patients, including different views. Reported effects of levocarnitine are: (1) improvement of renal anemia, (2) improvement of cardiac functions, (3) effects on muscle spasm and asthenia, (4) anti-atherogenic effects, (5) anti-oxidant and anti-inflammatory effects, and (6) inhibitory effects on dialysis hypotension. SUMMARY: Here, I present the effects of levocarnitine on renal anemia in hemodialysis patients with carnitine deficiency, focusing on the effect on dose reduction in erythropoiesis-stimulating agents and the influence on erythropoiesis resistance index. We also describe the effects on cardiac functions based on changes in cardiac ultrasonography. Key Message: To confirm the efficacy of levocarnitine therapy clinical studies would be required as well as the study of carnitine supplementation therapy for hemodialysis patients with carnitine deficiency.

Impact of intestinal mannitol on hyperammonemia, oxidative stress and severity of hepatic encephalopathy in the ED.

Hyperammonemia results from hepatic inability to remove nitrogenous products generated by protein metabolism of intestinal microbiota, which leads to hepatic encephalopathy (HE) in chronic liver disease (CLD). In ammonium neurotoxicity, oxidative stress (OxS) plays a pathogenic role. Our objective was to evaluate if intestinal mannitol is as effective and safe as conventional treatment for diminishing hyperammonemia, OxS, and HE in patients with CLD. MATERIAL AND METHODS: We included 30 patients with HE classified by "Haven Criteria for Hepatic Encephalopathy". They were randomized into two groups: 1) Mannitol Group (MG) with mannitol 20% administered into the intestine by an enema, 2) conventional group (CG) with lactulose 40 g enema both substances were diluted in 800 mL of double distilled solution every 6 h; all patients received neomycin. We evaluated ammonia concentration, plasma oxidative stress, HE severity, intestinal discomfort and adverse effects. RESULTS: Hyperammonemia (171 ±â€¯104 vs 79 ±â€¯49 µmol ammonia/L, p < 0.01), and oxidative stress (MDA 29 vs 27%, formazan 15 vs 11%, carbonyls 16 vs 9% and dityrosines 10 vs 5%) were reduced in MG and CG respectively. The HE severity decreased by two degrees compared to baseline values in both groups. Intestinal discomfort and electrolyte plasma alterations were less frequent (p < 0.05) in MG than CG. CONCLUSIONS: Intestinal mannitol is as effective and safe as conventional treatment for reducing hyperammonemia, oxidative stress, and hepatic encephalopathy of CLD patients in the emergency room. Likewise, mannitol is better tolerated than conventional treatment.

Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 µM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 µg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] µg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] µg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P < 0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. CONCLUSION: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).

Sudden valproate-induced hyperammonemia managed with L-carnitine in a medically healthy bipolar patient: Essential review of the literature and case report.

RATIONALE: Valproic Acid is a commonly used psychiatric drug primarily used as a mood stabilizer. Mild hyperammonemia is a Valproic Acid common adverse effect. This report presents an example of treated hyperammonemia on Valproic acid therapy managed with L-carnitine administration in BD patients characterized by sudden vulnerability. PATIENT CONCERNS: We report the case of a 29-year-old man suffering from bipolar disorder (BD) and substance use disorder who exhibited sudden altered mental status upon admittance to the inpatient unit. The patient was started on Valproic acid with no improvement. DIAGNOSES: The patient had remarkably high ammonia levels (594 µg/dL) without hepatic insufficiency, likely due to his valproate treatment. INTERVENTIONS: The patient was administered lactulose, intravenous hydration, and i.v. levocarnitine supplementation 4.5 g/day. OUTCOMES: The administration leads to reduction of ammonia levels to 99 µg/dL within 12 hours upon initiation of carnitine therapy and progressive restore of his mental status within 24 hours. LESSONS: Resolution of hyperammonemia caused by Valproic acid therapy may be enhanced with the administration of L-carnitine. An interesting aspect of this case was how rapidly the patient responded to the carnitine therapy.

Urea cycle pathway targeted therapeutic action of naringin against ammonium chloride induced hyperammonemic rats.

Ammonia is a well-known neurotoxin that causes liver disease and urea cycle disorder. Excessive ammonia content in the blood leads to hyperammonemic condition and affects both excitatory and inhibitory neurotransmission including brain edema and coma. Naringin, a plant bioflavonoid present in various citrus fruits and mainly extracted from the grape fruit. This study was designed to assess the protective effect of naringin on ammonium chloride (NH4Cl) induced hyperammonemic rats. Experimental hyperammonemia was induced by intraperitoneal injections (i.p) of NH4Cl (100mg/kg body weight (b.w.)) thrice a week for 8 consecutive weeks. Hyperammonemic rats were treated with naringin (80mg/kg b.w.) via oral gavage. Naringin administration significantly augmented the level of blood ammonia and plasma urea. Naringin also upregulate the expression of urea cycle enzymes such as carbamoyl phosphate synthase I (CPS I) and ornithine transcarbamylase (OTC), arininosuccinate synthase (ASS), argininosuccinate lyase (ASL) and arginase I (ARG) and metabotropic glutamate receptors (mGluRs) such as mGluRs I and mGluRs V and down regulate the expression of inflammatory markers like tumor necrosis factor (TNF-α), nuclear factor kappa B (NF-kB), Interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS). In addition, to this, the protective effect of naringin was also revealed through the immunohistochemical changes in tissues. Thus our present study result suggest that naringin modulates the expression of proteins involved in urea cycle pathway and suppresses the expression of inflammatory markers and acts as a potential agent to treat condition in rats.

[The decreased level of plasma carnitine in patients with epilepsy]. / Snizhenie kontsentratsii karnitina u patsientov s épilepsiei.

Antiepileptic drugs (AEDs) have long been known to affect carnitine metabolism, dropping the plasma free carnitine. Valproate (VPA) was considered to be the strongest carnitine-reducing agent. VPA-induced hyperammonemic encephalopathy and hepatotoxicity are well known, and pre-existing carnitine deficiency can be a predisposing factor, especially in congenital metabolic disorders. Several studies have shown that carnitine supplementation in patients receiving VPA to result in subjective and objective improvements and to prevent VPA-induced hepatotoxicity and encephalopathy, in parallel with increases in carnitine serum concentrations. Level of free plasma carnitine <20 micromol/l (syn. carnitine deficiency) in patients with epilepsy (in 15-30% of cases) may occur not only with administration of VPA but with administration of other AEDs (phenobarbital, phenytoin, carbamazepine) and low nutritional intake of carnitine. Some findings indicate that the number of AEDs used is a risk factor for carnitine deficiency. It was established that body weight, height and multidrug therapy are significantly associated with low level of free plasma in epileptic patients. Carnitine deficiency can have severe consequences; but most epileptic patients suffering from it are asymptomatic. Although carnitine deficiency is not uncommon among patients receiving AEDs, it seems not necessary to routinely monitor carnitine levels in epileptic ambulatory patients, this is reasonable only in groups of risk. L-carnitine supplementation is clearly indicated in case of VPA-induced hepatotoxicity (i.v. administration) VPA overdose (i.v. administration), primary carnitine-transporter defect and is strongly recommended in specific secondary carnitine deficiency syndromes, symptomatic VPA-associated hyperammonemia, infants and young children receiving VPA, especially those younger than 2 years, patients with a complex neurologic disorder, who are receiving multiple AEDs, patients who have risk factors for hepatotoxicity and carnitine insufficiency. In the absence of double blind trials, clinical practice is based on empiric observation, clinical experience, and theory. Well-designed studies of specific and general uses of L-carnitine replacement therapy in patients with epilepsy are needed.

L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report.

Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia, valproic acid, 4-en-valproic acid, and carnitine levels were monitored. Her ammonia level was elevated and her carnitine level was at the inferior limit of the population range. She was supplemented with carnitine at 1 g/day. After 1 month, her ammonia level decreased, her carnitine level increased, and her seizures were better controlled. Carnitine supplementation was useful for reversal of her hyperammonemia, allowing her to continue valproic acid for seizure control.

L-Arginine in the treatment of valproate overdose - five clinical cases.

BACKGROUND: Valproic acid and its metabolites - particularly valproyl-CoA - are inhibitors of the enzyme N-acetylglutamate synthetase. The amino acid l-arginine can stimulate N-acetylglutamate synthetase activity and could be potentially used therapeutically to correct hyperammonemia caused by valproate therapy or overdose. Severely valproic-acid-poisoned patients are usually treated with l-carnitine or hemodialysis in order to decrease hyperammonemia. We herein report of five cases, in which l-arginine was administered. METHODS: Observational study on five cases. Patients with hyperammonemia (i.e., ammonia 80 > µg/dL) and symptoms consistent with valproate overdose (i.e., drowsiness, coma) were selected for treatment with l-arginine. Data was collected retrospectively. RESULTS: l-Arginine decreased ammonia levels in a close temporal relation (case I ammonia in EDTA-plasma [µg/dL] decreased from 381 to 39; case II from 281 to 50; case III from 669 to 74; case IV from 447 to 56; case V from 202 to 60). In cases I and II, hemodialysis was performed and l-carnitine was given before the administration of l-arginine. In case III, hemodialysis was performed after the administration of l-arginine was already started. In cases IV and V, treatment with l-arginine was the sole measure to decrease ammonia levels in plasma. CONCLUSION: The results suggest that l-arginine may be beneficial in selected cases of valproate overdose complicated by hyperammonemia. l-Arginine could extend our conventional treatment options for valproic acid overdose.

Dilated Cardiomyopathy as the Only Clinical Manifestation of Carnitine Transporter Deficiency.

The authors present a case of carnitine transporter deficiency, which was unmasked after an episode of respiratory distress resistant to treatment with bronchodilators. Chest radiograph showed cardiomegaly; electrocardiogram showed left ventricular hypertrophy and echocardiography revealed dilated cardiomyopathy. Heart failure therapy was initiated and metabolic screening was requested, as family history was indicative of inborn errors of metabolism. Very low levels of free carnitine and carnitine esters in blood were found and genetic testing confirmed the diagnosis of carnitine transporter deficiency. After oral supplementation with L-carnitine, symptoms gradually ameliorated and heart function had fully recovered. Sequence analysis in the SLC22A5 gene revealed the missense mutation c.1319C > T (p.Th440Met) in homozygous state. Homozygous c.1319C > T (p.Th440Met) mutation has not been associated with a pure cardiac phenotype before.

Primary Carnitine Deficiency - A Rare Treatable Cause of Cardiomyopathy and Massive Hepatomegaly.

Systemic primary carnitine deficiency (CDSP) is a rare autosomal recessive disorder caused by a defect in plasma membrane uptake of carnitine due to SLC22A5 gene mutations. A nine-mo-old boy presented with hypertrophic cardiomyopathy, massive hepatomegaly and jaundice. Metabolic testing revealed very low free carnitine levels. Genetic analysis using Sanger sequencing method revealed compound heterozygous mutations in SLC22A5 gene, c. 1354 G > A (p. Glu452Lys, previously reported) and c.231_234del (novel frame-shift). Oral carnitine supplementation resulted in improved clinical outcome with ejection fraction to 75 % and normalization of liver size and enzymes after 3 mo.

Naringin regulates glutamate-nitric oxide cGMP pathway in ammonium chloride induced neurotoxicity.

Naringin, plant bioflavonoid extracted mainly from grapefruit and other related citrus species. This study was designed to assess the neuroprotective effect of naringin on ammonium chloride (NH4Cl) induced hyperammonemic rats. Experimental hyperammonemia was induced by intraperitonial injection (i.p) of NH4Cl (100mg/kg body weight (b.w.)) thrice a week for 8 consecutive weeks. Hyperammonemic rats were treated with naringin (80mg/kg b.w.) via oral gavage. Naringin administration drastically restored the levels of blood ammonia, plasma urea, nitric oxide (NO), glutamate, glutamine, lipid peroxidation, lipid profile, activities of liver marker enzymes, antioxidant status and sodium/potassium-ATPase (Na+/K+-ATPase). In addition, naringin supplementation reverted back the pathological changes of liver, brain and kidney tissues, the expressions of Glutamine synthetase (GS), Na+/K+-ATPase, neuronal nitric oxide (nNOS) and soluble guanylate cyclase (sGC) in hyperammonemic rats. Hence, this study suggested that nargingin exhibited their protective effect against NH4Cl induced toxicity via enhancing the activities of antioxidant enzymes and inhibiting the lipid peroxidation process. Take together, this study provides data that naingin effectively reduced neurotoxicity by attenuating hyperammonemia, suggesting that naringin act as a potential therapeutic agent to treat hyperammonemic rats.