RESUMEN
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.
Asunto(s)
Sobredosis de Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hiperamonemia , Humanos , Ácido Valproico , Carnitina/uso terapéutico , Hiperamonemia/inducido químicamente , Hiperamonemia/tratamiento farmacológico , Amoníaco/efectos adversos , Farmacología en Red , Suplementos Dietéticos , Anticonvulsivantes/uso terapéuticoRESUMEN
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.
Asunto(s)
Hiperamonemia , Neoplasias del Recto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estado de Conciencia , Femenino , Fluorouracilo/efectos adversos , Humanos , Hiperamonemia/inducido químicamente , Hiperamonemia/diagnóstico , Hiperamonemia/tratamiento farmacológico , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias del Recto/tratamiento farmacológicoRESUMEN
OBJECTIVE: Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. METHODS: Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3 months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18 years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. RESULTS: We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991 ± 286 mg/d (range 660-1320 mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89 ± 8.72 mg/kg/d, which is lower than what is typically recommended in children (50 mg/kg/d). SIGNIFICANCE: We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.
Asunto(s)
Amoníaco , Anticonvulsivantes/efectos adversos , Carnitina/administración & dosificación , Dioxolanos/efectos adversos , Epilepsias Mioclónicas/tratamiento farmacológico , Hiperamonemia/inducido químicamente , Adulto , Amoníaco/sangre , Anticonvulsivantes/administración & dosificación , Estudios de Cohortes , Dioxolanos/administración & dosificación , Epilepsias Mioclónicas/sangre , Femenino , Humanos , Hiperamonemia/sangre , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
INTRODUCTION: FOLFOX therapy is the main chemotherapy regimen for colorectal cancer. Peripheral neuropathy, hematotoxicity, and digestive symptoms are known to be the most frequent adverse events. Hyperammonemia and lactic acidosis rarely occur simultaneously during treatment with FOLFOX therapy; the number of case reports is limited worldwide. We report a case of disturbance of consciousness, considered to be caused by hyperammonemia and lactic acidosis that occurred during treatment with mFOLFOX6 therapy that was administered as postoperative adjuvant treatment for rectal cancer. PATIENT CONCERNS: This case was of a 71-year-old man who had been receiving oral treatment for chronic kidney disease and diabetes mellitus. Laparoscopic low anterior resection and artificial anal construction surgery were performed for stage III rectal cancer. As adjuvant postoperative therapy, mFOLFOX6 therapy was started but was followed by a disturbance of consciousness. DIAGNOSES: Results of the blood tests revealed notable hyperammonemia (ammonia level, 1,163âµg/dl) and lactic acidosis (pH 7.207; lactate, 17.56âmmol/L); however, imaging diagnosis did not reveal intracranial lesions that could cause disturbance of consciousness. INTERVENTIONS: For hyperammonemia, branched-chain amino acid agents and Ringers solution supplementation were administered. For acidosis, 7% sodium hydrogen carbonate was administered as treatment. OUTCOMES: The disturbance of consciousness improved within 12âhours of initiating the treatment, and the patient was discharged with no sequelae on 7th day after hospitalization. CONCLUSION: In patients with chronic kidney disease, FOLFOX regimen may confer risks of hyperammonemia and lactic acidosis.
Asunto(s)
Acidosis Láctica/complicaciones , Antimetabolitos Antineoplásicos/efectos adversos , Trastornos de la Conciencia/etiología , Fluorouracilo/efectos adversos , Hiperamonemia/complicaciones , Acidosis Láctica/inducido químicamente , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Hiperamonemia/inducido químicamente , Masculino , Neoplasias del Recto/tratamiento farmacológicoRESUMEN
A 66-year-old woman was diagnosed with stage IVb sigmoid colon cancer. Modified FOLFOX-6 (mFOLFOX-6; levofolinateâfluorouracilâoxaliplatin) 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.
Asunto(s)
Neoplasias Colorrectales , Hiperamonemia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Estado de Conciencia , Femenino , Fluorouracilo/efectos adversos , Humanos , Hiperamonemia/inducido químicamente , Hiperamonemia/tratamiento farmacológico , Leucovorina/efectos adversosRESUMEN
BACKGROUND: Fatigue is a common adverse event during lenvatinib treatment in patients with hepatocellular carcinoma. One mechanism contributing to development of fatigue might involve abnormal adenosine triphosphate synthesis that is caused by carnitine deficiency. To address this possibility, we examined the relationship between carnitine levels and fatigue during lenvatinib treatment. METHODS: This prospective study evaluated 20 patients with hepatocellular carcinoma who underwent lenvatinib treatment. Both blood and urine samples were collected from the patients before starting lenvatinib therapy (day 0), and on days 3, 7, 14, and 28 thereafter. Plasma and urine concentrations of free and acyl carnitine (AC) were assessed at each time point. The changes in daily fatigue were evaluated using the Brief Fatigue Inventory (BFI). RESULTS: Plasma levels of free carnitine (FC) at days 3 and 7 were significantly higher compared with baseline (p = 0.005, p = 0.005, respectively). The urine FC level at day 3 was significantly higher compared with baseline (p = 0.030) and that of day 7 tended to be higher compared with baseline (p = 0.057). The plasma AC concentration at days 14 and 28 was significantly higher compared with that of baseline (p = 0.002, p = 0.005, respectively). The plasma AC-to-FC (AC/FC) ratio on days 14 and 28 was significantly higher compared with baseline (p = 0.001, p = 0.003, respectively). There were significant correlations between the plasma AC/FC ratio and the change in the BFI score at days 14 and 28 (r = 0.461, p = 0.041; r = 0.770, p = 0.002, respectively). CONCLUSIONS: Longitudinal assessments of carnitine and fatigue in patients with hepatocellular carcinoma suggest that lenvatinib affects the carnitine system in patients undergoing lenvatinib therapy and that carnitine insufficiency increases fatigue. The occurrence of carnitine insufficiency may be a common cause of fatigue during the treatment.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Cardiomiopatías/inducido químicamente , Carnitina/deficiencia , Fatiga/etiología , Hiperamonemia/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Enfermedades Musculares/inducido químicamente , Compuestos de Fenilurea/efectos adversos , Quinolinas/efectos adversos , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/orina , Cardiomiopatías/sangre , Cardiomiopatías/complicaciones , Cardiomiopatías/dietoterapia , Carnitina/administración & dosificación , Carnitina/sangre , Carnitina/orina , Suplementos Dietéticos , Fatiga/sangre , Fatiga/diagnóstico , Fatiga/prevención & control , Femenino , Humanos , Hiperamonemia/sangre , Hiperamonemia/complicaciones , Hiperamonemia/dietoterapia , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/orina , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedades Musculares/sangre , Enfermedades Musculares/complicaciones , Enfermedades Musculares/dietoterapia , Estudios Prospectivos , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Hiperamonemia , Neoplasias del Colon Sigmoide , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estado de Conciencia , Femenino , Fluorouracilo/efectos adversos , Humanos , Hiperamonemia/inducido químicamente , Hiperamonemia/tratamiento farmacológico , Leucovorina/efectos adversos , Recurrencia Local de Neoplasia , Neoplasias del Colon Sigmoide/tratamiento farmacológico , Neoplasias del Colon Sigmoide/cirugíaRESUMEN
A 26-year-old man presented at the emergency department with confusion and decreased consciousness after several days of vomiting. In the preceding 6 months, he had used a 2-litre tank of nitrous oxide (N2O) weekly. His metabolic encephalopathy was caused by hyperammonaemia which probably resulted from interference of N2O-induced vitamin B12 deficiency with ammonia degradation. A catabolic state might have contributed to the hyperammonaemia in this case. After treatment with vitamin B12 and lactulose, both his consciousness and hyperammonaemia improved. He reported no residual complaints after 3 months of follow-up. Since N2O is increasingly used as a recreational drug, we recommend considering hyperammonaemia as a cause of metabolic encephalopathy in cases of N2O use and altered mental status.
Asunto(s)
Encefalopatías Metabólicas/inducido químicamente , Confusión/diagnóstico , Trastornos de la Conciencia/diagnóstico , Hiperamonemia/inducido químicamente , Óxido Nitroso/efectos adversos , Adulto , Encefalopatías Metabólicas/tratamiento farmacológico , Confusión/etiología , Trastornos de la Conciencia/etiología , Diagnóstico Diferencial , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Humanos , Hiperamonemia/complicaciones , Lactulosa/administración & dosificación , Lactulosa/uso terapéutico , Masculino , Resultado del Tratamiento , Vitamina B 12/administración & dosificación , Vitamina B 12/uso terapéutico , Deficiencia de Vitamina B 12/complicaciones , Complejo Vitamínico B/administración & dosificación , Complejo Vitamínico B/uso terapéutico , Vómitos/diagnósticoRESUMEN
A case of hyperammonemia induced by chemotherapy, including high-dose fluorouracil(5-FU), for advanced unresectable large intestinal cancer has been reported. This case involved an 81-year-old female who was diagnosed with pT4bcN2M1 (multiple hepatic metastases; stage â £; KRAS: mutant)after emergency surgery for sigmoid colon cancer and diffuse peritonitis. Post-operation, the 4 courses of mFOLFOX6 plus Bmab therapy was started for advanced unresectable recurrent large intestinal cancer; 48 hours later, she developed consciousness disorder(JCS â ¢-300). The disorder promptly disappeared after discontinuation of high-dose 5-FU. Because high-dose 5-FU was inferred to be the main cause of hyperammonemia, XELOX plus Bmab therapy was started as a post-treatment. She did not develop hyperammonemia; therefore, 8 courses were administered. The patient is being followed-up now.
Asunto(s)
Fluorouracilo/efectos adversos , Hiperamonemia , Neoplasias Hepáticas , Neoplasias del Colon Sigmoide , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trastornos de la Conciencia , Femenino , Humanos , Hiperamonemia/inducido químicamente , Leucovorina , Neoplasias Hepáticas/secundarioRESUMEN
A 60-year-old woman was administered mFOLFOX6 therapy as postoperative adjuvant chemotherapy for fStage III a ascending colon cancer. The patient developed a disorder of consciousness(Japan Coma Scale[JCS]III-200)immediately after the completion of the therapy. Blood ammonia levels were high at 319 mg/dL, and a diagnosis of disturbance of consciousness due to hyperammonemia was made. The patient's state of consciousness improved on the following day as blood ammonia levels decreased due to treatment with branched chain amino acid(BCAA)formulation and oxygen. Two months later, mFOLFOX6 therapy was again administered with strengthening measures for side effects to nausea and vomiting and reducing 5-FU, but the patient again developed a disorder of consciousness(JCS III-200). The 5-FU administration rate was considered as a potential cause of hyperammonemia. Hyperammonemia induced by 5-FU is relatively rare, with a reported incidence of 5-9%; however, caution is required with high dosage regimens of 5-FU that are currently recommended for colorectal cancer therapy because hyperammonemia is an important side effect.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Encefalopatías/etiología , Colon Ascendente , Neoplasias del Colon/tratamiento farmacológico , Hiperamonemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Colon Ascendente/cirugía , Neoplasias del Colon/cirugía , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Persona de Mediana Edad , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéuticoRESUMEN
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 (594âµg/dL) without hepatic insufficiency, likely due to his valproate treatment. INTERVENTIONS: The patient was administered lactulose, intravenous hydration, and i.v. levocarnitine supplementation 4.5âg/day. OUTCOMES: The administration leads to reduction of ammonia levels to 99âµg/dL within 12 hours upon initiation of carnitine therapy and progressive restore of his mental status within 24âhours. 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.
Asunto(s)
Antimaníacos/efectos adversos , Trastorno Bipolar/tratamiento farmacológico , Carnitina/administración & dosificación , Hiperamonemia/tratamiento farmacológico , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Ácido Valproico/efectos adversos , Adulto , Humanos , Hiperamonemia/inducido químicamente , Masculino , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Cloruro de Amonio/farmacología , Flavanonas/farmacología , Hiperamonemia/tratamiento farmacológico , Urea/metabolismo , Animales , Biomarcadores/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Flavonoides/farmacología , Hiperamonemia/inducido químicamente , Hiperamonemia/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Hyperammonemia is a serious complication of liver disease and may lead to encephalopathy and death. This study investigated the effects of Commiphora molmol resin on oxidative stress, inflammation, and hematological alterations in ammonium chloride- (NH4Cl-) induced hyperammonemic rats, with an emphasis on the glutamate-NO-cGMP and Nrf2/ARE/HO-1 signaling pathways. Rats received NH4Cl and C. molmol for 8 weeks. NH4Cl-induced rats showed significant increase in blood ammonia, liver function markers, and tumor necrosis factor-alpha (TNF-α). Concurrent supplementation of C. molmol significantly decreased circulating ammonia, liver function markers, and TNF-α in hyperammonemic rats. C. molmol suppressed lipid peroxidation and nitric oxide and enhanced the antioxidant defenses in the liver, kidney, and cerebrum of hyperammonemic rats. C. molmol significantly upregulated Nrf2 and HO-1 and decreased glutamine and nitric oxide synthase, soluble guanylate cyclase, and Na+/K+-ATPase expression in the cerebrum of NH4Cl-induced hyperammonemic rats. Hyperammonemia was also associated with hematological and coagulation system alterations. These alterations were reversed by C. molmol. Our findings demonstrated that C. molmol attenuates ammonia-induced liver injury, oxidative stress, inflammation, and hematological alterations. This study points to the modulatory effect of C. molmol on glutamate-NO-cGMP and Nrf2/ARE/HO-1 pathways in hyperammonemia. Therefore, C. molmol might be a promising protective agent against hyperammonemia.
Asunto(s)
Elementos de Respuesta Antioxidante , Commiphora/química , GMP Cíclico/metabolismo , Ácido Glutámico/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , Hiperamonemia/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico/metabolismo , Extractos Vegetales/farmacología , Cloruro de Amonio/toxicidad , Animales , Modelos Animales de Enfermedad , Hiperamonemia/inducido químicamente , Masculino , Extractos Vegetales/química , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Anticonvulsivantes/efectos adversos , Cardiomiopatías/inducido químicamente , Carnitina/sangre , Carnitina/deficiencia , Epilepsia/sangre , Epilepsia/tratamiento farmacológico , Hiperamonemia/inducido químicamente , Enfermedades Musculares/inducido químicamente , Anticonvulsivantes/uso terapéutico , Peso Corporal , Carbamazepina/efectos adversos , Carbamazepina/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Carnitina/uso terapéutico , Niño , Femenino , Humanos , Hiperamonemia/tratamiento farmacológico , Lactante , Masculino , Enfermedades Musculares/tratamiento farmacológico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Factores de Riesgo , Ácido Valproico/efectos adversos , Ácido Valproico/uso terapéuticoRESUMEN
OBJECTIVE: Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones. METHODS: We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls. RESULTS: There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 µmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three. CONCLUSIONS: Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes.
Asunto(s)
Amoníaco/sangre , Anticonvulsivantes/efectos adversos , Epilepsia del Lóbulo Frontal/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/inducido químicamente , Hiperamonemia/inducido químicamente , Ácido Valproico/efectos adversos , Accidentes por Caídas , Adulto , Anticonvulsivantes/uso terapéutico , Progresión de la Enfermedad , Epilepsia del Lóbulo Frontal/sangre , Femenino , Trastornos Neurológicos de la Marcha/sangre , Humanos , Hiperamonemia/sangre , Masculino , Ácido Valproico/uso terapéuticoRESUMEN
PURPOSE: High-dose 5-fluorouracil (5-FU) containing chemotherapy occasionally causes hyperammonemia and can be lethal. However, the mechanism of 5FU-associated hyperammonemia has not been known. The aim of this study was to reveal the pharmacokinetics of 5-FU-associated hyperammonemia in a recurrent colorectal cancer patient with end-stage renal disease (ESRD). METHODS: We experienced a case of hyperammonemia during mFOLFOX6 plus bevacizumab therapy for recurrent colorectal cancer. He was a dialyzed patient due to diabetic nephropathy and was registered to prospective blood sampling for pharmacokinetics analysis during chemotherapy. Blood concentrations of 5-FU and its catabolites were determined by inductively coupled plasma-mass spectrometry. RESULTS: The patient developed hyperammonemia encephalopathy 41 h after the initiation of continuous 5-FU infusion (on the third day). Before onset of hyperammonemia encephalopathy, serum alpha-fluoro-beta-alanine (FBAL, 59.2 µg/ml) and fluoro mono acetate (FMA, 905.8 ng/ml) were gradually increased. After hemodialysis for hyperammonemia, FBAL and FMA were collaterally decreased and his symptom was improved. Other intermediate catabolites of 5-FU, dihydrofluorouracil, and alpha-fluoro-beta-ureidopropionic acid were not changed. CONCLUSION: We found increases of serum FBAL and FMA under the condition of hyperammonemia in the patient with ESRD during mFOLFOX6 plus bevacizumab therapy. This research supported the hypothesis that impairment of tricarboxylic acid (TCA) cycle by FMA would cause 5-FU-associated hyperammonemia.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Fluoroacetatos/sangre , Fluorouracilo/efectos adversos , Hiperamonemia/inducido químicamente , Hiperamonemia/metabolismo , beta-Alanina/análogos & derivados , Anciano , Amoníaco/sangre , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Terapia Combinada , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/terapia , Fluorouracilo/uso terapéutico , Humanos , Hiperamonemia/terapia , Masculino , Diálisis Renal , beta-Alanina/sangreRESUMEN
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.
Asunto(s)
Cloruro de Amonio , GMP Cíclico/metabolismo , Flavanonas/farmacología , Ácido Glutámico/sangre , Hiperamonemia/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Síndromes de Neurotoxicidad/prevención & control , Óxido Nítrico/sangre , Amoníaco/sangre , Animales , Antioxidantes/metabolismo , Biomarcadores/sangre , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Modelos Animales de Enfermedad , Glutamato-Amoníaco Ligasa/genética , Glutamato-Amoníaco Ligasa/metabolismo , Hiperamonemia/sangre , Hiperamonemia/inducido químicamente , Hiperamonemia/genética , Riñón/efectos de los fármacos , Riñón/enzimología , Peroxidación de Lípido/efectos de los fármacos , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Síndromes de Neurotoxicidad/sangre , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/genética , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo I/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Guanilil Ciclasa Soluble/genética , Guanilil Ciclasa Soluble/metabolismo , Factores de TiempoRESUMEN
Sunitinib has become a standard treatment agent for metastatic renal cell carcinoma (RCC) for several years. However, various adverse events have been reported. We present a rare adverse effect of hyperammonemic encephalopathy induced by sunitinib. A 66-year-old woman with metastatic RCC referred to the emergency department with confusion that developed 14 days after the initiation of 50 mg/d of sunitinib. Her serum ammonia and thyroid-stimulating hormone levels were markedly elevated (146 µg/dL and 27.27 µIU/mL, respectively). Sunitinib was discontinued, and an enema with lactulose and L-thyroxine were administered. Her mental status and neurologic symptoms were normalized 7 days after the treatment. Serum ammonia level decreased to 61 µg/dL and thyroid stimulating hormone level decreased 22.34 µIU/mL. The incidence of sunitinib-induced hyperammonemia is rarely reported. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. Sunitinib-induced hyperammonemia is very rare, and to the best of our knowledge, this is fourth case hyperammonemia and first case hyperammonemic encephalopathy with hypothyroidism as an adverse effect. Therefore, it is important for clinicians to be aware of hyperammonemia that can occur in several days after the initiation of sunitinib treatment in metastatic RCC.
Asunto(s)
Antineoplásicos/efectos adversos , Encefalopatías/inducido químicamente , Carcinoma de Células Renales/tratamiento farmacológico , Hiperamonemia/inducido químicamente , Hipotiroidismo/inducido químicamente , Indoles/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Pirroles/efectos adversos , Anciano , Carcinoma de Células Renales/secundario , Femenino , Humanos , Neoplasias Renales/patología , SunitinibRESUMEN
Fluorouracil (5-FU; Adrucil®) is a pyrimidine analog antineoplastic chemotherapy agent which works by interfering with DNA and RNA synthesis. It has an uncommon toxicity called hyperammonemic encephalopathy. This neurotoxicity is associated with a high-dose administration of 5-FU (2,600 mg/m(2)/week), with an incidence rate of 5.7%, and is not normally seen with the current dose of 1,200 mg/m(2) infused over 46 h. The mechanism behind this neurotoxicity is not known but is possibly due to accumulation of fluorocitrate, a byproduct of 5-FU metabolism. This by-product inhibits the Krebs cycle, which causes impairment of the adenosine triphosphate-dependent urea cycle. By impairing this cycle, ammonia is not converted to urea, which in turn this leads to an accumulation of ammonia. The accumulated ammonia in the brain is metabolized to glutamine, which has been suggested to cause an increase in intracranial pressure and cerebral edema. This case report discusses how a 40-year-old male with colorectal cancer experienced 5FU-induced hyperammonemia and was treated for it and how reducing the dose by 50% led to resolution of this symptom from reoccurring.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/efectos adversos , Hiperamonemia/inducido químicamente , Adulto , Humanos , MasculinoRESUMEN
We describe a case of a 35-year-old woman who presented with bilateral leg weakness and encephalopathy while on long-term valproate therapy. She was diagnosed with valproate-induced encephalopathy due to carnitine deficiency. Clinical improvement occurred with oral carnitine supplementation. Our case report highlights the importance of considering carnitine deficiency in patients presenting with unexplained neurological signs while on long-term valproate treatment.