fumarates and Liver-Diseases

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCDs), a group of inborn errors of hepatic metabolism that often result in life-threatening hyperammonemia. Argininosuccinate lyase (ASL) catalyzes the fourth reaction in this cycle, resulting in the breakdown of argininosuccinic acid to arginine and fumarate. ASL deficiency (ASLD) is the second most common UCD, with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal-onset form with hyperammonemia within the first few days after birth or as a late-onset form with episodic hyperammonemia and/or long-term complications that include liver dysfunction, neurocognitive deficits, and hypertension. These long-term complications can occur in the absence of hyperammonemic episodes, implying that ASL has functions outside of its role in ureagenesis and the tissue-specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype or enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with hyperammonemia involves discontinuing oral protein intake, supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen-scavenging therapy. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management. Orthotopic liver transplantation (OLT) is best considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy.

Topics: Arginine; Argininosuccinate Lyase; Argininosuccinic Acid; Argininosuccinic Aciduria; Child, Preschool; Citrulline; Cognition Disorders; Diet, Protein-Restricted; Fumarates; Genetic Testing; Glucose; Humans; Hyperammonemia; Hypertension; Infant; Infant, Newborn; Lipids; Liver Diseases; Liver Transplantation; Neonatal Screening; Phenylbutyrates; Sodium Benzoate

Technosphere® [Bis-3,6(4-fumarylaminobutyl)-2,5-diketopiperazine (FDKP)] microparticles, the integral component of the Technosphere inhalation system, deliver drugs to the deep lung and have been used to administer insulin and glucagon-like peptide-1 via inhalation in clinical studies. Three studies were conducted to characterize FDKP pharmacokinetics, including assessments in subjects with diabetic nephropathy (DNP), in subjects with chronic liver disease (CLD), and in healthy subjects.. An open-label, nonrandomized, two-period, fixed-sequence crossover absorption, distribution, metabolism, and excretion (ADME) study was conducted in six healthy nonsmoking men who received single intravenous and oral doses of [(14)C]FDKP solution, with serial sampling of blood, urine, feces, and expired air. Additionally, two single-dose, open-label, parallel-design studies with 20 mg of inhaled FDKP were conducted in (1) 12 diabetic subjects with normal renal function and 24 DNP subjects and (2) 12 healthy subjects and 21 CLD subjects.. In the ADME study, >95% of the intravenous dose and <3% of the oral dose were recovered in urine, with no evidence of metabolism. No significant pharmacokinetic differences were observed between healthy subjects and CLD subjects [geometric mean (% coefficient of variation) area under the curve from time 0 to 480 minutes (AUC(0-480)): 26,710 (34.8) and 31,477 (28.8) ng/ml·min, respectively]. Maximum observed drug concentration (C(max)) and AUC(0-480) were higher in DNP subjects than in subjects with normal renal function [C(max): 159.9 (59.4) ng/ml versus 147.0 (44.3) ng/ml; AUC(0-480): 36,869 (47.2) ng/ml·min versus 30,474 (31.8) ng/ml·min]. None of the differences observed were considered clinically significant.. Fumaryl diketopiperazine is predominantly cleared unchanged by the kidney with essentially no oral bioavailability. Technosphere is a safe delivery vehicle for medications administered via inhalation.

Topics: Administration, Inhalation; Adult; Aged; Chronic Disease; Diabetic Neuropathies; Drug Delivery Systems; Excipients; Female; Fumarates; Humans; Injections, Intravenous; Kidney; Liver Diseases; Male; Microspheres; Middle Aged; Piperazines

Aliskiren is the first in a new class of orally active, direct renin inhibitors for the treatment of hypertension. This open-label, nonrandomized, single-center, parallel-group study compared the pharmacokinetics and safety of a single 300-mg oral dose of aliskiren in patients with mild, moderate, or severe hepatic impairment to that in healthy subjects. When pooled across subgroups, there were no significant differences between patients with hepatic impairment and healthy subjects in aliskiren AUC(0-infinity) (ratio of geometric means, 1.12; 90% confidence interval, 0.85, 1.48) or Cmax (mean ratio, 1.19; 90% confidence interval, 0.84, 1.68), and there was no correlation between severity of hepatic impairment and either AUC(0-infinity) or Cmax. Aliskiren was well tolerated by healthy subjects and patients with hepatic impairment. In conclusion, hepatic impairment has no significant effect on the pharmacokinetics of aliskiren following single-dose administration, and dosage adjustment is unlikely to be needed in patients with liver disease.

Topics: Amides; Antihypertensive Agents; Fumarates; Humans; Liver Diseases; Renin

Sepsis is a potentially fatal illness that can lead to impairment of multiple organs such as liver. The condition is deeply associated with oxidative stress and inflammation. Monomethyl fumarate (MMF) has manifested antioxidant and immunomodulatory properties. The aim of current study was to evaluate protective effects of MMF in sepsis-induced hepatic dysfunction.. Sepsis was induced by cecal ligation and puncture (CLP). Wistar rats were assigned to one of sham, CLP, CLP + dexamethasone (as positive control of inflammation) and CLP + MMF groups. Levels of serum IL-1β, IL-6, IL-10, AST, ALT and γ‑GT were quantified. Furthermore, Hepatic levels of GSH and MDA and mRNA expression of TNF and NFKBIA along with hepatic protein level of TLR-4 were assessed. Also, histopathological study of liver was carried out to evaluate hepatic injuries.. Septic rats demonstrated risen levels of IL-1β, IL-6, IL-10, AST, ALT and γ‑GT, while treatment with dexamethasone or MMF attenuated these levels. Moreover, enhancements in protein level of TLR-4 and mRNA levels of TNF and NFKBIA were observed in CLP rats. These elevations were mitigated in CLP-induced rats that were treated with either dexamethasone or MMF. Treatment with dexamethasone or MMF also shifted sepsis-induced disturbance in the levels of GSH and MDA towards sham levels. Hepato-protective effects of dexamethasone and MMF were further confirmed by histopathological observations.. Our findings imply that MMF alleviates sepsis-induced hepatic dysfunction by mitigating the inflammatory and oxidative state and this effect is at least partly mediated by the inhibition of TLR-4/NF-κB signalling pathway.

Topics: Animals; Antioxidants; Dexamethasone; Disease Models, Animal; Fumarates; Inflammation; Liver Diseases; Male; Maleates; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidative Stress; Rats; Rats, Wistar; RNA, Messenger; Sepsis; Signal Transduction; Toll-Like Receptor 4

Fumaric acid esters (FAE) have been used to treat severe psoriasis in northern Europe for over 20 years. A recent systematic review has shown FAE to be an effective systemic treatment for severe psoriasis. However, FAE remain unlicensed in the U.K.. To present data relating to the efficacy and tolerability of FAE in severe psoriasis and report our experiences of FAE therapy at one U.K. centre.. Patients who had received FAE for severe psoriasis at one U.K. regional referral centre between June 1999 and October 2003 were identified from pharmacy records. Their records were analysed retrospectively.. Fifty-eight patients (25 women, 33 men) were identified. Fifty-five (95%) of the 58 patients had previously used other systemic antipsoriatic therapies with over 70% previously using two or more agents. Thirty-two patients (55%) showed improvement in their psoriasis with 10 (17%) being rated as 'clear' or 'virtually clear' by the attending physician. No improvement was seen in 28% patients and 16% showed worsening of their disease. Adverse events were common and were reported in 66% patients. These mainly consisted of abdominal pain (61%), diarrhoea (55%), flushing (45%), nausea (21%) and malaise (15%). They led to discontinuation of treatment in 15 patients after a mean period of 4.7 months. Lymphocytopenia developed during treatment in 57% of patients, all of whom had had a baseline value within the normal range. In only one patient was this considered severe enough to warrant withdrawal of treatment.. Our study has shown that FAE are an effective therapy in selected patients with severe psoriasis, even in those who have previously been intolerant of systemic therapy or where it has failed.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Chi-Square Distribution; Dimethyl Fumarate; Eosinophilia; Female; Fumarates; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Lymphopenia; Male; Middle Aged; Psoriasis; Retrospective Studies; Treatment Outcome

In 28 patients with fulminant hepatic failure alkalaemia was present in 49 of a total of 65 observations. Alkalaemia was due primarlily to a low Pa, C02 in 30 instances and to raised plasma bicarbonate in 16 instances. Blood lactate, pyruvate, and acetoacetate were significantly raised, and in individual cases, blood citrate, succinate, and fumarate were elevated. Blood citrate rose progressively as the clinical condition worsened. Metabolic acidosis was only present in four patients. In three of these patients, all of whom had taken an overdose of paracetamol, the acidosis was severe, present before the onset of clinical heparic failure, and associated with hypoglycaemiaand mild hypotension. In two of these patients the acidosis was shown to be due to accumulation of lactic acid. Plasma free fatty acid concentrations were elevated out of proportion to the degree of ketosis.

Topics: Acetoacetates; Acid-Base Equilibrium; Acidosis; Acute Disease; Alkalosis; Bicarbonates; Carbon Dioxide; Citrates; Fatty Acids, Nonesterified; Fumarates; Hepatic Encephalopathy; Humans; Ketoglutaric Acids; Ketone Bodies; Lactates; Liver Diseases; Oxygen; Partial Pressure; Pyruvates; Succinates; Triglycerides

Topics: Alanine Transaminase; Alkaline Phosphatase; Arginine; Aspartate Aminotransferases; Bilirubin; Biopsy; Blood Proteins; Cholesterol; Chronic Disease; Clinical Enzyme Tests; Creatine Kinase; Fumarates; Hepatitis; Hepatitis A; Humans; L-Lactate Dehydrogenase; Liver; Liver Diseases; Liver Neoplasms; Lyases; Methods; Neoplasm Metastasis; Succinates