Disease relevance of ANP 3624

• Acute renal failure from ticrynafen [1].
• Ticrynafen is useful in the treatment of hypertension and in selected cases of chronic congestive heart failure [2].
• The third group included drug-induced hepatitis with special antibody:iproniazid-induced hepatitis with antimitochondrial antibody 6 and tienilic acid (ticrynafen)-induced hepatitis with antiliver/kidney microsome antibody 2 (anti-LKM2) [3].
• Antibodies against cytochrome P-450 are found in some children with autoimmune hepatitis (antiliver/kidney microsome 1) and in patients with ticrynafen hepatitis (antiliver/kidney microsome 2) [4].
• Three of 10 sera from patients receiving tienilic acid but without overt liver damage also induced significant cytotoxicity to these hepatocytes, however, although none of 20 normal controls or of 16 patients with other liver diseases did so [5].

Psychiatry related information on ANP 3624

• Thus, ticrynafen is a promising therapeutic agent in hypertension, adding a unique uricosuric effect that should improve patient compliance [6].

High impact information on ANP 3624

• However, these reactions illustrate the potential hazards from widespread substitution of ticrynafen for thiazide diuretics in the treatment of hypertension [7].
• In a double-blind study, 20 hypertensive patients were randomly assigned to a six-week regimen of either ticrynafen or hydrochlorothiazide [8].
• Blood pressure was significantly reduced with both medications, although most patients required an increase in dosage from 250 to 500 mg ticrynafen daily [8].
• Tienilic acid hepatitis sera contain antibodies against this tienilic acid adduct, in addition to the previously described anticytochrome P450 autoantibodies [9].
• Patients with tienilic acid hepatitis exhibit autoantibodies that recognize unalkylated cytochrome P450 2C9 in humans but recognize 2C11 in rats [9].

Chemical compound and disease context of ANP 3624

• Biochemical and haematological changes induced by tienilic acid combined with propranolol in essential hypertension [10].
• To examine the ticrynafen-warfarin interaction, normal subjects received large single doses of 1.5 mg/kg racemic warfarin with and without daily oral doses of 250 mg ticrynafen beginning 3 days before warfarin and continuing for the duration of hypoprothrombinemia [11].
• Results of qualitative and quantitative covalent binding of tienilic acid metabolite(s) to human liver microsomes were then compared to those obtained with two drugs leading to direct toxic hepatitis, namely, acetaminophen and chloroform [12].
• Other than eventual hyperbilirubinemia with slightly increased biliary bilirubin, a single oral treatment of EHBR with tienilic acid at 300 mg/kg caused no changes in serum alanine aminotransferase and alkaline phosphatase, bile flow rate and biliary bile acid secretion, or hepatic morphology [13].
• It is concluded that ticrynafen is a useful diuretic in the treatment of congestive heart failure and has the advantage of lowering serum uric acid rather than producing hyperuricemia [14].

Biological context of ANP 3624

• It is also shown that anti-cytochrome P-450-8 antibodies as well as human serum containing anti-LKM2 antibodies specifically inhibit the hydroxylation of tienilic acid by human liver microsomes [15].
• Ticrynafen produced diuresis and increased clearances of Na, K, and Cl [16].
• In order to investigate the mechanisms underlying the hepatotoxicity associated with tienilic acid (Ticrynafen) ingestion we have looked for evidence of sensitisation to drug altered liver cell determinants using an indirect antibody dependent, cell mediated cytotoxicity assay (ADCC) [5].
• Urate excretion per unit of glomerular filtration rate and urate clearance (Curate) per unit of glomerular filtration rate were increased after the administration of SKF-62698 [17].
• Ticrynafen in anephric patients: effects on uric acid and pharmacokinetics [18].

Anatomical context of ANP 3624

• Rats were treated with tienilic acid and hepatocytes were isolated [9].
• Cytochrome P450 2C11 was the main microsomal or plasma membrane protein that was alkylated by tienilic acid [9].
• Basophil count and haemoglobin were lower after tienilic acid treatment than they had been at the start of the study [10].
• Effect of ticrynafen on aqueous humor dynamics in monkeys [19].
• Comparative effects of ticrynafen and hydrochlorothiazide on blood pressure, renal function, serum uric acid and electrolytes, and body fluid spaces in hypertensive man [20].

Associations of ANP 3624 with other chemical compounds

• The effects of tienilic acid and propranolol on blood-pressure were additive and there were no statistically significant interactions [10].
• Serum creatinine and blood urea nitrogen rose slightly more with ticrynafen than with hydrochlorothiazide [21].
• Thiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid [22].
• Its interaction with several substrates (tienilic acid and two derivatives, lauric acid and diclofenac) and with a specific inhibitor, sulfaphenazole, was studied by UV-visible and 1H NMR spectroscopy [23].
• We have accumulated evidence that autoimmune antibodies observed in sera of patients with tienilic acid induced hepatitis (anti-liver kidney microsome 2 or anti-LKM2 antibodies) specifically recognize the cytochrome P-450 involved in the mephenytoin hydroxylation polymorphism [24].

Gene context of ANP 3624

• In hepatitis induced by tienilic acid, tienilic acid is activated by and covalently bound to cytochrome P450 2C9 [25].
• This recognition was decreased by adsorption with tienilic acid or by preexposure to the anti-tienilic acid or the anti-cytochrome P450 2C11 antibody [9].
• Tienilic acid enhances hyperbilirubinemia in Eisai hyperbilirubinuria rats through hepatic multidrug resistance-associated protein 3 and heme oxygenase-1 induction [13].
• We demonstrated that tienilic acid, a diuretic drug withdrawn from the market because of hepatic failure, enhanced hyperbilirubinemia in Eisai hyperbilirubinuria rats (EHBR) with a defect of canalicular multidrug resistance-associated protein 2 (Mrp2) [13].
• Antigenic targets in tienilic acid hepatitis. Both cytochrome P450 2C11 and 2C11-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera [9].

Analytical, diagnostic and therapeutic context of ANP 3624

• Tienilic acid hepatitis sera that were preadsorbed on microsomes from untreated rats (to remove autoantibodies), poorly recognized untreated hepatocytes in flow cytometry experiments, but better recognized tienilic acid-treated hepatocytes [9].
• Hemodialysis (5 hr) reduced levels of ticrynafen by 38% but had less effect on metabolite levels [18].
• Application of this HPLC/ESI-MS technique made the detection of the covalent modification to P450 2C9 following mechanism-based inactivation by tienilic acid possible [26].
• METHODS: In normotensive eyes, facility (perfusion) was measured shortly before and after bolus or exchange intracameral infusion of ticrynafen or vehicle in opposite eyes, and 3.5 to 4.5 hours after 5 days of twice-daily 2% ticrynafen or vehicle ointment [19].
• Urinary output and serum or plasma levels of ticrynafen and its two metabolites were measured in specimens from human volunteers receiving one 250-mg tablet [27].

References