Hepatic and extensive. Metabolized to the active metabolite sulfoxide, and several inactive metabolites. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against <i>Mycobacterium tuberculosis</i>.
Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis .
IDENTIFICATION: Ethionamide is a drug for the treatment of tuberculosis. Ethionamide is a yellow crystalline powder. Soluble in 1 in 30 of alcohol. Very sparingly soluble in water. Slightly soluble in chloroform. Slightly soluble in ether. Soluble in methyl alcohol. Sparingly soluble in propylene glycol. Indications: For the treatment of pulmonary and extrapulmonary tuberculosis in conjunction with other antituberculous agents (when resistance to primary agents has developed). For the treatment of leprosy, as part of multi-drug regimens. In the treatment of pulmonary disease in Mycobacterium kansasii and other atypical mycobacteria. HUMAN EXPOSURE: Main risks and target organs: Most common adverse reactions are gastrointestinal disturbances including anorexia, nausea, vomiting, excessive salivation, a metallic taste, stomatitis and diarrhoea and hepatitis. Central nervous system effects include dizziness, drowsiness, headaches, convulsions, peripheral neuropathy, tremors and paraesthesias. There is no experience in acute overdose of ethionamide. One of the metabolites resembles isoniazid and one should watch for similar symptoms. Summary of clinical effects: Gastrointestinal: Anorexia, vomiting, stomatitis, diarrhea, System: excessive salivation, metallic taste, hepatotoxicity. Central Nervous: Mental depression, anxiety or psychosis, System: encephalopathy with pellagra-like symptoms, dizziness, drowsiness, headache, convulsion, peripheral neuropathy, tremors, paresthesias. Eye: Optic neuritis, optic atrophy, diplopia. Nose: olfactory disturbances Ear: Deafness Endocrine: Hypothyroidism, gynecomastia, impotence, menorrhagia, hypoglycemia. Integumentary: Alopecia, acne, severe allergic rashes, photodermatitis. Hematology: Thrombocytopenia Skeletal system: Rheumatic pains Cardiovascular: Postural hypotension Contraindications: Ethionamide should not be given to pregnant women unless the benefits outweigh its possible risk. To be used with caution in women of child-bearing age. Individuals with severe liver disease. Severe hypersensitivity. Note: Caution is necessary in administering ethionamide to patients with depression or other psychiatric diseases, chronic alcoholism, epilepsy, hypothyroidism or diabetes mellitus. Routes of entry: Oral: This is the usual route of administration for therapeutic use. Parenteral: Ethionamide hydrochloride has been given intravenously, but there is no commercial preparation. Other: Ethionamide has been administered as rectal suppositories. Absorption by route of exposure: Approximately 80% of a gastrointestinal oral dose of ethionamide is rapidly absorbed from the gastrointestinal tract. After oral administration, the bioavailability is about 100%. Relative bioavailability after rectal administration was 57.3% of that following oral administration. Distribution by route of exposure: It is widely distributed throughout body tissues and fluids. It crosses the placenta and penetrates the meninges, appearing in the CSF in concentrations equivalent to those in the serum. Protein binding is low (10%). Biological half-life by route of exposure: Half-life is 2 to 3 hours. Ethionamide is extensively metabolized, probably in the liver, to ethionamide sulfoxide, 2-ethylisonicotinic acid and 2-ethylisonicotinamide. The sulfoxide is the main active metabolite. Elimination by route of exposure: Less than 1% of a dose appears in the urine as unchanged drug, the remainder is excreted in the urine as inactive metabolites. Mode of action: Toxicodynamics: In view of the structural similarity of the metabolite 2-methylisonicotinic acid to isoniazid, it has been suggested that toxicity is due to pyridoxine deficiency. Pharmacodynamics: Ethionamide inhibits the synthesis of mycolic acids and stimulates oxidation reduction reactions. Treated cells lose acid fastness. Both the drug and the sulfoxide metabolite are active against M.tuberculosis. 2-ethylisonicotinic acid and 2-ethylisonicotinamide are not active metabolites. It is bacteriostatic against M. tuberculosis at therapeutic concentrations, but may be bactericidal at higher concentrations. It is bactericidal against M. lepra. Resistance develops rapidly if used alone and there is complete cross-resistance with prothionamide, thiacetazone and thiambutosine. Toxicity: Adults: In clinical use, neuropsychiatric symptoms, such as headache, sleeping, insomnia, depression and paresthesia may occur. Elevation of liver transaminase enzymes has been known to develop. No special precautions are required due to age, as doses are adjusted according to patient response. However, dose should be modified depending on liver and renal status. Interactions: Ethionamide taken with pyrazinamide may lead to abnormalities of liver function and the use of these two agents together should be avoided. The use of rifampicin with the thioamides (ethionamide or prothionamide) as part of the treatment of multibacillary leprosy has been associated with an unexpectedly high incidence of hepatotoxicity. Adverse nervous system effects of ethionamide, cylcoserine and isoniazid may be additive. The side effects of other tuberculostatic agents may be enhanced when ethionamide is administered concomitantly. Alcohol may contribute to psychotropic reactions in an ethionamide treated patient. More study is needed to clarify the clinical significance of this interaction. Main adverse effects: The most common adverse effects are dose-related, viz: gastrointestinal disturbances, including anorexia, excessive salivation, a metallic taste, nausea, vomiting, stomatitis, diarrhea and hepatitis. Dizziness, drowsiness, headache, postural hypotension and asthenia may also occur occasionally. Other side effects reported include acne, allergic reactions alopecia, convulsions, deafness, dermatitis (including photodermatitis), visual disturbances, tremors, gynecomastia, impotence, menstrual disturbances, olfactory disorders, peripheral and optic neuropathy, thrombocytopenia and rheumatic pains. Mental disturbances, including depression, anxiety and psychosis have been provoked. A pellagra-like syndrome with encephalopathy has been reported rarely. A tendency towards hypoglycemia may occur and could be of significance in patients with diabetes mellitus. Hypothyroidism has also occurred. Racial differences in tolerance may occur, e.g. Chinese and Africans are often more tolerant of ethionamide than are Europeans. ANIMAL/PLANT STUDIES: A rat study showed the sublethal neurotoxicity which included paralysis, loss of screen grip and decreased motor activity. Teratogenicity: Teratogenic effects have been reported in rabbits, mice and rats, in which high doses have led to abortions and some malformations. Mutagenicity: Ethionamide was not found to be mutagenic as shown by Ames Salmonella and micronuclei assay test.
Ethionamide therapy has been linked to elevations in serum aminotransferase levels in a proportion of patients, but these elevations are typically self-limited and asymptomatic. More importantly, ethionamide has been linked to many instances of clinical apparent acute liver injury that arise in up to 5% of patients and can be severe and even fatal. The time to onset and clinical features of hepatic injury due to ethionamide resemble those of isoniazid, the latency ranging from 2 weeks to more than 6 months after starting (most arise within 1 to 3 months), and the pattern of enzyme elevations typically being hepatocellular and resembling acute viral hepatitis. Features of hypersensitivity (rash, fever and eosinophilia) are uncommon. Like isoniazid, ethionamide therapy may be associated with development of autoantibodies (typically ANA), but titers are generally low and rarely accompanied by autoimmune conditions. Cases of severe hypersensitivity reaction including Stevens Johnson Syndrome and DRESS which can be accompanied by liver injury have been described with ethionamide.
Essentially completely absorbed following oral administration and not subjected to any appreciable first pass metabolism. Bioavailability approximately 100%.
[EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
申请人：MERCK SHARP & DOHME
公开号：WO2015054038A1
公开（公告）日：2015-04-16
This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
[EN] ISOXAZOLE-THIAZOLE DERIVATIVES AS GABA A RECEPTOR INVERSE AGONISTS FOR USE IN THE TREATMENT OF COGNITIVE DISORDERS<br/>[FR] DÉRIVÉS D'ISOXAZOLE-THIAZOLE COMME AGONISTES INVERSES DU RÉCEPTEUR GABA A, UTILES DANS LE TRAITEMENT DE TROUBLES COGNITIFS
申请人：HOFFMANN LA ROCHE
公开号：WO2010127974A1
公开（公告）日：2010-11-11
The present invention is concerned with isoxazole-thiazole derivatives of formula I, having affinity and selectivity for GABA A α5 receptor, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful as cognitive enhancer or for the therapeutic and/or prophylactic treatment of cognitive disorders like Alzheimer's disease.
本发明涉及式I的异恶唑-噻唑衍生物，具有对GABA A α5受体的亲和力和选择性，其制备、含有它们的药物组合物以及它们作为治疗活性物质的用途。本发明的活性化合物可用作认知增强剂或用于治疗和/或预防认知障碍，如阿尔茨海默病。
[EN] VIRAL POLYMERASE INHIBITORS<br/>[FR] INHIBITEURS DE POLYMERASE VIRALE
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2004065367A1
公开（公告）日：2004-08-05
An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein wherein A, B, R2, R3, L, M1, M2, M3, M4, Y1, Y0, Z and Sp are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.
[EN] OXAZOLIDINONE COMPOUNDS AND METHODS OF USE THEREOF AS ANTIBACTERIAL AGENTS<br/>[FR] COMPOSÉS OXAZOLIDINONE ET PROCÉDÉS D'UTILISATION DE CES DERNIERS EN TANT QU'AGENTS ANTIBACTÉRIENS
申请人：MERCK SHARP & DOHME
公开号：WO2017066964A1
公开（公告）日：2017-04-27
The present invention relates to oxazolidinone compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, E, and R1 are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosiscomprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or apharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.
The present invention provides AA targeting compounds which comprise AA targeting agent-linker conjugates which are linked to a combining site of an antibody. Various uses of the compounds are provided, including methods to treat disorders connected to abnormal angiogenesis.
