Isoniazid appears as odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8. (NTP, 1992)
颜色/状态：
COLORLESS OR WHITE CRYSTALS, OR A WHITE, CRYSTALLINE POWDER
蒸汽压力：
4.6X10-5 mm Hg at 25 °C /Estimated/
水溶性：
0.01
稳定性/保质期：
STABLE AT ROOM TEMP FOR MORE THAN 14 DAYS IN AQ SOLN AND MORE THAN 6 WK WHEN STORED AT ABOUT 4 °C.
分解：
When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
解离常数：
pK1= 1.75; pK2= 3.57; pK3= 10.75
碰撞截面：
125.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
Primarily hepatic. Isoniazid is acetylated by N -acetyl transferase to N -acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system. The rate of acetylation is genetically determined. Slow acetylators are characterized by a relative lack of hepatic N -acetyltransferase.
Isoniazid is inactivated in the liver, mainly by acetylation and dehydrazination. Metabolites of the drug include acetylisoniazid, isonicotinic acid, monoacetylhydrazine, diacetylhydrazine, and isonicotinyl glycine.
/IN MAN/ ... MOST IMPORTANT METABOLITES OF INH IN URINE /WERE FOUND/ TO BE 1-ACETYL-2-ISONICOTINOYLHYDRAZINE (ACETYL INH), N-ACETYL-N'-ISONICOTINIC ACID, ISONICOTINYLGLYCINE, PYRUVIC ACID ISONICOTINYLHYDRAZONE AND ALPHA-OXOGLUTARIC ACID ISONICOTINYLHYDRAZONE ... .
来源:Hazardous Substances Data Bank (HSDB)
代谢
活体兔中INH的代谢...产生异烟酸和氨，后者来自肼基团的快速分解...。
IN VIVO METABOLISM OF INH IN RABBIT ... YIELDS ISONICOTINIC ACID AND AMMONIA, LATTER BEING DERIVED FROM RAPID BREAKDOWN OF HYDRAZINE GROUP ... .
Acetylation of acetylisoniazid results in the formation of monoacetylhydrazine which has been shown to be a potent hepatotoxin in animals. Microsomal metabolism of monoacetylhydrazine in animals results in production of a reactive acylating species capable of covalently binding with tissue macromolecules (i.e., liver protein) and subsequently causing hepatic necrosis.
IDENTIFICATION: Isoniazid is used for the treatment of tuberculosis. Isoniazid is a colorless, odorless, white crystalline powder slowly affected by exposure to air and to light. It is soluble in water, alcohol, slightly soluble in chloroform and very slightly soluble in ether. Isoniazid is an antimycobacterial agent which is bactericidal for both extracellular and intracellular organisms. It is the primary drug for the treatment of tuberculosis when the disease is caused by isoniazid-sensitive strains of the Mycobacterium tuberculosis. In combination with rifampicin, ethambutol or pyrazinamide, isoniazid INH line agent in the treatment of pulmonary and extrapulmonary tuberculosis. It is a component of all combined antituberculosis chemotherapy regimens. Isoniazid may be used for tuberculosis prophylaxis. HUMAN EXPOSURE: Main risks and target organs: CNS is the target organ of isoniazid acute toxicity. Isoniazid induces generalized convulsions, coma and metabolic acidosis. Death may occur from acute respiratory failure or hypotension. Liver and peripheral nervous and hematologic systems are the main target organs of isoniazid chronic toxicity. Isoniazid INH may induce acute hepatitis, peripheral neuropathy, haemolytic anemia. Summary of clinical effects: Toxicity appears after a short delay of 0.5 to 4 hours following ingestion. Symptoms may include: slurred speech, hallucinations, coma; generalized convulsions, status epilepticus; respiratory failure, hypotension; severe metabolic acidosis, fever; rhabdomyolysis; gastrointestinal symptoms (nausea, vomiting) are frequent prior to the onset of convulsions. Hepatitis, peripheral neuropathy and hemolytic anemia are manifestations of chronic toxicity. Severe isoniazid poisoning is characterized by the clinical triad of: repetitive convulsions not responsive to usual treatment; metabolic acidosis and coma. Chronic isoniazid toxicity produces nausea, vomiting, restlessness, fever and many other signs and symptoms. Toxic hepatitis and hemolytic anemia may be observed, as well as other hematological effects and psychosis. Contraindications: Known severe adverse reactions or hypersensitivity due to the drug. Previous hepatitis associated with isoniazid. Isoniazid should not be used in patients with acute liver disease. Isoniazid may precipitate porphyria. Convulsions may be precipitated in patients with epilepsy. Liver function should be monitored regularly in patients with previous hepatic disease. Routes of entry: Oral: This is the most frequent route of intoxication because the drug is usually administered orally. Parenteral: No case has been reported, but isoniazid intoxication may occur after parenteral administration. Absorption by route of exposure: Oral: isoniazid is rapidly and almost completely (90-95%) absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 1 to 2 hours after ingestion. When INH is administered with food, the extent of absorption and the peak plasma concentration may be reduced. Distribution by route of exposure: Protein binding is less than 10 to 15 %. Isoniazid is distributed into all body tissues and fluids (pleural, ascitic fluids, saliva, CSF) with tissue or fluid levels similar to serum levels. Skin contains large amounts and acts as a storage depot. Isoniazid penetrates well into caseous lesions. Isoniazid readily crosses the placenta. The concentrations in milk are approximately equal to plasma maternal concentrations. Biological half-life by route of exposure: The plasma half-life in patients with normal renal and hepatic function is 1 to 4 hours, depending on the rate of metabolism: it is 0.5 to 1.6 hours in fast acetylators and 2 to 5 hours in slow acetylators. The plasma halflife may be prolonged to 4.3 hours in patients with impaired hepatic function or severe renal impairment. Plasma half life may also be prolonged in acute overdose. Metabolism: The major route of isoniazid metabolism is hepatic acetylation by N-acetyl transferase which produces acetylisoniazid. The rate of acetylation is genetically determined. Acetyisoniazid is further hydrolysed to isonicotinic acid and acetylhydrazine, both of which are excreted in the urine. Isonicotinic acid is conjugated with glycine. Acetylhydrazine is further metabolized to diacetylhydrazine and may be converted by the hepatic microsomal enzymes to the reactive metabolite (presumed to be hydrazine) which are thought responsible for isoniazid-induced hepatotoxicity. Elimination and excretion: Kidney: In adults with normal renal function, approximately 50 to 70% of a 5 mg/kg oral dose is excreted in urine within 24 hours as unchanged drug and as metabolites. The percentage of the different compounds excreted varies with the acetylator phenotype. Breast milk: 0.75 to 2.3% of the dose is excreted into breast milk in 24 hours. This corresponds to 6-20% of a usual therapeutic pediatric dose. Other routes: Small amounts of the drug are excreted in saliva, sputum and feces. Mode of action: Toxicodynamics: Tonic-clonic seizures and severe metabolic acidosis are the most common features in isoniazid overdose. Seizures: The precipitating mechanism of the seizures is not exactly known but it may be related to the isoniazid induced deficiency of pyridoxine. INH produces pharmacologic changes in pyridoxine metabolism. Increased renal excretion of pyridoxine by formation of isoniazid pyridoxine hydrazones. The hydrazones competitively inhibit pyridoxine kinase, the activating enzyme that converts pyridoxine to the physiologically active pyridoxal phosphate. Inactivation of the pyridoxal containing enzymes. The subsequent reduction in pyridoxine and pyridoxal phosphate inhibits the formation of the inhibitory neurotransmitter, gamma aminobutyric acid or GABA. This reduction in GABA levels may explain the seizures in patients with isoniazid poisoning. Metabolic acidosis: The metabolic acidosis may be related to: a lactic acidosis due to the seizures, a blockage in the conversion of lactate to pyruvate, an increased metabolism of fatty acids resulting from an impaired glucose metabolism with hyperglycemia and ketonuria. Neuropathy: Peripheral neuropathy secondary to chronic exposure is due to the deficiency of pyridoxine and pyridoxal phosphate. Hepatitis: Hepatitis is due to a toxic metabolite of monoacetyl hydrazine, which binds covalently to liver proteins. In some patients an allergic mechanism has also been proposed: acylation of hepatic macromolecules by acetyl hydrazine may lead to the release of antigenic macromolecules which induce the formation of antibodies directed against the liver. Pharmacodynamics: The exact mechanism of action of isoniazid is not known. Isoniazid may act by inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms. Since mycolic acids are unique to mycobacteria, this action explains the high degree of selectivity of the antimicrobial activity. Mutation conferring resistance may occur in susceptible microorganisms. There is a cross resistance between isoniazid, rifampicin and ethambutol. However the simultaneous use of two of these drugs markedly delays the emergence of resistant mutants either agent. Carcinogenicity: There is no evidence to support carcinogenic effects in humans. A recent study did not detect an increase in cancer deaths in a series of 338 women treated with INH for pulmonary tuberculosis. Several other studies fail to show a carcinogenic effect, including a study in which 25,000 patients followed up for 9 to 14 years and a study of 3,842 patients in the UK. Interactions: Several drugs may interact with INH: Drugs which interfere with INH pharmacokinetics: Aminosalicylic acid, procainamide, propranolol increase INH serum levels by reduction of the acetylation. Aluminium-containing antacids decrease the gastrointestinal absorption of the drug. Pyrazinamide decreases the serum levels of INH. Drugs which decrease serum levels when used with INH: Cyclosporine, enflurane, folic acid, ketoconazole, verapamil. Drugs which increase serum levels when used with INH: Carbamazepine, diazepam, dicoumarol, ethosuximide, phenytoin, primidone, theophylline. Other interactions: The concomitant administration of INH and the following drugs may produce: psychiatric responses: tricyclic antidepressants; hyperglycaemia: chlorpropamide; agitation or parkinsonian tremor: levodopa; hypotension: pethidine (meperidine); increased incidence of hepatotoxicity: rifampicin; hypertension, tachycardia, hyperthermia: monoamine oxidase inhibitors. Main adverse effects: Peripheral neuropathy and hepatotoxicity are the most frequently observed adverse effects of INH. Hepatotoxicity: Asymptomatic elevation of serum aspartate transferase (SGOT) is noted in 10-20 % of the patients. This increase is usually transient and the level returns to normal with continuing therapy. INH should be discontinued in patients with a transaminase level three times greater than normal. Hepatitis with jaundice may occur (0.5 %). In most cases, hepatitis occurs within the 3 months following the onset of the treatment. Some factors predisposing to INH hepatotoxicity include: age, alcohol, rapid acetylator status, concomitant administration of isoniazid and rifampicin. Peripheral neuropathies: Peripheral neuropathy is the most common side effect of INH. It is secondary to a pyridoxine deficiency. The predisposing factors are: alcohol, slow acetylator status, diabetes, malnutrition, pregnancy. Peripheral neuropathy is dose-related: it is uncommon at low doses and very frequent with high doses. Treatment and prophylaxis are based on administration of pyridoxine. Other adverse reactions: Hematologic: disseminated intravascular coagulation; granulocytosis, eosinophilia, anemia (hemolytic, aplastic, sideroblastic, megaloblastic), thrombocytopenia. Neurologic: peripheral neuropathy, hypersensitivity meningitis, dystonias, encephalopathy, seizures, cerebellar syndromes. Psychiatric: confusional states, transient memory impairment, delirium. Endocrine/metabolic: hyperglycemia, hypocalcemia, porphyria, gynecomastia. Gastrointestinal: abdominal pain, acute pancreatitis. Kidney: nephrotoxicity is a very rare complication, (1 case of acute renal insufficiency has been described). Ocular: optic neuropathy (especially when combined therapy with INH and ethambutol); optic atrophy Dermatologic: pellagra (due to a nicotinic acid deficiency), exfoliative dermatitis, Steven-Johnson syndrome; cutaneous reactions (2%), urticaria, angioneurotic oedema, morbilliform eruptions, purpura, acneiform eruptions, photosensitivity. Musculoskeletal: arthritis, arthralgias, systemic lupus erythematosis; antinuclear antibodies in the serum may appear, especially in slow acetylators, approximately five months after the onset of therapy.
Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular <i>Mycobacterium tuberculosis</i> organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from <i>Mycobacterium tuberculosis</i>, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.
Despite its limited use, isoniazid remains one of the most common causes of serious, idiosyncratic liver injury in the United States. Therapy with isoniazid is associated with transient serum aminotransferase elevations in 10% to 20% of patients, and levels rising above 5 times the upper limit of the normal range (ULN) in 3% to 5%. These enzyme elevations are usually asymptomatic and often resolve even with continuation of therapy without dose adjustment (Case 1 and 2).
In addition, isoniazid can also cause clinically apparent acute liver injury with jaundice, which arises in 0.5% to 1% and is fatal in 0.05 to 0.1% of recipients. Rates of hepatic injury vary greatly in the published literature. A major determinant of the variability is probably age. The rates of clinically apparent hepatitis due to isoniazid are estimated at 0.5% in patients 20 to 35 years of age, 1.5% in those 35 to 50 years of age, and 3% or higher in persons above the age of 50 years. Isoniazid hepatotoxicity is rare in children (but still occurs and can be fatal). Other risk factors are preexisting liver disease (hepatitis B or C), concurrent use of rifampin or pyrazinamide, and possibly alcoholism, black race and genetic factors. The typical time to onset of injury ranges from 2 weeks to 6 months, but can be as long as one year and as short as one week. The onset is usuallly insidious and resembles acute viral hepatitis with a prodromal period of nausea, anorexia, abdominal discomfort and fatigue, which is followed by dark urine and jaundice (Case 3 and 4). The pattern of liver enzyme elevations is typically hepatocellular with marked increases in ALT levels (>10 times ULN) and minimal increases in alkaline phosphatase values (usually
Likelihood score: A (well established cause of clinically apparent liver injury).
Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.
来源:DrugBank
吸收、分配和排泄
消除途径
从50%到70%的异烟肼剂量在24小时内通过尿液排出。
From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours.
ISONIAZID DIFFUSES READILY INTO ALL BODY FLUIDS AND CELLS. THE DRUG IS DETECTABLE IN SIGNIFICANT QUANTITIES IN PLEURAL AND ASCITIC FLUIDS; CONCENTRATIONS IN CEREBROSPINAL FLUID ARE SIMILAR TO THOSE IN THE PLASMA. ISONIAZID PENETRATES WELL INTO CASEOUS MATERIAL. THE CONCENTRATION OF THE AGENT IS INITIALLY HIGHER IN THE PLASMA AND MUSCLE THAN IN THE INFECTED TISSUE, BUT THE LATTER RETAINS THE DRUG FOR A LONG TIME IN QUANTITIES WELL ABOVE THOSE REQUIRED FOR BACTERIOSTASIS.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
从75%到95%的异烟肼剂量在24小时内以代谢物的形式通过尿液排出。
FROM 75 TO 95% OF A DOSE OF ISONIAZID IS EXCRETED IN THE URINE WITHIN 24 HR, MOSTLY AS METABOLITES.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
易于口服吸收；然而，可能会经历显著的首过代谢。当与食物一同服用异烟肼时，吸收和生物利用度降低。
Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability were reduced when isoniazid was administered with food.
Probing the catalytic mechanism of bovine CD38/NAD+glycohydrolase by site directed mutagenesis of key active site residues
摘要：
Bovine CD38/NAD(+) glycohydrolase catalyzes the hydrolysis of NAD(+) to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism. Our recent crystallographic study of its Michaelis complex and covalently-trapped intermediates provided insights into the modalities of substrate binding and the molecular mechanism of bCD38. The aim of the present work was to determine the precise role of key conserved active site residues (Trp118, Glu138, Asp147, Trp181 and Glu218) by focusing mainly on the cleavage of the nicotinamide-ribosyl bond. We analyzed the kinetic parameters of mutants of these residues which reside within the bCD38 subdomain in the vicinity of the scissile bond of bound NAD(+). To address the reaction mechanism we also performed chemical rescue experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. The crucial role of Glu218, which orients the substrate for cleavage by interacting with the N-ribosyl 2'-OH group of NAD(+), was highlighted. This contribution to catalysis accounts for almost half of the reaction energy barrier. Other contributions can be ascribed notably to Glu138 and Asp147 via ground-state destabilization and desolvation in the vicinity of the scissile bond. Key interactions with Trp118 and Trp181 were also proven to stabilize the ribooxocarbenium ion-like transition state. Altogether we propose that, as an alternative to a covalent acylal reaction intermediate with Glu218, catalysis by bCD38 proceeds through the formation of a discrete and transient ribooxocarbenium intermediate which is stabilized within the active site mostly by electrostatic interactions. (C) 2014 Elsevier B.V. All rights reserved.
[EN] PYRAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS DE PYRAZOLE UTILES COMME INHIBITEURS DE FAAH
申请人：MERCK & CO INC
公开号：WO2009151991A1
公开（公告）日：2009-12-17
The present invention is directed to certain imidazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer disease, and Parkinson's disease
SUBSTITUTED ARYL AND HETEROARYL CARBOXYLIC ACID HYDRAZIDES OR SALTS THEREOF AND USE THEREOF TO INCREASE STRESS TOLERANCE IN PLANTS
申请人：BAYER CROPSCIENCE AKTIENGESELLSCHAFT
公开号：US20180206495A1
公开（公告）日：2018-07-26
Substituted aryl- and heteroarylcarbonyl hydrazides
The invention relates to substituted aryl- and heteroarylcarbonyl hydrazides of the general formula (I) or salts thereof
where the radicals of the formula (I) are each as defined in the description for enhancing stress tolerance in plants to abiotic stress, and for enhancing plant growth and/or for increasing plant yield.
[EN] THIOPHENE DERIVATIVES FOR THE TREATMENT OF DISORDERS CAUSED BY IGE<br/>[FR] DÉRIVÉS DE THIOPHÈNE POUR LE TRAITEMENT DE TROUBLES PROVOQUÉS PAR IGE
申请人：UCB BIOPHARMA SRL
公开号：WO2019243550A1
公开（公告）日：2019-12-26
Thiophene derivatives of formula (I) and a pharmaceutically acceptable salt thereof are provided. These compounds have utility for the treatment or prevention of disorders caused by IgE, such as allergy, type 1 hypersensitivity or familiar sinus inflammation.
The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.
[EN] POLYCONJUGATES FOR DELIVERY OF RNAI TRIGGERS TO TUMOR CELLS IN VIVO<br/>[FR] POLYCONJUGUÉS POUR L'ADMINISTRATION DE DÉCLENCHEURS D'ARNI À DES CELLULES TUMORALES IN VIVO
申请人：ARROWHEAD RES CORP
公开号：WO2015021092A1
公开（公告）日：2015-02-12
The present invention is directed compositions for delivery of RNA interference (RNAi) triggers to integrin positive tumor cells in vivo. The compositions comprise RGD ligand- targeted amphipathic membrane active polyamines reversibly modified with enzyme cleavable dipeptide-amidobenzyl-carbonate masking agents. Modification masks membrane activity of the polymer while reversibility provides physiological responsiveness. The reversibly modified polyamines (dynamic polyconjugate or conjugate) are further covalently linked to an RNAi trigger.
