Hydralazine is N-acetylated in the bowel and/or the liver. The rate of acetylation is genetically determined; about half of the people in the United States acetylate rapidly and half do so slowly.
Since the systemic clearance exceeds hepatic blood flow, extrahepatic metabolism must occur. ... Hydralazine rapidly combines with circulating alpha-keto acids to form hydrazones, and the major metabolite recovered from the plasma is hydralazine pyruvic acid hydrazone.
... Pharmacokinetic data indicate hydralazine ... has an extensive and complex metabolism depending on acetylator status: slow acetylators undergo primary oxidative metabolism, while rapid acetylators are acetylated. ...
IDENTIFICATION: Hydralazine, hydralazine hydrochloride are antihypertension agents. Hydralazine is a white to off-white crystalline powder. It is odorless to almost odorless compound. Solubilities are: soluble in water, slightly soluble in ethanol and in methanol; practically insoluble in ether or chloroform. Hydralazine is used to treat arterial hypertension (primary; malignant; pulmonary; pre-eclampsia and eclampsia), congestive heart failure, pulmonary hypertension in chronic obstructive pulmonary disease, and aortic regurgitation. Some benefit may be seen if used in primary oesophageal motility disorders and psoriasis. Recent observations indicate that it can be used to withdraw patients from dobutamine in severe congestive heart failure. Infants with chronic heart failure and left-to-right shunts may experience some benefit with hydralazine use. HUMAN EXPOSURE: Main risks and target organs: Hypotension, sinus tachycardia, palpitations, sweating, flushing, and headache are the most commonly reported side effects. Severe hypotension may result in myocardial and/or cerebral ischemia. Congestive heart failure, peripheral neuropathy, paresthesia, hepatotoxicity, drug fever, nausea, vomiting and diarrhea are also possible side effects but are most commonly related to chronic use. A lupus-like syndrome may be seen in 15 per cent of patients taking 400 mg or more of hydralazine daily. A higher percentage of patients develop circulating antinuclear antibodies. This syndrome is less common in patients who receive less than 200 mg per day. The cardiovascular system is mainly affected by hydralazine. The nervous system, the liver, the gastrointestinal and the immunologic systems are also target organs. Summary of clinical effects: Signs and symptoms of poisoning depends on the dose taken and the time of exposure. These include severe hypotension, reflex tachycardia, palpitations, cardiac arrhythmias, syncope, sweating, cerebral and/or myocardial ischemia, headache and dizziness. Nausea, vomiting and diarrhoea are also observed. Hypokalemia and lactic acidosis can occur. Ten to twenty per cent of patients taking 400 mg or more of hydralazine can be affected by a lupus like syndrome. This effect is almost exclusively seen in slow acetylators. Chronic use may also lead to fluid retention, peripheral neuropathy and paresthesia. Bioavailability: Hydralazine bioavailability is variable, ranging from 50 to 90% of a single oral dose. Depending on the dose, peak plasma levels occur from 0.3 to 1.0 hour after a single oral dose. With increasing oral dose, there is a non-proportional increase in the hydralazine plasma levels. A saturation in the metabolic pathways (gut, liver) may be responsible for this phenomenon. Hydralazine undergoes first-pass metabolism which is determined by the acetylator phenotype. Therefore, different bioavailability patterns are expected: it is greater in slow acetylators than in fast acetylators. Food may interfere with hydralazine bioavailability. It has been demonstrated that plasma levels and area under the curve bioavailability is reduced up to 46 % if the drug is administered 45 minutes after a meal. Contraindications: With the exception of a history of systemic lupus erythematosis there are no absolute contraindications to hydralazine use if combined with an adrenergic blocker. Relative Contraindications: Hydralazine should be used cautiously in patients with dissecting aortic aneurysm, heart failure with high output, cor pulmonale or myocardial insufficiency caused by mechanical obstruction due to valvular diseases. It should also be used with caution in patients with coronary and/or cerebrovascular diseases because of increased ischemia. Renal failure requires dose adjustment despite the acetylator phenotype. In geriatric patients it is wise to start with lower doses (about one-half of the adult normal dose), with subsequent titration. Postural hypotension and other side effects are more common in older people. Routes of entry: Oral: Oral ingestion is most likely the most common route of poisoning. Parenteral: Poisoning may occur by intravenous administration. Parenteral therapy is recommended only when the oral route is not feasible. Absorption by route of exposure: By the oral route, hydralazine absorption is variable and ranges from 50 to 90 %. Bioavailability is greater in slow compared to fast acetylators. Increasing the dose, there is a non-proportional increase in the serum levels, possibly because of saturation in the metabolic pathways of hydralazine. Peak plasma levels are achieved in about 60 minutes after ingestion. The maximum hypotensive effect occurs from 2 to 4 hours after ingestion and may persist for up to 24 hours. Distribution by route of exposure: Binding to plasma proteins is reported to be greater than 87 %. Hydralazine can be found in high concentrations in liver, kidneys, lungs, adrenals and arteries. Biological half-life by route of exposure: Biological half-life is about 3 to 4 hours and is not related to the rate of acetylation. However, the half-life of its antihypertensive effect may last up to 100 hours. The effects may be prolonged with renal failure. Metabolism: Hydralazine undergoes first pass metabolism by acetylation which is genetically determined. The gastro-intestinal mucosa and the liver are the main sites of this saturable metabolic pathway. The major metabolites are: MTP; the acetylation product (3-methyl-1,2,4-triazolo-(3,4a)phtalazine); HPH hydralazine pyruvic acid hydrazone), which is the major plasma metabolite; N-AcHPZ (4-(2-acetylhydrazino) phthalazin-1-one, which is mostly found in the urine and 3-OHMTP (3-hydroxymethyl-1,2,4-triazolo(3,4a) phtalazine. Systemic metabolism is dependent on hydroxylation followed by conjugation with glucuronic acid in the liver, which is not dependent on the rate of acetylation. Therefore, the half-life does not differ very much between slow and fast acetylators. Biotransformation of xenobiotics containing an aromatic amine or a hydrazine group by N-acetylation is dependent on the N-acetyltransferases enzymes which in humans are expressed by only two different enzymes, known as NAT1 and NAT2. Genetic polymorphism determines a reduction in the activity/stability of the NAT2 enzyme which is observed in slow acetylators. Elimination by route of exposure: About 65% of the total dose is excreted in the urine in 24 hours. Slow acetylators eliminate 15 to 20% as N-AcHPZ and 10% as conjugated 3-OHMTP. In fast acetylators, 30% is excreted in the urine as N-AcHPZ, as well as 10 to 30% as conjugated 3-OHMTP. The fecal contend of hydralazine is about 10% of the dose. Mode of action: Toxicodynamics: Hydralazine is a potent arteriolar vasodilator by producing relaxation of vascular smooth muscle. The vasodilation is most marked in the splanchnic, coronary, cerebral and renal arterial beds. Some of the symptoms may be caused by vasodilation and histaminic effects. Iron chelation may lead to anemia. A hydralazine-DNA pyrimidine interaction resulting in immune responses to hydralazine and nuclear antigens in which antibodies to native DNA occur can explain the hydralazine-induced lupus erythematosis. Recent observations have demonstrated that in the presence of metal ions or peroxidase hydrogen peroxide, hydralazine increased free radical production and site specific DNA-damage. It was suggested that this could be a possible explanation for hydralazine induced lupus, mutation and cancer. Slow acetylators produce hydralazine degradation to phthalazine through the intermediate of nitrogen-centered free radical and carbon centered free-radicals. In human red blood cells, hydralazine increases hydrogen peroxide production and proteolysis has been noted. As far as the hydralazine-induced lupus syndrome is concerned, since it is a rheumatic and febrile disease, and as a collagen simulating disease, it has become evident that this syndrome is indistinguishable from that of systemic lupus erythematous. Since then, it has been confirmed by several observations that anti-nuclear antibodies are almost always seen in the patients affected with the disease. These antibodies may persists for up to nine years after hydralazine exposure. A relationship between the phenotype acetylator activity to the antinuclear antibodies production and toxic symptoms in hypertensive patients was demonstrated. Slow acetylator Caucasian people are at higher risk. Pharmacodynamics: The mechanism of action of the vasodilation induced by hydralazine is not yet well understood. Recent observations suggest that it inhibits calcium release of the vascular smooth muscle sarcoplasmic reticulum by blocking the inositol trisphosphate (IP3)-induced calcium release, therefore reducing calcium turnover inside the cell. The resultant vasodilation reduces cardiac afterload, increasing cardiac function in patients with heart failure. However, some evidence exists concerning a direct action in the myocardium by an increase in calcium influx through the sarcolemma. This may be partially due to the stimulation of the beta-adrenoreceptors. However, a study describing a large number of patients found no evidence that hydralazine alters the risk of gut and lung cancer. Hydralazine readily crosses the placental blood-barrier but has no effect on the placental circulation. It has minimal effects on isolated human umbilical vessels. Human data have demonstrated that there is no increased risk of congenital malformations in the offspring of women treated with hydralazine, even during the first trimester of pregnancy. Some cases of hydralazine-induced neonatal thrombocytopenia with increased risk of bleeding were reported to the Swedish. Interactions: Indomethacin may produce a clinically important decrease in the hypotensive effects of hydralazine, however, such effects have been demonstrated only in healthy volunteers. Some pharmacokinetic interactions have been described with the concomitant administration of hydralazine and beta-blockers. Increased bioavailability of propranolol, and of metoprolol were observed in these circumstances. This interaction was not seen with a sustained release preparation of propranolol. Pyridoxine can reverse the neuropathy produced by hydralazine. Severe hypotensive sequelae of combined diazoxide and hydralazine therapy was observed in some patients. Beta-blockers can reduce the side effects produced by sympathetic stimulation when hydralazine is clinically used to treat hypertension. However, when used in pregnancy associated with propranolol, some negative effects on fetal development may occur. These effects are not seen with the combination of pindolol and hydralazine. Combined with propranolol, there may be a reduction in the activity of lipoprotein lipase activity, and alteration of the lipid profile. Organic nitrates when associated with hydralazine may have beneficial effects in patients with long-standing mitral regurgitation. In patients with heart failure, the combination of hydralazine and dinitrate isosorbide has a better survival rate compared to placebo. Main adverse effects: Hypotension, syncope, headache, myocardial and/or cerebral ischemia, flushing, nasal congestion, angina pectoris, fluid retention, edema of the lower extremities, palpitations, tachycardia, nausea and vomiting. Myocardial infarction and sudden death can occur. Antinuclear antibodies and lupus-like syndrome may occur. ANIMAL/PLANT STUDIES: Combined with prenalterol, hydralazine exhibits a cardiotoxic effect by enhancing myocardial necrosis in rats. This effect could not be reproduced in rabbits. Carcinogenicity: Hydralazine has been associated with the appearance of lung carcinogenesis in mice. In mice and rabbits, hydralazine can produce skeletal malformations due to its effect on the collagen synthesis. When given to pregnant rats in doses non-toxic to the mother, hydralazine does not have teratogenic or fetotoxic effects. Mutagenicity: Hydralazine can induce structural and/or conformational changes in DNA. It has a clastogenic effect in the liver which can be the main target site of genotoxicity.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
人类致癌性证据不足。动物致癌性证据有限。总体评估：第3组：该物质对人类致癌性不可分类。
Inadequate evidence of carcinogenicity in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.
◉ Summary of Use during Lactation:Limited milk level and infant serum level data and a long history of use in postpartum mothers indicate that hydralazine is an acceptable antihypertensive in nursing mothers, even those nursing newborns.
◉ Effects in Breastfed Infants:No adverse effects reported in one infant breastfed for 8 weeks.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
...The possibility exists that nialamide may prolong and intensify the antihypertensive action of hydralazine by inhibiting its metabolism and by an additive effect of interfering with adrenergic functional transmission.
One patient receiving both hydralazine and hexamethonium several times a day after bilateral sympathectomy for systemic hypertension developed a myopia of more than one diopter in definite association with the use of these drugs.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
肼屈嗪通过胃肠道吸收良好，但系统性生物利用度较低（快乙酰化者为16%，慢乙酰化者为35%）。
Hydralazine is well absorbed through the GI tract, but the systemic bioavailability is low (16% in fast acetylators and 35% in slow acetylators).
The peak concentration of hydralazine in plasma and the peak hypotensive effect of the drug occur within 30 to 120 minutes of ingestion. Although its half-life in plasma is about an hour, the duration of the hypotensive effect of hydralazine can last as long as 12 hours. There is no clear explanation for this discrepancy.
A Convenient Synthesis of 4-Acetyl-5-hydroxy-3-methyl-1-substituted Pyrazoles
摘要：
Reaction of 1-(5-hydroxy-3-methyl-1-substituted-4-pyrazolyl)-1, 3-butanediones (1a-d) with 1-hydrazinophthalazine hydrochloride leads to the formation of 4-acetyl-5-hydroxy-3-ethyl-1-substitutedpyrazoles (3a-d) along with 3-methyl-s-triazolo[3,4-a] phthalazine (4) in good yields.
A stabilized preparation which comprises: a unstable drug in a polyethylene glycol-containing preparation; and a coating agent comprising a copolyvidone instead of polyethylene glycol with which the drug is coated.
Sulfonyl-containing 2,3-diarylindole compounds, methods for making same, and methods of use thereof
申请人：——
公开号：US20040058977A1
公开（公告）日：2004-03-25
The present invention relates to sulfonyl-containing 2,3-diarylindole, especially to new compounds of general Formula, to a preparation method for their preparation, to pharmaceutical compositions containing said compound, and to the medical use thereof in the treatment of diseases relating to the inhibition of cyclooxygenase-2 (COX-2).
The present invention relates to novel compounds that are useful in the treatment of metabolic disorders, particularly type II diabetes mellitus and related disorders, and also to the methods for the making and use of such compounds.
[EN] FUMAGILLOL COMPOUNDS AND METHODS OF MAKING AND USING SAME<br/>[FR] COMPOSÉS DE FUMAGILLOL, ET LEURS PROCÉDÉS DE FABRICATION ET D'UTILISATION
申请人：ZAFGEN INC
公开号：WO2018031877A1
公开（公告）日：2018-02-15
Disclosed herein, in part, are fumagillol compounds and methods of use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making fumagillol compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
The present invention provide a heterocyclic compound having a HDAC inhibitory action, and useful for the treatment of autoimmune diseases and/or inflammatory diseases, graft versus host disease, cancers, central nervous diseases including neurodegenerative diseases, Charcot-Marie-Tooth disease and the like, and a pharmaceutical composition comprising the compound.
The present invention relates to a compound represented by the formula (I):
wherein each symbol is as defined in the specification, or a salt thereof.
