Two isomers of methyldopa undergo different metabolic pathways. L-α-methyldopa is biotransformed to its pharmacologically active metabolite, alpha-methylnorepinephrine. Methyldopa is extensively metabolized in the liver to form the main circulating metabolite in the plasma, alpha (α)-methyldopa mono-O-sulfate. Its other metabolites also include 3-O-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; and 3-O-methyl-α-methyldopamine. These metabolites are further conjugated in the liver to form sulfate conjugates. After intravenous administration, the most prominent metabolites are alpha-methyldopamine and the glucuronide of dihydroxyphenylacetone, along with other uncharacterized metabolites. D-α-methyldopa, which is the inactive isomer of methyldopa, is also metabolized to 3-O-methyl-α-methyldopa and 3,4-dihydroxyphenylacetone to a minimal extent; however, there are no amines (α-methyldopamine and 3-O-methyl-α-methyldopamine) formed.
...ADMIN IP TO RATS (14)C-METHYLDOPA IS EXCRETED IN URINE AS...3-O-METHYL-METHYLDOPA (14%), METHYLDOPAMINE & ITS CONJUGATES (2%), 3-O-METHYL-METHYLDOPAMINE & ITS CONJUGATES (6%), 3-METHOXY-4-HYDROXYPHENYLACETONE (6%), & 3,4-DIHYDROXYPHENYLACETONE (10%).
IDENTIFICATION: Methyldopa is a colorless or almost colorless crystal or a white to yellowish-white fine powder which may contain friable lumps. Slightly soluble in water and alcohol; practically insoluble in chloroform and ether; dissolves in dilute mineral acids. Practically insoluble in the common organic solvents. Indications: Treatment of moderate to severe hypertension usually in combination with diuretic or a beta-blocking agent. Methyldopa has been used in the treatment of severe dyskinesias. HUMAN EXPOSURE: Main risks and target organs: Acute overdose: the target organs are the central nervous system and the cardiovascular system. The main risks are hypotension, bradycardia, cardiac arrhythmia and hypothermia. Chronic poisoning and adverse effects: the target organs are the central nervous system, cardiovascular system, liver, pancreas and immunological system. Acute: drowsiness, coma, hypotension, bradycardia, dry mouth, impairment of atrioventricular conduction, and hypothermia. Chronic: CNS manifestations: sedation, parkinsonism, choreoathetoid movements, headache and vertigo. Cardiovascular effects: bradycardia, prolonged carotid sinus hypersensitivity, myocarditis, pericarditis, aggravation of angina pectoris, postural hypotension, first-degree heart block. Gastrointestinal effects diarrahea, colitis, dryness of the mouth, black tougue, reversible malabsorption, pancreatitis. Liver disorders: hepatitis. Hypersensitivity reactions: rash, urticaria, eczema, lichenoid eruptions. Hematological manifestations : positive Coomb's test, leucopenia, hemolysis. Contraindications: Active hepatic disease, such as acute hepatitis and active cirrhosis.Methyldopa is not recommended for patients with pheochromocytoma. Rarely, involuntary choreoathetoid movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease should avoid methyldopa. Older patients with advanced arteriosclerotic disease should be given lower dose of methyldopa to avoid syncope. Methydopa should be used with caution in patients with impaired kidney function or mental depression. Methydopa has been reported to aggravate porphyria. Oral : Intentional ingestion of large doses may occur. When administered orally, methyldopa is absorbed by an active amino acid transport. Methyldopa is incompletely and variably absorbed from the gastrointestinal tract. Oral bioavailability is variable (50%). Peak concentrations in plasma occur after 2 to 3 hours. Plasma level of methyldopa does not correlate with its clinical effect. Methyldopa crosses the placenta. Methyldopa crosses the blood brain barrier. The transport of methyldopa into CNS is apparently an active process. Methyldopa is partly conjugated, mainly to the methyldopa-O-sulfate. The major metabolite probably contributes little to the therapeutic effect except in patients with renal failure. Other metabolites include methyldopamine, methylnorepinephrine, and O-methylated compounds. Methyldopa is excreted by the kidneys. Elimination is phasic. 95% of the drug is eliminated in the initial phase with a half-life of 0.21 hour. In the second phase, the limitation half-life averages 1.28 hours. Twenty-five percent of unchanged methyldopa is excreted in the urine within 24 hours. Methyldopa reduces vascular resistance. The fall in arterial pressure is maximal 6 to 8 hours after an oral. Hypotension can be increased by concurrent administration of diuretics and other antihypertensive agents, and general anesthetics. Concomittant use of methyldopa and digoxin may produce symptomatic sinus bradycardia. Concomitant use of metyldopa and lithium carbonate appeared to induce signs of lithium toxicity.The action of methyldopa may be decreased by simultaneous use of non-steroidal anti-inflamatory agents. CNS depressants including alcohol and narcotic analgesics, may potentiate the hypotensive action of methyldopa to a dangerous degree. When methyldopa is administered with sedatives, hypnotics, tranquilizers, or other central nervous system depressants, further central nervous system depression may occur. The hypotensive action of methyldopa may be inhibited by amphetamines and other sympathomimetic drugs, monoamine oxidase inhibitors, and tricyclic antidepressants. Methyldopa may increase the hypoglycemic effects of tolbutamide. Methyldopa may increase prothrombin time if added to treatment with anticoagulants. Methyldopa may decrease the effect of ephedrine, since it reduces the quantity of norepinephrine in sympathetic nerve endings. Methyldopa used with haloperidol and chlorpromazine may produce psychomotor retardation, memory impairment, and inability to concentrate. Methyldopa used with monoamine oxidase inhibitor drugs may produce headache and hypertension. Sedation, headache, asthenia, drowsiness, depression, impaired mental acuity, impaired ability to concentrate, lapses of memory, nightmares, nausea, dryness of the mouth, nasal stuffiness, dizziness, vertigo, edema, disorders of sexual function, weight gain, orthostatic hypotension with lightheadedness. Breast enlargement, lactation, hyperprolactinemia, black or sore tongue, salivary gland inflammation, pancreatitis, paresthesias, Bell's palsy, parkinsonism, diarrhea, constipation, fever, arthralgia, myalgia, uremia, myocarditis, aggravation of angina pectoris, bradycardia, atrioventricular conduction disturbances. A paradoxical pressor response is seen after intravenous methyldopate hydrochloride. Rebound hypertension has been reported after abrupt withdrawal of oral administration. Thrombocytopenia, Leucopenia, granulocytopenia, hemolytic anemia have been reported along with fever, jaundice and liver damage. Systemic lupus erythematosus like syndrome, rash, urticarria, eczema and hyperkeratosis. Infrequent CNS effects include reversible mild psychosis, depression blurred vision.
Although the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa) - the precursor of norepinephrine - and of 5-hydroxytryptophan (5-HTP) - the precursor of serotonin - in the CNS and in most peripheral tissues.
Drug induced liver injury due to methyldopa was identified shortly after its introduction into medical use in the 1960’s. Chronic use of methyldopa is associated with mild and transient elevations in serum aminotransferase levels in 5% to 35% of patients, these elevations often resolving despite continuation of the medication. In contrast, clinically apparent or significant liver injury from methyldopa is relatively uncommon, although several hundred cases have been reported. Two patterns of hepatotoxicity have been described: an acute hepatitis that appears within weeks to months of starting treatment, and a chronic hepatitis that arises months to years after initiation of methyldopa therapy.
The acute liver injury from methyldopa generally arises within 2 to 12 weeks of starting therapy and is typically hepatocellular with marked elevations in ALT and AST (5- to 100-fold) and modest increases in alkaline phosphatase, although in a small proportion of patients the pattern of enzyme elevations is mixed or cholestatic (Case 1 and 2). Most patients become jaundiced. Symptoms resemble those of acute viral hepatitis, including fever, headache, fatigue, anorexia and nausea. Signs of hypersensitivity other than fever are uncommon. The injury can be severe and fatal. While some cases are associated with marked cholestasis and prolonged jaundice, most patients recover within 4 to 12 weeks. Autoantibodies including Coombs and antinuclear antibody positivity may be present (but also can arise independent of liver injury). Liver biopsy shows an acute hepatitis-like picture with marked inflammatory infiltrates and fatty change, with variable amounts of necrosis. Rechallenge leads to rapid recurrence of liver injury and can result in severe hepatitis, acute liver failure and death.
The chronic liver injury from methyldopa usually arises after 6 months, but may become first evident after several years of therapy (Case 3). This chronic hepatitis-like clinical picture has a more insidious onset typically with fatigue, weakness and nausea associated with mild or no jaundice. Clinical features may include liver enlargement and tenderness and spider angiomata. The clinical and laboratory pattern often resembles autoimmune hepatitis, with moderate to marked elevations in ALT and AST, modest alkaline phosphatase elevations, increases in immunoglobulin levels (particularly IgG), and high titers of autoantibodies such as antinuclear antibody (ANA) and smooth muscle antibody (SMA). Liver biopsy demonstrates findings of chronic active hepatitis with variable amounts of fatty change and fibrosis. Plasma cell infiltrates may be prominent. Cirrhosis and end stage liver disease can occur if the drug is continued. The disease resolves slowly but completely with discontinuation of methyldopa. Chronic liver injury now appears to be the most common form of drug induced liver injury from this agent. Some cases of methyldopa induced liver injury have features of both acute and chronic injury and the two forms of hepatic injury may share a common etiology.
African Americans appear to have a higher risk for liver injury from methyldopa than Caucasians or Hispanic individuals. The course may be more severe and outcome less favorable in Africans Americans as well. Granulomatous hepatitis can also occur with methyldopa therapy, usually in association with drug fever and systemic symptoms (and granulomas elsewhere), and sometimes with granulomatous myocarditis which can be fatal. In these situations, the liver injury is usually mild and anicteric.
Likelihood score: A (well known cause of clinically apparent liver injury).
Methyldopa is incompletely absorbed from the gastrointestinal tract following oral administration. In healthy individuals, the inactive D-isomer is less readily absorbed than the active L-isomer. The mean bioavailability of methyldopa is 25%, ranging from eight to 62%. Following oral administration, about 50% of the dose is absorbed and Tmax is about three to six hours.
Approximately 70% of absorbed methyldopa is excreted in the urine as unchanged parent drug (24%) and α-methyldopa mono-O-sulfate (64%), with variability.3-O-methyl-α-methyldopa accounted for about 4% of urinary excretion products. Other metabolites like 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine are also excreted in urine. Unabsorbed drug is excreted in feces as the unchanged parent compound. After oral doses, excretion is essentially complete in 36 hours. Due to attenuated excretion in patients with renal failure, accumulation of the drug and its metabolites may occur, possibly leading to more profound and prolonged hypotensive effects in these patients.
The apparent volume of distribution ranges between 0.19 and 0.32L/kg and the total volume of distribution ranges from 0.41 to 0.72L/kg. Since methyldopa is lipid-soluble, it crosses the placental barrier, appears in cord blood, and appears in breast milk.
来源:DrugBank
吸收、分配和排泄
清除
正常受试者的肾清除率约为130 mL/min，而在肾功能不全的患者中会降低。
The renal clearance is about 130 mL/min in normal subjects and is decreased in patients with renal insufficiency.
(14)C-METHYLDOPA ADMIN ORALLY TO HYPERTENSIVE PT IS RECOVERED EQUALLY FROM URINE & FECES; PRODUCT IN FECES IS UNCHANGED METHYLDOPA, & IN URINE METHYLDOPA & ITS ETHEREAL SULFATE, TOGETHER WITH SMALL AMT OF 3-O-METHYL-METHYLDOPA & METHYLDOPAMINE.
New Derivatives of 3,4-Dihydroisoquinoline-3-carboxylic Acid with Free-Radical Scavenging, D-Amino Acid Oxidase, Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activity
ACYL-HYDRAZONE AND OXADIAZOLE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND USES THEREOF
申请人：Universidade Federal de Santa Catarina
公开号：US20150191445A1
公开（公告）日：2015-07-09
The present invention relates to acyl-hydrazone compounds, in particular 3,4,5-trimethoxyphenyl-hydrazide derivatives, as well as the oxadiazole analogs thereof and other similar compounds, and to the pharmaceutical use of the same for the treatment of various diseases associated with cell proliferation, such as leukemias, including acute lymphoblastic leukemia (ALL), tumours and inflammation. Acyl-hydrazones have been obtained having activity similar to that of the compound used as a standard in experiments (colchicine). The greater selectivity of the compounds according to the invention is an important feature, associated with fewer side effects than the pharmaceuticals used at present in clinical treatments. The synthetised acyl-hydrazones, more particularly the compounds 02 and 07, exhibited important antileukemic activity, which suggests 02 and 07 as candidates to pharmaceutical prototypes, or to pharmaceuticals for the treatment of leukemias, in particular acute lymphoblastic leukemia (ALL), tumours and other proliferative diseases, such as inflammation. The action mechanism of the most active compounds was determined by using DNA microarrays and subsequent tests indicated by the chip, besides selectivity studies in healthy human lymphocytes.
[EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
申请人：UNIV EMORY
公开号：WO2013181135A1
公开（公告）日：2013-12-05
The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.
Compounds, pharmaceutical compositions, kits and methods are provided for use with Renin that comprise a compound selected from the group consisting of: wherein the variables are as defined herein.
Substituted 1,3-thiazole compounds, their production and use
申请人：——
公开号：US20040053973A1
公开（公告）日：2004-03-18
(1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.
The present invention relates to compounds of formula I
wherein R
1
to R
4
and G are as defined in the description and claims and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.
