Levodopa is either converted to dopamine by aromatic-L-amino-acid decarboxylase or O-methylated to 3-O-methyldopa by catechol-O-methyltransferase. 3-O-methyldopa cannot be metabolized to dopamine. Once levodopa is converted to dopamine, it is converted to sulfated or glucuronidated metabolites, epinephrine E, or homovanillic acid through various metabolic processes. The primary metabolites are 3,4-dihydroxyphenylacetic acid (13-47%) and homovanillic acid (23-39%).
MOST IS CONVERTED TO DOPAMINE... BIOTRANSFORMATION OF DOPAMINE PROCEEDS RAPIDLY...EXCRETION PRODUCTS, 3,4-DIHYDROXYPHENYLACETIC ACID...& 3-METHOXY-4-HYDROXYPHENYLACETIC ACID... SOME BIOCHEMICAL EVIDENCE INDICATES THAT ACCELERATION OF LEVODOPA METABOLISM OCCURS DURING PROLONGED THERAPY, POSSIBLY DUE TO ENZYME INDUCTION.
MORE THAN 95%...IS DECARBOXYLATED...BY...AROMATIC L-AMINO ACID DECARBOXYLASE. ... A SMALL AMT /OF L-DOPA/ IS METHYLATED TO 3-O-METHYL-DOPA... MOST IS CONVERTED TO DOPAMINE, SMALL AMT OF WHICH IN TURN ARE METABOLIZED TO NOREPINEPHRINE & EPINEPHRINE.
IDENTIFICATION: Levodopa is used as a drug for treating Parkinsons disease. Levodopa is white or almost white crystalline powder, which darkens on exposure to air and light. Levodopa is odourless and almost tasteless. It is slightly soluble in water. Soluble in aqueous solutions of mineral acids and alkali carbonates; practically insoluble in alcohol, chloroform, and ether. HUMAN EXPOSURE: Main risks and target organs: The principal target organ is Central Nervous System. The main risks are cardiovascular. Additional risks are associated with the gastrointestinal tract, and the peripheral as well as the central nervous system. Summary of clinical effects: Nausea and anorexia commonly occur and may be accompanied by vomiting. Another effect includes abdominal pain, constipation, diarrhea and dysphagia; dyspepsia and gastrointestinal bleeding. The commonest cardiovascular effect is postural hypotension, with faintness and dizziness. There may be palpitations often accompanied by excess sweating. Cardiac arrhythmias, particularly atrial and ventricular ectopic beats, have been reported and hypertension has occasionally occurred. Psychiatric symptoms include agitation, anxiety, elation and insomnia or some times drowsiness and depression. More severe effects include aggression, paranoid delusions, hallucinations, suicidal behaviour and unmasking of dementia. Involuntary movements are very common and usually start in the mouth, jaws or tongue. Abnormal limb movements often develop after several months and severe choreoathetoid movements may also occur after prolonged high doses. Oculogyric movements may rarely be exacerbated and muscle twitching and blepharospasm occur occasionally. Headache, weakness, ataxia, and rarely paraesthesia and convulsions have occurred. Polyuria, incontinence, and difficulty in micturition may occur. Blurred vision, mydriasis, diplopia and glaucoma are rare. Uncommon effects include transient rises in tests for liver function and blood urea nitrogen, abnormal respiratory movements, loss of hair, skin rashes, activation of Horner's syndrome, weight changes, and rarely agranulocytosis or hemolytic anemia. Administration without benserazide: The dose producing maximal improvement with tolerated side effect must be determined and carefully titrated for each individual patient. Contraindications: Levodopa is contraindicated for melanoma and glaucoma in patients with known hypersensitivity to the drug. Levodopa should be administered cautiously to patients with severe cardiovascular or pulmonary disease, asthma, renal, hepatic or endocrine disease. Care should be exercised in administering levodopa to patients with history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias. If levodopa is necessary in this type of patient, it should be used in a facility with a coronary care unit or an intensive care unit. One must be on the alert for the possibility of upper gastrointestinal hemorrhage in those patients with a past history of peptic ulcer disease. Levodopa is contraindicated in patients with severe psychotic disorders, it should be used with caution in patients with psychiatric disturbance. This drug should not be used in pregnancy and should not be used in nursing mothers. The safety under the age of 12 has not been established. Routes of entry: Oral: The route of entry of levodopa is oral. Absorption by route of exposure: Levodopa is rapidly absorbed from the small intestine by an active transport system for aromatic amino acids. Concentrations of drug in plasma usually peak between 0.5 and 2 hours after an oral dose. The rate of absorption of levodopa is greatly dependent upon the rate of gastric emptying, the pH of gastric juice and the length of time the drug is exposed to the degradative enzymes of the gastric mucosa and intestinal flora. Hyperacidity of gastric juice, and competition for absorption sites in the small intestine by amino acids each may interfere with the bioavailability of vodopa. Distribution by route of exposure: It is widely distributed to most body tissues, but less to the central nervous system (CNS). Little unchanged drug reaches the cerebral circulation and probably less than 1% penetrates into the CNS. Biological half-life by route of exposure: Levodopa has relatively short plasma half-life of 1 to 3 hours. Metabolism: More than 95% of levodopa is decarboxylated by the widely distributed extracerebral aromatic l-amino acid decarboxylase. The drug is extensively decarboxylated in its first passage through the liver, which is rich in decarboxylase. A small amount is methylated to 3-0-methyldopa, which accumulates in the CNS due to its long half-life. Most is converted to dopamine, small amounts of which in turn are metabolized to norepinephrine and epinephrine (adrenaline). Biotransformation of dopamine proceeds rapidly to yield the principal excretion products, 3-4-dihydroxy-phenylacetic acid (DOPAC) and 3-methoxy-4-hydroxy-phenylacetic acid (homovanillic acid, HVA). At least 30 metabolites of levodopa have been identified. The evidence indicates that the metabolism of levodopa may be accelerated during prolonged therapy possibly due to enzyme induction. Elimination by route of exposure: Oral: Excretion: Metabolites of dopamine are rapidly excreted in the urine; 80% of a radioactively labelled dose is recovered within 24 hours. The principal metabolites DOPAC and HVA account for up to 50% of the administered dose. Negligible amounts are found in the feces. Mode of action: Toxicodynamics: Peripheral decarboxylation of levodopa markedly increases the concentration of dopamine in blood. Dopamine is a pharmacologically active catecholamine with prominent effects of alpha and beta adrenergic receptors, and this point give the potentially toxic effects. Pharmacodynamics: Levodopa is the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the basal ganglia. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease, because it replaces depleted brain dopamine in these patients. Interactions: Doses of pyridoxine that are only modestly in excess of the recommended dietary allowance enhance the extracerebral metabolism of levodopa at this step. Antipsychotic drugs, such as phenothiazines, butyrophenones and reserpine can produce a parkinsonism-like syndrome, and since these drugs interfere with the therapeutic effects of levodopa, they are contraindicated. Therefore the phenothiazines should not be used to combat the emetic effect of levodopa. Nonspecific monoamine oxidase inhibitors interfere with inactivation of dopamine, norepinephrine and other catecholamines. Hence, they unpredictably exaggerate the central effects of levodopa and its catecholamine metabolites. Hypertensive crisis and hyperpyrexia are very real and dangerous sequelae of concurrent administration of two such drugs. Anticholinergic drugs such as phenidyl, benztropine, procyclidine and others act synergistically with levodopa to improve certain symptoms of parkinsonism, especially tremor. However, large doses of anticholinergic drugs can slow gastric emptying sufficiently to cause a delay in reabsorption of levodopa by the small intestine. The effect of levodopa is enhanced by amantadine, benserazide, carbidopa, atropine and amphetamine. Concurrent administration of levodopa with guanethidine, methyldopa and other antihypertensive agents may cause increased hypotension. Cardiac arrhythmias due to levodopa may be augmented by anaesthetic agents, such as cyclopropane or halothane. Sympathomimetic agents such as epinephrine (adrenaline) or isoprenaline may also enhance the cardiac side effects of levodopa. Beta-adrenergic blocking agents such as propranolol may enhance the action of levodopa on tremor and diminish the cardiac side effects. In some patient the administration of antacids with levodopa may enhance the gastrointestinal absorption of levodopa. Main adverse effects: Rarely, oculogyric crises, sense of stimulation, hiccups, edema, loss of hair hoarseness, priapism and activation of latent Horner's syndrome have been observed. Elevation of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein-bound iodine have been reported, occasional reduction in WBC, hemoglobin and haematocrit have been noted. Leucopenia has occurred and requires cessation at least temporarily, of levodopa administration. Acute poisoning: Ingestion: Spasm or closing of eyelids are possible early sign of overdose. Nausea, vomiting, cardiac arrhythmias, involuntary movements of the body, including the face, tongue, arms, hand, head, and upper body; choreiform and other involuntary movements occur in 50% to 80% of patients. This effect is dose related. Psychiatric disturbances are usually present. Hypotension, hemolytic anemia, urinary retention, duodenal ulcer, sialorrhea, ataxia, abdominal pain, dry mouth, nightmares, tachypnea, bruxism, confusion, insomnia also occur. Special risks: Pregnancy, breast-feeding: Levodopa represent a risk for pregnancy and the nursing mother. Use of medication should be carefully considered in conjunction with bronchial asthma, emphysema and other severe pulmonary cardiovascular disease; history of convulsive disorders, diabetes, endocrine diseases, glaucoma, hepatic function impairment, history of suspected melanoma, history of myocardial infarction with residual history of peptic ulcer, psychotic states, renal function impairment, urinary retention. ANIMAL/PLANT STUDIES: Teratogenicity: Studies in rabbits have shown that levodopa causes visceral and skeletal malformations in offspring.
Striatal dopamine levels in symptomatic Parkinson's disease are decreased by 60 to 80%, striatal dopaminergic neurotransmission may be enhanced by exogenous supplementation of dopamine through administration of dopamine's precursor, levodopa. A small percentage of each levodopa dose crosses the blood-brain barrier and is decarboxylated to dopamine. This newly formed dopamine then is available to stimulate dopaminergic receptors, thus compensating for the depleted supply of endogenous dopamine.
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
◉ Summary of Use during Lactation:Limited data indicate that levodopa is poorly excreted into breastmilk and that the sustained-release product may result in a smaller amount of drug transferred to the breastfed infant than with the immediate-release product. Several studies indicate that levodopa can decrease serum prolactin during lactation. The prolactin level in a mother with established lactation may not affect her ability to breastfeed. The effect of long-term use of levodopa on breastfeeding has not been adequately evaluated, although some mothers were able to successfully breastfeed her infant without apparent harm while using relatively low doses of levodopa and carbidopa for Parkinson's disease.
◉ Effects in Breastfed Infants:One mother with Parkinson's disease took sustained-release levodopa 200 mg and carbidopa 50 mg 4 times daily. She successfully breastfed her infant whose development was normal at 2 years of age.
A 37-year-old Israeli woman with Parkinson's disease became pregnant while taking a continuous infusion of levodopa 20 mg/mL and carbidopa 5 mg/mL gel. She breastfed her infant for 3 months while receiving the drug, although the extent of breastfeeding and the dosage of the gel is not clear from the paper. At 10 months of age, the infant's psychomotor development was deemed to be normal.
◉ Effects on Lactation and Breastmilk:Levodopa decreases serum prolactin in normal women and those with hyperprolactinemia and can suppress inappropriate lactation in galactorrhea, although not consistently. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
One mother with Parkinson's disease took sustained-release levodopa 200 mg and carbidopa 50 mg 4 times daily. She successfully breastfed her infant.
On postpartum day 3, 5 women were given a single oral dose of 500 mg of levodopa or bromocriptine 5 mg followed by a single oral dose of metoclopramide 10 mg 3 hours later. Bromocriptine suppressed basal serum prolactin to a greater extent than levodopa. Over the next 3 hours, serum prolactin increased after metoclopramide in the patients who received levodopa, but not in those who received bromocriptine.
Six women who were 2 to 4 days postpartum, but were not nursing, were given 500 mg of levodopa orally on one day and 100 mg of levodopa plus 35 mg of carbidopa orally on the next day. Both regimens suppressed basal serum prolactin levels. However, levodopa alone caused an 78% decrease in prolactin while the lower dose combination produced only a 51% decrease. The maximal effect occurred about 2 hours after the dose with both regimens.
Seven women in the first week postpartum who were breastfeeding about 7 times daily were given levodopa 500 mg orally and their serum prolactin responses was studied. The following day, they started carbidopa 50 mg orally every 6 hours for 2 days. On the third day, they received a single dose of carbidopa 50 mg plus levodopa 125 mg orally. Decreases in basal serum prolactin occurred by 30 minutes after the levodopa and after 45 minutes with the combination. Decreases were maximum at 120 minutes after the dose and were 62% with levodopa alone and 48% with the combination, although the difference between the 2 regimens was not statistically significant.
A 37-year-old Israeli woman with Parkinson's disease became pregnant while taking a continuous infusion of levodopa 20 mg/mL and carbidopa 5 mg/mL gel. She breastfed her infant for 3 months while receiving the drug, although the extent of breastfeeding and the dosage of the gel is not clear from the paper.
Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide.
Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients.
[EN] TARGETED DELIVERY AND PRODRUG DESIGNS FOR PLATINUM-ACRIDINE ANTI-CANCER COMPOUNDS AND METHODS THEREOF<br/>[FR] ADMINISTRATION CIBLÉE ET CONCEPTIONS DE PROMÉDICAMENTS POUR COMPOSÉS ANTICANCÉREUX À BASE DE PLATINE ET D'ACRIDINE ET MÉTHODES ASSOCIÉES
申请人：WAKE FOREST SCHOOL OF MEDICINE
公开号：WO2013033430A1
公开（公告）日：2013-03-07
Acridine containing cispiaiin compounds have been disclosed that show greater efficacy against cancer than other cisplatin compounds. Methods of delivery of those more effective eisp!aiin compounds to the nucleus in cancer ceils is disclosed using one or more amino acids, one or more sugars, one or more polymeric ethers, C i^aikylene-phenyl-NH-C(0)-R.15, folic acid, av03 iniegriii RGD binding peptide, tamoxifen, endoxifen, epidermal growth factor receptor, antibody conjugates, kinase inhibitors, diazoles, triazol.es, oxazoies, erlotinib, and/or mixtures thereof; wherein R]§ is a peptide.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
[EN] COMPOUNDS FOR THE TREATMENT OF AMYLOID-ASSOCIATED DISEASES<br/>[FR] COMPOSÉS POUR LE TRAITEMENT DE MALADIES ASSOCIÉES À LA SUBSTANCE AMYLOÏDE
申请人：REMYND NV
公开号：WO2016083490A1
公开（公告）日：2016-06-02
This invention provides novel compounds of formulae (I) or (II) or a stereoisomer, enantiomer, racemic, or tautomer thereof, (I) (II) wherein the substituents are as defined in the specification. The present invention also relates to the novel compounds for use as a medicine, more in particular for the prevention or treatment of amyloid-related diseases, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such amyloid-related diseases. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.
Chromenone derivatives useful for the treatment of neurodegenerative diseases
申请人：AxoGlia Therapeutics S.A.
公开号：EP2112145A1
公开（公告）日：2009-10-28
Compounds of general formula (I) and (II)
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the meanings given in the specification, are useful in the treatment of neurodegenerative disease.
[EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
申请人：BIAL BIOTECH INVEST INC
公开号：WO2021055627A1
公开（公告）日：2021-03-25
The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
