In rats, orally administered reserpine is rapidly hydrolysed to methyl reserpate; and in mice, orally or intravenously administered reserpine is metabolized to trimethoxybenzoic acid. In rats, methyl reserpate appears to be formed in the intestinal mucosa. Trimethoxybenzoic acid is rapidly eliminated in the urine of mice.
来源:Hazardous Substances Data Bank (HSDB)
代谢
消除途径：利血平被广泛代谢为无活性化合物。它通过尿液和粪便缓慢排出。
Route of Elimination: Reserpine is extensively metabolized to inactive compounds. It is slowly excreted via the urine and feces.
IDENTIFICATION: Reserpine is an antihypertensive agent. Origin of the substance: An alkaloid from the roots of certain species of Rauwolfia, usually Rauwolfia serpintina or R. vomitoria. Reserpine can also be synthesized. Color: White or pale buff to slightly yellow colored. It is insoluble in water, freely soluble in chloroform and acetic acid, and very slightly soluble in alcohol and ether. Bioavailability: The reported bioavailability after oral ingestion is approximately 50%. Indications: Description: Hypertension; Raynaud's phenomenon; possibly for prevention of attacks of familial Mediterranean fever. Possibly for treatment of thyroid storm not responsive to standard therapy. HUMAN EXPOSURE: Main risks and target organs: The main risks associated with reserpine poisoning are central nervous system depression, the development of psychiatric depression, cardiovascular toxicity, and gastrointestinal irritation. The main target organs are the central nervous system, cardiovascular system, and gastrointestinal tract. Summary of clinical effects: The clinical effects include sedation and lethargy, which can rarely progress to coma, and gastrointestinal irritation which includes nausea, vomiting, and abdominal cramping. Gastrointestinal irritation can be severe and result in ulceration, perforation, and hemorrhage. Psychiatric depression can be severe and lead to suicidal thoughts and there can be nightmares, and vertigo. Cardiovascular effects include hypotension and bradycardia. Nasal congestion and flushing are also frequent. Hypothermia has also been described. These effects are generally more common with poisonings. The most commonly reported effects were facial flushing, lethargy which rarely progressed to coma, hypotension and bradycardia. Death has been described from hypotension in two patients. Contraindications: Absolute: Pregnancy, psychiatric depression, active peptic ulcer disease; ulcerative colitis; Parkinson's disease; pheochromocytoma and hypersensitivity to any rauwolfia alkaloid Relative contraindications where the use of reserpine should be undertaken with caution and started with lower doses: Elderly patients, cardiac arrhythmias; myocardial infarction; renal insufficiency and asthma. Routes of entry: Oral: The most common route of administration and poisoning. Parenteral: Intramuscular injection has been used for the urgent treatment of hypertension. Intra-arterial injection has been described in Raynaud's syndrome, but appears to be ineffective. Absorption by route of exposure: The reported bioavailability is approximately 50% to 70% after oral ingestion. Absorption is relatively rapid, with peak concentrations achieved approximately 1 to 2 hours after administration of an oral solution. Slower absorption, with peak concentrations at 2 to 4 hours has also been reported. Distribution by route of exposure: The volume of distribution has not been reported. It is widely distributed into the brain, liver, spleen, kidney, and adipose tissue. Reserpine binds to red blood cells and in the peripheral neuron at its site of action. It is reported not to bind to plasma protein. Reserpine crosses the placental barrier, and is found in breast milk. An initial half-life of distribution of approximately 4 to 5 hours is observed after oral administration. Biological half-life by route of exposure: Reserpine can be described using a two compartmental pharmacokinetic model. The elimination half-life ranges from 45 to 168 hours in plasma. Because of binding to red blood cells, the terminal elimination half-life is longer when whole blood levels is measured, and has been reported to be 386 hours. The half-life is longer in patients with renal insufficiency. The elimination half-life was significantly prolonged in patients with creatinine clearance values of less than 10 mL/min. Metabolism: Hepatic metabolism accounts for less than 50% of the elimination of reserpine, with the remainder being eliminated in the feces, and some unmetabolized reserpine and metabolites being eliminated in the urine. In man, metabolites are methylreserpate and trimethoxybenzoic acid. Metabolism may be more important with intramuscular administration. Elimination by route of exposure: The elimination of reserpine and its metabolites in the feces ranges from 30% after intramuscular administration to approximately 60% after oral administration, primarily as unmetabolized reserpine, over a 4 day period. Over the same time period approximately 8% of the administered dose was recovered in the urine, primarily as the trimethoxybenzoic acid metabolite. Pharmacology and toxicology: Mode of action: Toxicodynamics: The mechanism of reserpine's toxic effects is similar to the mechanism of it's pharmacologic effects. Reserpine inhibits normal sympathetic activity in both the CNS and peripheral nervous system by binding to catecholamine storage vesicles. This prevents the normal storage of catecholamines and serotonin in the nerve cell, with the result being catecholamine depletion. Reserpine has also been described as inhibiting catecholamine synthesis by blocking the uptake of dopamine into the storage vesicle. Pharmacodynamics: Reserpine inhibits normal sympathetic activity by decreasing the storage of catecholamines at the pre-synaptic, CNS, and peripheral neuron. Reserpine binds to the storage vesicles, causing catecholamines to leak into the synapse so that they are not available for release when the pre-synaptic neuron is stimulated. The process appears to affect serotonin storage in a similar manner. These actions result in a reduction in both cardiac output and peripheral vascular resistance with long term therapy, which takes approximately 3 weeks to develop after the initiation of therapy. Heart rate and renin concentrations decrease, and there is sodium and water retention. Human data: Adults: There are few reported cases of reserpine poisoning in adult patients. In a series of 151 cases reported from the United States from 1959 to 1960 only 4% were adults. Nausea, vomiting, hypotension, sedation, and coma were described in these patients. Psychiatric depression is historically the most important adverse effect associated with the chronic administration of reserpine for the treatment of hypertension. The depression is most common with higher daily doses, and the frequency is significantly decreased when the dose is lower. The depression is often severe, can occur in patients without a prior history of depressive illness, and may last for months after reserpine is discontinued. Children: Most of the reported cases of reserpine poisoning have been in children. One hundred forty two of the 151 cases of rauwolfia poisoning were in children less than 13 years of age. Approximately 40% of the cases had some symptoms, Mild CNS depression such as lethargy or sedation was the most common symptom, and facial flushing the next most common. Hospitalization for toxicity was needed in 24 of the 142 pediatric cases. Nausea, vomiting, hypotension and vertigo were also described. Individual cases of toxicity include information about potential doses of reserpine ingested and the time course of toxicity. A 20 month old male who ingested reserpine had symptoms of lethargy, flushing, rapid pulse rate and slowed respiration. Within 21 hours the symptoms had primarily resolved without any specific therapy other than a cathartic. A mild leukocytosis resolved within 2 weeks. Three cases of reserpine ingestion in children between 30 months and 4 years of age, who ingested large doses of reserpine (2 cases), and an unknown dose (1 case), demonstrated a wide range of toxicity. All cases had some lethargy and CNS depression which progressed to coma. Bradycardia and hypothermia was also documented in all cases, while the youngest child also had an episode of hypertension and tachycardia starting about 10 hours after ingestion. Carcinogenicity: There does not appear to be an association between reserpine administration and cancer. Teratogenicity: In 48 cases of mothers who had taken reserpine during their first trimester of pregnancy, the incidence of birth defects was 8%, higher than expected, although no major types of malformations were seen. There was no increased risk of birth defects in women who ingested reserpine at any time during their pregnancy. Interactions: The following drugs have been reported to interact with reserpine: Alcohol and CNS depressant drugs: increased sedation Nonsteroidal anti-inflammatory drugs: increased risk of gastric irritation Drugs with antimuscarinic actions: increased gastric acid secretion Beta-adrenergic blocking agents: additive beta adrenergic blockade Bromocriptine: increased serum prolactin and decreased bromocriptine activity Digitalis glycosides: possible increase in bradycardia and arrhythmias Quinidine: possible increase in arrhythmias Estrogens: decrease antihypertensive effects of reserpine Drugs causing extrapyramidal adverse effects: potentiate extrapyramidal activity Antihypertensive agents: hypotension Levodopa: decreased efficacy of levodopa Monoamine oxidase inhibitors: increased CNS depression or increased blood pressure and CNS stimulation Sympathomimetics: decreased effects of reserpine Main adverse effects: The main adverse effects described with the therapeutic administration of reserpine include lethargy and sedation, psychiatric depression, hypotension, nausea, vomiting, abdominal cramping, gastric ulceration, nightmares or vivid dreams, bradycardia, and bronchospasm (in asthmatics) Much less common are symptoms of skin rash or itching, Parkinsonian effects, and thrombocytopenia. Adverse effects are more common with daily doses of reserpine of 0.5 mg or greater. The lethargy and sedation is more common when other CNS depressant drugs are being used concurrently. Adverse reactions were reported in 26 of 231 hospitalized patients who received reserpine. Three reactions after intramuscular reserpine doses of 0.5 mg or greater were considered life-threatening (hypotension in 2 patients, cerebral edema in 1 patient), but no deaths were attributed to reserpine. Bronchospasm has been described when reserpine is administered to asthmatics, and may be relatively common. A case of withdrawal psychosis has been described. Clinical effects: Acute poisoning: Ingestion: Poisoning with reserpine most commonly results in lethargy, sedation, and infrequently results in coma. Other effects include psychiatric depression, hypothermia, facial flushing, nausea, vomiting, abdominal cramping, and cardiovascular toxicity including hypotension and bradycardia. Parenteral exposure: After intramuscular injection of therapeutic doses of reserpine, hypotension, bronchospasm, lethargy and sedation have occurred. These effects are most commonly secondary to larger doses, and are not expected to be any different than the adverse effects associated with oral reserpine administration. Chronic poisoning: Ingestion: The development of psychiatric depression, which can be severe, and gastric ulceration and hemorrhage are the most severe adverse effects of chronic reserpine therapy. Nasal congestion, dry mouth, diarrhea, abdominal pain, lethargy, Parkinsonian features, breast enlargement, galactorrhea, impotence, sodium retention, peripheral edema, and weight gain have been reported much less commonly. Parenteral exposure: The administration of intramuscular reserpine results in adverse effects similar to those seen with oral administration. They are more commonly reported following intramuscular injection because of the larger doses administered and the increased bioavailability associated with this route. Course, prognosis, cause of death: Symptoms of toxicity develop over the first 4 hours after ingestion. Symptoms generally resolve over 18 to 24 hours. The prognosis is generally very good, and patients recover without sequelae. The psychiatric depression can take months to resolve. Two deaths following reserpine poisoning have been reported in the Russian literature. Both cases were adults who died of cardiovascular collapse and multi-organ system failure in the first few days after ingestion. Systematic description of clinical effects: Cardiovascular: Cardiovascular effects associated with reserpine poisoning are relatively uncommon, with only two cases of hypotension reported in a total of 151 patients. Bradycardia is also described, and there is one case of tachycardia and hypertension which developed approximately 10 hours after ingestion. Angina-like symptoms, and dysrhythmias are possible when reserpine is administered to patients taking a digitalis glycoside, quinidine or procainamide. Respiratory: Upper respiratory bronchospasm and nasal congestion may occur. Neurological: CNS: The most common symptoms with poisoning are lethargy and sedation, which occurred in 44% of 151 rauwolfia poisonings. Coma is much less common. A decrease in body temperature may develop. With poisonings, psychiatric depression may occur, however, it is more commonly described with chronic reserpine use. Additional CNS effects include nightmares and vivid dreams, vertigo, headache, dizziness, nervousness, anxiety, and rarely deafness. The development of extrapyramidal symptoms including dystonia and Parkinson's symptoms is reported, though it is not clear whether these develop after poisonings, or only with chronic therapy. There is a case of reserpine withdrawal psychosis which developed over 1 week after a 66 year old female ceased the daily ingestion of 3 mg of reserpine. Reserpine lowers the seizure threshold, however, clonic seizures have been described in only one case. Peripheral nervous system: The effects of reserpine on the peripheral nervous system catecholamine stores would be expected to diminish the responsiveness of the reserpine poisoned patients to indirect acting vasoconstrictors such as dopamine. Direct acting agents such as phenylephrine, metaraminol, and norepinephrine are suggested as vasoconstrictors for the treatment of hypotension which is unresponsive to intravenous fluids. Autonomic nervous system: No direct effects are described. The development of gastrointestinal ulceration is described as being due to increased gastric acid secretion which could be due to changes in autonomic nervous system function. Skeletal and smooth muscle: Gastric cramping is described. Muscle weakness can also occur. Gastrointestinal: Abdominal cramping, nausea, vomiting. Gastric ulceration and hemorrhage are less common. Urinary: Other: Painful or difficult urination is described as a rare adverse effect of chronic therapy. Endocrine and reproductive systems: Chronic therapy is associated with breast engorgement and galactorrhoea. Gynecomastia, increased prolactin concentrations, decreased libido and impotence are also potential adverse effects of chronic therapy. It is not known whether these effects occur with acute poisonings. Dermatological: Facial flushing, rashes, and pruritis. Eye, ear, nose, throat: local effects: Nasal congestion, sialorrhea, slight decrease in color vision, conjunctival injection, lacrymation, and miosis. Hematological: Thrombocytopenic purpura Immunological: Angioimmunoblastic lymphadenopathy Metabolic: Fluid and electrolyte disturbances: Sodium and water retention with the development of edema. Allergic reactions: There is cross sensitivity with reserpine among the different rauwolfia substances. Reports of allergic reactions were not identified. Special risks: The administration of reserpine at the end of pregnancy can cause nasal congestion, respiratory distress, cyanosis, poor feeding, and lethargy in the newborn infant. Reserpine is accepted therapy during breastfeeding. ANIMAL/PLANT STUDIES: Carcinogenicity: Studies in rats and mice using doses at least 100 fold greater than the usual human dose have demonstrated an increased incidence of mammary fibroadenomas, malignant tumors of the seminal vesicles, and malignant adrenal medullary tumors. Teratogenicity: Reserpine administered in large doses has been demonstrated to be teratogenic in rats and guinea pigs. Mutagenicity: Recent studies have suggested a lack of mutagenic, genotoxic, and recombinogenic effects.
Reserpine's mechanism of action is through inhibition of the ATP/Mg<sup>2+</sup> pump responsible for the sequestering of neurotransmitters into storage vesicles located in the presynaptic neuron. The neurotransmitters that are not sequestered in the storage vesicle are readily metabolized by monoamine oxidase (MAO) causing a reduction in catecholamines.
Serum aminotransferase elevations during reserpine therapy are uncommon, but specific rates of such elevations in comparison to placebo treatment have not been reported. Despite many decades of use, reserpine has been implicated in few instances of clinically apparent acute liver injury, and none of them were particularly convincing. Published cases were marked by jaundice and abdominal pain arising a year after starting reserpine, but in combination with other known hepatotoxic agents (dihydrazine, phenobarbital, quinidine). The few cases that have been reported were self-limiting and resolved within a few months of stopping therapy. The last case of suspected reserpine associated liver injury was published more than 50 years ago.
In man, after oral admin of 0.25 mg (3)H-reserpine, tritium was rapidly absorbed into the blood, reaching a peak within 1-2 hr. Radioactivity was tightly bound to red blood cells and remained constant over a 96 hr period. ... Six percent of the dose was excreted in the urine by 24 hr, mainly as trimethoxybenzoic acid; but radioactivity was still detectable in plasma, urine, and feces 11-12 days after drug admin.
PARENTERAL ADMIN OF RESERPINE PRODUCES GREATER CONCN IN NEONATAL RAT BRAIN THAN IN ADULT ANIMALS ... PARALLELED BY GREATER DEPLETION OF NOREPINEPHRINE IN INFANT THAN IN ADULT BRAIN. THIS MAY BE DUE TO LESSER CAPACITY OF RAT NEONATES TO METABOLIZE RESERPINE ... MIGHT ALSO EXPLAIN HIGHER PLASMA & TISSUE LEVELS IN HUMAN ADULTS.
RESERPINE LEAVES BLOOD WITHIN FEW MIN AFTER IV INJECTION & ACCUMULATES IN FATTY TISSUES ... MAX CONCN IN 4-6 HR. LIVER ALSO ACCUMULATES RESERPINE. MOST OF SINGLE DOSE HAS LEFT FAT & LIVER IN 48 HR. BRAIN RETAINS ... RESERPINE & ... METABOLITES ... 5 DAYS AFTER SINGLE DOSE.
... CLAIMED TO BE ADEQUATELY ABSORBED FROM GI TRACT, BUT DIFFERENCE IN EFFICACY OF ORAL & IV DOSES RAISES DOUBTS ABOUT ADEQUACY OF ABSORPTION. ... HAS LONG LATENCY OF ONSET & PROLONGED DURATION OF ACTION.
[EN] METHODS OF TREATMENT OF AMYLOIDOSIS USING ASPARTYL-PROTEASE INIHIBITORS<br/>[FR] PROCEDES DE TRAITEMENT D'AMYLOIDOSE UTILISANT DES INHIBITEURS DE PROTEASE ASPARTYLE
申请人：ELAN PHARM INC
公开号：WO2005070407A1
公开（公告）日：2005-08-04
The invention relates to acetyl 2-hydroxy-1,3-diaminospirocyclohexanes and derivatives thereof that are useful in treating diseases, disorders, and conditions associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.
Methods of treatment of amyloidosis using bi-aryl aspartyl protease inhibitors
申请人：John Varghese
公开号：US20060014737A1
公开（公告）日：2006-01-19
The invention relates to novel compounds and methods of treating diseases, disorders, and conditions associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.
The present invention addresses the problem of providing an inhibitor which has an excellent inhibitory activity on a p21-activated kinase. The present invention, by which has been solved the above-mentioned problem, is a p21-activated kinase 1 inhibitor containing, as an active ingredient, one or more compounds selected from the group consisting of dehydrokawain compounds, derivatives of dehydrokawain compounds, mimosine, derivatives of mimosine, and cucurbitacin compounds.
TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
申请人：Arvinas, Inc.
公开号：US20180125821A1
公开（公告）日：2018-05-10
The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
[EN] PROCESS FOR THE SYNTHESIS OF 9,9-BIS(METHOXYMETHYL)FLUORENE<br/>[FR] PROCÉDÉ DE SYNTHÈSE DE 9,9-BIS(MÉTHOXYMÉTHYL)FLUORÈNE
申请人：SABIC GLOBAL TECHNOLOGIES BV
公开号：WO2016193212A1
公开（公告）日：2016-12-08
The present invention relates to a novel process for the synthesis of 9,9-bis(methoxymethyl)fluorene. The syntheses from fluorene to 9,9-bis(hydroxymethyl)fluorene via a hydroxymethylation and further to 9,9-bis(methoxymethyl)fluorene via a etherification are known. 9,9-bis(methoxymethyl)fluorene is a compound that is used as an electron donor for Ziegler-Natta catalysts. The present invention is related to an improvement in the synthesis of 9,9-bis(methoxymethyl)fluorene leading to a decrease in the amount of solvent used and an easier work up while achieving high yield and purity.
