Solutions of timolol maleate are stable up to a pH of 12. In general, timolol ophthalmic solutions should be protected from light and stored in tight containers at 15-30 °C and protected from freezing. ... Timolol gel-forming ophthalmic solution should be stored at 15-25 °C. /Timolol Maleate/
Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19. 15-20% of a dose undergoes first-pass metabolism. Despite its relatively low first pass metabolism, timolol is 90% metabolized. Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant.
来源:DrugBank
代谢
它被肝脏广泛代谢，只有少量未改变的药物出现在尿液中。
It is metabolized extensively by the liver, and only a small amount of unchanged drug appears in the urine.
The metabolism of timolol maleate to its ring cleavage ethanolamine and glycine products was studied in 108 patients with essential hypertension who received 10 mg oftimolol maleate, administered as a single oral dose. The metabolism of timolol maleate was determined to be partly under monogenic control of the debrisoquine-type. The mean plasmatimolol maleate concentration in poor metabolizers of debrisoquine were double that of extensiv metabolizers. /Timolol maleate/
IDENTIFICATION: Timolol is an adrenergic beta-receptor blocking agent and a Class II antiarrhythmic drug. The drug is a white, odorless powder. Soluble in water, alcohol, in chloroform; soluble in methanol; practically insoluble in ether. HUMAN EXPOSURE: Main risks and target organs: Beta-blocking agents exert their effects by competing with endogenous and/or exogenous beta-adrenergic agonists. Timolol is a non-cardioselective beta-blocker (it has similar affinity for beta1 and beta2 receptors) and it has no intrinsic sympathomimetic or membrane stabilizing effect. The main risks might be an impairment of atrioventricular conduction and a negative inotropic effect. Summary of clinical effects: Only one case of acute poisoning after ingestion in a 24 year old man has been reported. The patient showed moderate toxic symptoms: drowsiness, vertigo, headache, and first degree atrioventricular block which was treated with atropine and isoproterenol. The patient recovered without sequelae. Adverse systemic effects have been reported in patients treated with timolol eye drops. Indications: Oral administration: Timolol has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmias, migraine and for the reduction of mortality following myocardial infarction. Ocular administration: Ophthalmic solutions of timolol are used in the treatment of glaucoma to reduce intraocular pressure. Contraindications: Timolol is contraindicated in patients with asthma, second and third degree AV block, and cardiogenic shock. Timolol should be used cautiously in patients with chronic obstructive pulmonary diseases, sinus bradycardia, cardiac failure, myasthenia gravis, Raynaud's syndrome. Timolol should not be administered with other beta-blockers. Routes of entry: Oral: Poisoning after ingestion of timolol tablets may occur but only one case has been actually reported. Eye: Systemic toxic symptoms may occur after treatment with timolol eye drops. Absorption by route of exposure: Oral: Timolol is almost completely (90%) absorbed from the gastrointestinal tract. The peak plasma concentration occurs 0.5-3 hours after ingestion. Timolol is subject to a moderate first pass effect. Ocular: The onset of the ocular hypotensive action occurs after 10-20 minutes and lasts for at least 24 hours. Timolol is absorbed systemically. Distribution by route of exposure: Oral: Bioavailability is about 60%. Apparent volume of distribution is 1.3 - 1.7 L/kg. Plasma protein binding is approximately 10%. Timolol crosses the placenta Ocular: Timolol is distributed in conjunctiva, cornea, sclera, iris, aqueous humor, liver, kidney and lung. Transdermal: After cutaneous application of timolol ointment, 50 to 60% is absorbed systemically. Biological half-life by route of exposure: Oral: After oral administration, the half-life is 2.5 - 5 hours. The half-life varies according to genetic differences in hepatic metabolism: half-lives of 3.7 and 7.5 hours were reported in extensive and poor metabolizers, respectively. Metabolism: Oral: Timolol is extensively metabolized in the liver by hydrolytic cleavage of the morpholino ring with subsequent oxidation. Following an oral dose, 80% is metabolized and 20% is eliminated unchanged in urine. Metabolism is dependent on genetic polymorphism. Elimination by route of exposure: Oral: Kidney: About 20% of the dose is eliminated unchanged in the urine and 40 to 60% as metabolites. Breast milk: Timolol is present in breast milk. Following a maternal oral dose, the milk/plasma ratio is 0.80. Ocular: Breast milk: Following ocular instilation, the concentration in breast milk was approximately 6 times higher than in serum. Pharmacology and toxicology: Mode of action: Toxicodynamics: At toxic doses, timolol may exert a pronounced negative chronotropic and negative inotropic cardiac effect. Pharmacodynamics: The exact mechanism whereby timolol reduces ocular pressure is still not known. The most likely action is by decreasing the secretion of aqueous humor. At therapeutic doses, timolol slightly decreases heart rate, supraventricular conduction and cardiac output. Adults: Only one case of acute poisoning with timolol has been reported; this patient showed moderately severe symptoms. Children: An 18 month old girl developed bradycardia, respiratory depression and cyanosis 30 minutes after the administration of timolol eye drops. Teratogenicity: No epidemiological studies of congenital abnormalities among infants born to women treated with timolol during pregnancy have been reported. Interactions: Sinus bradycardia has been reported after concomitant treatment with timolol eye drops and quinidine. Clinical effects: Acute poisoning: Eye contact: Adverse systemic effects have been reported after treatment with ophthalmic solutions of timolol. Chronic poisoning: Eye contact: Dryness of the eye has been reported in a man treated with timolol 75 mg daily. Corneal anesthesia was observed in a patient treated with timolol eye drops. Systematic description of clinical effects: Cardiovascular: Acute: First-degree atrioventricular block has been reported after ingestion of blood pressure was 120/80 mmHg and the heart rate was 58/min. Bradycardia, hypotension, atrioventricular block and congestive cardiac failure may occur after administration of timolol. Respiratory: Acute: Reversible respiratory arrest was observed in a 62-year-old woman after instillation of timolol eye drops and may occur after oral administration. Bronchospasm may occur in susceptible patients after administration of timolol. Neurological: CNS: Acute: Drowsiness, vertigo, headache have been reported in one case. Fatigue, confusion, depression, hallucinations have been reported after administration of timolol. Peripheral nervous system: Acute: Worsening of myasthenia gravis may occur after administration of timolol. Autonomic nervous system: Acute: Effects of beta-blockade. Gastrointestinal: Acute: abdominal pain, nausea, vomiting and diarrhea may occur after administration of timolol orally or as eye drops. Dermatological: Acute: Urticaria may be observed. Eye, ear, nose, throat: local effects: Acute: Eyelid erythema and edema has been reported following ocular administration. Metabolic: Acid-base disturbances. Fluid and electrolyte disturbances: Hyperkalemia has been reported. Other clinical effects: Sexual dysfunction following usual doses of topical ocular timolol has been reported and may also occur after oral administration. Special risks: Timolol is eliminated in breast milk. No epidemiological studies of congenital anomalies among infants born to women treated with timolol during pregnancy have been reported.
Mild-to-moderate elevations in serum aminotransferase levels occur in less than 2% of patients on timolol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its wide spread use, timolol has not been convincingly linked to instances of clinically apparent liver injury. Other beta-blockers have been implicated in rare instances of acute liver injury with a latency to onset ranging from 2 to 24 weeks, a hepatocellular pattern of serum enzyme elevations and a mild, self-limiting course without evidence of hypersensitivity or autoimmune reactions.
The systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5%, indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers. The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop administration.
来源:DrugBank
吸收、分配和排泄
消除途径
Timolol 及其代谢物主要在尿液中排出。
Timolol and its metabolites are mainly found excreted in the urine.
来源:DrugBank
吸收、分配和排泄
分布容积
1.3 - 1.7 升/公斤 酮洛尔分布到以下组织：结膜、角膜、虹膜、巩膜、房水、肾脏、肝脏和肺。
1.3 - 1.7 L/kg Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung.
One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers.
The degree of systemic absorption of timolol after topical application to the eye has not been fully elucidated; however, some absorption can apparently occur, since adverse systemic effects have occurred following ophthalmic instillation of the drug. Following topical adminstration of timolol 0.5% solution twice daily to the eye in a limited number of individuals, mean peak plasma concentrations were 0.46 or 0.35 ng/ml following the morning or afternoon dose, respectively. In individuals receiving topical timolol 0.5% as the gel-forming ophthalmic solution once daily in the morning, mean peak plasma concentrations following the dose were 0.28 ng/ml. Following topical application to the eye of a 0.25 or 0.5% solution of the drug, reduction in IOP usually occurs within 15-30 minutes, reaches a maximum within 1-5 hours, and persists about 24 hours.
Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines
摘要：
An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (+/-)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively. (c) 2007 Elsevier Ltd. All rights reserved.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
[EN] QUINONE BASED NITRIC OXIDE DONATING COMPOUNDS<br/>[FR] COMPOSÉS DONNEURS D'OXYDE NITRIQUE À BASE DE QUINONE
申请人：NICOX SA
公开号：WO2013060673A1
公开（公告）日：2013-05-02
The present invention relates to nitric oxide donor compounds having a quinone based structure, to processes for their preparation and to their use in the treatment of pathological conditions where a deficit of NO plays an important role in their pathogenesis.
[EN] NOVEL COMPOUNDS, THEIR PREPARATION AND USE<br/>[FR] NOUVEAUX COMPOSES, LEUR PREPARATION ET LEUR UTILISATION
申请人：NOVO NORDISK AS
公开号：WO2005105736A1
公开（公告）日：2005-11-10
Novel compounds of the general formula (I), the use of these compounds as phar- maceutical compositions, pharmaceutical compositions comprising the compounds and methods of treatment employing these compounds and compositions. The present compounds may be useful in the treatment and/or prevention of conditions mediated by Peroxisome Proliferator-Activated Receptors (PPAR), in particular the PPARδ suptype.
Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.
Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
申请人：——
公开号：US20030166644A1
公开（公告）日：2003-09-04
Use of compounds to inhibit hormone-sensitive lipase, pharmaceutical compositions comprising the compounds, methods of treatment employing these compounds and compositions, and novel compounds. The present compounds are inhibitors of hormone-sensitive lipase and may be useful in the treatment and/or prevention of medical disorders where a decreased activity of hormone-sensitive lipase is desirable.
