Animal studies show that prazosin hydrochloride is metabolized extensively in the liver, principally by demethylation and conjugation, and excreted as unchanged drug (5-11%) and metabolites. Four of the metabolites have been shown to possess 10-25% of the hypotensive activity of prazosin and they may contribute to the antihypertensive effect of the drug.
The 6-O-demethyl and 7-O-demethyl analogues of the new antihypertensive drug prazosin [2-[4-(2-furoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline hydrochloride] have been unequivocally synthesized via separate 10-step reaction sequences starting from isovanillin and vanillin, respectively. The 6-O-demethyl derivative was found to be identical with the major prazosin metabolite formed in dog and rat, while the 7-O-demethyl derivative was identical with another, less prevalent but significant metabolite. Two minor metabolites of prazosin, 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline and 2,4-diamino-6,7-dimethoxyquinazoline, are also described. All 4 metabolites are less potent blood pressure lowering agents in dogs than prazosin but may contribute to its antihypertensive effect, since they account for a major portion of the administered dose.
When prazosin is administered with diuretics or other hypotensive agents, particularly beta-adrenergic blocking agents (eg, propranolol), the hypotensive effect of prazosin may be increased.
... prazosin hydrochloride has been administered without any adverse drug interaction in limited clinical experience to date with the following: cardiac glycosides -- digitalis and digoxin; hypoglycemics -- insulin, chlorpropamide, phenformin, tolazamide, and tolbutamide; tranquilizers and sedatives -- chlordiazepoxide, diazepam, phenobarbital; antigout -- allopurinol, colchicine, and probenecid; antiarrhythmics -- procainamide, propranolol and quinidine; analgesics, antipyretics and anti-inflammatories -- propoxyphene, aspirin, indomethacin, and phenylbutazone.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
在报告的少数过量病例中，支持性治疗包括静脉输液和血管加压药（如多巴胺）是有效的。
Treatment with supportive care including intravenous fluid boluses and vasopressors such as dopamine were effective in the few overdose cases reported.
Maintain an open airway and assist ventilation if necessary.Hypotension usually respondes to supine positioning and iv crystalloid fluids. Occasionally pressor therapy is needed. there is no specific antidote. Administer activated charcoal.
There is intraindividual and interindividual variation in the rate of absorption and plasma concentrations of prazosin. The absolute oral bioavailability of prazosin is also variable but is reported to average about 60% (range: 43-82%). Results of one study indicate that the presence of food may delay absorption of the drug in some patients, but does not affect the extent of absorption.
Following oral administration of prazosin hydrochloride, plasma concentrations of the drug reach a peak in 2-3 hrs in most fasting patients. Plasma concentrations of prazosin generally do not correlate with therapeutic effect. One manufacturer reports that plasma concentrations of the drug after a single 5 mg dose range from 0.01-0.075 ug/ml. Blood pressure begins to decrease within 2 hr after an oral dose; the maximum decrease occurs in 2-4 hr. The hypotensive effect of prazosin lasts less than 24 hr.
Animal studies indicate that prazosin is widely distributed in body tissues. After iv administration in dogs, highest concentrations of the drug are found in the lungs, coronary arteries, aorta, paw arteries and heart; the lowest concentrations are in the brain. During prazosin therapy, approximately 97% of the drug in plasma is bound to proteins. It is not known whether the drug crosses the placenta. Prazosin is distributed into milk in small amounts.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
大约6-10%的剂量通过尿液排出，其余通过胆汁在粪便中排出。
Approximately 6-10% of a dose is excreted in urine and the remainder in feces via bile.
The drug /prazosin hydrochloride/ is tightly bound to plasma proteins (primarily alpha1-acid glycoprotein), and only 5% of the drug is free in the circulation; diseases that modify the concentration of this protein (e.g., inflammatory processes) may change the free fraction. Prazosin is extensively metabolized in the liver, and little unchanged drug is excreted by the kidneys.
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.
The present invention relates to compounds of formula I
wherein A and R
1
to R
4
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.
BENZOFURAN AND BENZOTHIOPHENE-2-CARBOXYLIC ACID AMIDE DERIVATIVES
申请人：Mohr Peter
公开号：US20090029976A1
公开（公告）日：2009-01-29
The present invention relates to compounds of formula I
wherein X, A and R
1
to R
4
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.
A dibenzylamine compound represented by the formula (1)
wherein R
1
and R
2
are each a C
1-6
alkyl group optionally substituted by halogen atoms and the like; R
3
, R
4
and R
5
are each a hydrogen atom, a halogen atom and the like, or R
3
and R
4
may form, together with carbon atoms bonded thereto, a homocyclic or heterocyclic ring optionally having substituent(s); A is
—N(R
7
) (R
8
) and the like; ring B is an aryl group or a heterocyclic residue; R
6
is a hydrogen atom, a halogen atom, a nitro group, a C
1-6
alkyl group and the like; n is an integer of 1 to 3, a prodrug thereof and a pharmaceutically acceptable salt thereof show selective and potent CETP inhibitory activity, and therefore, they can be provided as therapeutic or prophylactic agents for hyperlipidemia or arteriosclerosis and the like.
4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
申请人：DeAngelis Alan
公开号：US20060058393A1
公开（公告）日：2006-03-16
The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR modulators to treat or inhibit the progression of, for example, dyslipidemia.
