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| __NOTOC__
| | #REDIRECT [[Doxazosin#Nonclinical Toxicology]] |
| {{Doxazosin}}
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| {{CMG}}; {{AE}} {{AK}}
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| ==DRUG INTERACTIONS==
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| Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of [[digoxin]], [[warfarin]], [[phenytoin]], or [[indomethacin]]. There is no information on the effect of other highly plasma protein- bound drugs on doxazosin binding. Doxazosin has been administered without any evidence of an adverse drug interaction to patients receiving [[thiazide ]]diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral [[cimetidine ]](400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p=0.006), and a slight but not statistically significant increase in mean Cmax and mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown.
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| In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Doxazosin tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., [[acetaminophen]], [[aspirin]], [[codeine ]]and [[codeine ]]combinations, [[ibuprofen]], [[indomethacin]]); 2) antibiotics (e.g., [[erythromycin]], [[trimethoprim ]]and [[sulfamethoxazole]], [[amoxicillin]]); 3) antihistamines (e.g., [[chlorpheniramine]]); 4) cardiovascular agents (e.g., [[atenolol]], [[hydrochlorothiazide]], [[propranolol]]); 5) [[corticosteroids]]; 6) gastrointestinal agents (e.g., [[antacids]]); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., [[diazepam]]); 9) cold and flu remedies.
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| Concomitant administration of doxazosin with a [[PDE5 inhibitor|phosphodiesterase-5 ]](PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic
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| hypotension (see[[Doxazosin dosage and administration|DOSAGE AND ADMINISTRATION]]).
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| ===Cardiac Toxicity in Animals===
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| An increased incidence of myocardial necrosis or fibrosis was displayed by Sprague-Dawley rats after 6 months of dietary administration at concentrations calculated to provide 80 mg doxazosin/kg/day, and after 12 months of dietary administration at concentrations calculated to provide 40 mg doxazosin/kg/day (AUC exposure in rats 8 times the human AUC exposure with a 12 mg/day therapeutic dose). Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months (exposure 8 times human AUC exposure in rats and somewhat equivalent to human Cmax exposure in mice). No cardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending on the study) in either species. These lesions were not observed after 12 months of oral dosing in dogs at maximum doses of 20 mg/kg/day [maximum plasma concentrations (Cmax) in dogs 14 times the Cmax exposure in humans receiving a 12 mg/day therapeutic dose] and in Wistar rats at doses of 100 mg/kg/day (Cmax exposures 15 times human Cmax exposure with a 12 mg/day therapeutic dose). There is no evidence that similar lesions occur in humans.
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| ===Carcinogenesis, Mutagenesis, Impairment of Fertility===
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| Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day.
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| Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.
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| Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = DOXAZOSIN TABLET [APOTEX CORP.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4fa5c2f7-cda9-56cd-622f-b3d05dc7c94b | publisher = | date = | accessdate = 7 March 2014 }}</ref>
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| ==References==
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| {{Reflist|2}}
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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