sabotage!

Thu Jun 05 12:00:37 -0400 2008

So, someone sabotaged all my posts so they pointed to non-links. And no one likes going to non-links. Although, to be fair it's not really sabotage when you expect it to happen. But as a consequence I've pulled all the new/edit/delete links and out of laziness I'm posting from script/console. So take that, bad guys!

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reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg kg day a dose producing AUCs for unbound tadalafil of 14 fold for males or 26 fold for females the exposures observed in human males given the MRHD of 20 mg In beagle dogs given tadalafil daily for 3 to 12 months there was treatment related non reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in of the dogs that resulted in a decrease in spermatogenesis in of the dogs at doses of 10 mg kg day Systemic exposure based on AUC at no observed adverse-effect level NOAEL 10 mg kg day for unbound tadalafil was similar to that expected in humans at the MRHD of 20 mg There were no treatment related testicular findings in rats or mice treated with doses up to 400 mg kg day for 2 years Animal Toxicology Animal studies showed vascular inflammation in tadalafil treated mice rats and dogs In mice and rats lymphoid necrosis and hemorrhage were seen in the spleen thymus and mesenteric lymph nodes at unbound tadalafil exposure of 2 to 33 fold above the human exposure AUCs at the MRHD of 20 mg In dogs an increased incidence of disseminated arteritis was observed in 1 and 6 month studies at unbound tadalafil exposure of 1 to 54 fold above the human exposure AUC at the MRHD of 20 mg In a 12 month dog study no disseminated arteritis was observed but 2 dogs exhibited marked decreases in white blood cells neutrophils and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 14 to 18 fold the human exposure at the MRHD of 20 mg The abnormal blood cell findings were reversible within 2 weeks upon removal of the drug Pregnancy Nursing Mothers and Pediatric Use Cialis is not indicated for use in newborns children or women Tadalafil and or its metabolites cross the placenta resulting in fetal exposure in rats Tadalafil and or its metabolites were secreted into the milk in lactating rats at concentrations approximately fold greater than found in the plasma Following a single oral dose of 10 mg kg approximately of the total radioactive dose was excreted into the milk within 3 hours It is not known if tadalafil and or its metabolites is excreted in human breast milk Use of tadalafil in nursing mothers is not recommended Pregnancy Category B There was no evidence of teratogenicity embryotoxicity or fetotoxicity in rat or mouse fetuses that received up to 1000 mg kg day during the major organ development Plasma exposure at this dose is approximately 11 fold greater than the AUC values for unbound tadalafil in humans given the MRHD of 20 mg In a rat prenatal and postnatal development study at doses of and 1000 mg kg there was a reduction in postnatal survival of pups The no observed effect level NOEL for maternal toxicity was 200 mg kg day and for developmental toxicity was 30 mg kg day which gives approximately 16 and 10 fold exposure multiples respectively of the human AUC for the MRHD dose of 20 mg There are no adequate and well controlled studies of tadalafil in pregnant women Geriatric Use Approximately 25 of patients in the primary efficacy and safety studies of tadalafil were greater than 65 years of age No overall differences in efficacy and safety were observed between older and younger patients No dose adjustment is warranted based on age alone However greater sensitivity to medications in some older individuals should be considered see Special Populations under CLINICAL PHARMACOLOGY Adverse Reactions Tadalafil was administered to over 5700 men mean age 59 range 19 to 87 years during clinical trials worldwide Over 1000 patients were treated for 1 year or longer and over 1300 patients were treated for 6 months or more In placebo controlled Phase 3 clinical trials the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was compared to in placebo treated patients When tadalafil was taken as recommended in the placebo controlled clinical trials the following adverse events were

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were as follows Placebo-subtracted mean maximum decrease in systolic blood pressure mm Hg Viagra 50 mg 95 CI Supine 5 68 Standing 7 90 Figure 6 Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of Viagra at the same times as those specified for the first doxazosin study There were two subjects who had a standing SBP of 85 mmHg In these two subjects hypotension was reported as a moderately severe adverse event beginning at approximately 1 hour after administration of Viagra 50 mg and resolving after approximately hours There was one subject with a decrease from baseline in standing systolic BP 30mmHg following Viagra 50 mg and one subject with a decrease from baseline in standing systolic BP 30 mmHg following both Viagra 50 mg and placebo There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study In the third study a single oral dose of Viagra 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH In dose period 1 subjects were administered open-label doxazosin and a single dose of Viagra 50 mg simultaneously after at least 14 consecutive days of doxazosin If a subject did not successfully complete this first dosing period he was discontinued from the study Subjects who had successfully completed the previous doxazosin interaction study using Viagra 50 mg including no significant hemodynamic adverse events were allowed to skip dose period 1 Treatment with doxazosin continued for at least 7 days after dose period 1 Thereafter Viagra 100mg or matching placebo was administered simultaneously with doxazosin 4 mg 14 subjects or doxazosin 8 mg 6 subjects in standard crossover fashion The mean subject age in this study was years Twenty-five subjects were screened Two were discontinued after study period 1 one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label Viagra 50 mg Of the twenty subjects who were ultimately assigned to treatment a total of 13 subjects successfully completed dose period 1 and seven had successfully completed the previous doxazosin study using Viagra 50 mg For the 20 subjects who received Viagra 100 mg and matching placebo the placebo-subtracted mean maximum decreases from baseline 95 CI in systolic blood pressure were as follows Placebo-subtracted mean maximum decrease in systolic blood pressure mm Hg Viagra 100 mg Supine 4 1 Standing -1 3 Figure 7 Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of Viagra at the same times as those specified for the previous doxazosin studies There were three subjects who had a standing SBP of 85 mmHg All three were taking Viagra 100 mg and all three reported mild adverse events at the time of reductions in standing SBP including vasodilation and lightheadedness There were four subjects with a decrease from baseline in standing systolic BP 30mmHg following Viagra 100 mg one subject with a decrease from baseline in standing systolic BP 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP 30 mmHg following both Viagra and placebo While there were no severe adverse events potentially related to blood pressure reported in this study one subject reported moderate vasodilatation after both Viagra 50 mg and 100 mg There were no episodes of syncope reported in this study When Viagra 100 mg oral was coadministered with amlodipine 5 mg or 10 mg oral to hypertensive patients the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic No significant interactions were shown with tolbutamide 250 mg or warfarin 40 mg both of which are metabolized by CYP2C9 Viagra 50 mg did not potentiate the increase in bleeding time caused by aspirin 150 mg Viagra 50 mg did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of In a study of healthy male volunteers sildenafil 100 mg did not affect the steady state pharmacokinetics of the HIV protease inhibitors saquinavir and ritonavir both of which are CYP3A4 substrates Sildenafil at steady state 80 mg t i d resulted in a 50 increase in AUC and a 42 increase in Cmax of bosentan 125 mg b i d Carcinogenesis Mutagenesis Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure AUCs for unbound sildenafil and its major metabolite of 29- and 42-times for male and female rats respectively the exposures observed in human males given the Maximum Recommended Human Dose MRHD of 100 mg Sildenafil was not carcinogenic when administered to mice for months at dosages up to the Maximum Tolerated Dose MTD of 10 mg kg day approximately times the MRHD on a mg m2 basis Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity There was no impairment of fertility in rats given sildenafil up to 60 mg kg day for 36 days to females and 102 days to males a dose producing an AUC value of more than 25 times the human male AUC There was no effect on sperm motility or morphology after single 100 mg oral doses of Viagra in healthy volunteers Pregnancy Nursing Mothers and Pediatric Use Viagra is not indicated for use in newborns children or women Pregnancy Category B No evidence of teratogenicity embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg kg day during organogenesis

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