Sildenafil manufacture

In the USA the Presidential Green Chemistry Challenge Awards [7] were introduced to stimulate the application of the principles of green chemistry and many chemical and pharmaceutical companies have received awards for the development of greener processes and products, e.g. Pfizer for developing a greener process for sildenafil manufacture (see Chapter 7). 

With no further purification. The commercial route was further optimized to minimize waste and maximize solvent recovery. Pfizer was awarded the Crystal Faraday Award for Green Chemical Technology by the Institute of Chemical Engineers in recognition of the environmentally-friendly manufacturing of sildenafil. 

Pfizer also received a Crystal Faraday Award for optimizing the process used to manufacture the active ingredient in Viagra , sildenafil citrate. Shown in Figure 3.6 is the solvent usage during each stage of process development for sildenafil citrate over a 15-year lime line [19]. 

PROTEASE INHIBITORS PHOSPHODIESTERASE TYPE 5 INHIBITORS-SILDENAFIL, TADALAFIL, VARDENAFIL t sildenafil, tadalafil and vardenafil levels Inhibition of CYP3A4- and possibly CYP2C9-mediated metabolism of sildenafil Use with caution monitor BP closely. UK manufacturers recommend avoiding co-administration of vardenafil with protease inhibitors in patients >75 years. US manufacturers recommend using with caution, starting with a daily dose of 2.5 mg... 

The use of phosphodiesterase inhibitors (e.g. sildenafil, tadaiafil and var-denafil) with sodium nitroprusside is contraindicated by the manufacturers, due to the risk of severe hypotension. See also Phosphodiesterase type-5 inhihitors +Nitrates , p.l272. A case report describes the therapeutic use of sildenafil to enhance the hypotensive effect of sodium nitroprusside and other antihypertensives in a patient with a hypertensive crisis. ... 

The manufacturers recommend that patients should be stable on an alpha blocker before sildenafil is started and that consideration should be given to starting sildenafil at the lowest dose (25 mg). " The UK manufacturer notes that a hypotensive effect is most likely within 4 hours of taking an alpha blocker. When starting an alpha blocker in a patient taking sildenafil, the US manufacturer states that the alpha blocker should be started at the lowest dose. ... 

The manufacturers report that in population pharmacokinetic analysis, there was no effect on sildenafil pharmacokinetics in those taking ACE inhibitors, calcium-channel blockers and tMazide and related diuretics whereas the AUC of the less potent active metabolite of sildenafil is increased by 62% by loop and potassium-sparing diuretics and by 102% by non-selective beta blockers, although these changes were not considered clinically relevant. ... 

The manufacturer notes that in population pharmacokinetic analysis of patients with pulmonary hypertension, there appeared to be an increase in sildenafil exposure when it was taken with beta blockers (none named) in combination with CYP3A4 substrates (none named). " The clinical relevance of this is uncertain, and fiuther study is needed. 

In an open label, randomised study in 12 healthy subjects, ketoconazole 200 mg daily increased the AUC of a single 10-mg dose of tadalafil by twofold, and ketoconazole 400 mg daily increased the AUC fourfold. The manufacturers predict that itraconazole will interact similarly. This prediction has been borne out by a case report of a 56-year-old man who was taking itraconazole 400 mg daily for 7 days each month. Within a few hours of his first 10-mg dose of tadalafil he developed priapism, which lasted for more than 4 hours. The same reaction occurred when he took tadalafil during the following month. He had seemingly previously taken sildenafil with itraconazole without adverse effect. ... 

For sildenafil, when used for erectile dysfunction, the manufacturers recommend that a low starting dose of sildenafil (25 mg) should be considered if ketoconazole or itraconazole are used concurrently. When used for pulmonary hypertension, the manufacturers say that concurrent use of sildenafil with ketoconazole and itraconazole is contraindicated in the UK, or not recommended in the US. ... 

On the basis of the 63% reduction in AUC seen with the moderate CYP3A4 indueer bosentan , (p.l274), the US manufacturer of sildenafil says that concurrent use with potent inducers of CYP3A4 such as rifampicin is predicted to cause a greater reduction in sildenafil levels. ... 

Although the manufacturer of vardenafii does not mention CYP3A4 inducers, like tadalafil and sildenafil, vardenafii is principally metabolised by CYP3A4, and its levels are markedly raised by CYP3A4 inhibitors such as ketoconazole , (p. 1270). It is therefore very likely that vardenafii levels will be reduced by rifampicin and similar drugs, and concurrent use should be monitored. 

For sildenafil, the manufacturers recommend that a low starting dose of sildenafil 25 mg should be considered in patients with erectile dysfunction taking inhibitors of CYP3A4 such as erythromycin. For pulmonary hypertension, the UK manufacturer says that a downward reduction of the sildenafil dose to 20 mg twice daily should be considered with erythromycin, and 20 mg once daily with clarithromycin or telithromycin, (however, note that erythromycin had a greater effect than clarithromycin in the studies above) whereas the US manufacturer says that no dose adjustment is needed with erythromycin. ... 

The manufacturer notes that population pharmacokinetie analysis of elin-ical study data indieate that inhibitors of cytochrome P450 isoenzyme CYP2D6 such as SSRIs and tricyclic antidepressants do not have any effect on the pharmacokinetics of sildenafil. However, in a double-blind, placebo-controlled study in healthy subjects, pre-treatment with fluvox-amine 50 mg daily for 3 days then 100 mg daily for 6 days increased the AUC of sildenafil 50 mg by 40%. This resulted in an inerease in the vascular effects of sildenafil. ... 

According to the manufacturers of sildenafil, priapism (painful prolonged abnormal erection) associated with its use is rare, and there appear to be no other reports about an interaction between sildenafil and dihydrocodeine. Excessively prolonged erections can have serious consequences and may need urgent treatment. Therefore, the authors suggest it would now be prudent to warn patients about this possible (though remote) problem if opioids are being used, and advise them to contact the prescrib-er if priapism occurs. ... 

Two nitrogen atoms Histidine Sildenafil (Viagra ) Caffeine An amino acid found in protein manufactured in the human body Pharmaceutical A stimulant in coffee... 

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