The metabolite at this step is cyclohexanol, and this is a relatively non-toxic compound which is advantageous to the design of the drug. The other aspect of the cascading prodrug is the O-CH-CH3 molecule which becomes converted into acetic acid, which is another product from the cascading side reaction. Similar to the insight from cyclohexanol, the metabolite of acetic acid relatively is non-toxic and thus less of a hazard if produced as the drug takes pharmacologic action. The use of a prodrug form increases the bioavailability of candesartan. Despite this, absolute bioavailability is relatively poor at 15% (candesartan cilexetil tablets) to 40% (candesartan cilexetil solution). Its IC50 is 15 μg/kg. Candesartan is not administered in its active form because the administration of the pro-drug would require greater doses and has an unfavorable adverse event profile. History
The compound known as TCV-116 (candesartan) was studied by Japanese scientists using standard laboratory rats. Animal studies were published showing the effectiveness of the compound in 1992–1993, with a pilot study on humans published in the summer of 1993. Names
The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand. It is available in generic form. == References ==
From this point on until at least 4–5 years, or even longer (6–9 years if needed), the brace is worn mostly while sleeping at night and during naps (12–14 hours per day). Bracing is essential in preventing recurrence of the deformity and is a major determinant of a childs long-term outcome.The Ponseti method is highly effective with short-term success rates of 90%. However, anywhere from 14% to 41% of children experience a recurrence of the deformity. The most common reason for this is inadequate adherence to bracing, such as not wearing the brace properly, not keeping it on for the recommended length of time, or not using it every day. Children who do not follow proper bracing protocol have up to seven times higher recurrence rates than those who follow bracing protocol, as the muscles around the foot can pull it back into the abnormal position. Low parental education level and failure to understand the importance of bracing is a major contributor to non-adherence. Relapses are managed by repeating the casting process. Relapsed feet may also require additional, more extensive surgeries and have a reduced chance of achieving subsequent correction.Another reason for recurrence is a congenital muscle imbalance between the muscles that invert the ankle (tibialis posterior and tibialis anterior muscles) and the muscles that evert the ankle (peroneal muscles). This imbalance is present in approximately 20% of infants successfully treated with the Ponseti casting method, and makes them more prone to recurrence.