Tadalafil
From Wikipedia, the free encyclopedia
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Tadalafil
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| Systematic (IUPAC) name | |
| (6R-trans)-6-(1,3-benzodioxol-5-yl)- 2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1', 2':1,6] pyrido[3,4-b]indole-1,4-dione | |
| Identifiers | |
| CAS number | |
| ATC code | G04 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C22H19N3O4 |
| Mol. mass | 389.404 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | varies |
| Protein binding | 94% |
| Metabolism | CYP3A4 (liver) |
| Half life | 17.5 hours |
| Excretion | feces (> 60%), urine (> 30%) |
| Therapeutic considerations | |
| Pregnancy cat. |
B |
| Legal status |
prescription only |
| Routes | oral |
Tadalafil is an orally administered drug used to treat male erectile dysfunction (impotence). It was initially developed by the biotechnology firm ICOS and subsequently developed and marketed worldwide by a joint venture of ICOS Corporation and Eli Lilly and Company (Lilly ICOS LLC) under the brand name Cialis. Cialis tablets are yellow, film-coated, and almond-shaped; produced in 5, 10, or 20 mg doses.
In the United States, tadalafil has Food and Drug Administration approval and became available in December, 2003 as the third impotence pill after sildenafil (Viagra) and vardenafil (Levitra). Due to its 36-hour effect it is also known as the weekend pill. As with sildenafil and vardenafil, it is recommended that tadalafil be used no more than once daily. Tadalafil is also currently undergoing Phase 3 clinical trials for the treatment of pulmonary arterial hypertension.
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[edit] History
The history of Cialis cannot be discussed without mentioning Pfizer's drug, Viagra (sildenafil). The FDA's approval of Viagra on March 27, 1998, was a groundbreaking event for the treatment of erectile dysfunction and sales eventually reached over a billion dollars. The FDA subsequently approved Levitra (vardenafil) on August 19, 2003, and Cialis (tadalafil) on November 21, 2003.
In 1993, the Bothell, Washington-based biotechnology company ICOS began studying IC351, which is a phosphodiesterase type 5 (PDE5) enzyme inhibitor. In 1994, Pfizer scientists discovered that sildenafil citrate, which also inhibits the PDE5 enzyme, caused patients that were participating in a clinical study of a heart medicine to have erections. Although the ICOS scientists were not testing the chemical compound IC351 for erectile dysfunction, it was recognized that the compound could have potential usefulness for the treatment of this disorder. Soon ICOS received a patent in 1994 for IC351, which is structurally different from sildenafil (and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, Phase 2 clinical studies were initiated in patients with erectile dysfunction and led to pivotal Phase 3 trials that supported approval.
In 1998, ICOS Corporation and Eli Lilly and Company formed a joint venture (Lilly ICOS LLC) to further develop and commercialize the drug for erectile dysfunction, and two years later they filed a New Drug Application with the U.S. Food and Drug Administration for IC351 (under the generic name tadalafil and the brand name Cialis). In May of 2002, Lilly ICOS reported to the American Urological Association that clinical trial testing in men with erectile dysfunction showed that tadalafil works for up to 36 hours, and one year later tadalafil was approved. One advantage that Cialis has over Viagra and Levitra is that tadalafil has a half-life of 17.5 hours[1] (and thus Cialis is advertised to work for up to 36 hours, after which time there is still about one quarter of the absorbed dose in the body) as compared to 4 hours half-life for sildenafil (Viagra).[2][3]
Eli Lilly purchased ICOS Corporation for $2.3 billion dollars in 2007. As a result, Eli Lilly gained complete ownership of Cialis and promptly shut down ICOS operations, terminating the joint venture and employment of most (> 500) ICOS personnel. An exception to this mass layoff was the retention of 127 employees working at the ICOS biologics facility, which was subsequently acquired by CMC Biopharmaceuticals A/S(CMC).
Some individuals with the surname of "Cialis" objected to Lilly's naming of the drug, but the company insists that the drug's trade name has nothing to do with the surname.[4]
[edit] Mechanism of action
Although Viagra, Levitra, and Cialis all work by inhibition of PDE5, tadalafil's distinguishing pharmacologic feature is its longer half-life (17.5 hours) compared with Viagra and Levitra (4-5 hours). This longer half-life results in a longer duration of action and is, in part, responsible for the Cialis nickname of the "weekend pill." This longer half-life also is the basis of current investigation for tadalafil's use in pulmonary arterial hypertension as a once-daily therapy. At present, sildenafil (trade name Revatio) is approved in various regions worldwide as a 3-times daily therapy for pulmonary arterial hypertension.
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil (as well as sildenafil and vardenafil) inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation. The recommended starting dose of Cialis in most patients is 10 mg, taken as needed before anticipated sexual activity (but no more than once daily). The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. To avoid the inconvience of men with erectile dysfunction needing to plan use of Cialis around anticipated sexual activity, Lilly ICOS embarked upon a clinical development program to evaluate the benefits and risks of chronic (once-a-day) use. In June 2007, the European Commission approved low-dose (2.5 mg and 5 mg) Cialis to be used as a once-a-day therapy for men with erectile dysfunction.
Tadalafil is currently undergoing clinical trials for the treatment of pulmonary arterial hypertension. In some patients with pulmonary arterial hypertension, it is believed that there is an imbalance of the PDE5/NO system in the pulmonary vasculature that favors selective vasoconstriction of the pulmonary arteries. Investigation of tadalafil in this disease assumes that PDE5 inhibition will result in pulmonary artery vasodilation, thus lowering pulmonary artery pressure and pulmonary vascular resistance. These physiologic changes may then reduce the workload of the right ventricle of the heart. Right heart failure and pulmonary oedema are the main consequences of pulmonary arterial hypertension.
[edit] Side effects
Tadalafil has been used in approximately 15,000 men participating in clinical trials, and over 8 million men wordwide (primarily in the post-approval/post-marketing setting). The most common side effects when using tadalafil are headache, indigestion, back pain, muscle aches, flushing, and stuffy or runny nose. These side effects reflect the ability of PDE5 inhibition to vasodilate (cause blood vessels to widen) and usually go away after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and the symptom usually disappears after 48 hours.
In May 2005, the U.S. Food and Drug Administration found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy) in certain patients taking these drugs in the post-marketing (outside of clinical trials) setting. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION unrelated to PDE5 use, including: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Given the small number of NAION events with PDE5 use (less than 1 in 1 million), the large number of users of PDE5 inhibitors (millions) and the fact that this event occurs in a similar population to those who do not take these medicines, the FDA concluded that they were not able to draw a cause and effect relationship, given these patients underlying vascular risk factors or anatomical defects. However, the label of all three PDE5 inhibitors was changed to highlight clinicians to a possible association.
In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including tadalafil, requires a more prominent warning of the potential risk of sudden hearing loss as the result of postmarketing reports of deafness associated with use of PDE5 inhibitors.[5]
[edit] Drug interactions
Since PDE5 inhibitors such as tadalafil may cause transiently low blood pressure (hypotension), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrites (such as the sex drug amyl nitrite) within this timeframe may increase the risk of life-threatening hypotension.
Since people who have taken tadalafil within the past 48 hours cannot take organic nitrates to relieve angina (such as glyceryl trinitrate spray), these patients should seek immediate medical attention if they experience anginal chest pain.[6] In the event of a medical emergency, paramedics and medical personnel should be notified of any recent doses of tadalafil.
[edit] Marketing
In the United States, Eli Lilly has a multiyear agreement to promote tadalafil (Cialis) with professional golf's PGA Tour.
Cialis is one of the most frequent offerings of E-mail spam.
[edit] References
- ^ Cialis - Safety Monitoring(s). Epocrates Rx software, produced by Epocrates, Inc.. Information also available online. Retrieved on 2007-04-06.
- ^ Viagra - Safety Monitoring(s). Epocrates Rx software, produced by Epocrates, Inc.. Information also available online. Retrieved on 2007-04-06.
- ^ (French) Sildenafil: Pharmaco-Cinétique. BIAM (April 20, 2001). Retrieved on 2007-04-06.
- ^ Revill, Jo. "Drugs giant says its new pill will pack more punch than rival Viagra", The Observer, February 2, 2003. Retrieved on 2007-04-06.
- ^ FDA Announces Revisions to Labels for Cialis, Levitra and Viagra. Food and Drug Administration (2007-10-18). Retrieved on 2007-12-08.
- ^ Cialis: Warnings, Precautions, Pregnancy, Nursing, Abuse. RxList (2007). Retrieved on 2007-04-06.
[edit] External links
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