Cialis / Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction (ED) under the name Cialis; it has recently been approved for the treatment of pulmonary arterial hypertension, and has been used for other conditions. It initially was developed by the biotechnology company ICOS, and then again developed and marketed world-wide by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company. Cialis tablets, in 5 mg, 10 mg, and 20 mg doses, are yellow, film-coated, and almond-shaped. The approved dose for pulmonary arterial hypertension is 40 mg, and will be marketed under the brand name Adcirca.

In December 2003, the Food and Drug Administration approved tadalafil (as Cialis) for sale in the United States as the third ED prescription drug pill (after sildenafil (Viagra) and vardenafil (Levitra)). Cialis's 36-hour effectiveness earned it the nickname, "The Weekend Pill"; like sildenafil and vardenafil, tadalafil is recommended as an 'as needed' medication. Cialis is the only one of the three that is also offered as a once-daily medication.

Moreover, tadalafil was approved in May 2009 in the United States for the treatment of pulmonary arterial hypertension and is currently under regulatory review in other regions for this condition. In late November 2008, Eli Lilly sold the exclusive rights to commercialize tadalafil for pulmonary arterial hypertension in the United States to United Therapeutics for an upfront payment of $150 million

History

The FDA's approval of Viagra on 27 March 1998 was a ground-breaking commercial event for the treatment of ED, with sales exceeding one billion dollars. Subsequently, the FDA approved Levitra (vardenafil) on 19 August 2003, and Cialis (tadalafil) on 21 November 2003.

Cialis was discovered by Glaxo Wellcome (now GlaxoSmithKline) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991.[1][2] In 1993, the Bothell, Washington, biotechnology company ICOS Corporation began studying compound IC351, a phosphodiesterase type 5 (PDE5) enzyme inhibitor. In 1994, Pfizer scientists discovered that sildenafil, which also inhibits the PDE5 enzyme, caused penile erection in men participating in a clinical study of a heart medicine. Although ICOS scientists were not testing compound IC351 for treating ED, they recognized its potential usefulness for treating that disorder. Soon, in 1994, ICOS received a patent for compound IC351 (structurally unlike sildenafil and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, the Phase 2 clinical studies were initiated for men experiencing ED, then progressed to the Phase 3 trials that supported the drug's FDA approval. Although Glaxo had an agreement with ICOS to share profits 50/50 for drugs resulting from the partnership, Glaxo let the agreement lapse in 1996 as the drugs developed were not in the company's core markets.[3]

In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, joint venture company to further develop and commercialize tadalafil as a treatment for ED. Two years later, Lilly ICOS, LLC, filed a New Drug Application with the FDA for compound IC351 (under the tadalafil generic name, and the Cialis brand name). In May 2002, Lilly ICOS reported to the American Urological Association that clinical trial testing demonstrated that tadalafil was effective for up to 36 hours, and one year later, the FDA approved tadalafil. One advantage Cialis has over Viagra and Levitra is its 17.5-hour half-life (thus Cialis is advertised to work for up to 36 hours, after which time there remains approximately 25 percent of the absorbed dose in the body) when compared to the four-hour half–life of sildenafil (Viagra). [4]

In 2007, Eli Lilly and Company bought the ICOS Corporation for 2.3 billion dollars. As a result, Eli Lilly owned Cialis and then closed the ICOS operations, ending the joint venture and firing most of ICOS's approximately 500 employees, except for 127 employees of the ICOS biologics facility, which subsequently was bought by CMC Biopharmaceuticals A/S(CMC).

Persons surnamed "Cialis" objected to Eli Lilly and Company's so naming the drug, but the company has maintained that the drug's trade name is unrelated to the surname. [5]

Mechanism of action

Although sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) all work by inhibiting PDE5, tadalafil's pharmacologic distinction is its longer half-life (17.50 hours) — compared to Viagra (4.0–5.0 hours) and Levitra (4.0–5.0 hours) — resulting in longer duration of action, and so partly responsible for "The Weekend Pill" sobriquet. Furthermore, the longer half-life is the basis for current investigation of tadalafil's daily therapeutic use in relieving pulmonary arterial hypertension. Currently, sildenafil (trade name Revatio) is approved in several world regions as a thrice-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 the smooth muscle of the corpus cavernosum. 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 relaxes smooth muscle and increases blood flow to the corpus cavernosum.

The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil (and sildenafil and vardenafil) inhibits PDE5, however, because sexual stimulation is required to initiate the local penile release of nitric oxide, tadalafil's inhibition of PDE5 will have no effect without direct sexual stimulation of the penis. The recommended Cialis starting dose for most men is 10 mg, taken as needed before sexual activity (but not more than once daily). The dose may be increased to 20 mg or decreased to 5mg, per its efficacy and the man's personal tolerance of the drug. To avoid the inconvenience of a man having to program and plan using Cialis around the time of his anticipated sexual activity, Lilly ICOS began a clinical development program to evaluate the risks and benefits of chronic, once-daily use of the drug. In June 2007, the European Commission approved low-dose (2.5 mg and 5 mg) Cialis to be used as single-daily ED therapy.

Moreover, tadalafil at a dose of 40 mg once daily has been approved in the United States in May 2009 for treating pulmonary arterial hypertension, and marketing approval in Canada, Mexico, Japan, and the European Union is pending. In some patients, there exists an imbalance of the PDE5/NO system in the pulmonary vasculature that favours selective vasoconstriction of the pulmonary arteries. Investigation of tadalafil in this disease presumes that inhibiting PDE5 will effect pulmonary artery vasodilation, thus lowering pulmonary arterial pressure and pulmonary vascular resistance. These physiologic changes may then reduce the workload of the heart's right ventricle. Right heart failure and pulmonary oedema are the principal consequences of pulmonary arterial hypertension.

Side effects

Tadalafil has been used in approximately 15,000 men participating in clinical trials, and over 8 million men worldwide (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 alert 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.[6]

Source: Wikipedia