Clinical trials
In 2010 ARIAD announced result from a Phase I study of ponatinib in patients with resistant and refractory chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). The study demonstrated that in chronic-phase CML patients treated with ponatinib, 66 percent of patients in the trial achieved a major cytogenetic response, including 100 percent of patients who also had a T315I mutation.The PACE (Ponatinib Ph+ ALL and CML Evaluation) pivotal phase II trial started enrolling patients in September 2010 and is designed to provide definitive clinical data for regulatory approval in this setting. Good results were reported in December 2012.The EPIC (Evaluation of Ponatinib versus Imatinib in CML) phase-III trial began in June 2012  and was halted on October 18, 2013. Mechanism of action
The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of CML and Ph+ ALL. CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to more aggressive phases such as accelerated or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors. Because both of these diseases express the BCR-ABL protein, this would render them potentially susceptible to treatment with ponatinib.
A urethral stricture is a narrowing of the urethra, the tube connected to the bladder that allows the passing of urine. The narrowing reduces the flow of urine and makes it more difficult or even painful to empty the bladder.Urethral stricture is caused by injury, instrumentation, infection, and certain non-infectious forms of urethritis The condition is more common in men due to their longer urethra. Signs and symptoms
The hallmark sign of urethral stricture is a weak urinary stream. Other symptoms include:
Splaying of the urinary stream
Urinary frequency
Urinary urgency
Straining to urinate
Pain during urination
Urinary tract infection
Prostatitis
Inability to completely empty the bladder.Some people with severe urethral strictures are completely unable to urinate. This is referred to as acute urinary retention, and is a medical emergency. Hydronephrosis and kidney failure may also occur. Complications
Causes
Urethral strictures most commonly result from injury, urethral instrumentation, infection, non-infectious inflammatory conditions of the urethra, and after prior hypospadias surgery. Less common causes include congenital urethral strictures and those resulting from malignancy.Urethral strictures after blunt trauma can generally be divided into two sub-types;

Pelvic fracture-associated urethral disruption occurs in as many as 15% of severe pelvic fractures. These injuries are typically managed with suprapubic tube placement and delayed urethroplasty 3 months later. Early endoscopic realignment may be used in select cases instead of a suprapubic tube, but these patients should be monitored closely as vast majority of them will require urethroplasty. Blunt trauma to the perineum compresses the bulbar urethra against the pubic symphysis, causing a "crush" injury.