Prostacyclin In PAH

Prostacyclin: A fundamental pathway in PAH

Adapted from Humbert.7 cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; IPAH: idiopathic pulmonary arterial hypertension.

In pulmonary arterial hypertension (PAH), prostacyclin and nitric oxide levels are decreased, and endothelin levels are increased.7 Reduced levels of prostacyclin synthase are found in patients with idiopathic pulmonary arterial hypertension (IPAH).8 Based on animal data, imbalances in prostacyclin and endothelin levels have been implicated in the following:

  • Vasoconstriction8-12
  • Cellular proliferation8,10,11,13
  • In situ thrombosis8,9,12,13
  • Hypertrophy8,13

The clinical significance of prostacyclin deficit in humans is unknown. Animal data cannot imply a benefit in humans.

     
  "Importantly, the pathways interact, modulating the effect of any single pathway." — McLaughlin and McGoon14  
     

The prostacyclin pathway is a key treatment target in PAH.

  • The absence of prostacyclin has been implicated as a key pathological feature of PAH7
  • The addition of prostacyclin has been shown to play a critical role in the management of PAH9,12
  • The interplay between the prostacyclin, nitric oxide, and endothelin pathways may have important treatment implications14

Frequency of positive PGI2 synthase (prostacyclin) expression in IPAH and normal lungs8

Frequency of positive PGI2 S expression in lungs of normal patients (n=7) and in patients with IPAH (n=12). Results shown are the mean percentages of positive vessels (p=0.015 for normal versus IPAH small vessels, and p=0.03 for normal versus IPAH medium-sized vessels; p=NS for normal versus PAH large vessels8).

Ventavis cellular effects

4-hour elevation of cAMP levels following single inhaled dose of Ventavis in 10 healthy adults7

Horizontal line = median value; box = lower and upper quartiles; whiskers = minimum and maximum.
*p<0.05 vs baseline.

Cyclic adenosine monophosphate (cAMP) is the main mediator of the vasodilatory and antiproliferative effects of prostacyclin analogs.16,17 Prostacyclin acts through activation of the cAMP-dependent pathways.7

The association between increased plasma cAMP levels and clinical outcomes in PAH has not been established.

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The Ventavis 20 mcg/mL concentration order form is intended for patients who are maintained at the 5 mcg dose and who have repeatedly experienced extended treatment times which could result in incomplete dosing. Ventavis 10 mcg/mL ampules are still available. Ventavis should be taken 6 to 9 times daily, at least 2 hours apart.

For more information about Ventavis, please call 1-866-ACTELION (1-866-228-3546).

Indication and Important Safety Information

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Indication:

Ventavis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominately patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue disease (23%).

Important Safety Information

Important Safety Information: Hypotension leading to syncope has been observed; Ventavis should therefore not be initiated in patients with systolic blood pressure less than 85 mmHg. Stop Ventavis immediately if signs of pulmonary edema occur; this may be a sign of pulmonary venous hypertension. Ventavis inhalation may cause bronchospasm and patients with a history of hyperreactive airway disease may be more sensitive. Serious adverse events reported at a rate of less than 3% included congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure. Vital signs should be monitored while initiating Ventavis. In clinical studies, the most common adverse events occurring more often (≥6%) in Ventavis-treated patients than in patients taking placebo included vasodilation (flushing) (27% vs 9%), cough (39% vs 26%), headache (30% vs 20%), trismus (12% vs 3%), and insomnia (8% vs 2%). Ventavis has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents. Ventavis also has the potential to increase risk of bleeding, particularly in patients maintained on anticoagulants.

Please see accompanying full Prescribing Information.