Prostacyclin in PAH

Prostacyclin: A fundamental pathway in PAH

cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; ETA: endothelin receptor type A; ETB: endothelin receptor type B; IP: prostacyclin receptor; PDE-5: phosphodiesterase type 5; pro-ET: pro-endothelin; sGC: soluble guanylate cyclase; SMCs: smooth muscle cells.

In pulmonary arterial hypertension (PAH), prostacyclin and nitric oxide levels are decreased, and endothelin levels are increased.5 Reduced levels of prostacyclin synthase are found in patients with idiopathic pulmonary arterial hypertension (IPAH).6 Based on animal data, imbalances in prostacyclin and endothelin levels have been implicated in the following:

  • Vasoconstriction6,8,9
  • Cellular proliferation8,9
  • In situ thrombosis6
  • Hypertrophy9

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

The prostacyclin pathway is a key treatment target in PAH.

  • The reduced level of prostacyclin has been implicated as an important pathological feature of PAH5
  • The addition of prostacyclin has been shown to play a critical role in the management of PAH7,10

Frequency of positive PGI2 (prostacyclin) synthase production in IPAH and normal lungs6

Frequency of positive PGI2 synthase production 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-value=nonsignificant for normal versus PAH large vessels6).

VENTAVIS cellular effects

4-hour elevation of cAMP levels following single inhaled dose of VENTAVIS® (iloprost) Inhalation Solution in 10 healthy adults21

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

Horizontal line = median value; box = middle quartiles; whiskers = minimum and maximum values.
p<0.05 vs baseline.21

Cyclic adenosine monophosphate (cAMP) is the main mediator of the vasodilatory and antiproliferative effects of prostacyclin, prostacyclin analogs, or nonprostanoid prostacyclin receptor agonists.5,12 Prostacyclin acts through activation of the cAMP-dependent pathways.5

INDICATION

VENTAVIS® (iloprost) Inhalation Solution 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 predominantly 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

WARNINGS AND PRECAUTIONS

Risk of Syncope

  • Vital signs should be monitored while initiating VENTAVIS. Hypotension leading to syncope has been observed; VENTAVIS should therefore not be initiated in patients with systolic blood pressure less than 85 mmHg.

Pulmonary Venous Hypertension

  • Stop VENTAVIS immediately if signs of pulmonary edema occur; this may be a sign of pulmonary venous hypertension.

Bronchospasm

  • VENTAVIS inhalation may cause bronchospasm and patients with a history of hyperreactive airway disease may be more sensitive.

ADVERSE REACTIONS

Serious Adverse Events

  • Serious adverse events reported include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.

Adverse Events

  • Adverse events reported in a Phase 3 clinical trial occurring with a ≥3% difference between VENTAVIS patients and placebo patients were vasodilation (flushing) (27% vs 9%), increased cough (39% vs 26%), headache (30% vs 20%), trismus (12% vs 3%), insomnia (8% vs 2%), nausea (13% vs 8%), hypotension (11% vs 6%), vomiting (7% vs 2%), alkaline phosphatase increased (6% vs 1%), flu syndrome (14% vs 10%), back pain (7% vs 3%), tongue pain (4% vs 0%), palpitations (7% vs 4%), syncope (8% vs 5%), GGT increased (6% vs 3%), muscle cramps (6% vs 3%), hemoptysis (5% vs 2%), and pneumonia (4% vs 1%).

DRUG INTERACTIONS

Antihypertensives and Vasodilators

  • VENTAVIS has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents.

Anticoagulants and Platelet Inhibitors

  • VENTAVIS also has the potential to increase risk of bleeding, particularly in patients maintained on anticoagulants or platelet inhibitors.

Please see full Prescribing Information.

INDICATION

VENTAVIS® (iloprost) Inhalation Solution 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 predominantly 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

WARNINGS AND PRECAUTIONS

Risk of Syncope

  • Vital signs should be monitored while initiating VENTAVIS. Hypotension leading to syncope has been observed; VENTAVIS should therefore not be initiated in patients with systolic blood pressure less than 85 mmHg.

Pulmonary Venous Hypertension

  • Stop VENTAVIS immediately if signs of pulmonary edema occur; this may be a sign of pulmonary venous hypertension.

Bronchospasm

  • VENTAVIS inhalation may cause bronchospasm and patients with a history of hyperreactive airway disease may be more sensitive.

ADVERSE REACTIONS

Serious Adverse Events

  • Serious adverse events reported include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.

Adverse Events

  • Adverse events reported in a Phase 3 clinical trial occurring with a ≥3% difference between VENTAVIS patients and placebo patients were vasodilation (flushing) (27% vs 9%), increased cough (39% vs 26%), headache (30% vs 20%), trismus (12% vs 3%), insomnia (8% vs 2%), nausea (13% vs 8%), hypotension (11% vs 6%), vomiting (7% vs 2%), alkaline phosphatase increased (6% vs 1%), flu syndrome (14% vs 10%), back pain (7% vs 3%), tongue pain (4% vs 0%), palpitations (7% vs 4%), syncope (8% vs 5%), GGT increased (6% vs 3%), muscle cramps (6% vs 3%), hemoptysis (5% vs 2%), and pneumonia (4% vs 1%).

DRUG INTERACTIONS

Antihypertensives and Vasodilators

  • VENTAVIS has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents.

Anticoagulants and Platelet Inhibitors

  • VENTAVIS also has the potential to increase risk of bleeding, particularly in patients maintained on anticoagulants or platelet inhibitors.

Please see full Prescribing Information.