Open Label Study of Sildenafil in Patients With Pulmonary Arterial Hypertension

• Change in the 6-minute Walk Distance From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：6-minute walk distance at Week 12 minus 6-minute walk distance at baseline. The 6-minute walk distance:total distance walked during the 6-minute walk test.
• Change in the Mean Pulmonary Arterial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change:Mean pulmonary arterial pressure at Week 12 minus mean pulmonary arterial pressure at baseline.
• Change in the Pulmonary Vascular Resistance From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Pulmonary vascular resistance at Week 12 minus pulmonary vascular resistance at baseline
• Change in the Cardiac Output From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, week 12 ] [ Designated as safety issue: No ]
  Change：Cardiac output at Week 12 minus cardiac output at baseline

• Change from baseline in the total distance walked during the 6-Minute Walk test at
• Week 12.; Change from baseline at Week 12 in haemodynamics parameters:
• mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR)
• and cardiac output (CO).

• Change in the 6-minute Walk Distance From Baseline at Week 8 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]

  Change：6-minute walk distance at Week 8 minus 6-minute walk distance at baseline.

  The 6-minute walk distance:Total distance walked during the 6- minute walk test.

• Change in the Systolic Pulmonary Arterial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Systolic pulmonary arterial pressure at Week 12 minus Systolic pulmonary arterial pressure at baseline.
• Change in the Diastolic Pulmonary Arterial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Diastolic pulmonary arterial pressure at Week 12 minus diastolic pulmonary arterial pressure at baseline.
• Change in the Systolic Systemic Blood Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Systolic systemic blood pressure at Week 12 minus systolic systemic blood pressure at baseline.
• Change in the Diastolic Systemic Blood Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Diastolic systemic blood pressure at Week 12 minus diastolic systemic blood pressure at baseline.
• Change in the Mean Systemic Blood Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]

  Mean systemic blood pressure:diastolic blood pressure+(systolic blood pressure-diastolic blood pressure)/3.

  Change：Mean systemic blood pressure at Week 12 minus mean systemic blood pressure at baseline.

• Change in the Pulmonary Capillary Wedge Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Pulmonary capillary wedge pressure at Week 12 minus pulmonary capillary wedge pressure at baseline.
• Change in the Right Atrial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Right atrial pressure at Week 12 minus right atrial pressure at baseline.
• Change in the Cardiac Index From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Cardiac index at Week 12 minus cardiac index at baseline.
• Change in the Heart Rate From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Heart rate at Week 12 minus heart rate at baseline.
• Change in the Pulmonary Vascular Resistance Index From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change:Pulmonary vascular resistance index at Week 12 minus pulmonary vascular resistance index at baseline.
• Change in the Systemic Vascular Resistance From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Systemic vascular resistance at Week 12 minus systemic vascular resistance at baseline.
• Change in the Systemic Vascular Resistance Index From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Systemic vascular resistance index at Week 12 minus systemic vascular resistance index at baseline.
• Change in the Mixed Venous Oxygen Saturation From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Mixed venous oxygen saturation at Week 12 minus mixed venous oxygen saturation at baseline.
• Change in the Arterial Oxygen Saturation From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Arterial oxygen saturation at Week 12 minus arterial oxygen saturation at baseline.
• Change in the Arterial Oxygen Partial Pressure From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Arterial oxygen partial pressure at Week 12 minus arterial oxygen partial pressure at baseline.
• Change in the Partial Pressure of Mixed Venous Oxygen From Baseline at Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Partial pressure of mixed venous oxygen at Week 12 minus partial pressure of mixed venous oxygen at baseline.
• Changes in the World Health Organization (WHO) Functional Class of Pulmonary Arterial Hypertension From Baseline at Weeks 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  The cross-tabulation table on the WHO functional classes of pulmonary arterial hypertension at baseline and Week 12. The WHO functional classes of pulmonary arterial hypertension:Class I (pulmonary arterial hypertension patients with no limitation in physical activity) to Class IV (pulmonary arterial hypertension patients who can not perform a physical activity without any symptoms).
• Changes in the BORG Dyspnoea Score From Baseline at Week 8 and Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 8, Week 12 ] [ Designated as safety issue: No ]
  Change：BORG dyspnoea score at Week 8 and Week 12 minus BORG dyspnoea score at baseline. BORG dyspnoea score:Scale 0 (no breathlessness at all) to 10 (maximum). The score reflected the maximum degree of dyspnoea that the participants experienced at any time during the 6-minute walk distance.
• Changes in the the Plasma Brain Natriuretic Peptide Level From Baseline at Week 4, Week 8 and Week 12 in Participants Who Entered the Study From Part I [ Time Frame: Baseline, Week 4, Week 8, Week 12 ] [ Designated as safety issue: No ]
  Change：Plasma brain natriuretic peptide level at Week 4, Week 8 and Week 12 minus plasma brain natriuretic peptide level at baseline
• Change in the 6-minute Walk Distance From Baseline at Week 12 in Participants Who Newly Entered the Study From Part II [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：6-minute walk distance at Week 12 minus 6-minute walk distance at baseline. The 6-minute walk distance:Total distance walked during the 6- minute walk test.
• Change in the World Health Organization (WHO) Functional Class From Baseline at Week 12 in Participants Who Newly Entered the Study From Part II [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  The cross-tabulation table on the WHO functional classes of pulmonary arterial hypertension at baseline and Week 12. The WHO functional classes of pulmonary arterial hypertension:Class I (pulmonary arterial hypertension patients with no limitation in physical activity) to Class IV (pulmonary arterial hypertension patients who can not perform a physical activity without any symptoms).
• Changes in the BORG Dyspnoea Score From Baseline at Week 12 in Participants Who Newly Entered the Study From Part II [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：BORG dyspnoea score at Week 12 minus BORG dyspnoea score at baseline. BORG dyspnoea score:Scale 0 (no breathlessness at all) to 10 (maximum). The score reflected the maximum degree of dyspnoea that the participants experienced at any time during the 6-minute walk distance.
• Changes in the the Plasma Brain Natriuretic Peptide Level From Baseline at Week 12 in Participants Who Newly Enterd the Study From Part II [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change：Plasma brain natriuretic peptide level at Week 12 minus plasma brain natriuretic peptide level at baseline
• Maximum Plasma Concentrations (Cmax) of Sildenafil and Sildenafil's Metabolite, UK-103,320 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing ] [ Designated as safety issue: No ]
  Maximum plasma concentrations was calculated from the observed value of plasma concentrations in each participant
• Time to First Occurrence of Maximum Plasma Concentrations (Tmax) of Sildenafil and Sildenafil's Metabolite, UK-103,320 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing ] [ Designated as safety issue: No ]
  Time to first occurrence of maximum plasma concentrations were calculated from the observed value of plasma concentrations in each participant.
• The Area Under the Curve (AUC) From Time 0 to Time 8 Hour of Sildenafil and Sildenafil's Metabolite, UK-103,320 [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing ] [ Designated as safety issue: No ]
  The area under the curve from time 0 to time 8 hour was calculated from area under the curve in each perticipant on the date of blood sampling using the linear/log trapezoidal rule
• The Average Plasma Concentration (Css,av) of Sildenafil at Steady State [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing ] [ Designated as safety issue: No ]
  The average plasma concentration of sildenafil at steady state was calculated from the area under the curve from time 0 to 8 hour/dosing interval (8 hours).
• The Average Plasma Trough Concentration (Ctrough) of Sildenafil [ Time Frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours after dosing ] [ Designated as safety issue: No ]
  The average plasma trough concentration of sildenafil was calculated from the observed value before administration of the drug in each participants.
• Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) [ Time Frame: Baseline up to 1.3 years ] [ Designated as safety issue: No ]
  The total number of participants with laboratory test abnormalities without regard to baseline abnormality.

• Change from baseline in the total distance walked during the 6-Minute Walk test at
• Week 8.;Change from baseline at Week 4, 8 and 12 in WHO function
• classification.; Change from baseline at Week 12 in the additional haemodynamics
• parameters.; Change from baseline at Week 8 and 12 in the BORG dyspnoea
• score.; Change from baseline at Week 4, 8 and 12 in the BNP.

To assess the safety of sildenafil 20 mg TID orally given to Japanese pulmonary arterial hypertension patients (Part 1 and 2) To assess the efficacy after 12 weeks of treatment of sildenafil 20 mg TID orally given to Japanese pulmonary arterial hypertension patients (Part 1)

Inclusion Criteria:

• Subjects aged 16 and over, and classified as having pulmonary arterial hypertension
• Subjects who meet the following conditions on right heart catheterization at screening or baseline: mean pulmonary arterial pressure of ≥ 25mmHg and pulmonary capillary wedge pressure of ≤ 15mmHg at rest
• Subjects whose baseline 6-Minute Walk test distance is >100 m and <450 m

Exclusion Criteria:

• Significant Hepatic and/or renal disorder
• Subjects with known hereditary degenerative retinal disorders (such as retinitis pigmentosa) or history of non-arteritic ischemic optic neuropathy (NAION)
• Subjects who are currently receiving nitrates or nitric oxide donors in any form, ritonavir, ketoconazole and itraconazole