Blood pressure lowering effects of a new long-acting inhibitor of phosphodiesterase 5 in patients with mild to moderate hypertension.
Inhibition of phosphodiesterase 5 is an attractive candidate mechanism for blood pressure (BP) lowering. In this study, a novel long-acting phosphodiesterase 5 inhibitor, PF-00489791, was evaluated in 133 patients with mild to moderate hypertension, randomized into 1 of 4 groups: placebo, 4 mg, 10 mg, and 20 mg titrated after 14 days of dosing to 40 mg. Study medication was administered once daily for 28 days. Ambulatory BP monitoring was used. There was a statistically significant decrease (compared with placebo) in mean daytime systolic BP on day 28 at the 10 and 20/40 mg doses (by approximately 5 and approximately 7 mm Hg, respectively). Changes in mean daytime diastolic BP corresponded with those in systolic BP. The magnitude of BP lowering was greater on day 1 than on days 14 and 28, but the response was sustained between days 14 and 28. PF-00489791 also exerted BP lowering effects on mean 24-hour ambulatory BP. There was a dose-related increase in plasma cGMP concentration (statistically significant at the 20/40 mg dose). There was an increased incidence of headaches at the 10 and 20/40 mg doses (22% and 21%, respectively, compared with 12% with placebo) and an increased incidence of dyspepsia/gastroesophageal reflux disease and musculoskeletal adverse events at the 20/40 mg dose. In conclusion, PF-00489791 causes a clinically meaningful and sustained BP lowering in patients with hypertension. It is generally safe and well tolerated at the clinically efficacious doses.
Wolk
Robert
R
Pfizer Global Research & Development, Pfizer Inc, New London, CT 06320, USA. Robert.Wolk@pfizer.com
Smith
William B
WB
Neutel
Joel M
JM
Rubino
John
J
Xuan
Dawei
D
Mancuso
James
J
Gilbert
James
J
Pressler
Milton L
ML
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D018660:Blood Pressure Monitoring, Ambulatory; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000008:administration & dosage; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D004364:Pharmaceutical Preparations; D058986:Phosphodiesterase 5 Inhibitors; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; D000959:Antihypertensive Agents; D003692:Delayed-Action Preparations; D004364:Pharmaceutical Preparations; D058986:Phosphodiesterase 5 Inhibitors; C000597368:ontamalimab; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5