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Role of Endothelin-A (ETA) and Endothelin-B (ETB) Receptors in the Vasodilatory Response to Endothelin-3 (ET-3)

Information source: University of Edinburgh
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pulmonary Arterial Hypertension; Vasodilation; Vasoconstriction

Intervention: Bosentan (Drug); Sitaxsentan (Drug); Placebo (Drug); Endothelin-3 (Biological)

Phase: Phase 0

Status: Completed

Sponsored by: University of Edinburgh

Summary

Endothelin-1 (ET-1) has been linked to a number of conditions including pulmonary arterial hypertension (PAH). ET-1 acts via 2 receptors, ETA and ETB. The ET-1 receptor blockers bosentan and sitaxsentan have been shown to be beneficial in patients with PAH. Bosentan blocks both ETA and ETB receptors. Sitaxsentan selectively blocks ETA receptors. Theoretically, selective ETA blockade may be associated with greater vasodilation and clearance of ET-1 by leaving the ETB receptor unblocked. This has not been directly studied in humans. We aim to investigate the endothelial ETB-mediated vascular responses between bosentan and sitaxsentan by using a ETB selective agonist (ET-3). We hypothesise that at clinically relevant doses:

- Bosentan will show evidence of ETB receptor blockade compared to sitaxsentan and

placebo.

- These effects will be confirmed by 2 functional markers of ETB receptor antagonism:

plasma ET-1 (a very sensitive, but not necessarily clinically relevant marker), and the forearm vasodilator response to ET-3.

Clinical Details

Official title: Characterisation of the Role of ETA and ETB Receptors in Regulating Plasma ET-1 and the Vasodilator Response to ET-3 in Man

Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Primary outcome:

Plasma ET-1 after 7-day administration of bosentan, sitaxsentan and placebo

Responses to ET-3 (maximum vasodilation after ET-3 administration and area under the curve of vasodilation) after bosentan compared with the results from sitaxsentan and placebo.

Eligibility

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Healthy men and post-menopausal women

- Age 18-70 years

- BMI 18-35 kg/m2

Exclusion Criteria:

- Are mentally or legally incapacitated

- Have donated blood within the last 4 weeks

- Have a history of past or present drug or alcohol abuse

- Have participated in another clinical trial within 1 month

- Are considered to be at a high risk of HIV or Hepatitis B

- Are taking routine medicines

- Are women taking hormone replacement therapy

- Have significant medical or psychiatric illness

Locations and Contacts

Clinical Research Centre, Western General Hospital, Edinburgh, Scotland EH4 2XU, United Kingdom
Additional Information

Starting date: January 2009
Last updated: July 20, 2015

Page last updated: August 23, 2015

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