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Peripheral Vascular Effects of Sulfhydryl-containing Antihypertensive Pharmacotherapy on Microvessels in Humans (H2SPharm)

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ClinicalTrials.gov Identifier: NCT03179163
Recruitment Status : Recruiting
First Posted : June 7, 2017
Last Update Posted : September 24, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Lacy M. Alexander, Penn State University

Brief Summary:
High blood pressure can cause physical changes to the blood vessels of the body (remodeling). If a person who has high blood pressure also has a lot of blood vessel remodeling with their condition, they are more likely to have poor results with medical treatment for hypertension. The researchers examine the impact of different classes of drugs that doctors use to treat high blood pressure (hypertension) on blood vessel remodeling. Some drugs that doctors prescribe for their patients contain a "sulfhydryl group" (a sulfur atom bonded to a hydrogen atom). Drugs that have the sulfhydryl group may reduce blood vessel remodeling more that drugs that do not. For this study, participants who have high blood pressure perform the experiments, take a drug for 16-weeks to lower blood pressure, and repeat the experiments. The researchers randomly assign one of three drugs to participants who have high blood pressure: a diuretic ("water pill"), a drug containing a sulfhydryl (SH) group, or a drug that does not contain a sulfhydryl group. Participants who do not have high blood pressure perform the experiments, but do not take any of the drugs. In some of our experiments, the researchers use a technique called "microdialysis" (MD). With MD, the researchers perfuse some research drugs into the skin on the forearm through tiny tubing that mimics capillaries. These MD drugs mimic or block substances the body naturally makes to control the small blood vessels in the skin. The drugs remain in nickel-sized areas around the tubing and do not go into the rest of the body. The researchers also analyze very small skin samples (skin biopsy) obtained from the forearm. Lastly, the researchers use a standard technique called "flow mediated dilation" (FMD) that uses blood pressure cuffs and ultrasound to look at the health of larger blood vessels in the body. FMD includes placing a small tablet of nitroglycerin under the tongue during part of the test.

Condition or disease Intervention/treatment Phase
Hypertension,Essential Drug: Captopril Pill Drug: Enalapril Pill Drug: Hydrochlorothiazide Phase 1 Phase 2

Detailed Description:

Upon initial screening and again within a week of testing, all subjects will have an assessment of 24-hour ambulatory blood pressure. Subject screening will be performed by the Penn State Clinical Translational Research Center (CTRC) medical staff and will include a physical exam by a clinician, anthropometry, and a chemical and lipid profile, liver and renal function. Women will be either postmenopausal (absence of menstruation of >1 year and Follicle Stimulating Hormone (FSH) >25 milli-international units per milliliter (mlU/ml)) and not be taking hormone replacement therapy, or normally menstruating and tested in the early follicular phase of their cycle. Subjects will also go through an assessment of conduit vessel endothelial and vascular smooth muscle function with brachial artery flow-mediated vasodilation (FMD), and sublingual nitroglycerin.

Subjects will undergo initial microdialysis experiments and biopsy samples will be obtained. Subjects will then be randomly assigned to treatment group. Blood pressure will be monitored every 2 weeks and weekly compliance checks will be made by the researcher's nurse coordinator. 24-hour ambulatory blood pressure monitoring will be conducted monthly to determine the efficacy of antihypertensive treatment and to inform dosing titration. Examining pharmacokinetic and dynamic data from the literature indicate that blood pressure lowing and peripheral vascular effects are maximized by 12 weeks of antihypertensive therapy and maintained thereafter. After 16 weeks of the assigned intervention, subjects will repeat microdialysis experiments and additional cutaneous biopsy samples will be obtained. Conduit artery measures including brachial artery FMD and responsiveness to sublingual nitroglycerin will also be evaluated at this time.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subjects are grouped as normal (<120/80 mmHg) and hypertensive (≥140/90 mmHg and <160/110 mmHg). All subjects undergo one round of experiments. Hypertensive subjects received randomly-assigned antihypertension medication (ACEi+SH, ACEi, or diuretic) for 16 weeks and then repeat experiments. Normotensive subjects receive no intervention and repeat experiments16 weeks after initial experiments as a time control.
Masking: Double (Investigator, Outcomes Assessor)
Masking Description: Investigator and Outcomes Assessor are masked according to treatment.
Primary Purpose: Basic Science
Official Title: Peripheral Vascular Effects of Sulfhydryl-containing Antihypertensive Pharmacotherapy on Microvascular Function and Vessel Remodeling in Hypertensive Humans
Actual Study Start Date : July 20, 2016
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: Normotensive
Blood Pressure <120/80 mmHg
Experimental: Hypertensive - ACEi +SH
Captopril Pill intervention Blood Pressure ≥140/90 mmHg and <160/110 mmHg
Drug: Captopril Pill
ACEi+SH
Other Name: National Drug Code (NDC) # 00781-8061-01

Experimental: Hypertensive - ACE inhibitor (ACEi)
Enalapril Pill intervention Blood Pressure ≥140/90 mmHg and <160/110 mmHg
Drug: Enalapril Pill
ACEi
Other Name: NDC# 51672-4039-03

Active Comparator: Hypertensive - Diuretic
Hydrochlorothiazide intervention Blood Pressure ≥140/90 mmHg and <160/110 mmHg
Drug: Hydrochlorothiazide
diuretic
Other Name: NDC# 00603-3857-32




Primary Outcome Measures :
  1. laser Doppler blood flow [ Time Frame: 16 weeks ]
    This measurement is performed using a laser Doppler flow meter. The flow meter produces a non-invasive qualitative and dimensionless index of blood flow in blood vessels.


Secondary Outcome Measures :
  1. Systolic Blood Pressure [ Time Frame: 16 Weeks ]
    Blood pressure is measured via brachial auscultation manually or with a critical care monitor. The peak blood pressure during a cardiac cycle when the heart contracts.

  2. Diastolic Blood Pressure [ Time Frame: 16 Weeks ]
    Blood pressure is measured via brachial auscultation manually or with a critical care monitor. The lowest blood pressure during a cardiac cycle when the heart is between beats.



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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Women and men
  • 40-65 years
  • Blood pressure: Normotensive <120/80 mmHg Hypertensive ≥140/90 mmHg and <160/110 mmHg
  • HbA1C of <6.5%
  • Women are post-menopausal and not taking hormone replacement therapy, or have normal cycles and are tested in the early follicular phase
  • Subjects may or may not be taking one doctor-prescribed drug to lower blood pressure (e.g. diuretic, ACE inhibitor).

    • Must be able to stop physician-prescribed antihypertensive drug for the duration of the subject's participation in the study (with the approval of their personal physician).

Exclusion Criteria:

Relevant to all subjects:

  • current medications which could conceivably alter the cardiovascular or thermoregulatory control or responses (e.g. beta blockers, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers)
  • taking a diuretic (also see below)
  • allergy to test substances
  • allergy to latex
  • nicotine use (smoking, chewing tobacco, etc.)
  • illegal/recreational drug use
  • pregnancy or breastfeeding
  • diabetes

Relevant to hypertensive subjects only:

  • contraindication for all three pharmacotherapy drugs used in this study

    o Note: Subjects who have a contraindication (e.g. a condition, medication with a known interaction, known allergy) to only one or two of the three pharmacotherapy drugs, may be assigned one of the pharmacotherapy drugs that is not contraindicated.

  • history of having taken an ACE inhibitor with antioxidant properties (e.g. Captopril, Zofenopril)
  • kidney problems
  • liver problems
  • history of heart disease or failure
  • history of blood clots or stroke
  • angioedema
  • electrolyte imbalance
  • planned surgery requiring general anesthesia during the pharmacotherapy period
  • peripheral vascular disease
  • diuretics (a subject taking only a diuretic to control the subject's hypertension may be included in the study if the subject stops taking the diuretic for the duration of the subject's participation in the study with the approval of the subject's personal physician.)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03179163


Contacts
Contact: Susan K Slimak, RN 814-863-8556 sks31@psu.edu
Contact: Sean W Shank, BS 814-863-8557 sqs6071@psu.edu

Locations
United States, Pennsylvania
Pennsylvania State University Recruiting
University Park, Pennsylvania, United States, 16802
Sponsors and Collaborators
Penn State University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Lacy M Alexander, PhD Penn State University

Responsible Party: Lacy M. Alexander, Associate Professor Kinesiology, Penn State University
ClinicalTrials.gov Identifier: NCT03179163     History of Changes
Other Study ID Numbers: STUDY3224
5R01HL093238 ( U.S. NIH Grant/Contract )
120058 ( Other Identifier: FDA )
First Posted: June 7, 2017    Key Record Dates
Last Update Posted: September 24, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lacy M. Alexander, Penn State University:
Hypertension
Blood Pressure
Cardiovascular Disease
ACE Inhibitor
Diuretic
Nitric Oxide
Hydrogen Sulfide
Captopril
Enalapril
Hydrochlorothiazide
Microcirculation
Skin

Additional relevant MeSH terms:
Antihypertensive Agents
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hydrochlorothiazide
Enalapril
Enalaprilat
Captopril
Diuretics
Angiotensin-Converting Enzyme Inhibitors
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Protease Inhibitors
Enzyme Inhibitors