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Water and Sudafed in Autonomic Failure

Information source: Vanderbilt University
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Shy-Drager Syndrome; Multiple System Atrophy

Intervention: Pseudoephedrine + 480 ml water (Drug); Pseudoephedrine + 50 ml water (Drug); Placebo + 480 ml water (optional) (Other); Placebo + 50 ml water (optional) (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: Vanderbilt University

Official(s) and/or principal investigator(s):
Emily M Garland, PhD, MSCI, Principal Investigator, Affiliation: Vanderbilt University

Overall contact:
Bonnie K Black, BSN, CNP, Email: adc.research@vanderbilt.edu

Summary

The specific aim of this study is to determine whether water ingestion potentiates the pressor response to pseudoephedrine in patients with primary disorders of autonomic failure. The study design will enable us to also evaluate the pressor response to water alone and to pseudoephedrine alone. In a secondary analysis, we will compare the results in patients with two autonomic disorders, pure autonomic failure (PAF) and multiple system atrophy (MSA). We hypothesize that drinking water following a dose of pseudoephedrine will lead to a greater increase in blood pressure than pseudoephedrine alone.

Clinical Details

Official title: Effect of Drinking Water on the Pressor Response to Pseudoephedrine in Patients With Autonomic Failure

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label

Primary outcome: The primary outcome measure in each Aim will be the peak increase in systolic blood pressure after pseudoephedrine or placebo relative to baseline (delta SBP).

Secondary outcome:

Change in diastolic blood pressure relative to baseline

Change in heart rate relative to baseline

Absolute systolic blood pressure after treatment

Absolute diastolic blood pressure after treatment

area under the curve for systolic blood pressure from baseline to 135 minutes post-treatment

Peak plasma norepinephrine concentration after treatment

Detailed description: The maximal pressor response to water is reached when other pressor agents are only beginning to act. In addition to the therapeutic value of water ingestion alone, the blood pressure-raising effects of agents that increase sympathetic nervous system tone, such as phenylpropanolamine, are potentiated by water drinking. These drug interaction effects can be exploited in the treatment of orthostatic hypotension with the combination of water and a sympathomimetic potentially able to increase blood pressure to a greater extent and for a longer period of time than either water or the medication alone. However, the interaction can also lead to potentially dangerous blood pressure surges. This protocol requires an initial screening history and physical of study participants, including safety labs and EKGs, and evaluation of their autonomic nervous system status following the consent process. If the patient meets study criteria and is willing to undergo study testing, the 4-way crossover protocol will follow. Study Testing days 1 and 2 Arm 1: Pseudoephedrine 30 mg PO + 50 ml water Arm 2: Pseudoephedrine 30 mg PO + 480 ml water

- Testing will be performed at the same time of day for all studies, at least 2 hours

after a meal to avoid any confounding effects from postprandial hypotension.

- A saline lock will be inserted for blood sampling at least 30 minutes before baseline

data collection.

- Participants will be asked to empty their bladders before beginning the test to avoid

any effect of a full urinary bladder on peripheral sympathetic activity.

- Participants will be seated comfortably in a chair. They will be asked to remain in

the seated position for the duration of the study.

- The Dinamap electrocardiographic and blood pressure (brachial cuff) recorder will be

attached to the patient and set up for measurements every 5 minutes throughout the study with digital download into the ADC (Autonomic Dysfunction Center) BP database.

- Participants will also be instrumented with EKG, finger cuff and sensor for continuous

monitoring of blood pressure, heart rate, respiration, SpO2, stroke volume, systemic vascular resistance, and cardiac output, using a Nexfin system and Ivy Biomedical Vital-Guard monitor.

- After a 30 minute baseline monitoring period (time -30 min to 0 min), 4 ½ teaspoons of

blood will be collected for osmolality measurement and assays of hormones that regulate blood pressure.

- The subject will then be given 30 mg of pseudoephedrine PO (time 0 min). Monitoring

will be continued for 45 minutes.

- At 45 minutes, the participant will be asked to drink 50 ml (Arm 1) or 480 ml (Arm 2)

of water.

- Additional blood samples (4 ½ teaspoons) for osmolality and BP-regulating hormones will

be collected 30 and 60 minutes after water (+75 and +105 minutes of study).

- Monitoring will be continued until + 135 min.

- At 135 minutes, the study will end for the day. The timing of pseudoephedrine

administration relative to water ingestion and the duration of the monitoring period are based on previous results3 and pharmacokinetic data7 reporting a Tmax for pseudoephedrine between 1 and 2 hours. Testing on study day 2 will be identical with the participant consuming the alternate water volume. Study Testing days 3 and 4 are optional Arm 3: Placebo PO + 50 ml water Arm 4: Placebo PO + 480 ml water Testing will be performed according to the same schedule as for Arms 1 and 2. Instrumentation will be limited to the Dinamap electrocardiographic and blood pressure (brachial cuff) recorder set up for measurements every 5 minutes throughout the study for Arms 3 and 4.

Eligibility

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age 18-80 years, with

- Neurogenic orthostatic hypotension, ≥30 mmHg drop in SBP within 5 minutes of

standing,

- Associated with impaired autonomic reflexes, as determined by absence of blood

pressure overshoot during phase IV of the valsalva maneuver,

- Absence of other identifiable causes of autonomic neuropathy, and

- Able and willing to provide informed consent

Exclusion Criteria

- Pregnancy

- Current smoking habit

- Systemic illnesses known to produce autonomic neuropathy, including but not limited

to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies.

- Known intolerance to pseudoephedrine

- Pre-existing sustained severe hypertension (BP > 180/110 mmHg in the sitting

position)

- Clinically unstable coronary artery disease or major cardiovascular or neurological

event in the past 6 months.

- Any other significant systemic, hepatic, cardiac or renal illness

- Use of MAO-I (i. e. selegiline; rasagiline - Azilect, linezolid and others) within 14

days

- Known closed-angle glaucoma

- Clinically meaningful arrhythmias

- Other factors which in the investigator's opinion would prevent the participant from

completing the protocol, including poor compliance during previous studies or an unpredictable schedule

Locations and Contacts

Bonnie K Black, BSN, CNP, Email: adc.research@vanderbilt.edu

Vanderbilt University, Nashville, Tennessee 37232, United States; Recruiting
Bonnie K Black, BSN, CNP, Email: adc.research@vanderbilt.edu
Additional Information

Related publications:

Jordan J, Shannon JR, Grogan E, Biaggioni I, Robertson D. A potent pressor response elicited by drinking water. Lancet. 1999 Feb 27;353(9154):723.

Jordan J, Shannon JR, Black BK, Ali Y, Farley M, Costa F, Diedrich A, Robertson RM, Biaggioni I, Robertson D. The pressor response to water drinking in humans : a sympathetic reflex? Circulation. 2000 Feb 8;101(5):504-9.

Jordan J, Shannon JR, Diedrich A, Black B, Robertson D, Biaggioni I. Water potentiates the pressor effect of ephedra alkaloids. Circulation. 2004 Apr 20;109(15):1823-5. Epub 2004 Apr 5.

Kobayashi S, Endou M, Sakuraya F, Matsuda N, Zhang XH, Azuma M, Echigo N, Kemmotsu O, Hattori Y, Gando S. The sympathomimetic actions of l-ephedrine and d-pseudoephedrine: direct receptor activation or norepinephrine release? Anesth Analg. 2003 Nov;97(5):1239-45.

Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA. In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther. 2003 Oct;307(1):138-45. Epub 2003 Sep 3.

Lu CC, Diedrich A, Tung CS, Paranjape SY, Harris PA, Byrne DW, Jordan J, Robertson D. Water ingestion as prophylaxis against syncope. Circulation. 2003 Nov 25;108(21):2660-5. Epub 2003 Nov 17. Erratum in: Circulation. 2005 Apr 5;111(13):1717.

Kanfer I, Dowse R, Vuma V. Pharmacokinetics of oral decongestants. Pharmacotherapy. 1993 Nov-Dec;13(6 Pt 2):116S-128S; discussion 143S-146S. Review.

Dupont WD, Plummer WD Jr. Power and sample size calculations. A review and computer program. Control Clin Trials. 1990 Apr;11(2):116-28.

Starting date: October 2014
Last updated: December 16, 2014

Page last updated: August 20, 2015

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