Clinical trial NCT01661595: The Effect of Sildenafil and Tadalafil on Skeletal Muscle and Perceptual Fatigue
Official title: The Effect of Sildenafil and Tadalafil on Skeletal Muscle and Perceptual Fatigue.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Fatigue
Keywords: Fatigue
Fatigability
Surface Electromyography (sEMG)
cyclic guanosine monophosphate (cGMP)
Nitric Oxide (NO)
NO-cGMP
Phosphodiesterase (PDE)
Sildenafil
Tadalafil
Isotope
Infusion
Anabolism
Upregulation
Accelerometer
Placebo
Nitrosylation
Lead sponsor: The University of Texas Medical Branch, Galveston
Sponsor class: OTHER
First posted: 2012-08-09
Enrollment: 30
Sex: ALL
Minimum age (years): 50
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Subjects were assigned to one of 4 arms:

1. Sildenafil (50mg/day) for weeks 0-4. Placebo for weeks 5-8.
2. Tadalafil (10mg/day) for weeks 0-4. Placebo for weeks 5-8.
3. Placebo for weeks 0-4. Sildenafil (50mg/day) for weeks 5-8.
4. Placebo for weeks 0-4. Tadalafil (10mg/day) for weeks 5-8.
Primary purpose: TREATMENT

Brief summary: This study is funded by the Moody Endowment. In this project, we will investigate the potential effect of skeletal muscle nitric oxide (NO) production on skeletal muscle anabolism, muscle strength, physical function, and body composition in older individuals. Further, we will determine whether augmentation of NO-mediated signaling reduces fatigue and fatigability.

Detailed description: The Investigators hypothesize that upregulation of skeletal muscle NO-cGMP mediated responses through phosphodiesterase (PDE) inhibition by sildenafil or tadalafil causes an acute anabolic response of skeletal muscle protein synthesis. NO is well-known to elicit vasodilation through stimulation of cGMP signaling, and NO-mediated changes in muscle perfusion may influence both skeletal muscle anabolism and perceptual fatigue. To measure skeletal muscle protein synthesis, we will infuse a stable isotope tracer of phenylalanine and measure its incorporation into skeletal muscle proteins following a dose of sildenafil, tadalafil, or placebo. The Investigators will also determine whether differences exist between men and women in response to PDE inhibition. As skeletal muscle NO-cGMP signaling has been implicated in fatigue responses, we will assess the acute effect of sildenafil and tadalafil on fatigue. Fatigue can be manifested both as a performance deficit at a local level (e.g., a reduced ability of skeletal muscle to produce power or force) as well as a subjective experience of lacking physical or mental energy. Accordingly, we will use more than one means (skeletal muscle performance, fatigue questionnaires, accelerometers) to study fatigue. The Investigators hypothesize that sildenafil or tadalafil will acutely reduce exercise-associated fatigability and skeletal muscle fatigue development

Eligibility criteria: Inclusion Criteria:

1. Age 50-60 years of age
2. Ability to sign consent form (score\>23 on the 30-item Mini Mental Status examination, MMSE)
3. Stable body weight for at least three months.

Exclusion Criteria:

1. Physical dependence or frailty (impairment in any of the Activities of Daily Living (ADL), history of falls (\>2/year) or significant weight loss in the past year).
2. Pregnancy
3. Significant heart, liver, kidney, blood or respiratory disease.
4. Peripheral vascular disease.
5. Diabetes mellitus or other untreated endocrine disease.
6. Active cancer
7. Use of nitrates.
8. Recent (within 6 months) treatment with anabolic steroids, or corticosteroids.
9. Alcohol or drug abuse.
10. Severe depression (\>5 on the 15-item Geriatric Depression Scale, GDS).
11. Cardiac abnormalities such as cardiac shunt or previously diagnosed pulmonary hypertension.
12. Systolic blood pressure \<100 or\>150, diastolic blood pressure \<60 or 90\>. This range is smaller than the acceptable range stated in the prescribing information for sildenafil/tadalafil (90/50 and \<170/110).

Primary outcomes:
measure: Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Placebo
timeFrame: after 4 weeks of placebo
measure: Skeletal Muscle Fatigue as Measured by Biodex 4 Pro After 4 Weeks of Active Drug
timeFrame: after 4 weeks of active drug
measure: Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Placebo
timeFrame: after 4 weeks of placebo
measure: Exercised Induced Fatigability as Measured by Fatigue Rating Scale After 4 Weeks of Active Drug
timeFrame: after 4 weeks of active drug
Secondary outcomes:
measure: Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo
timeFrame: after 4 weeks of placebo
measure: Maximum Peak Isometric Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug.
timeFrame: after 4 weeks of active drug
measure: Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Placebo.
timeFrame: after 4 weeks of placebo
measure: Maximum Peak Isokinetic Leg Strength as Measured by Biodex Pro4 After 4 Weeks of Active Drug
timeFrame: after 4 weeks of active drug
measure: Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0.
timeFrame: week 0
measure: Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4.
timeFrame: week 4
measure: Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8.
timeFrame: week 8
measure: Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 0.
timeFrame: week 0
measure: Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 4.
timeFrame: week 4
measure: Fat Mass as Measured by Dual Energy X-ray Absorptiometry at Week 8.
timeFrame: week 8
measure: Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Placebo
timeFrame: after 4 weeks of placebo
measure: Walking Distance at 100% Effort as Measured by Walking Test After 4 Weeks of Active Drug
timeFrame: after 4 weeks of active drug
measure: Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 0
timeFrame: Week 0
measure: Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 4
timeFrame: week 4
measure: Perceptual Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form Total Score at Week 8
timeFrame: week 8
Other outcomes:
measure: Hemoglobin Level at Week 0
timeFrame: week 0
measure: Hemoglobin Level Measured at Week 4
timeFrame: week 4
measure: Hemoglobin Level Measured at Week 8
timeFrame: week 8
measure: Hematocrit Level Measured at Week 0
timeFrame: week 0
measure: Hematocrit Level Was Measured at 4 Weeks
timeFrame: 4 weeks
measure: Hematocrit Level Measured at Week 8
timeFrame: week 8
Locations:
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
Study officials:
affiliation: University of Texas Medical Branch, Galveston
name: Melinda Sheffield-Moore, PhD
role: PRINCIPAL_INVESTIGATOR
References: