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Slow recruitment, lack of continued funding
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The purpose of this study is to determine whether sildenafil improves parameters of vascular function and blood markers involved in development of heart disease in patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is associated with a 2-fold increased risk of cardiovascular disease (CVD), which is not explained by traditional cardiovascular (CV) risk factors alone; this risk is likely mediated in part through systemic inflammation. Indeed, RA itself is deemed to impart a CV risk equivalent to diabetes mellitus (DM). However, unlike in DM, optimal CV management strategies in RA are lacking. Despite improved anti-inflammatory therapies for RA, the mortality gap in RA compared to the general population is still widening, in part due to suboptimal primary and secondary CV preventive care in RA. To date, there have been no published controlled intervention trials for primary CV prevention in RA, despite this clearly urgent unmet need.
One of the early stages of atherogenesis is endothelial dysfunction, and drugs that target improvement in this are promising novel strategies for CVD prevention. The fundamental feature of endothelial dysfunction is impaired nitric oxide (NO) bioavailability. Sildenafil improves endothelial function by increasing NO signaling by inhibition of phosphodiesterase-5 (PDE5). PDE5 inhibitors improve endothelial function in pulmonary hypertension and DM, and were safe and well tolerated in patients with erectile dysfunction and other CV comorbidities. Furthermore, PDE inhibitors have immunomodulatory properties that may be utilized to treat autoimmune conditions like RA. The investigators' central hypothesis is that sildenafil is a uniquely suited agent targeting endothelial dysfunction as a novel adjunctive CV prevention strategy and immunomodulatory agent in RA. Specifically, their goal is to determine if sildenafil use in RA improves endothelial dysfunction and atherosclerosis biomarkers.
The proposed study is a phase II, randomized double-blind placebo-controlled crossover efficacy trial of 60 RA patients, with no known history of CVD but at least one traditional CV risk factor, on stable baseline doses of RA medications; randomized 1:1 to receive either sildenafil 50 mg or placebo orally once daily for 3 months, with a 2-week washout before the crossover phase for another 3 months. Vascular studies validated in assessing endothelial dysfunction and laboratory studies for selected atherosclerosis biomarkers will be performed at baseline, 3 months pre- and post-washout, and 6 months. Adverse events will be collected to assess safety. The Specific Aims are:
The results of this study will serve as preliminary data for future larger trials evaluating sildenafil as a CV prevention strategy by reducing endothelial dysfunction in RA. It will provide needed data on potential benefits of sildenafil for immunomodulation and CV prevention in this high-risk population.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Initial Sildenafil | Experimental | Sildenafil 50 mg orally once daily for first 3 months, then after 2-week washout, Placebo orally once daily for 3 months |
|
| Initial Placebo | Placebo Comparator | Placebo orally once daily for first 3 months, then after 2-week washout, Sildenafil 50 mg orally once daily for 3 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sildenafil | Drug | Sildenafil 50 mg once daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months | The methods of assessment of endothelial function via FMD will be performed following guidelines. Using Duplex ultrasound with a high-resolution linear array transducer, the difference between the maximum brachial artery diameter (BAD) postocclusion and the baseline diameter will be calculated, expressed as a percentage (%BAD). Generally, %BAD values below 5-7% represent endothelial dysfunction, which is associated with CV risk factors, future CVD and mortality. | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months | PAT measured by the EndoPAT 2000 device is a non-invasive method to assess endothelial function. It is a standardized, rapid, and easy to apply method, and has been found to correlate with multiple traditional CV risk factors and to be responsive to interventions. PAT is a validated alternative measure to brachial arterial FMD in assessing endothelial function, and is less operator-dependent than FMD. FMD directly measures the dilation capability of the large-conduit artery, whereas PAT measures flow response hyperemia, which is related to endothelial function of small arteries of microcirculation. PAT measures endothelium-mediated changes in vascular tone using bio-sensors placed on fingertips. The semi-automatically calculated result (Reactive Hyperemia Index) is an index of endothelial function. LnRHI is a Reactive Hyperemia Index after natural log transformation with a matched cutoff: Normal: LnRHI > 0.51 and Abnormal: LnRHI <= 0.51 cut-off. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kimberly P Liang, MD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh | Pittsburgh | Pennsylvania | 15213 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Initial Sildenafil | Sildenafil 50 mg orally once daily for first 3 months, then after 2-week washout, Placebo orally once daily for 3 months Sildenafil: Sildenafil 50 mg once daily Placebo: Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill |
| FG001 | Initial Placebo | Placebo orally once daily for first 3 months, then after 2-week washout, Sildenafil 50 mg orally once daily for 3 months Sildenafil: Sildenafil 50 mg once daily Placebo: Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Initial Sildenafil | Sildenafil 50 mg orally once daily for first 3 months, then after 2-week washout, Placebo orally once daily for 3 months Sildenafil: Sildenafil 50 mg once daily Placebo: Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill |
| BG001 | Initial Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Brachial Artery Flow Mediated Dilation (FMD) Without Nitroglycerin at 3 Months | The methods of assessment of endothelial function via FMD will be performed following guidelines. Using Duplex ultrasound with a high-resolution linear array transducer, the difference between the maximum brachial artery diameter (BAD) postocclusion and the baseline diameter will be calculated, expressed as a percentage (%BAD). Generally, %BAD values below 5-7% represent endothelial dysfunction, which is associated with CV risk factors, future CVD and mortality. | The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | percent of BAD | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
Adverse event data were collected over the entire study duration for each participant (i.e., 6 months and 2 weeks).
The definition of adverse event and/or serious adverse event did not differ from the clinicaltrials.gov definitions.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sildenafil Period | Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kimberly P. Liang, MD, MS | University of Pittsburgh | 412-586-3550 | liangkp@upmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 10, 2019 | Jun 2, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| D050197 | Atherosclerosis |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| ID | Term |
|---|---|
| D000068677 | Sildenafil Citrate |
| ID | Term |
|---|---|
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013450 | Sulfones |
| D013457 |
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| Placebo | Other | Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill |
|
| Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in hsCRP at 3 Months | High-sensitivity CRP (hsCRP) measured using standard clinical laboratory protocols | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in ESR at 3 Months | Erythrocyte sedimentation rate (ESR) measured using standard clinical laboratory protocols | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months | Interleukin (IL)-6 measured using enzyme linked immunosorbent assay (ELISA) (pg/mL). Since very few subjects had detectable IL-6 levels, the outcome measure reports the number of participants with detectable IL-6 rather than mean levels. | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in RF at 3 Months | Rheumatoid factor (RF) measured using standard clinical laboratory protocols | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in CCP at 3 Months | Anti-cyclic citrullinated peptide antibody (CCP) measured using standard clinical laboratory protocols. Note, the universal unit of measure for CCP is "Units." | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in E-selectin at 3 Months | Leukocyte adhesion molecule E-selectin measured using enzyme linked immunosorbent assay (ELISA) | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in ICAM-1 at 3 Months | Intercellular adhesion molecule (ICAM)-1 measured using enzyme linked immunosorbent assay (ELISA) | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in VCAM-1 at 3 Months | Vascular cell adhesion molecule (VCAM)-1 measured using enzyme linked immunosorbent assay (ELISA) | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in CD40L at 3 Months | CD40 ligand (CD40L) measured using enzyme linked immunosorbent assay (ELISA) | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in MMP-9 at 3 Months | Matrix metalloproteinase-9 (MMP-9) measured using enzyme linked immunosorbent assay (ELISA) | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Change From Baseline in MPO at 3 Months | Myeloperoxidase (MPO) measured using enzyme linked immunosorbent assay (ELISA) | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
| Serious Adverse Events (SAE) | SAEs include death, hospitalization or prolonged existing hospitalization, life threatening, persistent or significant disability, birth defect/congenital anomaly, or medically significant event. | 6 Months and 2 Weeks from Baseline Visit |
| Adverse Events (AE) Related to Treatment | AEs related to sildenafil treatment may include headache, flushing, indigestion, or visual disturbance, among others. | 6 Months and 2 Weeks from Baseline Visit |
Placebo orally once daily for first 3 months, then after 2-week washout, Sildenafil 50 mg orally once daily for 3 months Sildenafil: Sildenafil 50 mg once daily Placebo: Placebo once daily with same size, shape, color, and texture as Sildenafil 50 mg pill |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Cardiovascular Risk Factors | Count of Participants | Participants |
|
Participants who received Sildenafil 50 mg once daily in either the first or last 3 months of the study |
| OG001 | Placebo Period | Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study |
|
|
|
| Secondary | Change From Baseline in Peripheral Arterial Tone (PAT) LnRHI at 3 Months | PAT measured by the EndoPAT 2000 device is a non-invasive method to assess endothelial function. It is a standardized, rapid, and easy to apply method, and has been found to correlate with multiple traditional CV risk factors and to be responsive to interventions. PAT is a validated alternative measure to brachial arterial FMD in assessing endothelial function, and is less operator-dependent than FMD. FMD directly measures the dilation capability of the large-conduit artery, whereas PAT measures flow response hyperemia, which is related to endothelial function of small arteries of microcirculation. PAT measures endothelium-mediated changes in vascular tone using bio-sensors placed on fingertips. The semi-automatically calculated result (Reactive Hyperemia Index) is an index of endothelial function. LnRHI is a Reactive Hyperemia Index after natural log transformation with a matched cutoff: Normal: LnRHI > 0.51 and Abnormal: LnRHI <= 0.51 cut-off. | The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | LnRHI | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
|
| Secondary | Change From Baseline in hsCRP at 3 Months | High-sensitivity CRP (hsCRP) measured using standard clinical laboratory protocols | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | mg/dL | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Change From Baseline in ESR at 3 Months | Erythrocyte sedimentation rate (ESR) measured using standard clinical laboratory protocols | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | mm/hr | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Change From Baseline in Number of Participants With Detectable IL-6 at 3 Months | Interleukin (IL)-6 measured using enzyme linked immunosorbent assay (ELISA) (pg/mL). Since very few subjects had detectable IL-6 levels, the outcome measure reports the number of participants with detectable IL-6 rather than mean levels. | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Count of Participants | Participants | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Change From Baseline in RF at 3 Months | Rheumatoid factor (RF) measured using standard clinical laboratory protocols | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | IU/ml | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Change From Baseline in CCP at 3 Months | Anti-cyclic citrullinated peptide antibody (CCP) measured using standard clinical laboratory protocols. Note, the universal unit of measure for CCP is "Units." | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | Units | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Change From Baseline in E-selectin at 3 Months | Leukocyte adhesion molecule E-selectin measured using enzyme linked immunosorbent assay (ELISA) | The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | ng/mL | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
|
| Secondary | Change From Baseline in ICAM-1 at 3 Months | Intercellular adhesion molecule (ICAM)-1 measured using enzyme linked immunosorbent assay (ELISA) | The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | ng/mL | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
|
| Secondary | Change From Baseline in VCAM-1 at 3 Months | Vascular cell adhesion molecule (VCAM)-1 measured using enzyme linked immunosorbent assay (ELISA) | The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | ng/mL | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
|
| Secondary | Change From Baseline in CD40L at 3 Months | CD40 ligand (CD40L) measured using enzyme linked immunosorbent assay (ELISA) | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | pg/mL | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Change From Baseline in MMP-9 at 3 Months | Matrix metalloproteinase-9 (MMP-9) measured using enzyme linked immunosorbent assay (ELISA) | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | ng/mL | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Change From Baseline in MPO at 3 Months | Myeloperoxidase (MPO) measured using enzyme linked immunosorbent assay (ELISA) | Pre-specified linear mixed model statistical analysis not conducted because not scientifically appropriate due to insufficient enrollment. The number of participants analyzed reflects those in each period who had evaluable data for the given outcome measure at both the Baseline and After 3 months of Study Drug use timepoints. | Posted | Mean | Standard Deviation | ng/mL | Baseline and After 3 months of Study Drug use (i.e., either at 3 months pre-washout or at 6 months, depending on group assignment) |
|
|
|
| Secondary | Serious Adverse Events (SAE) | SAEs include death, hospitalization or prolonged existing hospitalization, life threatening, persistent or significant disability, birth defect/congenital anomaly, or medically significant event. | Posted | Count of Participants | Participants | 6 Months and 2 Weeks from Baseline Visit |
|
|
|
| Secondary | Adverse Events (AE) Related to Treatment | AEs related to sildenafil treatment may include headache, flushing, indigestion, or visual disturbance, among others. | Posted | Count of Participants | Participants | 6 Months and 2 Weeks from Baseline Visit |
|
|
|
| 0 |
| 25 |
| 0 |
| 25 |
| 3 |
| 25 |
| EG001 | Placebo Period | Participants who received Placebo tablets (matching Sildenafil 50 mg) once daily in either the first or last 3 months of the study | 0 | 25 | 0 | 25 | 3 | 25 |
| Headache | Nervous system disorders | Systematic Assessment |
|
| Insomnia | Nervous system disorders | Systematic Assessment |
|
| Joint Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
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| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Sulfur Compounds |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |