Sympathetic Vasoconstriction Blockade for Obesity

Overseen By Italo Biaggioni, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Vanderbilt University Medical Center

Must be taking: Metformin

Must not be taking: SNRIs, NET inhibitors, PDE5 inhibitors, anticoagulants

Disqualifiers: Pregnancy, Smoking, Cardiovascular disease, others

Compensation: Varies

Number of Visits: Unknown

Duration: 2 sessions, at least 4 weeks apart

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if blocking certain nerve signals can enhance insulin use, potentially improving glucose uptake in individuals with obesity. It will test two treatments: phentolamine (a medication that blocks specific nerve signals) and sodium nitroprusside, along with a placebo. Suitable candidates for this trial include those with obesity, a body mass index (BMI) between 30 and 40, and difficulty processing insulin, but without severe diabetes. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as serotonin-norepinephrine reuptake inhibitors, norepinephrine transporter inhibitors, phosphodiesterase 5 inhibitors, anticoagulants, and chronic systemic glucocorticoid therapy. If you are on these medications, you may need to stop them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that phentolamine is generally safe for certain medical conditions, primarily managing high blood pressure in specific situations. Tingling at the injection site is a common side effect, but it is usually not serious. Patients should exercise caution when taking phentolamine with other medications that affect heart rate or blood pressure, as this can cause slower heartbeats or low blood pressure.

Studies on sodium nitroprusside indicate that it effectively lowers blood pressure, but it must be used with caution. Rapid drops in blood pressure can lead to serious health problems. In rare cases, prolonged use or large doses can cause a dangerous buildup of cyanide in the body.

Overall, both phentolamine and sodium nitroprusside are considered safe in medical settings. However, they require careful monitoring to avoid potential side effects, particularly those affecting heart rate and blood pressure. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Phentolamine and Sodium Nitroprusside as potential treatments for obesity because they work differently compared to standard options like lifestyle changes, medications targeting appetite, or bariatric surgery. Phentolamine is unique because it blocks sympathetic vasoconstriction, which can affect how the body regulates blood flow and energy balance, potentially offering a novel approach to weight management. Meanwhile, Sodium Nitroprusside acts as a vasodilator, which can improve blood flow and may have a role in managing obesity by influencing metabolic processes. These approaches could provide new pathways for treating obesity, particularly for individuals who do not respond well to existing treatments.

What evidence suggests that this trial's treatments could be effective for obesity?

In this trial, participants will receive different treatments to study their effects on blood flow and insulin response. Research has shown that Phentolamine, administered to participants in the "Blocked Day" arm, can block the process where nerves cause blood vessels to narrow, potentially improving blood flow and insulin use. Although specific data on Phentolamine and obesity is lacking, its effects suggest it might enhance the body's insulin response.

Participants in the "Vasodilator Comparison" arm will receive Sodium Nitroprusside. Studies indicate it helps blood vessels relax and widen, which can lower high blood pressure and improve blood flow. In animal studies, its effects on blood vessels were similar regardless of diet, suggesting it might improve circulation in various conditions. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with obesity (BMI between 30-40) and insulin resistance, but not severe diabetes. Participants can be well-controlled type 2 diabetics on metformin. Exclusions include those on anticoagulants, with morbid obesity or cardiovascular disease, drug abuse history, heavy smokers, or certain medication users.

Inclusion Criteria

I have insulin resistance or am a well-controlled type 2 diabetic on metformin.

Able and willing to provide informed consent

I have insulin resistance or am a well-controlled type 2 diabetic on metformin.

Exclusion Criteria

Previous allergic reaction to study medications

Other factors which in the investigator's opinion would prevent the subject from completing the protocol (i.e., clinically significant abnormalities on clinical, mental examination or laboratory testing or inability to comply with protocol)

You have a history of alcohol or drug abuse.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo two separate experimental sessions with either phentolamine or saline control to assess insulin-mediated microvascular recruitment and glucose uptake

2 sessions, at least 4 weeks apart

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Phentolamine
• Saline
• Sodium Nitroprusside

Trial Overview The study tests if blocking sympathetic vasoconstriction improves insulin-induced vasodilation and glucose uptake in obese individuals. It involves administering Phentolamine (blocks adrenaline effects), Saline (a placebo), and Sodium Nitroprusside (enhances blood flow).

How Is the Trial Designed?

Group I: Blocked Day Experimental Treatment 1 Intervention

Phentolamine

Group II: Vasodilator Comparison Active Control 1 Intervention

Sodium Nitroprusside

Group III: Intact Day Placebo Group 1 Intervention

Saline

Phentolamine is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Regitine for:

• Hypertension
• Pheochromocytoma

Approved in Canada as Phentolamine for:

• Hypertension
• Pheochromocytoma

Approved in European Union as Phentolamine for:

• Hypertension
• Pheochromocytoma

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37254688/

Clinical outcomes associated with drugs for obesity and ... Semaglutide and phentermine/topiramate were associated with greater body weight loss and waist circumference reduction at 12 months than all other drugs.

2. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/oby.23152

Efficacy and Safety of Phentermine/Topiramate in Adults ... Phentermine/topiramate treatment resulted in a moderate reduction of absolute weight in adults with overweight and obesity.

3. medrxiv.org medrxiv.org/content/10.1101/2020.10.26.20215475.full

Efficacy and safety of phentermine/topiramate in adults with ... The primary outcomes of the study were change in weight (kg) and weight loss percentage between baseline and weight loss in subjects receiving ...

4. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK482165/

Topiramate and Phentermine - StatPearls - NCBI Bookshelf Phentermine on its own has been used for short-term treatment of obesity in combination with exercise and caloric restriction.

5. 2024.sci-hub.se 2024.sci-hub.se/8537/ce2931b2d11cfccc65c2f8d21fd49c65/[e-mail]

Efficacy and Safety of Phentermine/Topiramate in Adults ... Objective: The study objective was to examine the association between phentermine/topiramate therapy and weight loss and adverse events in.

6. drugs.com drugs.com/sfx/regitine-side-effects.html

Regitine Side Effects: Common, Severe, Long Term Phentolamine injected into the penis may cause tingling at the tip of the penis. This is no cause for concern.

7. reference.medscape.com reference.medscape.com/drug/regitine-oraverse-phentolamine-342392

Regitine, OraVerse (phentolamine) dosing, indications, ... Avoid or Use Alternate Drug. Avoid coadministration with other drugs that decrease pulse or blood pressure to mitigate risk of excessive bradycardia and ...

8. go.drugbank.com go.drugbank.com/drugs/DB00692

Phentolamine: Uses, Interactions, Mechanism of Action Phentolamine is used to prevent or control hypertensive episodes that may occur in a patient with pheochromocytoma due to stress or manipulation.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4125319/

Safety of antiobesity drugs - PMC - PubMed Central Recently lorcaserin and topiramate plus phentermine have been approved for the treatment of obesity but long-term safety data are lacking. Keywords: antiobesity ...