Carnosine for Peripheral Vascular Disease
Keywords
Abstract
Description
Peripheral vascular disease (PVD) has high prevalence of 10-15% in Australia and is caused by atherosclerotic occlusion of the arteries supplying the lower extremities which reduces blood flow and leads to intermittent claudication and critical limb ischaemia. No effective medication is currently available. Although surgical or endovascular revascularisation are available treatments, not all patients are suitable for the procedure, and grafts can fail, and dilated arteries can restenose. Structured exercise, both supervised and home-based, improves walking endurance in patients with PVD to a similar extent as revascularisation and effects are longer lasting but the pain associated with exercise is a major limitation. Therefore, there is a need to develop safe interventions synergistic with exercise that can prompt revascularisation and preserve limb viability.
Angiogenesis plays an essential role for recovery from critical limb ischaemia. Hypoxia inducible factor 1α (HIF1-α), a master regulator of angiogenic genes, has been implicated . Under normal conditions, HIF1-α is targeted for proteasomal degradation through the activity of prolyl hydroxylases (PHDs). PHDs require iron for their activity and their inactivation by metal chelators or pharmacological inhibitors stabilises HIF1-α and has been shown to improve blood flow in the ischaemic limb. However, metal chelators cannot be used as an intervention due to their toxicity.
Recent studies have shown that supplementation of carnosine (β-alanyl-L-histidine), a naturally occurring histidyl dipeptide in skeletal muscle with an excellent safety profile, improves exercise performance in athletes as well as in patients with chronic heart failure. The investigators and others have shown that carnosine supplementation also improves cardiometabolic risk factors. No clinical trial has yet to investigate whether carnosine improves walking endurance in patients with PVD. Carnosine has anti-inflammatory, antioxidative, anti-glycating and anti-atherosclerotic properties. It also has the ability to chelate metals, form conjugates with reactive aldehydes, and has lactate buffering capacity. In addition, carnosine has been found to be very effective in reducing ischaemia-reperfusion damage in several organs. Our preliminary results using a murine model of hind limb ischaemia (HLI) showed that administration of carnosine over 21 days increased HIF1-a and VEGF levels in the ischaemic muscle and improved tissue perfusion. Furthermore, mobilisation of pro-angiogenic endothelial progenitor cells (EPCs) and the ambulatory movement were increased in carnosine treated HLI mice compared to controls. The investigators propose a randomised clinical trial to investigate whether administration of carnosine for 6-month in addition to exercise could improve walking endurance and quality of life in patients with PVD compared to placebo and exercise.
Dates
| Last Verified: | 01/31/2019 |
| First Submitted: | 02/11/2019 |
| Estimated Enrollment Submitted: | 02/13/2019 |
| First Posted: | 02/17/2019 |
| Last Update Submitted: | 02/13/2019 |
| Last Update Posted: | 02/17/2019 |
| Actual Study Start Date: | 02/28/2019 |
| Estimated Primary Completion Date: | 02/29/2020 |
| Estimated Study Completion Date: | 02/29/2020 |
Condition or disease
Intervention/treatment
Drug: Intervention
Drug: Control
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Active Comparator: Intervention Each participant will be given a daily oral dose 2 g of carnosine for 6 months | Drug: Intervention Each participant will be given a daily oral dose 2 g of carnosine for 6 months |
| Placebo Comparator: Control Each participant will be given a daily oral dose 2 g of placebo for 6 months | Drug: Control Each participant will be given a daily oral dose 2 g of methycellulose powder for 6 months |
Eligibility Criteria
| Ages Eligible for Study | 40 Years To 40 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: - Age >=40or <80 years - Clinical diagnosis Peripheral Vascular disease - Rutherford Grade 1-3 - No significant kidney, cardiovascular, haematological, respiratory, gastrointestinal, or central nervous system disease, as well as no psychiatric disorders, no active cancer within the last five years; no presence of acute inflammation (by history, physical or laboratory examination) - Intermittent claudication on treadmill between 30m and 200m - Ankle Brachial index 0.6-1 at rest with minimum post exercise drop in ABI of 0.1 Exclusion Criteria: - Age < 40 or > 80 years - Pregnant or lactating - Limb threatening ischaemia- Rutherford grades 4-6, manifested by ischaemic rest pain, ulceration, or gangrene; acute limb-threatening ischaemia - lower limb surgical or endovascular interventions in the preceding 6 months - planned lower limb endovascular or surgical intervention within the next 6 months on either limb - taking medication for PVD (Cilostazol and Pentoxifylline) - inability to complete the treadmill walking test for reasons other than claudication - myocardial infarction within last 3 months - deep vein thrombosis within 3 months - estimated life expectancy < 1 year - alcohol and illicit drug abuse. |
Outcome
Primary Outcome Measures
1. walking endurance [6 months]
