Scientific Vascular disease prevention alluded to by Clinuvel


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To follow on from the idea that Clinuvel is interested in treating the root causes of related ailments I went back to this communique for clues. In the scientific communique prior to this one, they talked in detail about melanogenesis, photoprotection and skin cancer. It is obvious through the clinical progress so far and the impending release of the OTCs that Clinuvel has taken a holistic approach to preventing skin cancer with DNA repair and photoprotection. This communique talks in detail about vascular health. I take it as a sign they are intent on treating or preventing vascular diseases through maintaining vascular health perhaps through a general prophylactic treatment with afamelanotide (Prenumbra Oral?).

Technically there is no cure for atherosclerosis, although in its early stages it can be mitigated or even slightly reversed with changes in diet and regular exercise. Atherosclerosis may not be the 6th, or even the 7th. But given their approach to skin cancer, and AIS progress (vascular anomalies as a cause), and running with the idea of Clinuvel wanting to have the broadest application possible for their drug through treating the root causes of global leading causes of death, it is a possibility they might use the same approach with vascular health.

Which disease to trial to prove afamelanotide’s vaso active properties? I think a good contender is vascular dementia: they might be able to show that improved vascular health coupled with neuroprotection could lead to a improved outcome, maybe even incremental reversals. However, the most likely would be atherosclerosis itself as vascular dementia is a fairly direct consequence of it. The following quotes from this communique might provide some insight into their intentions:

- “Sufficient concentrations of NO can therefore stimulate vasoprotective changes in diseases who origins result from a loss of NO production or availability”

- “ A number of disorders, including atherosclerosis, hypertension, and diabetes are associated with the loss of NO signalling.”

- “ A deficit of eNOS derived NO signalling corresponds to a variety of diseases that lead to poor vascular health.”

- “Emerging evidence has shown α-melanocyte stimulating hormone (α-MSH) and its analogues to be positive regulators of NO”


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"Considering the pathogenesis of atherosclerosis, a combination of lifestyle modifications and pharmacological interventions have been the mainstays of treatment to reduce disease progression, although in contemporary medicine particular attention has been paid to treatments that target the final and most detrimental stage of atherogenesis in a means to directly prevent the occurrence of an ischaemic stroke.” (Root cause prevention)

“Despite this, atherosclerosis still remains the leading cause of mortality and disability worldwide, with figures rapidly rising in developing counties. In addition, aging populations and elevations in care costs have led to some countries predicting the economic burden of diseases secondary to atherogenesis, such as strokes, will increase by nearly 200% between 2015 and 2035.”

"This therefore demonstrates that despite current management of risk factors and progresses in treatments for atherosclerosis, improvements are still needed to curtail the occurrence of ischaemic stroke which comprise most stroke cases.”

"In a following SCIENTIFIC COMMUNIQUÉ we will discuss the current therapies for both atherosclerosis and ischaemic strokes, reviewing the effectiveness of existing treatments."
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"This therefore demonstrates that despite current management of risk factors and progresses in treatments for atherosclerosis, improvements are still needed to curtail the occurrence of ischaemic stroke which comprise most stroke cases.
Important to note they talk about lifestyle changes and contemporary medicine focussing on the the final stages of atherogenesis and yet in spite of this, atherosclerosis is still a major killer. This is a problem I talked about in the main thread, the invisibility of the disease and how people are unlikely to act on atherosclerosis until it is too late, or their doctor catches the problem in time and recommends lifestyle changes to prevent early onset of death yet complications may arise such as disability etc. Is it better to take a preventative so you don have to worry about the health of your vascular system, something you can't see even if you wanted to?

Currently, statins are one drug used to assist with high cholesterol and resulting atherosclerosis, but from what I've read this has mixed results. When put together, perhaps atherosclerosis has no effective treatment, whereas afamelanotide has the ability to stimulate vasoprotective changes in related diseases (as per Communique 5). This is very significant IMO.
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"We found that transgenic MSH-OE improved glucose tolerance and limited atherosclerotic plaque formation particularly in Western diet-fed mice."

"In terms of aortic vasoreactivity, MSH-OE blunted alpha1-adrenoceptor-mediated vasoconstriction and enhanced relaxation response to acetylcholine, indicating improved endothelial function. In addition, MSH-OE markedly attenuated Western diet-induced upregulation of proinflammatory cytokines (Ccl2, Ccl5 and Il6) that contribute to the pathogenesis of atherosclerosis. These results show that the activation of the melanocortin system improves glucose homeostasis and limits diet-induced vascular inflammation and atherosclerotic plaque formation."

Western society plagued by self induced atherosclerosis through Western diets.

"Cholesterol is an important risk factor and driving force of atherosclerosis development. However, mounting evidence demonstrates that cholesterol triggers inflammation, which, in turn, promotes atherosclerosis. Given that MSH-OE did not change plasma cholesterol concentration, the reduced plaque accumulation in MSH-OE mice is likely explained by the reduced proinflammatory cytokine levels in the aorta".

This is incredible. Essentially, you can eat a western diet and maintain levels of cholesterol consistent with that diet but the inflammation that cholesterol causes leading to atherosclerosis is curtailed by a-msh. As mentioned before, lifestyle changes such as eating healthier food and exercising regularly haven't been able to reduce the number of associated deaths globally. And even then its not guaranteed you will avoid having a stroke. Perhaps a combination of healthier diets, regular exercise and an a-msh based prophylactic treatment would provide optimal vascular health.
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After further reading about atherosclerosis, it is an affliction that is heavily weighted to occur in developing countries (low to middle income) something around 60-70% of total global numbers. At last glance the global figure was approx 17 million people affected. So we can say roughly 5 million+ people in the Western world are affected by the condition. I’m coming around to the view that atherosclerosis maybe one of the final indications because of its ubiquity, it would require substantial trials to get to a prophylactic stage and even then it’s not guaranteed to work (how would that look, a pill form?)
I think the next 2-3 indications will be targeted for their immediate positive impact, among other characteristics (no competition, effectiveness etc), on the bottom line for Clinuvel, and at this time atherosclerosis may take too much blood and treasure to bring to the fore.
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An opportune time to revisit this thread. Its very rare that Clinuvel provides a sneak peek into what they are doing behind the scenes independent of those studies already announced, but the revelation in the 2021 annual report that they are looking at treatment for stroke patients post-recovery who are at risk of incurring a second fatal stroke immediately threw up many possibilities. But these possibilities all lead back to Scientific Communique V, in which it talks of the role of melanocortins in the vascular system. These Communiques are road markers on the path Clinuvel is taking, and they deserve attention to try and figure out where the company is heading.

As mentioned in the main thread today, the drugs used for stroke patients to minimise the risk of a second stroke incident includes aspirin, anti hypertensive and anti platelet drugs, statins, and ACE inhibitors. These drugs work to reduce cholesterol, thin the blood, relax blood vessels and improve blood flow, and reduce high blood pressure.
A-MSH/afamelanotide has the ability to perform the same functions of at least two of these common post- stroke drugs, while assisting in reducing vascular inflammation caused by cholesterol: primarily it can improve NO (nitric oxide) availability in the vascular system, of which a deficiency in NO availability gives rise to atherosclerosis which causes a range of associated ailments such as hypertension and kidney failure. Its not clear to me whether afamelanotide can assist with platelet aggregation at the infarct sites in the brain, but I imagine if it helps with the other functions that would provide the optimal conditions for anti platelet drugs to do its work.

Although the potential to treat a range of vascular diseases is clear, the pathway to treating them is not. But by going after prevention of recurring stokes, they can show afamelanotide working across several pathological processes, of which the results should prove advantageous in preparing to treat these and other vascular ailments in the future.
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Arterial Disease
Peripheral Artery Disease
Like the blood vessels of the heart (coronary arteries), your peripheral arteries (blood vessels outside your heart) also may develop atherosclerosis, the build-up of fat and cholesterol deposits, called plaque, on the inside walls. Over time, the build-up narrows the artery. Eventually the narrowed artery causes less blood to flow, and a condition called ischemia can occur. Ischemia is inadequate blood flow to the body's tissue. Types of peripheral arterial disease include:
  • Peripheral artery disease: A blockage in the legs can lead to leg pain or cramps with activity (claudication), changes in skin color, sores or ulcers and feeling tired in the legs. Total loss of circulation can lead to gangrene and loss of a limb.
  • Intestinal ischemic syndrome: A blockage in the blood vessels leading to the gastrointestinal system
  • Renal artery disease: A blockage in the renal arteries can cause renal artery disease (stenosis). The symptoms include uncontrolled hypertension (high blood pressure), congestive heart failure, and abnormal kidney function.
  • Popliteal Entrapment Syndrome: a rare vascular disease that affects the legs of some young athletes. The muscle and tendons near the knee compress the popliteal artery, restricting blood flow to the lower leg and possibly damaging the artery.
  • Raynaud's Phenomenon consists of spasms of the small arteries of the fingers, and sometimes, the toes, brought on by exposure to cold or excitement.
  • Buerger's Disease most commonly affects the small and medium sized arteries, veins, and nerves. Although the cause is unknown, there is a strong association with tobacco use or exposure. The arteries of the arms and legs become narrowed or blocked, causing lack of blood supply (ischemia) to the fingers, hands, toes and feet. Pain occurs in the arms, hands, and more frequently the legs and feet, even at rest. With severe blockages, the tissue may die (gangrene), requiring amputation of the fingers and toes. Superficial vein inflammation and symptoms of Raynaud's occur commonly in patients with Buerger's Disease.
Carotid Artery Disease
Venous Disease
Veins are flexible, hollow tubes with flaps inside, called valves. When your muscles contract, the valves open, and blood moves through the veins. When your muscles relax, the valves close, keeping blood flowing in one direction through the veins.
If the valves inside your veins become damaged, the valves may not close completely. This allows blood to flow in both directions. When your muscles relax, the valves inside the damaged vein(s) will not be able to hold the blood. This can cause pooling of blood or swelling in the veins. The veins bulge and appear as ropes under the skin. The blood begins to move more slowly through the veins, it may stick to the sides of the vessel walls and blood clots can form.
  • Varicose veins are bulging, swollen, purple, ropy veins, seen just under your skin, caused by damaged valves within the veins.
  • Spider veins are small red or purple bursts on your knees, calves, or thighs, caused by swollen capillaries (small blood vessels)
  • Klippel-Trenaunay syndrome (KTS), a rare congenital vascular disorder
  • May-Thurner syndrome (MTS) is caused when the left iliac vein is compressed by the right iliac artery, which increases the risk of deep vein thrombosis (DVT) in the left extremity.
  • Thoracic outlet syndrome (TOS) is a group of disorders that occur when there is compression, injury, or irritation of the nerves and/or blood vessels (arteries and veins) in the lower neck and upper chest area
  • Chronic venous insufficiency (CVI) is a condition that occurs when the venous wall and/or valves in the leg veins are not working effectively, making it difficult for blood to return to the heart from the legs.
Blood Clots
A clot forms when clotting factors in the blood cause it to coagulate or become a solid, jelly-like mass. When a blood clot forms inside a blood vessel (a thrombus), it can dislodge and travel through the blood stream, causing a deep vein thrombosis, pulmonary embolis, heart attack or stroke.
Blood clots in the arteries can increase the risk for stroke, heart attack, severe leg pain, difficulty walking, or even the loss of a limb.usually caused by:
  • Hypercoagulable states are conditions that put people at increased risk for developing blood clots.
  • Deep vein thrombosis (DVT) is a blood clot occurring in a deep vein.
  • Pulmonary embolism is a blood clot that breaks loose from a vein and travels to the lungs.
  • Axillo-subclavian vein thrombosis, also called Paget-Schroetter Syndrome, is a most common vascular conditions to affect young, competitive athletes. The condition develops when a vein in the armpit (the axilla) or in the front of the shoulder (the subclavian vein) is compressed by the collarbone (clavicle), the first rib, or the surrounding muscle, increasing risk for blood clots.
  • Superficial thrombophlebitis is a blood clot in a vein just under the skin
Aortic Aneurysm
An aneurysm is an abnormal bulge in the wall of a blood vessel. Aneurysms can form in any blood vessel, but they occur most commonly in the aorta (aortic aneurysm) which is the main blood vessel leaving the heart:
Fibromuscular Dysplasia (FMD)
Fibromuscular dysplasia (FMD) is a rare medical condition. Patients with FMD have abnormal cellular growth in the walls of their medium and large arteries. This can cause the arteries with the abnormal growth to look beaded. The arteries may also become narrow (stenosis).
Other vascular conditions include:
Blood Clotting Disorders
Blood clotting disorders are disorders that make the blood more likely to form blood clots (hypercoagulable) in the arteries and veins. These conditions may be inherited (congenital, occurring at birth) or acquired during life and include:
  • Elevated levels of factors in the blood which cause blood to clot (fibrinogen, factor 8, prothrombin)
  • Deficiency of natural anticoagulant (blood-thinning) proteins (antithrombin, protein C, protein S
  • Elevated blood counts
  • Abnormal Fibrinolysis (the breakdown of fibrin)
  • Abnormal changes in the lining of the blood vessels (endothelium)
The lymphatic system is a circulatory system that includes an extensive network of lymph vessels and lymph nodes. The lymphatic system helps coordinate the immune system's function to protect the body from foreign substances. Lymphedema is an abnormal build-up of fluid that causes swelling, most often in the arms or legs. Lymphedema develops when lymph vessels or lymph nodes are missing, impaired, damaged or removed.
Primary lymphedema is rare and is caused by the absence of certain lymph vessels at birth, or it may be caused by abnormalities in the lymphatic vessels. Secondary lymphedema occurs as a result of a blockage or interruption that alters the lymphatic system.
Secondary lymphedema can develop from an infection, malignancy, surgery, scar tissue formation, trauma, deep vein thrombosis (DVT), radiation or other cancer treatment. Doctors vary in quality due to differences in training and experience; hospitals differ in the number of services available. The more complex your medical problem, the greater these differences in quality become and the more they matter.



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Illuminating paper concerning MC1R and human artery endothelial cell migration (Credit Uhoh @GG)


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