The inhibition of blood vessel formation (anti-angiogenesis), which caused birth abnormalities when administered to pregnant women, has sparked interest in thalidomide’s therapeutic value in other domains.
New findings, published today in Nature Cardiovascular Research, reveal a significant reduction in symptoms and an increase in quality of life after the use of thalidomide in patients with severe arteriovenous malformations (AVMs)
AVMs are aberrant blood vessel tangles that connect arteries and veins and disrupt normal blood flow. They are excruciatingly painful, and they result in hemorrhage, distortion of the affected bodily portion, and cardiac difficulties. They’re usually congenital, and they don’t show up until the person reaches puberty or age. Surgery or embolization (the injection of a substance that destroys local blood arteries, causing scarred tissue) are commonly used to treat severe cases, however neither is always effective and can make things worse.
Although some people with AVMs can lead reasonably normal lives, there is always the chance that the aberrant tangles of blood arteries in the brain will burst and cause a stroke. Every year, about one out of every hundred AVM patients has a stroke.
“Our group has been studying the causes of vascular abnormalities for 30 years,” says Professor Miikka Vikkula, from the de Duve Institute, adding “We have identified several genetic causes and have been able to show that certain mutations activate the signalling inside the blood vessel wall -cells and this promotes the abnormal formation of blood vessels (angiogenesis). This led us to wonder about the possibility of using thalidomide to inhibit abnormal blood vessel formation .”
Professor Laurence Boon alongwith Prof Vikkula, enrolled 18 patients with AVMs to an analysis of the use of thalidomide in their condition after showing that a vascular malformation could be corrected in a mouse model. They were between the ages of 19 and 70, and they all had severe malformations that could not be fixed in the traditional manner. Patients were required to agree to use contraception for at least four weeks before commencing thalidomide and for another four weeks after treatment ended. As thalidomide is found in sperm, males were also required to agree to wear condoms during sexual activity.
For two to 52 months, patients were given 50mg, 100mg, or 200mg of thalidomide each day. After a mean of 54 months without thalidomide, eight AVMs remained stable, while four recurred after a mean of 11.5 months. The thalidomide dose was reduced to 50mg per day in five individuals after combining treatment with embolization, which involves blocking arteries or veins within the AVM with an agent that damages vascular wall cells. Prof Vikkula emphasizes the need of lowering the dose where possible because a greater dose was linked to adverse effects such as fatigue and peripheral neuropathy, or damage to nerves outside the brain and spinal cord that causes weakness and numbness, notably in the hands and feet.
Prof Vikkula notes, “All the patients experienced a rapid reduction of pain, together with cessation of bleeding and the healing of ulcers where these were present.”
The professor adds: “The three patients with cardiac failure also saw their problems resolved, and one AVM appeared to be completely cured after 19 months of thalidomide and an eight-year follow-up.”
“We know that thalidomide acts through vascular endothelial growth factor (VEGF) a signalling protein that promotes the growth of new blood vessels. VEGF levels are high in vascular abnormalities such as AVMs and is therefore likely that thalidomide reduces signalling via the angiogenesis-promoting pathways. Although our study is only small, the results are convincing, and we hope that they will be confirmed by larger trials .”
The use of thalidomide in the treatment of AVMs also has a cost advantage. Two other medications, which were recently created for use in oncology and are being investigated to treat AVMs, cost up to twelve times as much and come with a slew of side effects.
“We had hypothesised that thalidomide should work in these patients, so our results did not come as a surprise,” Prof Vikkula says, “but it was great to have clinical confirmation that we were right.”
“In our view, this is a breakthrough finding and provides a solid basis for the development of molecular treatments for AVMs.”
“This study shows not only the healthcare and economic benefits of repurposing drugs – even the most maligned – but also how genetic research can lead to real breakthroughs in therapies for difficult to treat, distressing conditions,” adds conference chair, Professor Alexandre Reymond.
Professor Miikka Vikkula will present the study’s findings at the European Society for Human Genetics’ annual conference on Sunday.
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