Viagra could help treat complications associated with sickle cell anemia

The current study is part of a Brazilian project focused on understanding the diseases that affect red blood cells and seeking new forms of treatment.

By Karina Toledo

Agência FAPESP – One of the possible adverse effects of drugs for erectile dysfunction is priapism – a painful, prolonged erection that can cause irreversible damage to the penile tissue. A study conducted under the auspices of the ongoing Thematic Project at the Universidade Estadual de Campinas (Unicamp) showed that, although it seems counterintuitive, the use of a medicine like Viagra (sildenafil citrate) may be a good option for the treatment of sickle cell anemia patients.

“Priapism is a common complication among men with sickle cell anemia; however, the cause of the problem is still not very clear. We know that the blood of these patients contains a smaller quantity of nitric oxide, which is a vasodilatory agent and the main mediator of penile erection. What is expected, therefore, is greater difficulty in obtaining an erection,” explains Carla Penteado, co-author of an article on the subject published in The Journal of Sexual Medicine.

But a study conducted in the United States showed that the amount of the enzyme phosphodiesterase 5, which is responsible for degradation of nitric oxide and restoration of the penile erection process, is also reduced in mice that have been genetically modified to develop a condition very similar to sickle cell anemia.

“This suggests that although these patients have smaller nitric oxide bioavailability, the degradation of this vasodilatory agent is also decreased; therefore, its concentration in the blood and tissues is high enough to prolong penile erection, leading to priapism,” explained Penteado.

Later, the investigations conducted by Mário Angelo Claudino and Edson Antunes of the Pharmacology Department of Unicamp’s School of Medical Sciences showed that the nitric oxide pathway is upregulated in the smooth muscles of the cavernous bodies of the genetically modified mice.

According to Penteado, these results suggest that drugs capable of intervening in nitric oxide signaling, such as Viagra, can help to prevent priapism in patients with sickle cell anemia. The difference is the dosage used for this distinct purpose. “One of the proposals is to use Viagra chronically in much smaller doses than recommended for treatment of sexual impotence,” she said.

According to the researchers, the scientific literature suggests that medicines like Viagra, if used continuously, can restore the levels of the enzyme responsible for nitric oxide degradation.

“This is still not very clear, but there are clinical studies underway in the United States evaluating the effects of Viagra and similar drugs on recurring priapism or stuttering in sickle cell anemia patients,” she said.

New prospects

Other discoveries during the Thematic Project, coordinated by Fernando Ferreira Costa of Unicamp’s Hematology and Hemotherapy Center (Hemocentro), may lead to the development of new treatments for sickle cell anemia and its complications, which affect more than 50,000 people in Brazil.

Common in populations of African descent, the disease is caused by a genetic alteration in hemoglobin, a protein found in red blood cells that helps to transport oxygen.

The mutation causes the blood cells to assume the form of a sickle after oxygen has been released to the tissue. Under low oxygen tension, the cells become deformed, rigid and apt to cluster: i.e., they form a cellular mass that sticks to the endothelium and makes blood circulation difficult – a process known as vascular occlusion.

In addition to chronic inflammation, vascular occlusion can cause necrosis in several tissues and can lead to intense pain. It is common for sickle cell patients to experience leg ulcers, retinal detachment, strokes, heart attacks, kidney failure and pulmonary failure. The disease also compromises bones and joints, and it tends to worsen as the years pass, reducing the life expectancy of carriers.

Currently, hydroxyurea is one of the most commonly used drugs in the treatment of sickle cell anemia because it can increase the production of another type of hemoglobin, known as fetal hemoglobin (found during the uterine period). High levels of fetal hemoglobin reduce both the polymerization of defective red blood cells and the risk of vascular occlusion.

Hydroxyurea is normally taken chronically by patients; however, in one of the lines of research under the Thematic Project coordinated by researcher Nicola Amanda Conran Zorzetto of Unicamp’s Hemocentro, the scientists showed that the drug can also alleviate symptoms in the acute phase of the disease, for which no therapeutic options are currently available (read more in http://agencia.fapesp.br/en/16495).

In another study developed during the post-doctoral studies of Flávia Cristine Mascia Lopes (a FAPESP fellow) under the supervision of Conran, the scientists showed that certain factors found in the plasma of sickle cell patients have pro-angiogenic activity: i.e., they stimulate the formation of new blood cells.

According to the researcher, this finding may be the cause of some complications of the disease, such as pulmonary hypertension and moyamoya syndrome, the latter of which is characterized by the formation of abnormal blood cells in the brain.

“We measured 15 different factors related to angiogenesis in the blood and saw that seven were altered in sickle cell patients. Some antiangiogenic factors were inhibited,” explained Conran.

Lopes then treated a culture of endothelial cells with the plasma of healthy patients and patients with sickle cell anemia. She verified increased formation of structures responsible for forming an internal layer within capillary vessels in the latter group of cells.

“The study also showed for the first time that hydroxyurea could be an inhibitor of angiogenesis because the blood factors that stimulate formation of vessels were reduced in the plasma of sickle cell patients who received this drug. At the moment, we are attempting to confirm this hypothesis through tests with transgenic mice,” commented Conran.

During FAPESP fellow Renata Proença Pereira’s doctoral studies, under the supervision of Conran, the group discovered that the platelets of sickle cell anemia patients have a greater capacity to adhere to endothelial cells, favoring the process of vascular occlusion.

“Our data suggest that adhesion to the endothelium activates the production of molecules that favor adhesion of white and red blood cells to the vascular wall, in addition to stimulating the production of pro-inflammatory molecules. This shows us that the platelets could be a therapeutic target. If we can find a drug capable of reducing the number of platelets in patients or platelet adherence, we could possibly avoid vascular occlusion,” stated Conran.

In another study developed in partnership with researchers at the School of Pharmaceutical Sciences at Universidade Estadual Paulista - Araraquara (FACFAr-Unesp), the researchers tested a new drug that brings together the benefits of hydroxyurea and the anti-inflammatory effects of thalidomide – without the adverse effects of the original drugs (read more at http://agencia.fapesp.br/en/17846).

Known as Lapdesf1, the drug showed good results in animal trials. The researchers are now seeking a partnership with the pharmaceutical industry to test the drug in humans.

Thalassemia

Another hereditary disease that affects red blood cells, which was also a focus of the Thematic Project, is thalassemia. This disease is much rarer in Brazil than is sickle cell anemia and is more prevalent among individuals of Mediterranean descent.

“Hemoglobin is formed by chains of a protein called globin. There is an alpha chain and a beta chain. In thalassemia, the production of one of these chains of hemoglobin is reduced or totally blocked, leading to a form of anemia that is potentially mild and asymptomatic, although it may be severe and require constant blood transfusions,” explained Ferreira Costa, coordinator of the Thematic Project.

One possible treatment for the most severe forms of this disease, according to Ferreira Costa, is to increase the production of fetal hemoglobin. “If we managed to discover the genetic mechanisms that lead to alterations known as hereditary persistence, we could find new ways to treat serious illnesses in the future,” he said.