{"id":110117,"date":"2013-03-19T16:12:32","date_gmt":"2013-03-19T19:12:32","guid":{"rendered":"http:\/\/revistapesquisa.fapesp.br\/?p=110117"},"modified":"2017-03-07T14:02:21","modified_gmt":"2017-03-07T17:02:21","slug":"relief-during-pregnancy","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/relief-during-pregnancy\/","title":{"rendered":"Relief during pregnancy"},"content":{"rendered":"

\"\"MARIANA ZANETTI<\/span>Preeclampsia, an illness unique to pregnant women, is characterized by increased blood pressure, swollen legs and feet, and protein in the urine, symptoms that appear in the second half of pregnancy. It can develop into a more serious form, called eclampsia, in which the patient suffers convulsions. The disease accounted for about 40% \u2013 or 687 \u2013 of the 1,719 deaths that occurred as a result of pregnancy or childbirth in Brazil in 2010. Estimates are that from 5% to 7% of pregnant women in Brazil acquire preeclampsia and that eclampsia manifests in 1.3 of every 1,000 births, a figure that ranges from 0.6 in developed countries to 4.5 in developing nations. Despite this high incidence, the causes of these two illnesses have yet to be properly identified and there are no drugs on the market that specifically target their treatment, while traditional medications can jeopardize fetal development. This treatment challenge may soon be overcome as an entirely new blood pressure medication appropriate for use during pregnancy has been developed by a group of Brazilian researchers at the Federal University of Minas Gerais (UFMG) and the Uni\u00e3o Qu\u00edmica company and has already passed the first phase of clinical trials.<\/p>\n

\u201cFrom 2009 to 2011, we gave the formulation to a group of 14 pregnant women with serious preeclampsia, where interrupting the pregnancy was recommended, and we saw that it improved blood vessel function while presenting no toxicity for either mother or fetus,\u201d states the physician Robson Augusto Souza dos Santos, professor at UFMG\u2019s Institute of Biological Sciences (ICB). The drug is based on a peptide (protein fragment) produced by the human body itself \u2013 angiotensin-(1-7) \u2013 which regulates cardiovascular function by helping to dilate artery walls. The levels of this substance in blood plasma are lower in pregnant women who suffer from preeclampsia. The next step in the research, scheduled for the first half of 2013, is to expand the trials to a larger sampling \u2013 this time of 100 women \u2013 and then incorporate other research centers in Brazil and possibly from abroad for a multicentric study.<\/p>\n

\u201cWe expect all clinical testing to be completed in two years, and a conservative forecast would be that the medication can be brought to market within five years. This timeframe will depend on the regulatory actions of the agencies involved,\u201d says Santos, who also coordinates the National Institute of Science and Technology in Nanobiopharmaceutics (INCT-NanoBiofar), whose main offices are at UFMG. Santos is also a founding partner of Labfar, an INCT spin-off that devises innovations in pharmaceuticals, chemicals, veterinary science, cosmetics, and medical equipment. Both NanoBiofar and Labfar are taking part in development of the drug, as is Brazilian-owned Uni\u00e3o Qu\u00edmica, which has licensed related patents from UFMG. <\/b><\/p>\n

Angiotensin-(1-7) \u2013 also called ang-(1-7) \u2013 is a substance made up of seven amino acids and is part of the renin-angiotensin system (RAS), which comprises <\/b>a set of peptides, enzymes, and receptors involved in regulating extracellular fluid volume and blood pressure. In broad terms, controlling the blood pressure of hypertensive patients is centered on angiotensin I, a hormone produced during blood circulation. When blood flows into the lungs, the angiotensin converting enzyme (ACE) transforms angiotensin I into angiotensin II, the latter being an enzyme that is seen as the main culprit behind hypertension because it both constricts arteries and stimulates the release of other blood-pressure-raising hormones. Conventional blood pressure drugs try to prevent ACE from breaking down angiotensin I and to block the effects of angiotensin II. This is how they act to inhibit increased blood pressure. The medication developed in Minas Gerais works differently. It acts on a woman\u2019s physiological mechanism, normalizing the concentration of vasodilating ang-(1-7) in her blood plasma (see how the new drug works in the infographic<\/a>)<\/i>.<\/p>\n

\"072-075_Anti-hipertensivo_203\"<\/a>\u201cCurrent medications for controlling blood pressure act on the renin-angiotensin system\u2019s vasoconstriction mechanism and are not endogenous, that is, produced by the body itself, but are molecules made in the laboratory. For this reason, they have side-effects,\u201d explains the INCT-Nanobiofar coordinator. \u201cThe drug we\u2019re developing doesn\u2019t occasion this problem as it consists of the peptide itself, synthesized by biochemical means but presenting the same composition as in the human body.\u201d According to Santos, when the medication is ready, it may also be used to treat general hypertension. \u201cPrior research has shown that this drug lowered blood pressure in hypertensive rats. The next step will be to test it on humans,\u201d he says.<\/p>\n

Prenatal care
\n<\/b>\u201cIt seems like a good proposal. Angiotensin-(1-7) is an active part of the renin-angiotensin system and has been shown to be a vasodilating agent, which means it acts as an antihypertensive,\u201d says Dr. Jos\u00e9 Carlos Pera\u00e7oli, professor with the School of Medicine\u2019s Department of Gynecology and Obstetrics at Universidade Estadual Paulista (Unesp) in Botucatu. \u201cThere\u2019s no treatment that will cure preeclampsia, except the end of the pregnancy. Preventing this disease is one of the main goals in prenatal care.\u201d<\/p>\n

The existence of ang-(1-7) was unknown until the 1980s and it was believed that the renin-angiotensin system was only vasoconstrictive when improperly activated \u2013 in other words, it only had adverse effects, such as hypertension. In 1980, however, while doing post-doctoral studies at the Cleveland Clinic Foundation in the United States, Santos discovered that ang-(1-7) was the main product of angiotensin I. \u201cThe first demonstration of the biological effect of this angiotensin occurred during research conducted on the hypothalamuses and pituitary glands of rats, published in the journal Proceedings of the National Academy of Science<\/i> (PNAS<\/i>), in 1988,\u201d Santos recalls. The following year, the Brazilian researcher Maria Jos\u00e9 Campagnole-Santos demonstrated the cardiovascular effects of this angiotensin on a live rat. Since then, hundreds of articles have been published on the topic.<\/p>\n

Back in Brazil, Dr. Santos glimpsed the possibility of developing an antihypertensive drug based on ang-(1-7). The research started at UFMG (initially at the ICB), and the first formulations were ready in 2003. Two years later, UFMG transferred the new drug formulations \u2013 one intravenous and the other oral \u2013 to Uni\u00e3o Qu\u00edmica. The company licensed a patent on the formulations and joined the team responsible for developing it. INCT-Nanobiofar has applied for around 15 patents related to commercialization of the treatment potential of ang-(1-7) and has already been granted eight.<\/p>\n

Funding for the clinical trials on the group of 14 pregnant women was provided by Uni\u00e3o Qu\u00edmica as well as Nanobiofar, which is financed by both the Ministry of Science and Technology (MCT) and the Minas Gerais Research Foundation (Fapemig). \u201cFunds from the National Council for Scientific and Technological Development (CNPq) and from Fapemig, in addition to money from UFMG itself, were important to <\/b>developing the concept and the formulations of angiotensin-(1-7). Professor Ruben Sinisterra Mill\u00e1n, of UFMG\u2019s Chemistry Department, collaborated during this stage,\u201d says Santos. \u201cWe invested R$1 million in the project in 2012 alone \u2013 money used to set up laboratories and purchase equipment,\u201d says Miguel Giudicissi Filho, medical director at Uni\u00e3o Qu\u00edmica.<\/p>\n

Labfar joined the project in 2010 to coordinate the clinical trials and conduct the analytical portion of the research. The company has a unit called Ang-Tec, which conducts R&D work on new products, based on the technological platform of ang-(1-7), and then markets the results. Labfar also has an international partnership with the Austrian firm Attoquant, which may participate in the new phase of ang-(1-7) tests.<\/p>\n

\"\"MARIANA ZANETTI<\/span>So far, the intravenous formulation has been used in phase 2A clinical trials (a limited group of pregnant women) and will be used in the trials scheduled for early 2013, which will involve 100 pregnant women who suffer from the disease. Uni\u00e3o Qu\u00edmica has already approved investments of R$400,000 to R$500,000 <\/b>for these tests. The oral formulation has been tested on rats and will be administered to healthy humans and hypertensive patients starting in 2013. \u201cWith the aid of Professor Robson, the company\u2019s R&D group in Brasilia recently developed angiotensin-(1-7) capsules of three dose sizes \u2013 0.35, 1.75, and 7 mg \u2013 indicated for women with preeclampsia, when the condition is reversible. Patients with eclampsia, in the acute phase, have to take the injection,\u201d says Giudicissi Filho.<\/p>\n

\u201cThese phases are necessary to guarantee that the medication is safe for use. If everything goes well, this might be an alternative for women who are at risk of developing preeclampsia,\u201d Santos emphasizes. He also <\/b>notes that it will be important to establish international partnerships to facilitate access to the world market. \u201cTo this end, initial talks are already underway with investors abroad,\u201d the researcher says, without revealing any names of those involved. \u201cThe idea is to launch the antihypertensive drug in Brazil and enter into international partnerships in order to occupy a significant space on the foreign market,\u201d says Fernando de Castro Marques, chairman of Uni\u00e3o Qu\u00edmica.<\/p>\n

*In collaboration with Dinorah Ereno<\/p>\n

Scientific articles<\/em>
\nFERREIRA, A.J.; R.A. SANTOS et al<\/em>. Angiotensin-(1-7)\/angiotensin-converting enzyme 2\/mas receptor axis and related mechanisms<\/a>. International Journal of Hypertension<\/strong>. Published online on 9 Apr.\u00a0 2012.
\nM.T. SCHIAVONE; R.A. SANTOS\u00a0et al<\/em>. Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide<\/a>. Proceedings of the National Academy of Sciences<\/strong>. v. 85, no. 11, pp. 4,095-98. Jun. 1988.<\/p>\n","protected":false},"excerpt":{"rendered":"Brazilian scientists develop a pioneer drug for treating hypertension","protected":false},"author":23,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[169],"tags":[211,247],"coauthors":[116],"class_list":["post-110117","post","type-post","status-publish","format-standard","hentry","category-technology","tag-biochemistry","tag-medicine"],"acf":[],"_links":{"self":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/110117","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/users\/23"}],"replies":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/comments?post=110117"}],"version-history":[{"count":0,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/110117\/revisions"}],"wp:attachment":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media?parent=110117"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/categories?post=110117"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/tags?post=110117"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/coauthors?post=110117"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}