Os desafios para construir uma indústria farmacêutica brasileira

Desafios para os medicamentos brasileiros

A grande dependência brasileira por importação de insumos, que são a base para a fabricação de fármacos e medicamentos, a formação de recursos humanos insuficiente em quantidade e qualidade, e a aquisição de laboratórios nacionais por empresas estrangeiras.

Estes são os principais desafios para o setor farmacêutico no Brasil, segundo pesquisadores que participaram da Reunião Anual da Sociedade Brasileira para o Progresso da Ciência (SBPC), em Goiânia.

Participaram da mesa redonda o diretor do laboratório da Fundação Oswaldo Cruz, o Farmanguinhos, Hayne Felipe da Silva, e o professor da Universidade Federal do Rio de Janeiro (UFRJ), Eliezer Barreiro, pesquisador com 14 pedidos de patente, e uma patente concedida via Tratado de Cooperação em Patentes (PCT).

Barreiro coordena o Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT Inofar).

Farmacêuticos

Ao abrir o evento, a professora e pesquisadora da UFG, Eliana Martins Lima, apontou o problema da formação dos farmacêuticos atualmente.

"Ainda que tivéssemos alguma parcela dos insumos, não temos farmacêuticos que sabem formular medicamento", disse.

Segundo ela, na formação dos farmacêuticos industriais hoje, o foco para os aspectos tecnológicos tem sido cada vez mais reduzido. "A formação desse profissional é mais curta, menos completa do que deveria ser", acrescentou.

Para ela, a qualificação de pessoal talvez seja um dos principais gargalos.

Importação de fármacos

O professor Eliezer Barreiro chamou a atenção para as importações brasileiras dos países asiáticos, em especial Índia, China e Coreia.

"Precisamos inverter o que eu chamo de caminho das Índias dos fármacos, corrigindo nossa dependência", afirmou Barreiro. "Devemos convocar a competência das universidades para dar essa contribuição."

O Brasil tem importado medicamentos prontos, além de fármacos, que são o princípio ativo de um medicamento, e adjuvantes, substâncias farmacologicamente inativas usadas como veículo para o princípio ativo.

Segundo o pesquisador, o mercado farmacêutico em 2010 ficou em US$ 850 bilhões. A indústria diz que investe cerca de 10% de seu faturamento em atividades de pesquisa e desenvolvimento, ou seja, seriam US$ 85 bilhões no ano passado direcionados para essas atividades.

"Esse investimento rendeu apenas 21 entidades químicas novas. Há 15 anos, este número era muito maior", contou. Em 1996, por exemplo, foram obtidas 53 novas entidades moleculares.

• Empresas farmacêuticas pesquisam menos e descobrem menos medicamentos novos

Faz-de-conta da inovação

Barreiro lembrou ainda que a indústria farmacêutica nacional não investe em projetos de risco e faz muito mais inovação incremental do que radical. Ele se diz um crítico da afirmação de que a indústria nacional está inovando.

"Criou-se no Brasil um faz-de-conta no qual estaríamos interessados em inovação radical, mas se um ator não está na mesa, no caso, as empresas, o setor avança com atrofia", apontou.

O pesquisador ressaltou que as empresas nacionais são de base familiar, avessas a correr os riscos dos processos de inovação que geram produtos de maior valor agregado. Essas companhias também têm dificuldades para internalizar novas tecnologias. "Como não emprega doutores, não tem qualificação científica e tecnológica para correr os riscos do desenvolvimento tecnológico", afirmou.

Laboratórios de escalonamento

Ele defendeu que o Brasil amplie a formação de recursos humanos, para ter mais profissionais, e que estes sejam mais bem formados.

Comentou que o país precisa também de laboratórios de escalonamento para fazer inovação radical e incremental. Esse tipo de laboratório faz testes em escala piloto, ampliando a produção feita na bancada dos laboratórios para escalas mais próximas da produção comercial.

"Capacitação para inovar em fármacos exige mais do que investimento e parceria universidade-empresa, parcerias público-privado e com o governo. Exige pessoal qualificado, ações articuladas, integradas, vontade política e coragem empresarial", comentou.

Área estratégica

Hayne Felipe da Silva, da Fiocruz, destacou que fármacos e medicamentos são áreas estratégicas na política industrial atual e biotecnologia é área de futuro.

Ressaltou iniciativas do governo como o Profarma, do Banco Nacional de Desenvolvimento Econômico e Social (BNDES), que financia projetos de inovação das empresas, as parcerias entre laboratórios públicos e empresas privadas para produção de medicamentos de interesse do Sistema único de Saúde (SUS), e a legislação que dá preferência a produtos desenvolvidos no Brasil no caso de compras públicas.

Ele defendeu a manutenção de uma política industrial com foco em saúde.

Ele também identificou como desafios o fortalecimento da regulação sanitária, pois hoje os produtos importados entram no País sem maiores exigências em termos de qualidade. Também destacou a isonomia tributária, a ampliação dos investimentos em C&T&I e em educação, e o uso do poder de compra do Estado. Também citou, como gargalo, a falta de locais capacitados para fazer ensaios clínicos e pré-clínicos.

Desnacionalização

Outro fator preocupante é um eventual processo de desnacionalização, que poderá se ampliar em virtude do potencial do mercado brasileiro.

De acordo com Eliezer Barreiro, da UFRJ, o Brasil ocupa o 10º lugar no mercado, movimentando US$ 15,7 bilhões - 88,2% do mercado nacional correspondem à venda de genéricos.

"A indústria de genéricos é a menina dos olhos, o mercado acena com crescimento na casa dos dois dígitos, e estamos muito próximos de um processo de desnacionalização", apontou Silva, do Farmanguinhos, se referindo às recentes compras de laboratórios nacionais por empresas estrangeiras.

Os pesquisadores lembraram ainda que a estratégia de P&D das grandes empresas farmacêuticas, hoje, é investir na parceria ou aquisição de pequenas companhias, geralmente spin offs de laboratórios de pesquisa de universidades e institutos.

Segundo Barreiro, após o fim da validade da patente do remédio Liptor, por exemplo, a Pfizer fechou um laboratório de pesquisa na Inglaterra que empregava 3 mil PhDs, mostrando a tendência de fazer inovação em parceria ou extramuro.

More Powerful 'Lab-On-A-Chip' Made for Genetic Analysis

ScienceDaily (July 26, 2011) — UBC researchers have invented a silicone chip that could make genetic analysis far more sensitive, rapid, and cost-effective by allowing individual cells to fall into place like balls in a pinball machine.

Microfluidic chip

The UBC device -- about the size of a nine-volt battery -- allows scientists to simultaneously analyze 300 cells individually by routing fluid carrying cells through microscopic tubes and valves. Once isolated into their separate chambers, the cells' RNA can be extracted and replicated for further analysis.

By enabling such "single-cell analysis," the device could accelerate genetic research and hasten the use of far more detailed tests for diagnosing cancer.

Single-cell analysis is emerging as the gold standard of genetic research because tissue samples, even those taken from a single tumour, contain a mixture of normal cells and various types of cancer cells -- the most important of which may be present in only very small numbers and impossible to distinguish.

So standard genetic tests, which require large numbers of cells, capture only an average "composite picture" of thousands or millions of different cells -- obscuring their true nature and the interactions between them.

"It's like trying to trying to understand what makes a strawberry different from a raspberry by studying a blended fruit smoothie," says Carl Hansen, an assistant professor in the Dept. of Physics and Astronomy and the Centre for High-Throughput Biology, who led the team that developed the device.

The device, described and validated in this week's issue of theProceedings of the National Academy of Sciences, was developed by Hansen's team, in collaboration with researchers from BC Cancer Agency and the Centre for Translational and Applied Genomics.

The device's ease of use and cost-effectiveness arise from its integration of almost the entire process of cell analysis -- not just separating the cells, but mixing them with chemical reagents to highlight their genetic code and analyzing the results by measuring fluorescent light emitted from the reaction. Now all of that can be done on the chip.

"Single-cell genetic analysis is vital in a host of areas, including stem cell research and advanced cancer biology and diagnostics," Hansen says. "But until now, it has been too costly to become widespread in research, and especially for use in health care. This technology, and other approaches like it, could radically change the way we do both basic and applied biomedical research, and would make single-cell analysis a more plausible option for treating patients -- allowing clinicians to distinguish various cancers from one another and tailor their treatments accordingly."

The research was funded by Genome BC, Genome Canada, Western Economic Diversification Canada, the Canadian Institutes of Health Research, the Terry Fox Foundation, and the Natural Sciences and Engineering Research Council.

IV Fluids May Reduce Severity of Kidney Failure in Kids With E. Coli Infection

ScienceDaily (July 26, 2011) — Infection with E. colibacteria can wreak havoc in children, leading to bloody diarrhea, fever and kidney failure.

E. coli O157:H7 infection has been caused by eating undercooked hamburger, sprouts, unpasteurized fruit juices, dry-cured salami, lettuce, game meat and unpasteurized milk products, as well as exposure to contaminated water and contact with cattle. 

But giving children intravenous fluids early in the course of an E. coliO157:H7 infection appears to lower the odds of developing severe kidney failure, according to researchers at Washington University School of Medicine in St. Louis and other institutions. The results are published online July 22, 2011, in theArchives of Pediatric and Adolescent Medicine.

Children infected with E. coliO157:H7 have a high risk of hemolytic uremic syndrome (HUS), the most common cause of short-term, sudden-onset pediatric kidney failure. About 15 percent to 20 percent of children with this type ofE. coli infection develop HUS. While most children recover and their kidneys heal, the syndrome can be lethal and may cause permanent kidney damage.

E. coli O157:H7 begins with diarrhea and severe abdominal pain and often progresses to bloody diarrhea. Kidney failure occurs because this strain of E. coli O157:H7 makes toxins, called Shiga toxins, that injure blood vessels. The kidneys are especially susceptible to the reduced blood flow that results from this injury. More than half of children with HUS develop kidney failure so severe that dialysis is required.

"HUS is like a heart attack to the kidneys," says Christina Ahn Hickey, MD, a third-year pediatrics resident at Washington University School of Medicine in St. Louis and St. Louis Children's Hospital and the first author on the study. "What we're trying to do is make sure the kidneys get enough blood flow. By giving intravenous fluids, we try to keep those kidneys working and to keep these children urinating. We think this will have a substantial impact on reducing the severity of kidney failure in these kids."

E. coli O157:H7 infection has been caused by eating undercooked hamburger, sprouts, unpasteurized fruit juices, dry-cured salami, lettuce, game meat and unpasteurized milk products, as well as exposure to contaminated water and contact with cattle. E. coli O157:H7 is the most common cause of acute kidney failure in otherwise healthy children in the developed world.

Hickey studied 50 children under 18 years old who were treated for diarrhea-associated HUS at 11 pediatric hospitals in the United States (St. Louis; Seattle; Sacramento, Calif.; Albuquerque, N.M.; Little Rock, Ark.; Milwaukee; Cincinnati and Columbus, Ohio; Indianapolis; and Memphis, Tenn.) and in Glasgow, Scotland. Her St. Louis collaborators were Robert J. Rothbaum, MD, the Centennial Professor of Pediatrics, and Anne M. Beck, MD, associate professor of pediatrics, both at Washington University School of Medicine.

In all, 68 percent of the children stopped urinating. Of the 25 patients who had received no intravenous fluids in the first four days of illness, 84 percent stopped urinating. But in the other 25 patients who were given IV fluids to keep their kidneys working, only 52 percent stopped urinating. Other factors did not seem to play a role, Hickey says.

"If a child is identified early as having an E. coli O157:H7 infection, we think that intravenous fluids can help protect the kidney and possibly help that child avoid dialysis," Hickey says. "The important thing is for providers to identify the kids at risk for E. coli O157:H7 infection early."

Intravenous fluids are more beneficial to children than oral fluids, Hickey says, because most of the children infected withE. coli O157:H7 are vomiting and having frequent bouts of diarrhea, so they cannot stay hydrated.

"To ensure that the kidneys get enough blood flow, we need to have sodium-containing fluid go straight to the blood vessels, and it's faster and more effective to use an IV," Hickey says.

Hickey says any child with bloody diarrhea needs to be seen by a health-care provider immediately.

"E. coli is very infectious," she says. "It takes less than 1,000 organisms of E. coli to infect someone else. When a child has diarrhea, there are 10 million to 100 million pathogens in each gram of stool. It is really important to get them away from other children immediately, and hospitalization can serve as effective infection control."

Phillip I. Tarr, MD, the Melvin E. Carnahan Professor of Pediatrics and director of the Division of Pediatric Gastroenterology, supervised Hickey on the study and is senior author of the paper.

Funding from Christina Ahn Hickey's Doris Duke Clinical Research Fellowship supported this research.

Newly Developed Fluorescent Protein Makes Internal Organs Visible

ScienceDaily (July 26, 2011) — Researchers at Albert Einstein College of Medicine of Yeshiva University have developed the first fluorescent protein that enables scientists to clearly "see" the internal organs of living animals without the need for a scalpel or imaging techniques that can have side effects or increase radiation exposure.

Liver cells in this mouse contain the fluorescent protein iRFP. The mouse was exposed to near-infrared light, which has caused iRFP to emit light waves that are also near-infrared. The composite image shows these fluorescent near-infrared waves passing readily through the animal's tissues to reveal its brightly glowing liver. 

The new probe could prove to be a breakthrough in whole-body imaging -- allowing doctors, for example, to noninvasively monitor the growth of tumors in order to assess the effectiveness of anti-cancer therapies. In contrast to other body-scanning techniques, fluorescent-protein imaging does not involve radiation exposure or require the use of contrast agents. The findings are described in the July 17 online edition of Nature Biotechnology.

For the past 20 years, scientists have used a variety of colored fluorescent proteins, derived from jellyfish and corals, to visualize cells and their organelles and molecules. But using fluorescent probes to peer inside live mammals has posed a major challenge. The reason: hemoglobin in an animal's blood effectively absorbs the blue, green, red and other wavelengths used to stimulate standard fluorescent proteins along with any wavelengths emitted by the proteins when they do light up.

To overcome that roadblock, the laboratory of Vladislav Verkhusha, Ph.D., associate professor of anatomy and structural biology at Einstein and the study's senior author, engineered a fluorescent protein from a bacterial phytochrome (the pigment that a species of bacteria uses to detect light). This new phytochrome-based fluorescent protein, dubbed iRFP, both absorbs and emits light in the near-infrared portion of the electromagnetic spectrum- the spectral region in which mammalian tissues are nearly transparent.

The researchers targeted their fluorescent protein to the liver -- an organ particularly difficult to visualize because of its high blood content. Adenovirus particles containing the gene for iRFP were injected into mice. Once the viruses and their gene cargoes infected liver cells, the infected cells expressed the gene and produced iRFP protein. The mice were then exposed to near-infrared light and it was possible to visualize the resulting emitted fluorescent light using a whole-body imaging device. Fluorescence of the liver in the infected mice was first detected the second day after infection and reached a peak at day five. Additional experiments showed that the iRFP fluorescent protein was nontoxic.

"Our study found that iRFP was far superior to the other fluorescent proteins that reportedly help in visualizing the livers of live animals," said Grigory Filonov, Ph.D., a postdoctoral fellow in Dr. Verkhusha''''s laboratory at Einstein, and the first author of the Nature Biotechnology paper. "iRFP not only produced a far brighter image, with higher contrast than the other fluorescent proteins, but was also very stable over time. We believe it will significantly broaden the potential uses for noninvasive whole-body imaging."

Dr. Filonov noted that fluorescent-protein imaging involves no radiation risk, which can occur with standard x-rays and computed tomography (CT) scanning. And unlike magnetic resonance imaging (MRI), in which contrasting agents must sometimes be swallowed or injected to make internal body structures more visible, the contrast provided by iRFP is so vibrant that contrasting agents are not needed.

Sea Squirt Cells Shed Light On Cancer Development

ScienceDaily (July 26, 2011) — Delicate, threadlike protrusions used by cancer cells when they invade other tissues in the body could also help them escape control mechanisms supposed to eliminate them, a research group led by led by Bradley Davidson in the University of Arizona's department of molecular and cellular biology reports in Nature Cell Biology.

Laser-confocal microscope image of two cells (green) extending invadopodia (bright green) into a wall of epithelial cells (red).

Studying embryos of the sea squirtCiona intestinalis, the researchers discovered that even non-invasive cells make the delicate, highly transient structures known as invadopodia. The group found that future heart cells in the Ciona embryo use invadopodia to pick up chemical signals from their surroundings. These so-called growth factors provide the cells with clues as to where they are in the developing embryo and what type of cell they are supposed to turn into.

The results suggest that this previously unknown role of invadopodia could also be at play in the case of cancer cells: Their invadopodia may serve to bind similar signaling molecules that protect them from the body's elimination processes, thereby ensuring their survival.

"These are special invasive protrusions and they are seen only in rare cell types and cancer cells. We are the first to see them in the developing Ciona embryo, and we certainly didn't expect to see them in that context," said Davidson, who is a member of UA's Arizona Cancer Center. "In Ciona, the cells that are making these special kinds of arms do not use them for invasion. Those cells behave very differently from cancer cells."

Cells form invadopodia in a process that resembles pitching a tent: They push a portion of their rigid, internal scaffolding into a portion of the cell membrane which envelopes the entire cell, thereby extending a long, thin protrusion outward.

"These structures are extremely fragile. The cells grow and retract them over short periods of time," Davidson said. "For that reason, they are almost impossible to see in fixed specimens. We think they are probably a lot more common than people realize."

Cancer cells have been known for a long time to use invadopodia to break through tissues that serve as natural barriers keeping cells in check and make sure they stay in their assigned locations.

"Most cells can never cross those epithelial barriers," Davidson said. "They play an important role in controlling the location and movement of cells, especially in a developing embryo."

"When a tumor spreads, its cells have to break out and escape to other tissues," Davidson explained. "To do that, they have to invade a blood vessel, travel to their new location and then get back out, which requires them to squeeze through the linings of blood vessels and invade similar barriers at their destination."

Because of the cancer cells' ability to break through barriers and invade tissues, researchers are very interested in the mechanisms allowing those cells to behave this way.

"There are a number of ways they can break through the barriers," Davidson explained. "Sometimes they'll actually fully disrupt the wall, make a break in the wall and push through. Cancer cell invadopodia secrete proteins that help make these breaks and also can physically push cells aside."

The cells in Ciona, however, use their invadopodia quite differently, the researchers discovered.

Inititally, the team was investigating a completely different scientific question: how the heart forms in the developing Ciona embryo. The sea squirt's simple body structure belies its close biological kinship to vertebrates, including humans.

In fact, Ciona shares most of its genes with vertebrates. Ciona has a brain, eyes, a mouth and a gut and a heart. While fundamentally similar, the developing Ciona embryo is much less complex than a vertebrate embryo. The combination of genetic similarity and anatomical simplicity makes the sea squirt an ideal model organism to disentangle biological processes that would be too complex to study in vertebrates.

Davidson is especially interested in figuring out the genes controlling heart development, with the goal of deciphering the underlying mechanisms of congenital heart defects in humans. Unlike its human counterpart, Ciona's heart is very simple and develops in a very specific and predictable process. One particular cell gives rise to all future heart cells. When that cell undergoes its first division resulting in two daughter cells, only one of them, and always the same one, becomes a heart progenitor cell continuing the lineage while the other gives rise to tail musculature.

"We were trying to figure out how the cells make that decision," Davidson said. "We knew that there are chemical signals, growth factors, that coax one of the cells into becoming a heart cell, but we had no idea why one cell responds to those signals and the other one doesn't."

When the researchers labeled the membranes of the cells to make them visible with a highly sensitive laser microscope, they discovered that the heart progenitor cell differed from its sister in that it made invadopodia. Unlike cancer cells, however, the cells in Ciona did not appear to use their invadopodia to invade tissues.

"They engulf an adjacent cell, but then pull back," Davidson said. "They never do anything else with their invadopodia, they never push through. That's what made us ask, why are they doing this?' It suggests they use their protrusions for something else."

The researchers then discovered that the cells making invadopodia responded much stronger to growth factor signaling than other cells, suggesting their invadopodia function as antennae to pick up signals that instruct the cell to become a heart progenitor cell.

This finding offers an intriguing possibility: Could it be that cancer cells too use their invadopodia as antennae, giving them the additional benefit of being more receptive to, or even independent of, growth factor signaling?

When cells become cancerous, they take on a dangerous life of their own. For example, a normal cell will not proliferate unless it is being told to do so by chemical signals such as growth factors. Likewise, a cell that is part of a tissue will stay in its assigned place.

Protective mechanisms are in place to prevent cells from going rogue. Most mutations that could make a cell cancerous trigger a genetic auto-destruction program. Cancer develops if a cell manages to accumulate cancerous mutations enabling it to wrestle itself free from such control mechanisms and proliferates even in the absence of growth factors or leaves its home tissue and invades other tissues.

"Our findings in Ciona may change the way we think about cancer," Davidson said. "Instead of starting out as a mass of cancer cells -- the tumor -- it is possible that small groups of cells or even single cells gain the ability to metastasize very early on by using invadopodia to boost their survival signaling."

"Such a cancer progenitor cell would be very difficult to detect because there is no tumor yet. There are likely specific proteins or specific components that allow a cell to use its invasion as an antenna. If we can find those components, they could be promising targets for cancer therapy because this is a process that most cells would never need to do. It's very specific to a cancer cell. So the hope would be to target those cells very early, before they start making tumors, without harming the rest of the cells."

Time-lapse movies of invadopodia made by the Davidson Lab:

This movie shows a cell pushing out and retracting two invadopodia over the course of less than 30 minutes:http://www.nature.com/ncb/journal/vaop/ncurrent/extref/ncb2291-s5.mov

A 3-D rotating view showing two cells with invadopodia. One of the cells completely engulfed another with its invadopodia, forming what looks like a box:http://www.nature.com/ncb/journal/vaop/ncurrent/extref/ncb2291-s2.mov

Caught in the act: In this Ciona embryo, a cell (labeled green) can be seen pushing invadopodia into the inside of the embryo's epidermis, only to retract them about 20 minutes later:http://www.nature.com/ncb/journal/vaop/ncurrent/extref/ncb2291-s6.mov