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Ready to start

Butantan is awaiting Anvisa's authorization to supply the Ministry of Health with medication that saves premature babies

Eduardo cesarThe first Brazilian manufacturer of pulmonary surfactant, established by the Butantan Institute in São Paulo, is ready to go on-stream. The facilities, capable of producing 100 thousand doses per year, will supply the drug to the Ministry of Health, which will distribute the product free of charge to the neonatal intensive care units in maternities and public hospitals throughout country. The distribution is expected to impact child mortality rates. Currently, some 36 thousand newborns, mostly premature, die in Brazil from respiratory distress syndrome (RDS), a disease characterized by the deficiency of pulmonary surfactant, a natural substance that protects the pulmonary alveoli, but it is only properly produced at the end of pregnancy – half the babies born before 32 weeks (8 months) have the problem. When the baby is premature and the alveoli do not open up, it is necessary to apply a dose of this surfactant in the trachea immediately. “To save the child, the medication must be available immediately after birth,” says Flávia Saldanha Kubrusly, a researcher at the Biotechnology Center at the Butantan Institute.

The imported versions of the product cost R$ 350 to R$ 500 each, whereas each dose of the Butantan surfactant will cost about R$ 100. For the time being, the facilities are working on an experimental basis only. There is no technical restriction for the operation’s start-up, but the Butantan Institute can only begin producing and supplying the surfactant when the medication is approved by Anvisa, the National Health Surveillance Agency. The authorization, pending since 2007, has not been released. The drug’s clinical tests were successfully carried out in 33 neonatal intensive care units in several Brazilian regions. Tests showed that the surfactant produced by the Butantan Institute is as safe and effective as those manufactured abroad and commercially available. The project that resulted in manufacturing this surfactant was financed jointly by FAPESP and the Ministry of Health.

Chilled transport
The bio-medication is produced from hog lungs. The institute established a partnership arrangement with food manufacturer Sadia to supply hog lungs, usually discarded in the processing of meat. The manufacturing process, developed as from 1997 and patented by Butantan, is based on new technology and on the recycling of input, which made it possible to reduce costs. When the surfactant was isolated for the first time, purification was possible thanks to repeated ultracentrifugation of the lungs. Butantan’s strategy is different. A refrigerated truck was purchased to pick up, once a week, 150 to 300 kilos of lungs at a Sadia slaughterhouse in Uberlândia (State of Minas Gerais). Initially, the lungs are washed and chopped. Then they undergo an extracting process. The two most expensive components in the process – a resin and one of the organic solvents – are almost fully recovered, causing expenditure on reactants to be very low.

eduardo cesarButantan facility: 100 thousand annual doseseduardo cesar

Virtuous cycle
There are two other projects connected with the pulmonary surfactant facilities that the Butantan researchers qualify as a “virtuous cycle,” for they may lead to an even greater use of the manufacturing structure. One of them involves the creation of a new surfactant formulation to be used by adults suffering from respiratory diseases. The idea is to purify and use one of the surfactant’s proteins (colectine SP-A) that is normally lost in the production process of the bio-medication. This protein is one of the four that compose the surfactants usually produced by the lungs, but the drug for newborns can actually do without it. “Since most adult respiratory diseases usually involve some lessening in the effect of the surfactants, medication enriched with this protein might increase the treatment’s success ratio,” says Flávia Kubrusly.

The second project is the use of pulmonary extracts to purify aprotinin, a protein that controls hemorrhage during bypass surgeries. Aprotinin is an enzyme inhibitor. One of them is elastase, which, during significant respiratory inflammations, such as those caused by pneumonia, attacks the lung and worsens the infection. The protein could be used as a protection factor. “The objective is to block the chemical mediators that damage the lung,” says Celso Moura Rebello, coordinator of the Experimental Research Unit at the Pediatric Department of the School of Medicine of the University of São Paulo (FMUSP), which took part in the surfactant’s development. A study by Butantan researchers, published in a recent issue of Biotechnology Letters, shows that hog lungs can also supply aprotinin; until then, it was believed that this could only be extracted from the lungs of ruminants, such as oxen.

Anvisa’s much awaited approval will also allow Butantan to start exporting its surfactant to countries such as Pakistan, India and South Korea, which have already shown some interest in purchasing this drug and the vaccines produced by the institute, such as the anti-rabies vaccine. Regarding Pakistan, it will be necessary to replace hog lungs with cattle lungs, since Islamism prohibits using hog products. In India, on the other hand, where the Hindi population venerates cows as sacred animals, the surfactant from hog lung is the appropriate choice.