If everything works out in the studies carried out in partnership between the School of Medicine of the University of São Paulo and Laboratório Catarinense, a Brazilian pharmaceutical manufacturer located in Joinville, Santa Catarina, doctors from all over the planet are going to have in their hands an unprecedented medicine for combating ventricular fibrillation. The dysfunction occurs when the cardiac muscle contracts in a disorganized and uncontrolled way, preventing the blood from being pumped through the ventricles, a situation that is present in several heart diseases, such as infarction of the myocardium (the wall of the heart muscle), or as a consequence of the ingestion of drugs and medicines.
When the individual is young, below the age of 40, there is a great chance for this kind of infarction to show ventricular fibrillation, because the collateral irrigation around the heart muscle is still very small. Nowadays, salvation is limited to applying, within a few minutes, an uncomfortable electric shock with an apparatus called a defibrillator, which puts the heart in the right rhythm again. The hope for a new medicine lies in the extract of a phytotherapeutic compound, produced by Laboratório Catarinense, which has the trade name of Catuama.
The final intention of the researchers and of the company is to arrive at the production of an intravenous medicine that may occupy the space of the electric shock. To guarantee the rights over the new drug, the researchers from USP, headed by Professor Irineu Velasco, from the Department of Clinical Medicine and Laboratório Catarinense filed the patent request in Brazil, in the United States, in the European Union and in Japan, during the months of June and August this year, to protect the use in defibrillation of the plants associated with Catuama: catuaba (Trichilia catigua), guarana (Paullinia cupana), muira puama (Ptychopetalum olacoides) and ginger (Zingiber officinale). “Now we are going to study the fractions of the extract to ascertain which of them, one or more, have the property for stopping arrhythmia”, Velasco explains. “We will then find out which is the molecule responsible for the therapeutic effect.”
As soon as they identify the molecule, the researchers are going to do the toxicological tests and find out what the genetic functioning is like, in relation to the proteins and to the possible genes involved in heart diseases. Finally, they will try to synthesize and reproduce the molecule in the laboratory. Only then will it be tested on humans. This whole itinerary should take from five to eight years.
Easy to use
“We want to arrive at this unprecedented medicine in injectable form and to be taken orally”, says Velasco. The injection is for emergency rooms and rescue teams who need to turn fibrillation around in cases of emergency. The pills will be useful in prevention for people with a propensity for this cardiac problem and who often use defibrillators implanted in their body in the same way as pacemakers. The adoption of a medicine would change a lot of things in the practice of defibrillation. “Nowadays, in many countries, particularly in Scandinavia (Norway, Sweden and Denmark), portable defibrillators are being placed at strategic points on the streets, subway stations and airports, to be used in cases of emergency, besides which people are being trained to use them.”
The production of a medicine and the good expectation of the researchers are based on laboratory experiments carried out on the hearts of rabbits and rats. “Actually, it all happened almost by chance, when we were testing Catuama (sold in liquid form or in capsules), says Velasco. “The tests were done in collaboration with pharmacologist João Batista Calixto, a professor from the Federal University of Santa Catarina (UFSC), who in 2002 was studying Catuama’s antidepressive activities, afterwards confirmed in the capturing and releasing of monoamines (serotonin, noradrenaline and dopamine), some of the neurotransmitters responsible for governing human behavior. “We were helping Professor Calixto to carry out the chemical control of the product. In an experiment, some hearts fibrillated. So we applied the medicine to see what would happen and, to our surprise, the arrhythmia stopped”, says Velasco.
To continue testing fibrillated hearts, they needed to develop a different model from the one normally used, which also cause infarction. “Using a technique developed by two scientific initiation students, Anezka Carvalho Rubim de Seles and André Ferrari de Franca Camargo, supervised by researcher Vera Pontieri, who put an electrode inside the heart to cause fibrillation, we achieved an exceptional model for our tests.” Usually, an arrhythmia of this kind has to be reversed in five minutes. With Catuama, the heart started beating again in a normal manner within this time. “To leave no doubts, we did fibrillation for 20 minutes, a length of time from which there is no return to normality, even with electric shocks. We applied Catuama, and the arrhythmia stopped. Better still, after the medicine, the heart did not start fibrillating again, even with electrical stimulation.”
Scientific curiosity and the need to identify what was making the heart stop fibrillating (since it would be impossible to apply the phytotherapic compound straight into the human heart) led the researchers from USP to test each one of Catuama’s plant extracts separately. They now know that one of the plants is directly responsible for the defibrillation, but even with the patent deposited in Brazil and in several other countries, the company does not want to reveal which. In this document, other associated plants are also mentioned, which may bring more rapidity to the defibrillating action of the principal plant.
Sodium channel
With the main extract in their hands, the researchers also carried out tests on equipment called a patch clamp, which is used to analyze cell channels. This apparatus was purchased in a thematic project coordinated by Professor Velasco and financed by FAPESP for studying hypertonic solution, a preparation with a very high concentration of salt (see issue 78 of Pesquisa FAPESP for an article on this subject and the first discoveries about Catuama). The test carried out with a cell from the heart showed that the plant extract inhibits the sodium channels and thereby produces a rearrangement of the electrical stimuli in the heart, performing the role of a defibrillator.
The next step is to establish new partnerships, to get finance from development agencies or multinational industries capable of allocating resources for the researches to make headway and for formatting the medicine. “We are analyzing whether we go into partnership with another company now or later on”, says physician Luc Raes, Laboratório Catarinense’s scientific director. “Whatever happens, we are not going to relinquish the control over the researches, which should be carried out in Brazil, and under the supervision of Professors Velasco and Calixto.”
Until the complete development of a synthetic product, tested on humans and with the medicine ready to be put onto the market, Raes calculates that from US$ 200 million to US$ 500 million will be spent, over a period of up to ten years. Laboratório Catarinense has sales of R$ 35 million a year, and 3% of this amount is invested in research, besides the finance obtained in partnership with other institutions. 85% of the income comes from phytotherapics like Catuama and the expectorant syrup Melagrião. “The rest comes from medicines like sulfas and analgesics and from a phytotherapic line made up of mono-drugs like Gingko biloba, for example.”
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