Project mutamba(dr paulo gouveia)

Project Mutamba

PAULO ANTONIO RODRIGUES GOUVEIA

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THE EFFICIENCY OF THE TANINN
EXTRACTED FROM THE Guazuma
ulmifolia IN THE REVERSE
TRANSCRIPTASE INHIBITION OF THE
HIV VIRUS PAULO ANTONIO RODRIGUES
GOUVEIA

Contents
1. INITIAL CONSIDERATIONS........................................................................................ 2
1.1 GUIDING QUESTIONS ........................................................................................... 4
1.2 OBJECTIVES ............................................................................................................ 4
General:........................................................................................................................ 4
Specific: ....................................................................................................................... 4
1.3 JUSTIFICATIVE ....................................................................................................... 4
2 THEORETICAL FUNDAMENTS ................................................................................... 6
3. METHODOLOGY ........................................................................................................ 16
REFERENCES .................................................................................................................. 17

http://www.slideshare.net/pauloantoniorodrigue/project-mutamba-29084969

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1. INITIAL CONSIDERATIONS
Virus is the smallest particle that exists; it only can be seen by the microscope. The virus,
so that it can live and multiply itself, needs to be inside of the cells of an organism where it can
assume the command, making them work to it(Adesokan et al, 2004).
The AIDS/SIDA “Acquired Immunodeficiency Syndrome” is caused by HIV, a virus that,
firstly, attacks the immune system; then, it can install itself in several parts of the body. When the
virus affects the immune system, its action becomes inefficient and the body becomes more
vulnerable to any disease that may occur (Barre-Sinoussi et al., 1983; Brown, 2000).
The HIV is a retrovirus, which means that its genetic material is in RNA shape instead of
DNA shape, and to replicate itself it must, firstly, create a DNA copy from its genetic material
(Buckheit Jr et al., 2001).
The HIV virion has a complex structure and it is grossly spherical, with a diameter of
approximately 1/10.000 mm. The virus external coverage is a double layer of lipidic molecules
sprinkled with proteins (the envelope proteins, gp120 and gp41).Inside of it, a layer of protein
matrix surrounds the conical capsid, or nucleus, that contains the RNA of the HIV(Brown, 2000).
A cell infection occurs when the HIV virion connects itself to a cellular receptor,
generally the CD4, through its protein gp120; then, the virus merges itself to the cellular
membrane and the content of the capsid is liberated in the cellular cytoplasm. The HIV enzyme,
the reverse transcriptase, catalyses the production of a DNA copy of the RNA from the HIV and
the component ribonuclease-H from the reverse transcriptase, finally, removes the RNA helix,
now redundant. The DNA copy of single helix is, then, converted by the reverse transcriptase
into a DNA copy of double helix, which is transported to the cellular nucleus where a second


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HIV enzyme, the integrase, catalyses the incorporation of the viral DNA to the host genetic
material (Adesokan, 2004).
The antiretroviral therapy is aimed to the prevention of the viral replication, with
different drugs addressed to various stages of the replication cycle. The antiretroviral drugs
currently available to treat the HIV infection are a series of inhibitors of the reverse transcriptase,
that act previously to the incorporation of the viral genetic material to the host chromosome and
the inhibitors of the protease, which act subsequently to this step and prevent the virion
formation with functional proteins, that is, of infectious virus. The cocktail is an association of
the two kinds of medicines (Chi et al., 2004).
The reverse transcriptase inhibitors prevent the virus transforming its genetic code from
ARN into ADN, a required operation to multiply itself inside the cells (Costi et al, 2004).
Several natural compounds are being studied about the retroviral inhibition of the HIV
reverse transcriptase; among them are the tannins, which are phenolic compounds, characterized
by their capacity of combining themselves with proteins and other polymers, such as
polysaccharides (Buolamwini e Assefa, 2002).
Studies have shown that the bark and the bast of the Guazuma ulmifolia (mutamba) are
rich in components with pharmacologic properties. It presents triterpenes, alkaloids and
reasonable amount of tannins (Costi et al., 2004).
The tannin properties are linked to its capacity of forming complexes with the proteins
that participate of the tissues in relation to the microbiological attacks. Besides, they confer taste
properties united under the term astringency, have anti-free radical power, and have the capacity
of consuming dissolved oxygen, that is, they have interesting antioxidant properties to the
pharmacologic function, and also show powerful activity against the HIV replication (Cocuzza,


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2001).

1.1 GUIDING QUESTIONS


Does the tannin extracted from the Guazuma ulmifolia show the best inhibitors
pharmacokinetic profiles of the HIV reverse transcriptase with fewer side effects?



Which molecular weight of the tannin has the retroviral inhibitor action of the
HIV reverse transcriptase with fewer toxicity?

1.2 OBJECTIVES
General:


To identify the efficiency of the Guazuma ulmifolia plant substracted as a viral
duplication inhibitor of the HIV reverse transcriptase with a lower toxicity risk.

Specific:


To identify the tannin molecular weight that has retroviral inhibitor action of the
HIV reverse transcriptase with lower toxicity risk.



To promote the reduction of the viral load preservating the function of the
immunologic system.



To postpone the illness evolution changing the HIV natural history.

1.3 JUSTIFICATIVE
Although the therapy appearance, which reduces the viral particles to undetectable levels,
the virus persists in reservoirs in the organism, as T sleepy lymphocytes. The emergence and the
appearance velocity of resistant strains to different medicine combinations available in the
market also is a limitant factor. But one of the factors that makes the anti-HIV therapy more


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difficult is the high incidence of side effects caused by the medicines currently available.
Searches realized by Ligani Jr. and partners showed to be this one the main cause of faults in the
antiretroviral therapy adherence (20,5%), characterized mainly by vomits, diarrhea, nauseas and
abdominal pain, beyond headaches and, even so, changes in skin color.
Despite several laboratories and search groups are working in the HIV inhibitors
development, no compound has arisen that can be effectively used in the therapeutic.
This fomenta great need of discovery and/or development of efficient drugs that act on
the reverse transcriptase (RT), on the protease (PR) and on other points of the viral replication
cycle. Then the great challenge is to find possible targets that effectively interrupt the virus cycle,
without harming the normal cell (Dayam, 2003).
The use of herbal medicines is the result of the secular accumulation of empirical
knowledge about the herbal action by different ethnic groups. However, there are questions about
the standardization of production techniques and herbal medicines marketing (De Clercq, 2000).
Some studies have treated about the anti-nutritional aspect of cultivars with high levels of
tannins and the resistance to pests and seasonality has been considered as an interesting factor to
some species (De Clercq, 2002).
It’s found, in the vegetables, relatively important amounts of phenolic compounds. Their
role is essentially to protect the issues against the attacks of insects, fungi, or bacteria. It’s
considered a passive defense system relatively efficient. The plants also can produce great
amounts of phenols based in an alteration in the live cells surface: it’s the active defense. The
best example is given by the bite from insects in the leaves that are the source of the galls
formation.
A mutamba tree had been observed for ten years and it was realized that in certain period


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of the year it was notorious the presence of dry galls nearly reaching 70% of length and as the
days went by, the plant recovered itself showing resistance to the pest that had affected it.
In 1946, in Faina – GO, the researcher Francisco Cabral de Melo, a pharmacist graduated
from UFRJ, and partners realized some tests, undocumented, in patients with yellow fever using
the mutamba tannin that has a low molecular weight, having favorable outcome, there was a cure
in 100% of the cases, with no toxicity demonstration.
Tannin molecules are being tested with the intention of discovering an efficient drug
against HIV. Kilkuskie and partners had observed that galotannins showed inhibitory activity
only in toxic concentrations, elagitannins and condensed tannins poorly inhibited the viral
replication and the complex tannins showed powerful activity against the HIV replication.
It justifies the great importance of a survey with tannins of low molecular weight and
smaller toxicity.
So, the interest in the survey begins because there is no cellular equivalent, what is an
advantage in relation to smaller chances of occurring side effects, and it has a social and
scientific relevance because there is no endogenous mediator which chemical structure can be
used as a prototype.

2 THEORETICAL FUNDAMENTS
The viruses are involved in a big variety of chronic and degenerative diseases, being
responsible for more than 60% of the human diseases (Korolkovas, 1988). The fight against viral
infections is hard, because the viral replication is an intracellular process, being closely related to
the metabolism of the infected cells (Barre-Sinoussi, 1983). One of the most studied virus
nowadays is named “Human Immunodeficiency Virus” (HIV), from retrovirus family (ANR


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compound); it is able to be parasitic upon man’s immune system, leading to an infectious disease
known as “Acquired Immuno Deficiency Syndrome” (AIDS) (Johnson, 1989).
HIV is different from the other viruses because it attacks and damages the immune
system, that is its main target in the human organism. One of the components of the immune
system are the T lymphocytes, that attack directly the invader microorganism. Among the T
lymphocytes there is a class called T4 (CD4+ T or T-helpers), which has a very important role in
the initiating of an immune response and in the coordination of the same response, being the HIV
main target (Gupta, 1979). This virus, when infecting the CD4+ T, lead to the lack of
coordination of the immune system and to its gradual in effectiveness, establishing an
immunodeficiency (De Clercq, 2000).
In Brazil, from 1980 to December 2002, 257.771 cases of the disease were reported, with
113.840 known deaths. Throughout serological tests conducted by the Brazilian Department of
Health, at least 536.000Brazilians are expected to be infected with HIV (Souza, 2003).
It’s worth highlighting three big stages in the epidemic’s evolution:


1 – an initial stage, characterized by the infection among men that have sexual
relations with other men, and by a patient’s high level of education;



2 – a second stage, characterized by an increase of cases due to the transmission
caused by injecting drug use, as the consequent reduction of the age group and
greater dissemination among heterosexual individuals;



3- third and current stage, when there is a growing trend to dissemination among
the heterosexuals, mainly the women (Goldgur at al., 1999).

This last observation deserves highlighting, because it has been reported in several
countries a process of the “feminization” of the HIV/SIDA epidemic. Regarding to the


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distribution of the cases according to age group, it was observed in the last decade an ageing of
it, with a persistent relevant growing of the age group over the age of 35, in both sexes. The age
group from 35 to 39 and 40 to 49, with an increase of the incidence among women (from about
6, 5 men to 1 woman, in the 1980s, to 1, 7 men to 1 woman in 2001) (De Clercq. 2001).
The morphological structures of the HIV viruses (1 and 2) include structural and
functional proteins and an RNA genome protected by the viral envelope. The envelope is made
of a lipid bilayer and contains a complex protein, known as env (Ferreira, 2002).
In the interior face, the HIV has a viral protein called p17 (matrix) and, enclosed by this
protein, there is the capsule composed by the p24 protein. In the most internal part, it’s found the
most important elements: two simple filaments of RNA, the p7 protein (nucleocapside) and three
essential enzymes, p51 (reverse transcriptase), p11 (protease) and p31 (integrase) (Goldgur, et
al., 1999).
The transcriptase is an enzyme that performs a contrary transcription process related to
the cellular standard. This enzyme polymerizes DNA molecules from RNA molecules, exactly
the opposite of what happens in the cells, where RNA is produced from DNA (Gupta, 1979;
2003).
That’s exactly for having this enzyme, which it acts “contrary”, that the HIV and other
similar viruses are called retroviruses. After being in the host cell, the reverse transcriptase uses
the nucleotides found in the cytoplasm to compose a DNA strand together with the virus RNA
strand. The RNA se-H enzyme is responsible for unbundling the RNA strand by hydrolysis and
let the RNA simple strand be free in the cytoplasm. The reverse transcriptase comes back to
complete this DNA strand, thus becoming the nucleotides double helix to be integrated in the
host-cell DNA helped by the integrase enzyme (Fox, 2002).


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In Brazil, the Law 9113/96 ensured everyone the access, without its cost, to the cocktail
of drugs. Introduced in 1996, this is a combination of drugs able to inhibit two stages of the viral
replication, with a possibility of reduction in 100 times of the virus production compared to the
mono-therapies used so far (Souza et al., 2003). Depending on the conditions and the age of the
patient, it can be composed by two or more different medicines of the following classes: (i)
nucleoside reverse transcriptase inhibitors (NRTIs); (ii) non-nucleoside reverse transcriptase
inhibitors (NNRTIs); (iii) protease inhibitors (PI) and, more recently, (iv) fusion inhibitors (FI),
and the latter was recently released to sale in Brazil (Goldgur, 1999).
The transcription process consists in the RNA synthesis, realized by an enzymatic
complex which key enzyme is the RNA polymerase, able to produce the viral proteins in the
polyproteins precursor’s form, long units composed of viral enzymes and assembled structural
proteins (Li, 1999).The fluoroquinolones are a class of synthetic compounds with strong
antimicrobial activity. Nowadays, this class of compounds also has been described as able to
interfere in the viral transcription process, thus preventing the replication. The K-37
fluoroquinolone has shown good results in the inhibition of that enzyme. The temacrazine and
the flavopiridol are other compounds able to inhibit this transcription enzyme, even in
chronically-infected cells (Cocuzza, 2001).
The protease inhibitors have the function of blocking one of the HIV components, the
protease. This way, the new copies of the virus don’t infect the new cells. The reverse
transcriptase inhibitors and the protease inhibitors act inside of the CD4 cell (Hazuda et al.,
2004).
The nucleocapside protein (NCp7) is an essential protein in different stages of the viral
replication, being important in the stage that involves the reverse transcriptase enzyme,


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participating of the RNA ringing (De Clercq, 2002).The AZDC (azodicarbonamide), is a
compound in clinical testing phase II and it’s able to become inactive that protein, by
complexation with its zinc atoms, preventing the viral replication of the integrase inhibitors. The
integrase enzyme is fundamental in the viral replication process, being responsible for the viral
DNA integration to the host chromosome, thus allowing for the continuation of the viral
replication cycle. The “L – quicórico" acid is able to inhibit the integrase enzyme activity of
different kinds of powerful HIV (De Clercq, 2001).
The fusion inhibitors (FI) represent a new approach in the combat strategy to the capacity
of the HIV replication in the organism. So that the HIV can complete its reproductive cycle, it
needs to merge itself with T lymphocytes, where it deposits its genetic information, giving rise to
a new virus. While the protease inhibitors (PIs) and the reverse transcriptase inhibitors (NRTIs
and NNRTIs) aim at interrupting the viral replication cycle in a stage that the HIV had already
infected lymphocytic target cell, the FIs were designed to prevent the virus penetration in the
lymphocytes and the beginning of an infection (Ikemoto, et al., 2001).
The virus needs to merge itself with a T lymphocyte to multiply, and it’s exactly this
action that the fusion inhibitors prevent. With this kind of medicine, the HIV can’t complete its
reproduction cycle, because it can’t infect the T lymphocytes and can’t create new virus copies.
The fusion inhibitors act outside the host cell (CD4 lymphocyte) at an earlier stage in the virus
reproduction cycle than the protease and the reverse transcriptase inhibitors (Heralth et al.,
2004).
To achieve more powerful new drugs, with better pharmacokinetic profiles, fewer sideeffects and wide range of activity to different resistant HIV viruses, new strategies have been
created. These strategies are based on the conception of new compounds able to inhibit different


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points of the viral replication (Jayasuriya et al., 2003).
In a memorandum from a WHO meeting, recommendations were made about the
research with natural substances for the treatment of AIDS. Several natural compounds that
belong to different structures have been appointed as reverse transcriptase inhibitors, such as
coumarins, flavonoids, tannins, lignins, alkaloids, terpenes, nafto, and anthraquinones and
polysaccharides (Kannan et al., 2001).
Compounds of natural source can be used as therapeutic agents to a great amount of
diseases. These also can become excellent prototype-compounds to the development of more
powerful derivatives or with improvement of some biological or physical-chemical property that
allows to be used as drugs (Huang et al., 2001).
The bark and the bast of the Guazuma ulmifolia (mutamba) is rich in components with
pharmacological properties. In addition, these isolated principles have been treated together with
the treatment of several diseases. So, the betasitosterol act against the hypoproteinemias; the
triterpenes are used as anti-inflammatories (pneumonia and bronchitis); the caffeine acts as
diuretics and stimulant of the CNS (Central Nervous System) and cardiac muscles; the alkaloids
are treated as anti-microbials, painkillers, antispasmodics and CNS stimulants, the tannins are
excellent in the combat of dysentery processes (Windholz, 1983; Almeida et al., 1998; Rizzo et
al., 1990; Rizzo et al. 1999; Tridente, 2002).
Guazuma ulmifolia, popularly known as mutamba, has been used by the population as
natural medicine in almost every place that it occurs. Generally, the used parts are the bark and
the leaves; however, there are some reports that the fruit can also be useful. The bark tea is used
in Brazil as a sudorific, also used in cases of fever, cough, bronchitis, asthma, pneumonia, and
liver problems. Several authors show some activities with mutamba extracts, among them they


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emphasize: anti-glucose, anti-bacterial and anti-fungus, cytotoxic and anti-secretory activities
(Johnson, 1989; Makhija, 2002).
Guazuma shows four species distributed through South America and Mexico, and two of
them are in Brazil: Guazuma ulmifolia Lam and Guazuma crinita Mart., both known as mutamba
(Huff, 1999).
Photochemical analysis realized with the mutamba bark showed positivity to the
flavonoid and tannin groups, among others. Spectrophotometers dosing 691 nm of tannins, show
that the period of the year can increase or decrease the tenor in the mutamba (Li, 1999).
Comparing the tenor of tannin in the leaves Crataegus oxyacantha L. (cratego),about 3%,
and the ratany barks (Krameria triandra), about 10%, with the mutamba barks, that present about
5%, the amount of tannins can be considered reasonable (Kim et al., 2005).
The tannins are phenolic compounds characterized by their capacity of combination with
the proteins and other polymers as the polysaccharides. This characteristic explains their
astringency caused by the precipitations of the proteins and by the spittle glycoproteins.
Tannins (from the French tannin) are polyphenols of plant origin, with molecular weights
generally between 500 and 3000. They inhibit the attack to the plants from vertebrates or
invertebrates herbivorous (reduction of palatability, digestion difficulties, toxic compounds
productions from tannin hydrolysis) and also from pathogenic microorganisms. The term is
widely used to designate any big polyphenol compound containing enough hydroxyl groups and
others (as carboxyl) to form strong complexes with proteins and other macromolecules.
Generally, they are divided in two kinds: hydrolysable and condensed tannins
(protoantocianidines).
Tannins from Quercus suber L. and Q. coccifera L. species show gastroprotector effect,


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changing from 66 to 91%.The tannin antimicrobial properties are well-known and documented.
Tannin molecules are being tested with the intention of finding a new efficient drug against HIV.
Kilkuskie and partners observed that the galotannins showed inhibitory activity only in toxic
concentrations, elagitannins and condensed tannins poorly inhibited the viral replication and the
complex tannins showed powerful activity against the HIV replication. They concluded that the
anti-HIV activity showed by the tannins is due to the reverse transcriptase inhibition, turning
difficult the viral replication.
The tannin properties are linked to its capacity of forming complexes with the proteins
that participate in this case, of the tissues protection in relation to the microbiological attacks.
Besides, they confer taste properties united under the term astringency, have anti-free radical
power, and have the capacity of consuming dissolved oxygen, that is, they have interesting
antioxidant properties to the pharmacologic function and also show agri-food activity
(Korolkovas, 1988; Makhija, 2001).
The link between tannins and proteins occurs, probably, through hydrogen bridges
between the tannins phenolic groups and certain proteins sites, lending a lasting stability to these
substances. To the formation of these links it’s necessary that the tannin molecular weight is
among clear limits; if it is very high, the molecule can’t be inserted among the interfibrilar spaces
of the proteins or of the macromolecules; if it is very low, the phenolic molecule can insert, but it
doesn’t form a sufficient amount of links that assure the combination stability. The tannins have
been the aim of several studies, but the majority has discussed ecological relationships between
vegetables and herbivorous, because it has been suggested that the tannin tenors can reduce the
rate of predation for they become unpalatable, taking away their natural predators. Researches on
tannins biological activities highlighted important action against certain microorganisms, as


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carcinogenic agents and the ones that cause hepatic toxicity. These last effects, with no doubt,
depend on the dosage and the kind of consumed tannin. The intake of green tea and diets rich in
fruit that contain tannins, for example, has been associated with anticarcinogenic activity.
Besides, they can act as anti-inflammatories and healings, and even so, as HIV reverse
transcriptase inhibitors.
This way, if the toxicity is due to its astringency, high toxicity is closely associated to the
bigger molecular weight. However, it doesn’t happen frequently, for example, the catechin shows
bigger toxicity than the tannins, although it has low affinity for proteins.
The complexes formed between tannins and proteins can be reversible or irreversible.
The reversible ones are established by hydrogen bridges and hydrophobic interactions, while the
irreversible ones occur in oxidative conditions by covalent bonds (Almeida, 1999; Buckheit Jr. et
al., 2001).
The hydrogen bridges probably are formed between the tannin phenolic hydroxyls and
the protein amine grouping. The hydrophobic interactions occur between the tannin aromatic
rings and the aliphatic side-chains or aromatic of the protein amino acids (Nair, 2004).It is
believed that the hydrophobic interactions act as initial traction forces in the complexation
between tannins and proteins in aqueous media. This initial association is reinforced in a second
stage with the formation of a polyfunctional net of hydrogen connections, in which each tannin
molecule can make a lot of connections with the protein, thus, acting like a polytoothed binder
(Peçanha, 2002).It was still observed a correlation between the polyphenol polarity and the kind
of interaction with the bovine serum albumin (BSA) (Almeida, 1999).
The reversible complexes can be soluble or insoluble, depending on the tannin/protein
proportion, on the ph and on the environment ionic strength. The addition of few quantities of


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proteins to a tannin solution produces a precipitate that is dissolved with the addition of more
protein (Young, 2001).Then, the maximum of precipitation occurs when there is an excellent
proportion between tannin and protein (Li, 1999), what is, however, dependent on the quantity of
bounding sites as phenolichydroxyls and galoia groups, inside the tannins (Almeida, 1999;
Okamoto, 2000).
The different tannins capacity of complexing with the proteins vary according to their
chemical structure. It was observed that the molecular weight and the molecule flexibility are
important factors in the complexation process (Oliveira, 2000).Several studies, comparing the
relative affinities of the galoia-steriles groups with a lot of proteins showed the decreasing
tendency in the penta- > tetra- > tri- > di > mono-galoil-glucose sequence, that is, the more
quantity of galoia groups, the more affinity for the proteins (Okamoto, 2000).On the other hand,
some factors in the protein structures such as conformation and polymer size also influence in
the affinity of these molecules with the tannins. Several studies show the great tannins affinity,
hydrolysable ad condensed ones, for proteins rich in proline, such as the proteins present in the
mammal’s spittle (Pluymers et al., 2002).
For these objectives to be achieved, it’s fundamental that the treatment must be applied
strictly and according to the doctor’s indication. If the patient doesn’t take the medication
adequately, the quantity of medicine that there is in the blood isn’t enough to inhibit the increase
of the virus and to reduce the viral load. It allows the virus to continue destroying the CD4 cells
and also to acquire resistance to the medicines that the patient is taking in a wrong way. On the
other hand, when it happens, there is a great possibility of occurring resistance to other
medicines that the patient isn’t taking, which belong to the same classes of those that he is taking
– it’s called Cross-Resistance (Pommier, 2000).


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3. METHODOLOGY
This subject is a qualitative approach, performed from a collection of data related to the
theme, based on information found in books, articles, specialized scientific magazines,
monographs, resource and illustration books and on observation.
To MINAYO (2002, 46):
The qualitative survey answers very private questions (...),
works with the deepest relation and phenomena universe that
can’t be reduced to several variable operationalizations.
The scene of the research is a private laboratory. Previously it will be asked authorization
to the accomplishment of this scientific research; as well, it will be submitted to the ethic and
survey committee of the institution.
To acquire data in this study, tests of the low molecular weight tannin dosages will be
done, in mice, extracted from the Guazuma ulmifolia; then, depending on the results, it will
address the possibilities of using it in human beings, considering the guiding questions of the
survey involving human beings. RESOLUTION N° 196/96 FROM THE BRAZILIAN
DEPARTMENT OF HEALTH that regulates the research involving human beings and it will be
put under evaluation by the Research Ethics Committee of the institution responsible for the
research.
The search data will be grouped in categories aimed at the results, and will suffer
analyses based on thematic benchmark about the subject.


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