Pharmacological and toxicological aspects of barbatimão ( Abarema cochliacarpos (GOMES) Barneby & J.W. Grimes)

— Goal: To observe pharmacological and toxicological studies of Abarema cochliacarpos (GOMES) Barneby & J.W. Grimes which indicate efficacy and safety in its use as an herbal medicine. Method: Systematic review study in the BVS, PubMed and SciELO databases. The descriptors “Abarema”, “cochliacarpos”, “pharmacological”, and “toxicological” and Boolean operator “AND” were used. Inclusion criteria: Abarema cochliacarpos (GOMES) Barneby & J.W. Grimes; pharmacological action; toxicological action. Exclusion criteria: review study and duplicated articles. The studies were analyzed regarding the in vivo characteristics (mice and rats) or in vitro (cell and bacterial lines), pharmacological or toxicological action, derived from plant drug/part of plant and authorship. Results: 11 articles selected in the review pointed out: analgesic activity tested in Swiss mice; antibacterial in lineages such as Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa; anti-inflammatory tested in Wistar Rats and Swiss mice; antioxidant in vitro model on oxidative damage and also in a Swiss mouse model; antiulcerogenic analyzed in Wistar rats; myoprotective in Swiss mice; estrogenic and thyroid modulation tested in cell lineage. The toxicological essay found approached the hepatotoxicity induced by A. cochliacarpos in Mus musculus mice. Conclusion: A. cochliacarpos has phytoactive constituents with analgesic action, antibacterial, myoprotective, anti-inflammatory, antioxidant, antiulcerogenic, estrogenic and thyroid modulation in animal models in vivo and in vitro, with the bark being the most used part in extracts and fractions. Faced with the need for proof of safety in the use of plants as herbal medicines, toxicological tests have to get conducted to ensure the safe use of the species, as correlated with the barbatimão.

known as barba-de-timão, casca-da-virgindade, faveira and barbatimão branco. The plant species evaluated by the National Health Surveillance Agency (ANVISA) and registered for using in phytotherapy is Stryphnodendron adstringens (MART.) Coville. However, other related species, native or exotic are also called barbatimão: Abarema cochliacarpos (Gomes) Barneby & J.W. Grimes, S. coriaceum Benth., S. pulcherrimum (Willd.) Hochr. and S. pumilum Glaz (Brasil,  The most of plant species used in folk medicine do not have pharmacological evidence, nor toxicological studies as recommended by resolution 90/2004 (Carvalho, Balbino, Maciel, & Perfeito, 2008), which governs plant toxicity studies for phytotherapeutic purposes. In addition, the designation of plants of several species with the same name (barbatimão), points to the need to verify scientific evidence of the efficacy and safety in the use as herbal medicine. This study aimed to observe pharmacological and toxicological studies of Abarema cochliacarpos (GOMES) Barneby & J.W. Grimes which indicate efficacy and safety in its use as an herbal medicine.

TYPE OF STUDY
This is a Systematic Review study according to the Preferred Reporting Items for Systematic Reviews (PRISMA) method (Moher, Liberati, Tetzlaff, & Altman, 2009).

STUDY LOCATION
The consulted databases were: the BVS (Biblioteca Virtual de Saúde), PubMed (National Library of Medicine -NIH) and SciELO (Scientific Electronic Library Online).

INSTRUMENTS AND TECHNIQUES RESEARCH
The search was carried out on February 26, 2021, and updated on June 6, 2021. It performed analysis of all studies which were published up to the year 2021. In this study were selected articles involving pharmacological and toxicological barbatimão tests. It was used the descriptors "Abarema", "cochliacarpos", "pharmacological", and "toxicological" associated with the Boolean operator "AND".

DATA EXTRACTION
Each article was examined for eligibility by two independent evaluators. A third evaluator resolved disagreements regarding to the inclusion of articles. Data on doses of A. cochliacarpos used, characteristics of in vivo and in vitro research, type of pharmacological or toxicological action, derived from a plant drug/part of the plant and the authorship of the studies were extracted for two tables pre-edited by two evaluators.

III. RESULTS
Observing the pharmacological and toxicological studies of A. cochliacarpos, in in vitro models (cell and bacterial lineages) and in vivo (mice and rats), 100 articles were found in the databases, 44 articles in the BVS portal, 25 articles in the PubMed portal and 31 articles in the SciELO portal ( Table 1). In compliance with the object of the study, 30 articles were excluded for not treating with A. cochliacarpos, or for portraying other species such as Abarema auriculata, Abarema pittier and Pithecellobium cochliocarpum; 14 were excluded for not being original articles and 45 articles were duplicated. Eleven articles remained to be analyzed in order to verify efficacy and safety in the use of A. cochliacarpos for therapeutic purposes (Figure 1).

CHARACTERIZATION OF THE STUDY
To understand the pharmacological potential of barbatimão, the original works were grouped by pharmacological activity involved in the studies, including analgesic ( Table 2). Regarding to the toxicological potential of A. cochliacarpos, the found study involved the hepatotoxic activity (Oliveira et al., 2013) ( Table 3).  cochliacarpos and a decrease (39%) of oedema with 400 mg/kg of the extract. When analyzed the functional motor activity in mice on the effect of Bothrops leucurus snake venom and treated with the extract, they observed that muscle fibers were preserved, the oedema and pain decreased and improvement in motor functional activity.
In another study (Silva et al., 2009), the analgesic action was verified through modulation in abdominal contractions induced by acetic acid, in mice treated with cold (CA) and hot (HA) aqueous extracts and methanolic (ME) extract of A cochliacarpos at 10 mg/kg, it occurred 73% of abdominal contortion by CA, 68% by HA and 39% by ME. The ME (10 mg/kg) also influenced the neurobiological response of animal defense reactions such as licking and/or biting when injected capsaicin, noting 62% inhibition.

Antibacterial Activity
The antibacterial action was tested by two studies. One of them used the hydroalcoholic extract of barbatimão at 1, 2 and 3 mg/mL doses against the following bacteria:   The myoprotective effect of the hydroethanolic extract of A. cochliacarpos in Swiss mice was evaluated after injecting the venom of B. leucurus (Saturnino-Oliveira et al., 2014). The myoprotective activity was observed in the microscopic evaluation, at which the treated muscles showed preserved structures, decreasing edema and inflammatory infiltrate compared with untreated animals. It was also noted that the extract of A. cochliacarpos reduced the myonecrotic effect induced by the snake venom, and less areas of hypercontracted myofilaments being able to be observed or hemorrhagic components with a decrease in edema and plasmatic creatine phosphokinase activity (Saturnino-Oliveira et al., 2014).

Estrogenic and thyroid modulating activity
Another pharmacological activity of A. cochliacarpos highlighted in the studies, using the methanolic extract obtained from several parts of the plant at the doses of 50 and 100 µg/mL is the positive modulation of the thyroid, increasing gene expression, comparing the effect with classic drugs such as 17ꞵ-estradiol and triiodothyronine. Phytoactive contituents present in A. cochliacarpos extracts were also able to activate estrogen receptor as far as the positive control (17ꞵ-estradiol) (Reis et al., 2018).

3.3.
CHARACTERIZATION OF THE TOXICOLOGICAL TEST

Hepatotoxic activity
The only study that presented toxicological tests during the search in the databases showed that phytoconstituents of the hydroalcoholic extract of the bark of A. cochliacarpos (125, 250, 500, 1000 mg/mL) and 1 mL of infusion of the plant bark, orally and nasograstric, induced hepatic steatosis (hepatotoxicity) in Mus musculus mice (R. Oliveira et al., 2013).

IV. DISCUSSION
Abarema cochliacarpos (GOMES) Barneby & JW Grimes is a related plant species of the Stryphnodendron adstringens (Mart.) Coville species, both popularly known as barbatimão. S. adstringens has a monograph organized by the Ministry of Health and ANVISA, which also deals with information on the safety and efficacy of the species in the use as an herbal medicine. However, Abarema cochliacarpos is identified as a correlated species of S. adstringens, which motivated the search for scientific evidence on its use in the phytotherapy (Brasil, 2014). The systematic review made it possible to realize that Abarema cochliacarpos has phytoactive substances with antioxidant, anti-inflammatory, antibacterial, myoprotective, estrogenic and thyroid modulator activities. The indications of S. astringens in phytotherapy point to antinociceptive (Melo et al., 2007), antibacterial (Ferreira et  The acute and chronic models of inflammation, in male Wistar rats, an anti-inflammatory action of the methanolic extract of the of S. adstringens stem is showed (Lima et al., 1998). One of the main effects of the action of snake venom of the species Bothrops leucurus in the tissue, due to the inflammatory reaction (local mediators such as histamine and serotonin) is the presence of oedema and necrosis that can lead to functional loss or even A gastric disease that affects many people is the peptic ulcer, which can be caused by reasons such as stress, alcohol, smoking, use of medications, among others. The gastroprotective effects of barbatimão in a stress gastric injury model was also tested in male Wistar rats by using extracts (100 and 400 mg/kg) of the bark of stem of the S. adstringens (Audi et al., 1999;Martins et al., 2002).
The monograph of S. adstringens (Brasil, 2014) does not approach studies with hepatotoxic action, but it is noteworthy that as the use of the infusion of the bark of barbatimão is widely popularly used to treat gastric conditions, it is necessary to carry out more studies on this respect because its use without a safe dosage can cause liver diseases (Rebecca et al., 2003). As the present data indicate, the regularization of the phytotherapy requires ethnobotany evidence, laboratory studies and pre-clinical tests necessary to ensure efficacy and toxicological tests recommended to ensure safety.

V. CONCLUSION
Pharmacological studies on A. cochliacarpos showed considerable heterogeneity in the pharmacological actions identified as analgesic, antibacterial, myoprotero, antiinflammatory, antioxidant, antiulcerogenic and estrogenic and thyroid modulation. The studies involved in vivo and in vitro animal models, with the bark of the plant being the most used part in extract and fraction production. Among 11 selected studies, only one study carried out a toxicological test, in which the hepatotoxicity of A. cochliacarpos was scored. In this sense, further studies on Abarema cochliacarpos (GOMES) Barneby & J.W. Grimes have to get conducted so that they can be used as a safe and effective correlated phytotherapeutic efect of Stryphnodendron adstringens. It is also important to prove its safety for using in folk medicine or phytotherapy in the long term, as the use of barbatimão can also be a cause of intoxication depending on the dose used and the time of use.