Pharmacological actions of bacuri butter (Platonia insignis Mart.): an integrative review

Objective: to identify the pharmacological activities of bacuri butter (Platonia insignis Mart.). Methods: an integrative review, carried out in the databases of Latin American and Caribbean Literature in Health Sciences, Cumulative Index to Nursing and Allied Health Literature, EMBASE, MEDLINE/PubMed, Web of Science, Cochrane Library and SCOPUS, without the time and language restriction. The selection consisted of 13 pre-clinical trials. The information assessment descriptively took place, comparing with the pertinent findings. Results: it was observed that 50.0% of the publications were indexed in MEDLINE/PubMed, most publications were from England (61.5%), followed by Brazil and the United States, both with 13.3%. It is noteworthy that 100.0% of the articles were pre-clinical trials; pharmacological activities for antioxidants (38.4%) and antileishmanicides (30.7%). It was found that 38.4% of the trials presented toxicity tests. Conclusion: bacuri butter (Platonia insignis Mart.) Showed pharmacological activities in pre-clinical trials, such as antioxidants, antileshimaniasis, anticonvulsant and wound healing. Descriptors: Clusiaceae; Benzophenones; Drug Compounding; Drug Synergism; Drug Therapy. RESUMO Objetivo: identificar as atividades farmacológicas da manteiga de bacuri (Platonia insignis Mart.). Métodos: revisão integrativa, realizada nas bases de dados Literatura Latino-americana e do Caribe em Ciências da Saúde, Cumulative Index to Nursing and Allied Health Literature, EMBASE, MEDLINE/PubMed, Web of Science, Cochrane Library e SCOPUS, sem delimitação temporal e de idioma. A seleção se constituiu de 13 ensaios pré-clínicos. A avaliação das informações ocorreu de forma descritiva, confrontando com os achados pertinentes. Resultados: observou-se que 50,0% das publicações foram indexadas na MEDLINE/PubMed, maioria das publicações ocorreram na Inglaterra (61,5%), seguidas do Brasil e dos Estados Unidos, ambos com 13,3%. Destaca-se que 100,0% dos artigos foram ensaios pré-clínicos; atividades farmacológicas para antioxidante (38,4%) e antileishmanicidas (30,7%). Registrou-se que 38,4% dos ensaios apresentaram testes de toxicidade. Conclusão: a manteiga de bacuri (Platonia insignis Mart.) apresentou atividades farmacológicas em ensaios pré-clínicos, como antioxidantes, antileshimaniose, anticonvulsivante e cicatrização de feridas. Descritores: Clusiaceae; Benzofenonas; Composição de Medicamentos; Sinergismo Farmacológico; Tratamento Farmacológico. 1Universidade Federal do Piauí. Teresina, PI, Brazil. Corresponding author: José Francisco Ribeiro Qd – 28; Cs-6; St – C; Mocambinho. CEP: 64010360. Teresina, PI, Brazil. E-mail: jotafribeiro@yahoo.com.br EDITOR IN CHIEF: Ana Fatima Carvalho Fernandes ASSOCIATE EDITOR: Renan Alves Silva José Francisco Ribeiro1 Maria do Livramento Fortes Figueiredo1 André Luís Menezes Carvalho1 Benedito Pereira de Sousa Neto1 How to cite this article: Ribeiro JF, Figueiredo MLF, Carvalho ALM, Sousa Neto BP. Pharmacological actions of bacuri butter (Platonia insignis Mart.): an integrative review. Rev Rene. 2021;22:e59963. DOI: https://doi.org/10.15253/2175-6783.20212259963 Ribeiro JF, Figueiredo MLF, Carvalho ALM, Sousa Neto BP Rev Rene. 2021;22:e59963. 2 Introduction The use of medicinal herbs is understood as a promising option. Vegetables are capable of biosynthesizing compounds for self-protection in response to environmental damage. The relevance is clarified by the wide diversity of metabolites generated by these species, with different chemical, physical and biological properties, most of which are possibly bioactive against various diseases, considering the empirical use. In this context, compounds synthesized by species native to Brazil that have pharmacological action and with low toxicity may represent alternatives for the treatment of many diseases(1). Platonia insignis, traditionally called bacurizeiro, a fruitful, woody tree, has a dense and diverse population, easily found from the Amazon to Piauí, in Brazil. It belongs to the family Clusiaceae, consisting of approximately one thousand species and forty-seven genus, spread in tropical, subtropical, and temperate regions. In Brazil, the use of Platonia insignis in medical practices is very common, being indicated as healing, antimicrobial, digestive, diuretic, antitumor, cytotoxic and antioxidant(2). Bacurizeiro (Platonia insignis Mart.) Is characterized by having fleshy fruits with more than one seed, with rounded, oval, or concave configuration and average weight according to the region. There are those who produce bulky fruits, weighing more than 1 kg. The number of seeds varies from one to six(3). The oil or butter extracted from the seeds of bacuri (Platonia Insignis Mart.) has been used as a raw material for making soap, as well as treating skin diseases and formulating healing substances for animal wounds(4). Currently, herbal medicine researchers have shown increasing interest in Platonia insignis (mainly seeds), to optimize the biological effects(4). Bacuri butter has excellent absorption, attributed to the components immersed in it, such as tripalmitin (50 to 55.0%), which guarantees a high permeability action on the skin. The palmitoleic acid (5.0%) has an emollient and humidifying pharmacological activity(3-4). In the hexane extract of bacuri seeds, a chemical compound, polyprenylated polycyclic acylfloroglucinol, was isolated, in tautomeric form, called garcinielliptone FC, a little-known compound in the genus Platonia, in which was found the polyprenylated benzophenone with several pharmacological activities(5). Polyprenylated benzophenones are secondary metabolites of plants causing increasing interest, mainly because of their pharmacological properties. Previous in vitro studies have shown that the compound garcinielliptone FC, a substance isolated from bacuri seeds, has an antioxidant, blood vessel relaxing and antiparasitic effect(6). Research related to the genus Platonia isolated several biologically active natural substances, xanthones and chloroglucinol derivatives, which constitute the main class of metabolites existing in the Clusiaceae family. These derivatives have been extensively investigated for biological activities, including pharmacological activities(7). Bacuri butter formulations are still at an early stage of discovery to officially work as drugs in the treatment of diseases in humans. However, pre-clinical trials are necessary. Given the context, this study aimed to identify the pharmacological activities of bacuri butter (Platonia insignis Mart.).


Introduction
The use of medicinal herbs is understood as a promising option. Vegetables are capable of biosynthesizing compounds for self-protection in response to environmental damage. The relevance is clarified by the wide diversity of metabolites generated by these species, with different chemical, physical and biological properties, most of which are possibly bioactive against various diseases, considering the empirical use. In this context, compounds synthesized by species native to Brazil that have pharmacological action and with low toxicity may represent alternatives for the treatment of many diseases (1) .
Platonia insignis, traditionally called bacurizeiro, a fruitful, woody tree, has a dense and diverse population, easily found from the Amazon to Piauí, in Brazil. It belongs to the family Clusiaceae, consisting of approximately one thousand species and forty-seven genus, spread in tropical, subtropical, and temperate regions. In Brazil, the use of Platonia insignis in medical practices is very common, being indicated as healing, antimicrobial, digestive, diuretic, antitumor, cytotoxic and antioxidant (2) .
Bacurizeiro (Platonia insignis Mart.) Is characterized by having fleshy fruits with more than one seed, with rounded, oval, or concave configuration and average weight according to the region. There are those who produce bulky fruits, weighing more than 1 kg. The number of seeds varies from one to six (3) .
The oil or butter extracted from the seeds of bacuri (Platonia Insignis Mart.) has been used as a raw material for making soap, as well as treating skin diseases and formulating healing substances for animal wounds (4) . Currently, herbal medicine researchers have shown increasing interest in Platonia insignis (mainly seeds), to optimize the biological effects (4) .
Bacuri butter has excellent absorption, attributed to the components immersed in it, such as tripalmitin (50 to 55.0%), which guarantees a high permeability action on the skin. The palmitoleic acid (5.0%) has an emollient and humidifying pharmacological activity (3)(4) .
In the hexane extract of bacuri seeds, a chemical compound, polyprenylated polycyclic acylfloroglucinol, was isolated, in tautomeric form, called garcinielliptone FC, a little-known compound in the genus Platonia, in which was found the polyprenylated benzophenone with several pharmacological activities (5) .
Polyprenylated benzophenones are secondary metabolites of plants causing increasing interest, mainly because of their pharmacological properties. Previous in vitro studies have shown that the compound garcinielliptone FC, a substance isolated from bacuri seeds, has an antioxidant, blood vessel relaxing and antiparasitic effect (6) .
Research related to the genus Platonia isolated several biologically active natural substances, xanthones and chloroglucinol derivatives, which constitute the main class of metabolites existing in the Clusiaceae family. These derivatives have been extensively investigated for biological activities, including pharmacological activities (7) .
Bacuri butter formulations are still at an early stage of discovery to officially work as drugs in the treatment of diseases in humans. However, pre-clinical trials are necessary. Given the context, this study aimed to identify the pharmacological activities of bacuri butter (Platonia insignis Mart.).

Methods
An integrative review was carried out, established by theoretical framework, following the steps: 1) choice of the guiding question, 2) sample or publication investigation, 3) recruitment of the sample's articles, 4) collecting of information from the included articles, 5) evaluation and meaning of the retrieved data and 6) presentation of the review or evaluation of the collected findings (8) .
For the creation of the guiding question, the acronym PICO was adopted, determining: P (population): Platonia insignis Mart., I (interest): Garcinielliptone FC; Clusiaceae, C (it does not have) and O (context): composition of medicines. Thus, the guiding question was: what are the pharmacological actions of bacuri butter (Platonia insignis)?
Primary original articles were included, without the time and language restriction, that addressed the pharmacological actions of bacuri butter (Platonia insignis Mart.). Congress abstracts, theses, dissertations, reviews, and editorials were excluded.
The investigation was carried out in June 2020, through searches carried out in the bases Medical Literature Analysis and Retrieval System Online (ME-DLINE) via PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Cochrane Library, Web of Science, SCOPUS and Latin American and Caribbean Literature in Health Sciences (LILACS). Interval interception was performed with the descriptors and the title words, using the Boolean operator and as a strict combination, applying the strategies: Meta-Analyzes protocol (9) . Teresina, PI, Brazil, 2020 and Garcinielliptone FC and drug compounding. The descriptors were accessed through the presence of the terms of the Medical Subject Headings (MeSH), Descriptors in Health Sciences (DeCS) and List of Headings of the Cumulative Index of Nursing Literature. The articles were accessed through the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Coordination for the Improvement of Higher Education Personnel). The selection was developed by two reviewers, independently, in two stages: the first, the title and abstract were read, and in the second, the full text. In cases of disagreement, there was a discussion between the two evaluators to reach a consensus.
The search resulted in 49 publications. In the first stage, according to established standards, 15 productions were selected. In the second, two productions were removed, totaling 13 articles, which comprised the total number of articles for analysis. Figure  1 outlines the selected articles.
The organization of the information retrieved from the articles was transcribed into a previously prepared document, considering information about the main author, journal and year of publication, design/sample, pharmacological action, and category of evidence.
The category of evidence was classified according to the model proposed by the authors (8) , who consider: category I -a systematic review or meta--analysis of valuable clinical trials; category II -very limited controlled randomized controlled trial; category III -clinical trial supported by a non-randomized design; category IV -cohort and case-control study with adequate design; category V -a systematic review of descriptive and qualitative research; category VI -descriptive or qualitative research; category VII -judgment of authorities or narratives of expert committees. The synthesis of the results was carried out quantitatively and descriptively. Brazil/2010 (10) Histologic study of skin of wounds healing using the cream of bacuri

Results
The results are shown in Figure 2, in the following order: main author, journal and year; design/ sample; and pharmacological action. It was observed that most of the articles came from international journals, published in the English language, only one in Portuguese and indexed in the MEDLINE/PubMed databases. The most evident country was England, with the largest number of publications (61.5%), followed by Brazil and the United States, both with 13.3%. It is noteworthy that 100% of the articles were evidence II pre-clinical trials. It was registered that 38.4% of the information indicated pharmacological actions for antioxidants; cutaneous leishmaniasis (30.7%); epilepsy (15.3%); scarring; schistosomiasis; cancer and immunomodulator were 3.9%, respectively. As for the toxicity represented by cytotoxicity, genotoxicity, and mutagenicity, it was observed that 38.4% had tests for toxicity associated with the pharmacological action ( Figure 2). England/2015 (16) Garcinielliptone FC: Antiparasitic action without cytotoxicity to mammalian cells England/2018 (20) Emulgel

Discussion
The insufficient production of scientific papers that addressed bacuri butter in clinical trials is considered an important limitation of this study. Thus, this study aims to contribute to research in natural products and the development of formulations containing bacuri butter for human treatments, because of the absorption potential and reduced adverse effect of this product.
It is highlighted that the investigation of new drugs from plants has supported the discovery of metabolites with important therapeutic potential for the development of new herbal medicines, through isolation, clarification of the structure, composition and bioactivity analysis (21) . The continuous search for robust pre-clinical trials with medicinal plants is evident, however, there is limited research that addres-ses the pharmacological actions of bacuri butter (Platonia insignis Mart.), mainly in clinical trials.
Cutaneous leishmaniasis is a condition with a high incidence and the ability to cause deformities. The first-choice treatment, recommended by the World Health Organization, with pentavalent antimonial, is offensive and very toxic. Therefore, the development of a drug for topical treatments can happen as a positive option and less harmful to the user's health (22) . As for the pharmacological action of bacuri butter for cutaneous leishmaniasis, it was observed in a preclinical trial that the authors detected that the compounds developed showed a promising antileishmanial action and a high potential for topical use (19) .
Traditionally, the leishmaniasis treatment is carried out with antimonial, drugs settled for use since 1945, marketed as N-methyl glucamine antimoniate (Glucantime), in Latin America and Africa, and the sodium stibogluconate Pentostam, in the United States and Europe. The antimonials marketed in India and China, Pentostam, show similar results for the clinical forms of American cutaneous leishmaniasis. The most common side effects of antimonials are: joint pain, muscle pain, anorexia, nausea, vomiting, epigastric discomfort, heartburn, itching, hyperthermia, migraine, increased liver enzymes and alkaline phosphatase, acute kidney disorder, by modifying the release of vasopressin and renal tubular cytotoxicity, pancreas inflammation (23)(24) . It was also evident in research whose purpose was to evaluate the cytotoxic and leishmanicidal effects of bacuri butter, using in vitro models, that the experimental findings showed that the benzophenone garcinielliptone poliisoprenilada, compounds of bacuri butter, has low toxicity to the host and high leishmanicidal toxicity (25) .
As for human schistosomiasis, a neglected tropical disease, originated by worms of the genus Schistosoma, responsible for more than 280,000 deaths per year, the treatment of this disease currently comes from a single drug, praziquantel (PZQ). The care with resistance to PZQ and the insensitivity of juvenile schistosomes has increased the interest in using me-dicinal plants for alternative drug therapies (26) . As an example, it was found that formulations with bacuri butter showed in vitro action for Schistosoma mansoni, granting toxicity to the cells of this helminth (15,26) . Besides bacuri formulations, there are other herbal medicines with pharmacological actions like bacuri butter.
Another research aimed at analyzing the effect of the hexane and crude ethanolic extracts obtained from Phyllanthus amarus (stone breaker), in mice infected with Schistosoma mansoni, the authors detected anti-schistosomiasis actions, however, acting differently, according to the parasite's age (27) .
Regarding epilepsy observed by a temporary and reversible change in brain activity, which has not been caused by fever, drugs or metabolic disorders and is expressed by repeated epileptic seizures, drug therapy, in some cases, requires regular adjustments of the drugs valproate, carbamazepine , lamotrigine and other anticonvulsants in addition or exchange to lithium (27) . As a future option for the epilepsy treatment, a behavioral and neurochemical study in mice provided anticonvulsant action (14) .
As for antioxidant agents, research on the role of cellular nutrients shows that certain nutritive substances from food have enhanced antioxidant action, showing a propensity to convert and decrease the oxidation action of free radicals, inhibiting the harmful consequences to the body and instability in the production of free radicals and their suppression by antioxidant protection, given that oxidative stress causes damage to cell membranes, as well as nucleic acids, proteins and polysaccharides, leading to initial changes and the spread of different diseases (28) . Pharmacological actions of bacuri butter as an antioxidant were also observed (9,16) . Bacuri seed and pulp are sources of vitamin C, which guarantees antioxidant action.
As for toxicity, it was found that 64.5% of preclinical trials did not reveal the existence of preclinical toxicity, such as cytotoxic, genotoxic, and mutagenic, it is believed that these experiments followed previous criteria of other research with bacuri butter, which analyzed the toxicity, considering that the test of this element presents itself as the first step in experimental studies.
It was detected in a topical formulation of amphotericin B with bacuri butter, to evaluate antileishmanial action, through in vitro tests, in which bacuri butter and the drug presented low toxicity to host cells. This proposition clarifies the need to perform toxicity tests in vitro and in vivo, recommended for the use of medicines for humans, issued by international or national regulatory bodies, analyzed, and then adopted to be used in the toxicity assessment. Thus, based on the compilation of these demonstrated regulations, tests are advised to assess toxicity in vitro cytotoxicity, genotoxicity, acute and repeated dose toxicity, carcinogenicity, reproductive and developmental toxicity, evidence of local tolerance, additional toxicokinetic and toxicity studies, including safety pharmacology (19,29) .
Herbal medicines, before being used by humans, must be assessed for toxicity, which aims to ensure its safety for the use. Bacuri butter showed significant action in terms of potential, low toxicity to cells was observed in preclinical tests and, in some cases, very toxic to the cells of agents harmful to the host organism (11,17,30) .
Regarding immunomodulatory action, bacuri butter (Platonia insignis Mart.) showed an increase in the organic response against certain microorganisms or substances unwanted to the organism, besides a high potential for immunomodulatory action, observed in the wound healing process and reduction of cancer cells (8,16) .

Conclusion
Evidence has shown that bacuri butter has pharmacological actions, such as antioxidants, antileishmanicides, antischistosomiasis, antiepileptics, anticancer and immunomodulators, according to preclinical tests carried out, findings of great relevance for the execution of robust clinical trials.

Collaborations
Ribeiro JF collaborated with the review's concept, analysis, and data interpretation. Figueiredo MLF and Carvalho ALM contributed to writing the article and relevant critical review of the intellectual content. Sousa Neto BP participated in the final approval of the version to be published.