Exploring The Therapeutic Potential of Brazilian Medicinal Plants For Anti-Arthritic and Anti-Osteoarthritic Applications

Biocatalysis and Agricultural Biotechnology 56 (2024) 103064
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Biocatalysis and Agricultural Biotechnology

journal homepage: www.elsevier.com/locate/bab
Exploring the therapeutic potential of Brazilian medicinal plants

for anti-arthritic and anti-osteoarthritic applications: A
comprehensive review
José Jailson Lima Bezerra *, Antônio Fernando Morais de Oliveira
Universidade Federal de Pernambuco, Departamento de Botânica, Av. da Engenharia, s/n, Cidade Universitária, 50670-420, Recife, PE, Brazil
ARTICLE INFO ABSTRACT
Handling Editor: Dr. Ching Hou Medicinal plants are used in several countries for the treatment of various diseases, including
arthritis and osteoarthritis, thus constituting a valuable alternative to commercial drugs. In
Keywords:
Brazil, several cultivated plants of economic interest have been indicated for the treatment of
Bioactive compounds
rheumatic diseases in ethnobotanical and ethnopharmacological surveys. From this perspective,
Bioprospecting
Medicinal plants
the present study aimed to review the literature on the anti-arthritic and anti-ostoarthritic poten-
Phytotherapy tial of plants traditionally used in Brazil. The scientific documents were retrieved from different
Rheumatic diseases databases, from the first report published in 1989 until December 2023. A total of 55 species dis-
tributed in 31 families are used for the treatment of arthritis and osteoarthritis in different Brazil-
ian states. The species Echinodorus grandiflorus, Pterodon emarginatus, Morinda citrifolia, Uncaria
tomentosa, and Miconia albicans stood out for the number of citations. Leaves (41%) are the parts
of plants most used in the medicinal preparations. Of the 55 species used by traditional communi-
ties, 24 had their anti-arthritic and anti-osteoarthritic activities investigated in preclinical mod-
els, and 14 in randomized clinical trials. Phenolic compounds, such as flavonoids, may be directly
involved with the reported anti-arthritic and anti-osteoarthritic activity. Many of the species
cited in ethnobotanical surveys carried out in Brazil still lack scientific investigations that prove
their anti-arthritic effects in preclinical and clinical trials. The exploration of novel phytopharma-
ceuticals derived from commonly utilized plant raw materials holds the potential to facilitate the
establishment of more readily accessible therapeutic alternatives for the general public.
1. Introduction
Rheumatic diseases are among the most prevalent chronic diseases of the musculoskeletal system and connective tissue, and can
affect different age groups of the population and negatively interfere with the quality of life of patients (Jokar and Jokar, 2018; Yi,
2018). Generally, rheumatic diseases are characterized by intermittent pain, swelling and limitation of movement or disability,
mainly affecting the joints, cartilage, and bones of individuals (Xu et al., 2022). There are more than 200 defined rheumatic diseases,
the best known being systemic lupus erythematosus, osteoarthritis (OA), rheumatoid arthritis (RA), gout, ankylosing spondylitis, pso-
riatic arthritis, and systemic sclerosis (Gupta et al., 2018; Mohsin et al., 2018; Xu et al., 2022). Although there are significant differ-
ences in the pathogenesis of RA and OA, the focus of our study, their clinical symptoms are similar and sometimes difficult to distin-
guish, especially in the case of unilateral RA of the knee, which is more difficult to distinguish from OA (Chen et al., 2018).
* Corresponding author.
E-mail address: josejailson.bezerra@hotmail.com (J.J.L. Bezerra).
https://doi.org/10.1016/j.bcab.2024.103064
Received 13 December 2023; Received in revised form 8 February 2024; Accepted 9 February 2024
Available online 10 February 2024
1878-8181/© 2024 Elsevier Ltd. All rights reserved.
J.J.L. Bezerra and A.F.M.d. Oliveira Biocatalysis and Agricultural Biotechnology 56 (2024) 103064
Rheumatoid arthritis is a chronic autoimmune disease of unknown origin that is characterized by inflammatory processes in
joints, cartilage and bones and, less frequently, in extra-articular regions (Lin et al., 2020; Scherer et al., 2020). This disease is more
prevalent in elderly women (Guo et al., 2018). The most common symptoms of RA are morning joint stiffness, swelling, fatigue,
arthralgia, redness, fever, weight loss, and rheumatoid nodules under the skin (Aletaha and Smolen, 2018; Bullock et al., 2018; Guo et
al., 2018). Unlike RA, OA is characterized by being a chronic degenerative disease of the diarthrodial joints, predominantly affecting
the spine and peripheral joints of the body, mainly hands, hips, knees, and feet (Cope et al., 2019). The degenerative processes of OA
eventually lead to irreversible destruction of the articular cartilage (Grässel and Muschter, 2020).
Currently, several commercial drugs are available for the treatment of rheumatic diseases, such as sulfasalazine, methotrexate,
leflunomide, and rituximab. However, these drugs have moderate and severe side effects on the body, including autoimmune throm-
bocytopenia (Narayan et al., 2017), toxicity (Wang et al., 2018), pulmonary arterial hypertension (Coirier et al., 2018), and interfer-
ence in the effectiveness of vaccination against other diseases (Tavakolpour et al., 2019), respectively. In contrast, considering the
benefits associated with the use of natural products, many studies have reported that medicinal plants can be an effective therapeutic
alternative with fewer side effects to help treat RA and OA (Choudhary et al., 2015; Abiri et al., 2018; Singh et al., 2020; Gandhi et al.,
2022; Sharma and Goel, 2023).
In Brazil, several cultivated plants of economic interest have been indicated for the treatment of arthritis in ethnobotanical and
ethnopharmacological surveys. Among these species, the following stand out: Ananas comosus (L.) Merril (Teixeira and Melo, 2006),
Persea americana Mill. (Vendruscolo and Mentz, 2006), Citrus limon (L.) Osbeck (Carneiro, 2009), Musa paradisiaca L. (Boscolo, 2013),
Annona muricata L. (Flor, 2014), and Morinda citrifolia L. (Sousa et al., 2021). Pharmacologically, products obtained from these plants
have been investigated in preclinical studies and randomized clinical trials and have shown relevant results, being considered sources
of bioactive molecules to aid in the treatment of arthritis and osteoarthritis (Wang et al., 2011; Foong and Hamid, 2012; Kargutkar
and Brijesh, 2016; Ahmed et al., 2018; Li et al., 2022).
Considering the evidence that many species cultivated in Brazil are promising for the treatment of rheumatic diseases, mainly
rheumatoid arthritis and osteoarthritis, the present study aimed to review the literature on the ethnomedicinal uses, pharmacological,
phytochemical, and toxicological tests of these plants.
2. Methodology
2.1. Databases
Scientific articles were retrieved from the Google Scholar (https://scholar.google.com/), Oasisbr (https://oasisbr.ibict.br/),
PubMed® (https://pubmed.ncbi.nlm.nih.gov/), SciELO (https://search.scielo.org/), Scopus® (http://www.scopus.com/), and Web
of Science™ (https://www.webofknowledge.com) databases. The following terms were used as search strategies: “ethnobotany AND
arthritis OR osteoarthritis AND Brazil”, “medicinal plants AND arthritis OR osteoarthritis AND Brazil”, “traditional uses AND arthritis
OR osteoarthritis AND Brazil”, “anti-arthritis OR anti-osteoarthritis AND medicinal plants”, “arthritis OR osteoarthritis AND medici-
nal plants AND randomized clinical trial”, “arthritis OR osteoarthritis AND medicinal plants AND phytochemistry”, and “arthritis OR
osteoarthritis AND medicinal plants AND toxicity”.
2.2. Inclusion and exclusion criteria

The literature was reviewed from the first report on the traditional use of medicinal plants for the treatment of arthritis and os-
teoarthritis in Brazil (Campelo and Ramalho, 1989) until December 2023. Studies on anti-arthritic and anti-osteoarthritic potential,
randomized clinical trials, phytochemistry, and toxicity of products extracted from plants were also selected. The scientific names of
the species were checked on the website Flora e Funga do Brasil© (http://floradobrasil.jbrj.gov.br/reflora/) and synonyms cited
when relevant. The plant habits of the species were also verified on the Flora e Funga do Brasil© platform. As inclusion criteria, arti-
cles, book chapters, undergraduate theses, Masters’ theses, PhD theses, and works published in technical or scientific events were se-
lected. To be selected, studies had to specifically mention the use of plants for the treatment of “arthritis” or “osteoarthritis” in Brazil.
As for the exclusion criteria, review articles and scientific articles that cited plants only at the genus level or that did not provide suffi-
cient ethnopharmacological information on traditional uses were excluded.
2.3. Data screening and categorization of information

After identifying the first article that reported the use of medicinal plants to treat arthritis or arthrosis in Brazil (Campelo and
Ramalho, 1989), another 164 studies were selected and included, resulting in a total of 165 scientific documents (Fig. 1). These stud-
ies address information on traditional uses (72), anti-arthritic and anti-osteoarthritic potential (41), randomized clinical trials (25),
phytochemistry (10), phytochemistry and anti-arthritic activity (6), and toxicity (11) of medicinal plants in Brazil. The results were
described in five categories: 1) “Cultivated plants traditionally used to treat arthritis and arthrosis in Brazil”, 2) “Anti-arthritic and
anti-osteoarthritic activity of plants cultivated in Brazil”, 3) “Clinical trials of plants used to treat arthritis and osteoarthritis in
Brazil”, 4) “Phytochemistry of plants used in the treatment of arthritis and osteoarthritis in Brazil”, and 5) “Toxicity related to plants
used to treat arthritis and osteoarthritis in Brazil”.
2.4. Statistical analysis

Studies that address ethnomedicinal information on the use of plants for the treatment of arthritis and osteoarthritis in different
regions of Brazil were statistically analyzed by relative frequency (RF) according to the formula by Sadat-Hosseini et al. (2017) with
2
Fig. 1. Flow diagram of selection of scientific documents included in this review.
modifications. The RF was obtained by dividing the number of documents per state (ND) by the total number of documents (N), ac-
cording to the following formula: RF = (ND/N) x 100.
3. Results and discussion

3.1. Cultivated plants traditionally used to treat arthritis and arthrosis in Brazil
Different cultivated species are used medicinally for the treatment of arthritis and osteoarthritis in the five geographic regions of
Brazil (Midwest, North, Northeast, South, and Southeast). Among the 26 Brazilian states, in addition to the Federal District, reports of
traditional uses were identified in 17 (seventeen) of them. The states with the highest number of indications for use, and their relative
frequencies (RF) were, respectively, Goiás (10.14%), Mato Grosso (10.14%), Minas Gerais (8.69%), Pará (8.69%), Ceará (8.69%),
Pernambuco (7.25%), Paraíba (7.25%), and Bahia (7.25%). The other states had a low RF (<6.0%) due to the lower number of eth-
nobotanical and ethnopharmacological records (Table 1).
Table 1
Number of scientific articles with indications of medicinal plants used for the treatment of arthritis by geographic region and state in Brazil.
a
Geographic region Brazilian state DN RF (%)
Northeast Ceará (CE) 6 8.69

Pernambuco (PE) 5 7.25
Paraíba (PB) 5 7.25
Bahia (BA) 5 7.25
Piauí (PI) 2 2.90
Alagoas (AL) 2 2.90
Maranhão (MA) 2 2.90
Midwest Goiás (GO) 7 10.14
Mato Grosso (MT) 7 10.14
North Pará (PA) 6 8.69
Amazonas (AM) 2 2.90
South Rio Grande do Sul (RS) 3 4.35
Santa Catarina (SC) 3 4.35
Southeast Minas Gerais (MG) 6 8.69
Espírito Santo (ES) 3 4.35
São Paulo (SP) 3 4.35
Rio de Janeiro (RJ) 2 2.90
Total 69 100
DN: document numbers per state; RF: relative frequency.
a Scientific documents that did not specify the Brazilian state where the research was carried out were not included in this Relative Frequency analysis.
3
A total of 55 species distributed in 31 families are cultivated in Brazil and used to treat arthritis and osteoarthritis by several tradi-
tional communities (Table 2). The most representative families in number of species were Asteraceae (8 spp.), Lamiaceae (5 spp.), and
Fabaceae (4 spp.) (Fig. 2). Our findings corroborate the study by Adams et al. (2009), who identified Lamiaceae and Asteraceae as the
families with species most used for the treatment of rheumatic diseases in Europe. Regarding the Fabaceae family, Kamal et al. (2016)
reported that this, along with Asteraceae, were the most dominant for the treatment of rheumatic diseases by traditional communities
in Pakistan. These data show that representatives of these families can be important sources of bioactives for the treatment of diseases
of this nature.
Leaves (41%) were the most used plant parts in traditional preparations for the treatment of arthritis and osteoarthritis (Fig. 3),
followed by fruits (12%), bark (12%), seeds (12%), and roots (11%). Comparatively, the leaves were also used more for the treatment
of rheumatic diseases in other countries. According to a survey carried out by Rahmatullah et al. (2010), the leaves are the most used
parts for the treatment of rheumatoid arthritis in different districts of Bangladesh. The leaves also stood out as the most used parts
against rheumatic diseases in Pakistan (Kamal et al., 2016).
Various forms of medicinal preparations such as teas (decoction, infusion, and maceration), poultice, “garrafada”, “emplastro”, “al-
coolatura”, juice, oil, ointment, tincture, syrup, gel, and cream were mentioned in this review (Table 2).
Among the 55 species used for this purpose in several Brazilian states, Echinodorus grandifloras (Cham. & Schltr.) Micheli, Pterodon
emarginatus Vogel, Morinda citrifolia L., Uncaria tomentosa (Willd. Ex Roem. & Schult.) DC., and Miconia albicans (Sw.) Steud. Stand
out. In addition to these, Ageratum conyzoides L., Copaifera langsdorffii Desf., Curcuma longa L., Rosmarinus officinalis L., and Solidago
chilensis Meyen are also commonly used for the treatment of arthritis and osteoarthritis in Brazil. Some products obtained from these
plants used in the treatment of arthritis and osteoarthritis can be observed in Fig. 4.
Morinda citrifolia (Fig. 4A), popularly known as “noni”, has indications of medicinal use for the treatment of rheumatic diseases
in other regions of the world. According to Girardi et al. (2015), the leaves and fruits of this species are used by inhabitants of the
Marquesas Islands in French Polynesia for the treatment of osteoarthritis, rheumatism, back pain, and joint problems. In an ethnob-
otanical survey carried out by Navia et al. (2021), the decoction of leaves and fruits of M. citrifolia is used by Indonesian inhabitants
for the treatment of gout arthritis. Wahyuni and Afidah (2022) reported that village heads, community leaders and residents of the
community of Rawang Kao Village, Siak, also in Indonesia, use the fruits of this species for the treatment of arthritis.
Popularly known as “unha-de-gato”, U. tomentosa (Fig. 4B) is another species belonging to the Rubiaceae family that also stands
out for its use in the treatment of arthritis in other countries, mainly in Peru. In this country, patients at the Anticona Clinic in El Por-
venir, Trujillo, use U. tomentosa for the treatment of various diseases, including rheumatic infections and arthritis (Bussmann et al.,
2007). In a study carried out by Polesna et al. (2011), shamans, herbalists and healers from the markets of Pucallpa, Coronel Portillo
Province of Ucayali Department, also in Peru, reported that the bark of this species is used in the treatment of arthritis, rheumatism,
among other disorders. Traditional healers and vendors of medicinal plants residing in northern Peru have reported that the leaves
and stem of U. tomentosa can be administered orally or topically for the treatment of rheumatic infections, arthritis, and other diseases
that affect the bones (Bussmann and Glenn, 2011).
Although products obtained from E. grandiflorus, M. albicans and P. emarginatus (Fig. 4C) are widely used for the treatment of
arthritis in Brazil, reports of ethnomedicinal uses of these species for the treatment of rheumatic diseases in other countries no were
found. Regarding the pharmacological potential, previous studies reported that the hydroethanolic extract of the leaves of E. grandi-
florus (Garcia et al., 2016) and the ethanolic extract of the leaves of M. albicans (Quintans-Júnior et al., 2020) showed anti-arthritic
activity in vivo.
Curcuma longa (Fig. 4D), popularly known as “cúrcuma” or “açafrão”, is a spice used as a condiment in cuisines in different re-
gions of the world (Hewlings and Kalman, 2017; Gopinath and Karthikeyan, 2018; Munekata et al., 2021). In addition to its food
applications, this plant has medicinal properties, being indicated by traditional Brazilian communities for the treatment of
rheumatic diseases such as arthritis and osteoarthritis (Gomes, 2014; Ventura et al., 2018; Alves et al., 2021). Several randomized
clinical trials have already proven that products based on this plant contribute significantly to providing a better quality of life for
patients affected by knee knee osteoarthritis (Madhu et al., 2013; Srivastava et al., 2016; Ross, 2016; Gomes et al., 2021).
3.2. Anti-arthritic and anti-osteoarthritic activity of plants cultivated in Brazil

Of the 55 species indicated for the treatment of arthritis and osteoarthritis by traditional Brazilian communities, only 24 had their
anti-arthritic and anti-osteoarthritic potential investigated in pharmacological assays (Table 3). According to the reviewed literature,
the following experimental models were used: membrane stabilization and protein denaturation, Complete Freund's Adjuvant-
induced arthritis, collagen-induced arthritis, zymosan-induced arthritis, formaldehyde-induced arthritis, streptococcal cell wall-
induced arthritis, monosodium iodoacetate-induced osteoarthritis, antigen-induced arthritis, and pain-induced functional impair-
ment. Most of these assays were performed in vivo with plant extracts, fixed and essential oils, and other by-products.
According to González-Trujano et al. (2007), the ethanolic extract of the aerial parts of R. officinalis (30–3000 mg/kg) not only sig-
nificantly increased functionality index (FI%) in rats, but also produced a pick in the antinociceptive effect at 100, 300, 1000 and
3000 mg/kg dosages (FI% values = 39, 42, 62, and 69, respectively) in the first 15–30 min of evaluation. In a study carried out by
Martínez et al. (2009), the essential oil of the aerial parts of R. officinalis at doses of 100–600 mg/kg showed a significant dose-
dependent reduction of the dysfunction induced by uric acid in the experimental model of pain-induced functional impairment (PI-
FIR) in vivo. These authors suggested that the compounds β-pinene, myrcene, eucalyptol, camphor, borneol, and borneol acetate can
be responsible for the observed pharmacological activity.
In addition to its known nutritional properties, Z. officinale has shown to be a promising species for the treatment of several dis-
eases, including arthritis and osteoarthritis (Shahrajabian et al., 2019; Garza-Cadena et al., 2023). Funk et al. (2009), for example, re-
4
Table 2
a
Medicinal plants cultivated in Brazil and traditionally used to treat arthritis and osteoarthritis. .
Family/Species Popular name Habit Part used Preparation mode Brazilian state References
ALISMATACEAE
Echinodorus grandiflorus (Cham. & Schltr.) Chapéu-de-couro Herb Leaves, – Goiás Carneiro (2009)
Micheli whole plant
Leaves Infusion, bath Espirito Santo Souza et al.
(2018)
Leaves Infusion, oral use Mato Grosso Leitzke (2012)
Whole Bath Goiás Silva (2007)
plant
Leaves The same recipe as above in Paraíba Agra et al.
decoction. It is for topical use (2007)
or as poultice
Leaves, Tea Pará Bitencourt et al.
stem (2014)
AMARANTHACEAE
Beta vulgaris L. Beterraba Herb Root, – Goiás Carneiro (2009)
leaves
Dysphania ambrosioides (L.) Mosyakin & Mastruz Herb, Leaves Juice Pará Freitas (2009)
Clemants [Syn. Chenopodium subshrub
ambrosioides L.]
ANACARDIACEAE
b
Schinus terebinthifolia Raddi [Syn. Schinus Aroeira, pimenta- Shrub, tree Bark, root, Tea, “garrafada” , infusion Pará Cajaiba et al.
terebinthifolius Raddi] rosa leaves (2016)
ANNONACEAE
Annona muricata L. Graviola Shrub, tree Leaves, Tea Pará Flor (2014)
fruit
APIACEAE
Petroselinum crispum (Mill.) Fuss Salsa Herb Leaves Infusion Mato Grosso Pinto et al.
do Sul (2017)
Pimpinella anisum L. Erva-doce Herb Seed – Espírito Santo Bispo et al.
(2021)
ARECACEAE
Acrocomia aculeata (Jacq.) Lodd. ex Mart. Macaúba Palm tree Fruit, seed Juice, decoction, oil Pernambuco Saraiva et al.
extraction, oral use (2015)
ASTERACEAE
Ageratum conyzoides L. Mentrasto Herb, Aerial parts Infusion, oral use Goiás Gonçalves (2016)
subshrub
Branch Ointment, tincture Pernambuco Oliveira (2007)
Leaves Infusion Minas Gerais Ferrão et al.
(2014)
Arctium lappa L. Bardana Herb Root Decoction, topical use Goiás Gonçalves (2016)
Leaves, Maceration, infusion Mato Grosso Ribeiro et al.
aerial parts, (2017)
root
Artemisia alba Turra [Syn. Artemisia Alcânfora, cânfora, Shrub, Leaves – Rio Grande Hentges (2015)
camphorata Vill] cânfora-de-jardim, subshrub do Sul
losna
d
Aerial parts “Alcoolatura” , topical use Minas Gerais Messias et al.
(2015)
Artemisia vulgaris L. Artemisia Herb Leaves – Minas Gerais Leite and
Oliveira (2013)
Bidens pilosa L. Picão Herb Leaves, Tea, bath São Paulo Souza and Dória
stem, root (2016)
Helianthus annuus L. Girassol Herb Seed, Infusion Ceará Sousa et al.
flower (2021)
Lactuca sativa L. Alface Herb Leaves – Piauí Silva et al.
(2015)
Mikania glomerata Spreng. Guaco Liana, Leaves – Bahia Brito et al.
scandent, (2015)
vine
Whole – Rio de Boscolo and
plant Janeiro Valle (2008)
BIGNONIACEAE
Handroanthus heptaphyllus (Vell.) Mattos Ipê-roxo Tree Bark – Rio Grande Hentges (2015)
do Sul
BORAGINACEAE
(continued on next page)
5
Table 2 (continued)
Symphytum officinale L. Cônfrei Herb Leaves Maceration, syrup Bahia Teixeira (2022)
BRASSICACEAE
Brassica oleracea L. Couve Herb, Leaves Tea Pernambuco Teixeira and
subshrub Melo (2006)
BROMELIACEAE
Ananas comosus (L.) Merril Abacaxi Herb Fruit Juice Pernambuco Teixeira and
Melo (2006)
CUCURBITACEAE
Cucumis melo L. Melão Liana, Fruit – Alagoas Campelo and
scandent, Ramalho (1989)
vine
EQUISETACEAE
Equisetum arvense L. Cavalinha Herb Leaves Infusion Minas Gerais Cardoso (2013)
Equisetum hyemale L. Cavalinha Herb Whole Decoction Santa Tribess et al.
plant Catarina (2015)
FABACEAE
Bowdichia virgilioides Kunth Sucupira Shrub, tree Seed Extract Bahia Oliveira et al.
(2020)
Bark – Pernambuco Albuquerque et
al. (2007)
Bark – Pará Breitbach et al.
(2013)
Copaifera langsdorffii Desf. Pau-dóleo, copaíba Tree Bark Tea, oil Minas Gerais Fagundes et al.
(2017)
– Oil Goiás Alves (2016)
– Oil Paraíba Gadelha et al.
(2015)
Libidibia ferrea (Mart. ex Tul.) Pau-Ferro, jucá Tree Bark, seed Decoction, pill Goiás Guimarães et al.
L.P.Queiroz [Syn. Apuleia ferrea (2022)
(Mart.) Baill., Caesalpinia ferrea Mart.
ex Tul.]
Stem bark, Infusion, decoction, syrup, Região Vieira (2012)
seed sauce Nordeste
Pterodon emarginatus Vogel Sucupira-branca, Tree Fruit, seed Tea Ceará Pereira et al.
sucupira (2014)
Seed, bark Tea, maceration in white Mato Grosso Leitzke (2012)
wine, oral use
Leaves, – Goiás Santos et al.
seed (2015)
Seed, bark – Bahia Brito et al.
(2015)
Bark, Decoction, infusion, Mato Grosso Ribeiro et al.
leaves, maceration, poultice (2017)
stem, seed
– Oil São Paulo Lima (2017)
GINKGOACEAE
Ginkgo biloba L. Gingobiloba Tree Leaves – Goiás Santos et al.
(2015)
IRIDACEAE
Crocus sativus L. Açafrão Herb Root – Goiás Santos et al.
(2015)
LAMIACEAE
Ocimum gratissimum L. Alfavacão Shrub, Leaves – Rio de Boscolo (2013)
subshrub Janeiro
Leaves – Rio de Boscolo and
Janeiro Valle (2008)
Origanum majorana L. Manjerona Herb, Leaves Tea Bahia Silva (2013)
subshrub
Rosmarinus officinalis L. Alecrim Shrub Leaves Tea Goiás Alves (2016)
Leaves – Goiás Santos et al.
(2015)
Flower, Bath, tea Pará Silva (2021)
leaves
Stachys byzantina K.Koch Cataflan, Herb, Leaves Infusion Santa Costa and Pereira
pulmonária subshrub Catarina (2016)
6
Table 2 (continued)
Vitex agnus-castus L. Pau-d'angola Shrub, tree Leaves, Maceration in alcohol, tea, Região Magalhães et al.
flower infusion, internal and Nordeste (2019)
external use
LAURACEAE
Persea americana Mill. Abacate, abacateiro Tree Seed, – Rio Grande Vendruscolo and
leaves do Sul Mentz (2006)
Leaves Infusion Pernambuco Albuquerque
(2001)
LINACEAE
Linum usitatissimum L. Linho, linhaça Herb Seed – Rio Grande Dluzniewski and
do Sul Müller (2018)
MELASTOMATACEAE
Miconia albicans (Sw.) Steud. Canela-de-velho Shrub, tree Leaves Tea, infusion Espirito Santo Brito and
Tavares (2022)
Leaves Infusion, decoction, Mato Grosso Ribeiro et al.
maceration (2017)
Leaves – Paraíba Medeiros et al.
(2019)
Leaves Tea, decoction Minas Gerais Guarneire (2018)
Leaves – Mato Grosso Castilho and
Silva (2022)
Leaves – Amazonas Silva et al.
(2022a)
Leaves, Maceration, cream Goiás Guimarães et al.
root (2022)
MELIACEAE
Carapa guianensis Aubl. Andiroba Tree Seed Oil, decoction Amazonas Carvalho (2019)
MUSACEAE
Musa paradisiaca L. Bananeira Herb Fruit peel, – Rio de Boscolo (2013)
fruit, sap Janeiro
Fruit peel, – Rio de Boscolo and
sap Janeiro Valle (2008)
MYRTACEAE
Psidium guineense Sw. [Syn. Psidium araça Araçá-do-campo Shrub, tree Root, stem Decoction Minas Gerais Cardoso (2013)
Raddi] bark
PEDALIACEAE
Harpagophytum procumbens (Burch.) DC. Garra-do-diabo Herb Root Infusion, oral use Goiás Gonçalves (2016)
ex Meisn.
Sesamum indicum L. Gergilim Shrub, Seed Syrup Bahia Teixeira (2022)
subshrub
PHYTOLACCACEAE
Petiveria alliacea L. Guiné Subshrub Leaves, Maceration with alcohol, Santa Ferreira et al.
root external use Catarina (2021)
Leaves, Infusion, poultice São Paulo Pereira (2006)
fruit
RUBIACEAE
Morinda citrifolia L. Noni Tree Fruit In natura Bahia Brito et al.
(2020)
c
Leaves, In natura, “emplastro” Mato Grosso Pinheiro et al.
fruit (2015)
Leaves, Tea, infusion Mato Grosso Pinto et al.
fruit do Sul (2017)
Leaves, “Garrafada” Maranhão Olanda et al.
fruit (2020)
Fruit Juice Ceará Sousa et al.
(2021)
Fruit Infusion, oral use Alagoas Griz et al. (2017)
Uncaria guianensis (Aubl.) J.F.Gmel. Unha-de-gato Liana, Whole Infusion, oral use Mato Grosso Leitzke (2012)
scandent, plant, bark
vine
Leaves, “Garrafada”, take 1 time a Maranhão Correia (2017)
bark day
Uncaria tomentosa (Willd. ex Roem. & Unha-de-gato Liana, Bark Tea, “garrafada” Pará Cajaiba et al.
Schult.) DC. scandent, (2016)
vine
7
Table 2 (continued)
Bark Decoction, oral use Goiás Gonçalves (2016)

Shoots of Decoction Ceará Silva Neto et al.
leaves (2019)
Leaves Infusion Ceará Lima and
Fernandes (2020)
Bark, root, – Amazonas Silva et al.
leaves (2022a)
Root Decoction Ceará Bitu et al. (2015)
RUTACEAE
Citrus limon (L.) Osbeck Limão Tree Leaves, – Goiás Carneiro (2009)
fruit, seed
Ruta graveolens L. Arruda Herb Leaves Tea, maceration Paraíba Araujo (2009)
Leaves Juice Ceará Ricardo (2011)
SIPARUNACEAE
Siparuna guianensis Aubl. Negramina Shrub, tree Vine, Decoction, infusion, Mato Grosso Ribeiro et al.
leaves maceration (2017)
SOLANACEAE
Brunfelsia uniflora (Pohl) D.Don Manacá Shrub Leaves, Tea, “garrafada”, juice Mato Grosso Campos et al.
root (2021)
Solanum lycopersicum L. [Syn. Tomateiro Shrub Fruit Juice Pernambuco Teixeira and
Lycopersicum esculentum Mill.] Melo (2006)
URTICACEAE
Parietaria officinalis L. Parietária Herb Leaves Decoction Minas Gerais Messias et al.
(2015)
ZINGIBERACEAE
Alpinia zerumbet (Pers.) B.L.Burtt & Colônia Herb Leaves Tea Mato Grosso Pereira et al.
R.M.Sm. (2016)
Curcuma longa L. Açafrão, cúrcuma Herb Root – Goiás Ventura et al.
(2018)
– Topical use Piauí Alves et al.
(2021)
Flower – Paraíba Gomes (2014)
Zingiber officinale Roscoe Gengibre Herb Root, Tea, syrup, “emplastro”, juice, Pará Carvalho (2015)
leaves oral and topical use
a The scientific names of the species and habit were checked on the website Flora e Funga do Brasil© (http://floradobrasil.jbrj.gov.br/reflora/).
b Mixture of medicinal herbs kept in water or brandy in a bottle.
c Therapeutic preparation intended for external use.
d Product of maceration of plant substrates with alcohol.
Fig. 2. Families with the highest number of species used in the treatment of arthritis and osteoarthritis by traditional communities in Brazil.
8
Fig. 3. Parts of plants used for the treatment of arthritis and osteoarthritis in Brazil.
Fig. 4. Parts of plants and other products obtained from medicinal species used in the treatment of arthritis and osteoarthritis commercialized in Recife, state of
Pernambuco, Brazil. A) Immature and mature fruits of “noni” Morinda citrifolia (Rubiaceae); B) Dehydrated stem bark of “unha-de-gato” Uncaria tomentosa (Rubi-
aceae); C) Industrialized product based on “canela-de-velho” Miconia albicans (Melastomataceae) and “sucupira” Pterodon emarginatus (Fabaceae); D) Powder from
the rhizomes of “cúrcuma” Curcuma longa (Zingiberaceae). Photos by: Bezerra, J.J.L.
ported that the dose of 26 mg/kg of the gingerol-containing fraction obtained from Z. officinale rhizomes significantly inhibited joint
inflammation in the acute and chronic phases of joint destruction in a streptococcal cell wall-induced arthritis model. In contrast, the
clinical score, disease incidence, body weight changes, and erythrocyte sedimentation rate levels of arthritic rats treated with
200 mg/kg hydroalcoholic extract of Z. officinale rhizomes or 2 mg/kg indomethacin did not were statistically different from the pa-
rameters observed in healthy rats (Fouda and Berika, 2009). On the mechanisms of action involved in the anti-arthritic activity of Z.
officinale, Hwang et al. (2017) suggested that the aqueous extract of this plant exerts an anti-arthritic effect by inhibiting the produc-
9
Table 3
Anti-arthritic and anti-osteoarthritic activity of medicinal plants cultivated and used in Brazil.
Species Plant Extract or fraction Dose Experimental model References

organ
Ageratum conyzoides L. Leaves Methanolic extract 50, 100 and Membrane stabilization and Kumar and
250 μg/mL protein denaturation (In vitro) Ghosh (2015)
Leaves Ethanolic extract 40, 80, and CFA-induced arthritis (In vivo) Harfiani et al.
160 mg/kg (2017)
Ananas comosus (L.) Merril Fruit peel Methanolic extract 50, 100, 250 and CFA-induced arthritis (In vivo) Kargutkar and
500 mg/kg Brijesh (2016)
Annona muricata L. Leaves Ethanolic extract 10, 30, 100 and CFA-induced arthritis (In vivo) Foong and
300 mg/kg Hamid (2012)
Bidens pilosa L. Aerial Aqueous fraction 12.5, 25, 50, 100 CFA-induced arthritis (In vivo) Chauhan et al.
parts and 200 mg/kg (2011)
– Total flavonoids 40, 80 and Collagen-induced arthritis (In vivo) Hong et al.
160 mg/kg (2021)
Brassica oleracea L. Whole Ethanolic extract 2 g/kg CFA-induced arthritis (In vivo) Prabowo (2019)
plant
Seed Methanolic extract 250 mg/kg CFA-induced arthritis (In vivo) Hamed et al.
(2021)
Carapa guianensis Aubl. Seed Fraction of 25, 50, 100 and Zymosan-induced arthritis (In vivo) Penido et al.
tetranortriterpenoids 200 mg/kg (2006)
Citrus limon (L.) Osbeck Fruit peel Essential oil 100 mg/kg CFA-induced arthritis (In vivo) Li et al. (2022)
Fruit peel Hydroethanolic extract 100 mg/kg CFA-induced arthritis (In vivo) Ahmed et al.
(2018)
Crocus sativus L. Stigma Aqueous extract 100, 200, 400 and CFA-induced arthritis (In vivo) Sahebari et al.
800 mg/kg (2011)
Stigma Ethanolic extract 25, 50, 100, 200, CFA-induced arthritis (In vivo) Rabe et al.
400 and 600 mg/kg (2015)
Stigma Ethanolic extract 100 mg/kg CFA-induced arthritis (In vivo) Rathore et al.
(2017)
Stigma Methanolic fraction 200, 400 and Formaldehyde-induced arthritis (In Dhar et al.
600 mg/kg vivo) (2018)
Stigma Ethanolic extract 25, 50, 100 mg/kg CFA-induced arthritis (In vivo) Rathore et al.
(2015)
Curcuma longa L. Rhizomes Powder suspended 200 mg/kg CFA-induced arthritis (In vivo) Ramadan et al.
(2011)
Rhizomes Essential oil 28 mg/kg SCW-induced arthritis (In vivo) Funk et al.
(2010)
Rhizomes Turmerosaccharides fraction 22.5, 45 and MIA-induced osteoarthritis (In Bethapudi et al.
90 mg/kg vivo) (2017)
Rhizomes Polar extract 22.5, 45 and MIA-induced osteoarthritis (In Murugan et al.
90 mg/kg vivo) (2017)
– Industrialized extract 30, 60 and Collagen-induced arthritis (In vivo) Anna et al.
110 mg/kg (2011)
Dysphania ambrosioides (L.) Leaves Hydroalcoholic extract 0.5, 5 and 50 mg/ MIA-induced osteoarthritis (In Calado et al.
Mosyakin & Clemants [Syn. kg vivo) (2015)
Chenopodium ambrosioides L.]
Leaves Hydroalcoholic extract 1 and 5 mg/kg Collagen-induced arthritis (In vivo) Pereira et al.
(2018)
Echinodorus grandiflorus (Cham. & Leaves Hydroethanolic extract 100, 300 and Antigen-induced arthritis (In vivo) Garcia et al.
Schltr.) Micheli 1000 mg/kg (2016)
Harpagophytum procumbens (Burch.) Roots Ethanolic extract 25, 50 and CFA-induced arthritis (In vivo) Andersen et al.
DC. ex Meisn. 100 mg/kg (2004)
Libidibia ferrea (Mart. ex Tul.) Leaves Aqueous extract 100, 200 and Zymosan-induced arthritis (In vivo) Falcão et al.
L.P.Queiroz 300 mg/kg (2019)
Linum usitatissimum L. Seeds Fixed oil 1, 2 and 3 mL/kg CFA-induced arthritis (In vivo) Singh et al.
(2012)
Seeds Fixed oil 1, 2 and 3 mL/kg CFA-induced arthritis (In vivo) Kaithwas and
Majumdar
(2010)
Miconia albicans (Sw.) Steud. Leaves Ethanolic extract 50 and 100 mg/kg CFA-induced arthritis (In vivo) Quintans-Júnior
et al. (2020)
Morinda citrifolia L. Leaves Hydroethanolic extract 200 and 400 mg/kg MIA-induced osteoarthritis (In Osman et al.
vivo) (2019)
Fruit Methanolic extract 250 and 500 mg/kg CFA-induced arthritis (In vivo) Geetha et al.
(2015)
10
Table 3 (continued)
Species Plant Extract or fraction Dose Experimental model References

organ
Ocimum gratissimum L. Leaves Ethanolic extract 500 mg/kg Collagen-induced arthritis (In vivo) Madhu and
Harindran
(2014)
Rosmarinus officinalis L. Aerial Essential oil 10, 30, 100, 300 Pain-induced functional Martínez et al.
parts and 600 mg/kg impairment (In vivo) (2009)
Aerial Essential oil 50 μL MIA-induced osteoarthritis (In Belkhodja et al.
parts vivo) (2017)
Aerial Ethanolic extract 30, 100, 300, 1000 Pain-induced functional González-
parts and 3000 mg/kg impairment (In vivo) Trujano et al.
(2007)
Aerial Ethanolic extract 1000 and Pain-induced functional Martínez et al.
parts 3000 mg/kg impairment (In vivo) (2013)
Ruta graveolens L. Aerial Methanolic extract 20 mg/kg CFA-induced arthritis (In vivo) Ratheesh et al.
parts (2009)
Aerial Alkaloid fraction 10 mg/kg CFA-induced arthritis (In vivo) Ratheesh et al.
parts (2010)
Schinus terebinthifolia Raddi [Syn. Leaves Hydroethanolic extract 3.123, 6.25, 12.5, Zymosan-induced arthritis (In vivo) Rosas et al.
Schinus terebinthifolius Raddi] 25, 50, 100 and (2015)
200 mg/kg
Leaves Methanolic extract 100 mg/kg CFA-induced arthritis (In vivo) Oliveira et al.
(2020)
Sesamum indicum L. Seeds Ethanolic extract 400 and 800 mg/kg CFA-induced arthritis (In vivo) Ruckmani et al.
(2018)
Siparuna guianensis Aubl. Leaves Dichloromethane fraction 100 mg/kg Zymosan-induced arthritis (In vivo) Conegundes et
al. (2021)
Uncaria tomentosa (Willd. ex Roem. Roots Dry extract 150 mg/kg CFA-induced arthritis (In vivo) Castilhos et al.
& Schult.) DC. (2015)
Zingiber officinale Roscoe Rhizomes Powder suspended 200 mg/kg CFA-induced arthritis (In vivo) Ramadan et al.
(2011)
Rhizome Dichloromethane extract, 26 mg/kg SCW-induced arthritis (In vivo) Funk et al.
gingerol fraction (2009)
Rhizome Hydroalcoholic extract 50, 100 and Collagen-induced arthritis (In vivo) Fouda and Berika
200 mg/kg (2009)
Rhizome Methanolic extract, ethyl 20, 40, 60, 80 and Protein denaturation inhibition, Murugesan et al.
acetate extract, hexane extract 100 mg/mL membrane stabilization, proteinase (2020)
inhibitory (In vitro)
Root Aqueous extract 100 and 200 mg/kg Collagen-induced arthritis (In vivo) Hwang et al.
(2017)
CFA: Complete Freund's Adjuvant. MIA: Monosodium iodoacetate. SCW: Streptococcal cell wall.
tion of the inflammatory cytokine Th1 IFN-γ and the cytokine Th17 IL-17, as well as the expression of MMP-1, MMP-3 and MMP-13 in
mice with collagen-induced arthritis and synovial cells activated by IL-1β.
Curcuma longa is another Zingiberaceae used as a condiment that has been shown to be an alternative for the development of
herbal medicines against arthritis and osteoarthritis. In a study carried out by Anna et al. (2011), the dose of 110 mg/kg of C. longa
extract prevented bone erosion in the ankle joints of rats with collagen-induced arthritis. After 6 h of administration of the 90 mg/
kg dose, the fraction rich in turmericsaccharides obtained from the rhizomes reduced by 57% the osteoarthritic pain evaluated by
the model of monosodium iodoacetate-induced osteoarthritis in rats (Bethapudi et al., 2017). According to Murugan et al. (2017),
the observed anti-arthritic activity of the polar extract of C. longa rhizomes by the model monosodium iodoacetate-induced os-
teoarthritis, can be attributed to the maintenance of the balance between the expression of the genes of the anabolic and catabolic
pathways involved in cartilage protection.
Antimicrobial, antidiabetic, antioxidant, cardioprotective, neuroprotective, anticancer, and anti-arthritic activities are reported
for C. sativus (Sahebari et al., 2011; Rabe et al., 2015; Rathore et al., 2015; Al-Snafi, 2016; Bukhari et al., 2018; Hosseini et al., 2018;
Butnariu et al., 2022). According to Sahebari et al. (2011), aqueous extract of C. sativus at a dose of 400 mg/kg can reduce chronic in-
flammatory responses associated with adjuvant-induced arthritis in rats. These authors suggested that these effects can be related to
the alkaloids and saponins present in this plant. Rathore et al. (2015) reported that the ethanolic extract of C. sativus stigma is able to
reduce pro-inflammatory cytokines such as TNF-α and IL-1β by the adjuvant-induced arthritis model in mice. Rabe et al. (2015) also
observed that the ethanolic extract of C. sativus stigmas was effective in alleviating the symptoms of adjuvant-induced arthritis in rats,
and that the extract did not induce any side effects in the treated animals.
3.3. Clinical trials of plants used to treat arthritis and osteoarthritis in Brazil
Of the total of 55 species indicated for the treatment of arthritis and osteoarthritis, only 14 were investigated through randomized
clinical trials, and 13 of these showed clinically relevant results: Arctium lappa L., Crocus sativus, Curcuma longa, Ginkgo biloba,
Harpagophytum procumbens (Burch.) DC. Ex Meisn., Linum usitatissimum L. Miconia albicans, Morinda citrifolia, Sesamum indicum L.,
11
Symphytum officinale L., Uncaria guianensis (Aubl.) J.F.Gmel., Uncaria tomentosa, and Zingiber officinale (Table 4). These results rein-
force that ethnomedicinal indications for the treatment of arthritis and osteoarthritis in Brazil may have some support in clinical trials
and in the possible development of herbal medicines for rheumatic diseases in the country.
The species Zingiber officinale (Haghighi et al., 2005; Paramdeep, 2013; Mozaffari-Khosravi et al., 2016; Yoosefinejad et al., 2021)
and Curcuma longa (Madhu et al., 2013; Srivastava et al., 2016; Ross, 2016; Wang et al., 2020; Gomes et al., 2021) stood out in rela-
tion to the large number of clinical trials based on the use of their herbal medicines. These studies reported that patients treated with
products from these species showed clinical improvement in the symptoms of knee osteoarthritis and, consequently, provided a better
quality of life. From this perspective, it is likely that the Zingiberaceae family represents an important source of bioactive molecules
for the treatment of rheumatic diseases.
The Rubiaceae Uncaria guianensis and Uncaria tomentosa are clinically effective in the treatment of rheumatic diseases. According
to a placebo-controlled double-blind clinical trial, it was observed that 100 mg of lyophilized aqueous extract encapsulated from U.
guianensis improved the quality of life of patients diagnosed with knee osteoarthritis (Piscoya et al., 2001). These authors reported
that the main benefit associated with treatment with the encapsulated extract was the relief of exercise-related pain. Mur et al. (2002)
demonstrated that the extract of U. tomentosa, free from tetracyclic oxindole alkaloids, was effective in treating patients with rheuma-
toid arthritis. Patients treated with 60 mg of the extract showed a reduction of up to 53.2% in joint pain compared to the placebo
group, which only had a 24.1% reduction in pain.
Morinda citrifolia is another species of Rubiaceae with clinically proven anti-osteoarthritic effect. Three daily doses of “noni” juice
(Tahitian Noni®) administered to adults of both sexes with a radiographic diagnosis of hip or knee osteoarthritis, reduced the symp-
toms of osteoarthritis and improved the patients' quality of life (Wang et al., 2011). Despite the benefits associated with this medici-
nal plant, cases of intoxication have been reported in the literature, raising an alert for the continuous use or high dosages of prod-
ucts obtained from M. citrifolia. Yu et al. (2011) reported the case of a previously healthy young man who presented a clinical picture
characterized by acute hepatotoxicity after consuming approximately 91 mg/kg of M. citrifolia juice.
Despite the ethnopharmacological importance of Ananas comosus (L.) Merril, a double-blind randomized parallel-group placebo-
controlled trial found that the 800 mg dose of Bromelain (Lichtwer Pharma UK) did not show efficacy for the treatment of moderate
or severe osteoarthritis in 14 adult patients aged over 40 years diagnosed with osteoarthritis in at least one knee joint (Brien et al.,
2006). In recent study, Sharma and Chaudhary (2021) developed bromelain loaded nanostructured lipid carriers (Br–NCs) that aug-
mented protection to bromelain from gastric milieu and potentiated its antioxidant and anti-inflammatory effect by counteracting the
inflammatory changes induced by CFA in rats. This may be an effective alternative to improve the clinical effects of this product in pa-
tients with rheumatoid arthritis or osteoarthritis.
Detailed information (species, study design, patients, products, doses, and recommendations) on randomized clinical trials of
medicinal species used in the treatment of arthritis and osteoarthritis in Brazil are presented in Table 4.
Regarding the gaps found in these studies, the need for in-depth pharmacokinetic and toxicokinetic investigations stands out,
mainly to ensure the safety and efficacy of herbal medicines evaluated in patients with rheumatic diseases. Among the 55 species al-
ready clinically evaluated, there are at least two dozen plants without any preclinical and clinical studies conducted.
3.4. Phytochemistry of plants used in the treatment of arthritis and osteoarthritis in Brazil
Several chemical compounds belonging to the phenolic classes (Kim et al., 1999; Gonçalves et al., 2018; Quintans-Júnior et al.,
2020; Conegundes et al., 2021; Hamed et al., 2021; Zhang et al., 2021), diarylheptanoids (Nonose et al., 2014), tricarboxylic acids
(Oliveira et al., 2018a, 2022), terpenoids (Murugesan et al., 2020; Xie et al., 2020; Li et al., 2022), and alkaloids (Rakhecha et al.,
2022), have been identified in cultivated plants reported for the treatment of arthritis and osteoarthritis in Brazil (Table 5).
In general, phenolic compounds stand out in relation to other classes of compounds, being the main constituents identified in ex-
tracts. The flavonoids luteolin, rutin, kaempferol, hesperidin, apigenin, and quercetin, for example, are known to have anti-arthritic
activity due to their effects against the inflammatory processes associated with rheumatoid arthritis in experimental models (Shi et
al., 2015; Sun et al., 2017; Pan et al., 2018; Qi et al., 2019; Li et al., 2019; Yuan et al., 2020; Tang et al., 2022). Compounds isolated
from Ginkgo biloba (Kim et al., 1999; Xie et al., 2020; Zhang et al., 2021), Echinodorus grandiflorus (Oliveira et al., 2018b, 2022), and
Rosmarinus officinalis (Wei et al., 2021) (Fig. 5) had their mechanisms of action investigated in experimental models of arthritis.
Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, reduced arthritic inflammation by 71 and 86% in rats at doses of 10 and
20 mg/kg, respectively, in an adjuvant-induced arthritis model (Kim et al., 1999). According to Xie et al. (2020), ginkgolide B iso-
lated from G. biloba leaves at doses of 10, 20 and 40 μM, reduced significant synovial hyperplasia, pannus formation, infiltration of in-
flammatory cells, and cartilage degeneration in the model of collagen-induced arthritis in mice. In addition, treatment with
ginkgolide B decreased levels of pro-inflammatory cytokines (IL-1β, IL-6, MCP-1, and TNF-α) and increased levels of anti-
inflammatory cytokines (IL-10).
Zhang et al. (2021) reported that at doses of 25 and 50 mg/kg, ginkgolic acid, isolated from leaves and fruits of G. biloba, signif-
icantly reduced the arthritic index score in rats by the Complete Freund's Adjuvant-induced arthritis (CFA) model. According to
these authors, the anti-arthritic properties of ginkgolic acid can be attributed to its capacity to prevent lipid peroxidation and the
infiltration of inflammatory cytokines, in addition to increasing enzymatic and non-enzymatic antioxidants and the level of the
anti-inflammatory cytokine IL-10.
Trans-Aconitic acid, isolated from E. grandiflorus, after oral administration in male Swiss mice at a dose of 30 mg/kg, significantly
reduced total leukocytes and neutrophils in the tibiofemoral joint (Oliveira et al., 2018b). cis-Aconitic acid, also isolated from E. gran-
diflorus, at a dose of 90 mg/kg markedly reduced the infiltration of inflammatory cells by the antigen-induced arthritis model. In ad-
12
Table 4
Randomized clinical trials of medicinal species used in the treatment of arthritis and osteoarthritis in Brazil.
Species Study design Patients Products Dose Recommendations References
Ananas comosus (L.) Double-blind Adults aged >40 years Bromelain 800 mg Bromelain is not effective as an Brien et al.
Merril randomized with a diagnosis of (Lichtwer Pharma adjunctive treatment of moderate to (2006)
parallel-group osteoarthritis in at least UK) severe osteoarthritis
placebo-controlled one knee joint
trial
Arctium lappa L. Randomized, Patients of both sexes aged Root tea 2g Root tea consumption may improve Maghsoumi-
single-blind, between 50 and 70 years lipid profile and blood pressure Norouzabad et
placebo-controlled suffering from bilateral status in patients with knee al. (2019)
clinical trial osteoarthritis of the knee osteoarthritis
Randomized, Patients of both sexes aged Root tea 2g Root tea improves the inflammatory Maghsoumi-
parallel clinical between 50 and 70 years status and oxidative stress in Norouzabad et
trial with knee osteoarthritis patients with knee osteoarthritis al. (2016)
Crocus sativus L. Randomized, Women over 18 years of Saffron 100 mg Saffron supplements can positively Hamidi et al.
double-blind, age with active supplements and significantly improve clinical (2020)
placebo-controlled rheumatoid arthritis (tablets) outcomes in patients with
clinical trial rheumatoid arthritis
Randomized, Patients with a mean age Pills containing 100 mg Patients who received saffron pills Sahebari et al.
double-blind, of 49.32 ± 12.37 years, pure saffron did not see a significant (2021)
placebo-controlled, with a predominance of powder improvement in their rheumatoid
clinical trial women arthritis
Curcuma longa L. Randomized, Patients of both sexes over NR–INF–02 500 mg The study demonstrates the safety Madhu et al.
single-blind, 40 years of age with (Turmacin™) and efficacy of NR–INF–02 as a (2013)
placebo-controlled, clinical evidence useful treatment option for patients
clinical trial confirming the diagnosis with primary painful knee
of osteoarthritis of the osteoarthritis
knee
Randomized, Participants over 40 years Aqueous-based 1000 mg The evaluated product was more Wang et al.
double-blind, of age with symptomatic extract effective than placebo for knee pain, (2020)
placebo-controlled knee osteoarthritis and standardized but did not affect knee effusion–
clinical trial ultrasonography-defined (Turmacin Plus) synovitis or cartilage composition
effusion-synovitis
Parallel-group, Patients of both sexes aged Extract from 500 mg Administration of the evaluated Srivastava et
double-blind, between 40 and 80 years rhizomes (Haridra) product suppresses inflammation al. (2016)
randomized, old who suffered from and brings clinical improvement in
placebo-controlled, primary osteoarthritis of patients with knee osteoarthritis
single-center the knee
clinical trial
Randomized, Patients aged 50 years or Curcumin extract 1500 mg Curcumin extracts are as effective as Ross (2016)
double-blind, older who met the primary ibuprofen in treating knee
controlled inclusion criteria for knee osteoarthritis pain
multicenter clinical osteoarthritis
trial
Longitudinal study Patients over 40 years of Capsules (Vida 1000 mg The study demonstrated that the Gomes et al.
of analysis, age with knee Ervas laboratory) product evaluated in the treatment (2021)
intervention and osteoarthritis of knee osteoarthritis positively
reanalysis interferes with pain and improves
the functionality of patients
Ginkgo biloba L. Double-blind, Patients of both sexes aged Standard extract 120 mg The evaluated product may provide Al-Haddad et
randomized between 38 and 75 years additional beneficial health effects al. (2022)
clinical trial diagnosed with knee for patients with osteoarthritis of the
osteoarthritis knee
Harpagophytum Double-blind, Patients of both sexes aged Teltonal® 480 mg Teltonal is an effective and safe Farpour et al.
procumbens randomized between 40 and 60 years treatment in patients with mild (2021)
(Burch.) DC. ex clinical trial with pain and other osteoarthritis of the knee in the
Meisn. clinical signs of knee short term
osteoarthritis
Double-blind, Patients aged between 30 Harpadol® 435 mg The study confirmed the efficacy Chantre et al.
randomized, and 79 years with active and very good tolerance of Harpadol (2000)
multicenter clinical osteoarthritis of the knee in the treatment of osteoarthritis.
trial or hip
Linum usitatissimum Randomized, Patients of both sexes aged Topical linseed oil 20 drops Linseed oil could be effective in the Mosavat et al.
L. placebo-controlled, between 40 and 70 years every 8 h management of clinical sign of knee (2018)
double-blind diagnosed with knee osteoarthritis, especially in
clinical trial osteoarthritis improving the severity of symptoms
and functional status
13
Table 4 (continued)
Species Study design Patients Products Dose Recommendations References
Miconia albicans Longitudinal study Patients over 40 years of Capsules (Bio Vittas 1000 mg The study demonstrated that the Gomes et al.
(Sw.) Steud. of analysis, age with knee laboratory) product evaluated in the treatment (2021)
intervention and osteoarthritis of knee osteoarthritis positively
reanalysis interferes with pain and improves
the functionality of patients
Morinda citrifolia L. Open intervention Patients of both sexes aged Tahitian Noni® 3 doses of The pilot intervention study suggests Wang et al.
pilot study between 40 and 75 years (juice) juice daily that noni juice is a potential, safe, (2011)
with a radiographic and effective agent that can reduce
diagnosis of osteoarthritis osteoarthritis symptoms and help
of the hip or knee improve quality of life
Sesamum indicum L. Randomized, Participants of both sexes Sesame oil 1.5 mL Topical use of sesame oil was non- Askari et al.
double-arm, aged between 30 and 70 inferior to diclofenac gel regarding (2019)
double-blind, years old with a diagnosis the reduction of the knee
active-controlled of osteoarthritis and osteoarthritis pain
clinical trial presence of pain in the
knee joint
Symphytum Double-blind, Patients of both sexes aged Kytta-Salbe® 6g The study has proven that the Grube et al.
officinale L. randomized, over 18 years with painful application of topical comfrey root (2007)
bicenter, placebo- osteoarthritis of the knee extract is a sensible treatment option
controlled clinical in osteoarthritis of the knee
trial
Multicenter, Patients of both sexes aged 4Jointz® Applied Both active topical comfrey Smith and
randomized, between 45 and 83 years topically formulations were effective in Jacobson
double-blind, with a primary diagnosis thrice relieving pain and stiffness and in (2011)
placebo-controlled of knee osteoarthritis daily improving physical functioning and
clinical trial were superior to placebo in those
with primary osteoarthritis of the
knee without serious adverse effects
Uncaria guianensis Randomized, Adult patients of either sex Reparagen® 1800 mg Reparagen represents a new natural Mehta et al.
(Aubl.) double-blind, and over 20 years of age productive alternative in the (2007)
J.F.Gmel. positive control, with mild to moderate management of joint health
multicenter clinical osteoarthritis
trial
Multicenter, Male patients aged Lyophilized and 100 mg The evaluated product is an effective Piscoya et al.
randomized, between 45 and 75 years encapsulated treatment for osteoarthritis (2001)
double blind, with knee osteoarthritis aqueous extract
placebo-controlled, and local pain
parallel clinical
trial
Uncaria tomentosa Randomized, Patients of both sexes over TOA-free extract 60 mg Treatment with the evaluated Mur et al.
(Willd. ex double-blind, 20 years of age with active product resulted in a reduction in (2002)
Roem. & placebo-controlled rheumatoid arthritis the number of painful joints
Schult.) DC. clinical trial compared to placebo
Zingiber officinale Randomized, open- Patients of both sexes, Encapsulated 750 mg Ginger powder has add-on effect on Paramdeep
Roscoe label clinical trial aged between 35 and 61 rhizome powder reducing the symptoms of (2013)
years with symptomatic osteoarthritis of the knee with
osteoarthritis of the knee acceptable safety profile
Randomized, Participants aged between Encapsulated 500 mg The study indicates that ginger Mozaffari-
double-blind, 50 and 70 years with rhizome powder supplementation may have Khosravi et al.
placebo-controlled osteoarthritis and presence promising benefits for osteoarthritis (2016)
clinical trial of knee pain of the knee
Randomized, Patients older than 45 Gel formulation – Ginger extract phonophoresis can Yoosefinejad
parallel-group years diagnosed with based on relieve pain and improve function et al. (2021)
clinical trial moderate knee hydroalcoholic compared to routine ultrasound
osteoarthritis extract of ginger therapy in patients with moderate
rhizomes osteoarthritis of the knee
Double-blind, Patients of both sexes aged Ethanolic extract 30 mg The study indicates that ginger Haghighi et al.
randomized, between 52 and 64 years of rhizomes extract can be used as an alternative (2005)
placebo-controlled and diagnosed with encapsulated to NSAIDs and as a complementary
clinical trial osteoarthritis medicine in patients with
osteoarthritis
TOA: Tetracyclic oxindole alkaloids. NSAIDs: Non-steroidal anti-inflammatory drugs.
dition, this compound also reduced the arthritis index, hypernociception and IL-1β levels in periarticular tissues compared to vehicle-
treated mice (Oliveira et al., 2022).
At a dose of 60 mg/kg, rosmarinic acid isolated from the leaves of R. officinalis caused a considerable alteration in the joint move-
ment of the rats by the CFA model, after 14 days of experiment. This compound also caused a significant decrease in serum levels of
tumor necrosis factor-α (TNF-α) compared to the control group (Wei et al., 2021). Treatment with 60 mg/kg of rosmarinic acid was
14
Table 5
Chemical compounds identified in medicinal plants used in Brazil with anti-arthritic and anti-ostearthritic potential.
Species Plant organ Compounds Type of extract/ Identification Experimental References

product method model
Brassica oleracea Seeds Kaempferol 3-O-(4-β-xylopyranosyl)-α-l- Methanolic UV, EI-MS, CFA-induced Hamed et al.
L. rhamnopyranoside-7-O-α-l-rhamnopyranoside, extract NMR arthritis (In vivo) (2021)
kaempferol 3,7-O-α-L-dirhamnopyranosid,
isorhamnetin 3-O-α-l-rhamnosyl (1‴→6″)-β-
glucopyranoside, quercetin 3-O-α-l-rhamnosyl
(1‴→6″)-β-glucopyranoside, quercetin-3-O-α-l-
rhamnopyranoside, quercetin-7-O-β-glucopyranoside,
kaempferol 3-O-α-l-rhamnopyranoside, kaempferol,
isorhametin, quercetin, caffeic acid, gallic acid
Cauliflower Nicotine Isolated HPLC Pro-inflammatory Rakhecha et
compound cytokines mRNA al. (2022)
expression and
anti-inflammatory
effects (In vitro)
Citrus limon (L.) Fruit peel d-limonene, linalool, linalyl acetate, α-terpinyl Essential oil GC-MS CFA-induced Li et al.
Osbeck acetate arthritis (In vivo) (2022)
Curcuma longa L. Rhizomes Galactouronic acid, glucose, galactose, mannose, Polar extract HPLC MIA-induced Murugan et
arabinose, xylose, rhamnose osteoarthritis (In al. (2017)
vivo)
Rhizomes Curcumin Isolated – Zymosan-induced Nonose et al.
compound arthritis (In vivo) (2014)
Echinodorus Leaves trans-aconitic acid Isolated UPLC-ESI-MS LPS-induced acute Oliveira et
grandiflorus compound arthritis (In vivo) al. (2018a,
(Cham. & 2018b)
Schltr.)
Micheli
Leaves cis-aconitic acid Isolated – Antigen-induced Oliveira et
compound Arthritis (In vivo) al. (2022)
Ginkgo biloba L. Leaves Ginkgolide B Isolated – Collagen-induced Xie et al.
Leaves, Ginkgolic acid Isolated – CFA-induced Zhang et al.
fruits compound arthritis (In vivo) (2021)
Leaves Ginkgetin Isolated TLC, HPLC Adjuvant-induced Kim et al.
Miconia albicans Leaves Pedunculagin, galic acid, ethyl gallate, myricetin-O- Ethanol extract HPLC-ESI-MS CFA-induced Quintans-
(Sw.) Steud. galloyl-hexoside, myricetin-O-hexoside, quercetin-O- arthritis (In vivo) Júnior et al.
galloyl-hexoside, rutin, isoquercitrin, quercetin-O- (2020)
pentoside, ellagic acid-O-deoxyhexoside, quercetin-
O-galloyl-pentoside, quercetin-O-deoxyhexose-
pentoside, isorhamnetin-O-hexoside, kaempferol-O-
pentoside, isorhamnetin-O-deoxyhexoside, quercetin-
O-galloyl-deoxyhexose, methyl ellagic acid-O-
acetate-deoxyhexoside, quercetin
Rosmarinus Leaves Caffeic acid hexoside, caffeic acid acetylhexoside, Aqueous extract LC-DAD- Adjuvant-induced Gonçalves et
n
officinalis L. caffeic acid, prolithospermic acid, yunnaneic acid F, ESI/MS arthritis (In vivo) al. (2018)
luteolin-3-O-glucuronide, acetylquercetin-O-
rutinoside, rosmarinic acid, luteolin-O-glucuronide,
salvianolic acid A, acetylluteolin-O-glucuronide
Leaves Rosmarinic acid Isolated TLC, HPLC, CFA-induced Wei et al.
compound IR arthritis (In vivo) (2021)
Siparuna Leaves Kaempferol-pentosyl-pentoside-rhamnoside, Dichloromethane UHPLC-MS Zymosan-induced Conegundes
guianensis kaempferol dirhamnoside, kaempferol-pentosyl- fraction arthritis (In vivo) et al. (2021)
Aubl. rhamnoside, rhamnosyl-kaempferol, kaempferol
dimethyl ether
Zingiber officinale Rhizomes Curcumene, β-sesquiphellandrene, zingiberene, Methanolic GC-MS Protein Murugesan
Roscoe zingerone, 6-gingerol, ferulic acid ethyl ester, extract denaturation et al. (2020)
hexadecanoic acid, 8-gingerol, octadecanoic acid, inhibition,
dihydrocapsaicin membrane
stabilization,
proteinase
inhibitory (In vitro)
CFA: Complete Freund's Adjuvant. EI-MS: Electron Ionization coupled to Mass Spectrometry. GC-MS: Gas Chromatography coupled to Mass Spectrometry. HPLC: High
Performance Liquid Chromatography. HPLC-ESI-MS: High Performance Liquid Chromatography with Electrospray Ionization coupled to Mass Spectrometry. IR: In-
n
frared Spectroscopy. LC-DAD-ESI/MS : Liquid Chromatography with Diode Array Detection, coupled to Mass Spectrometry with Electrospray Ionization. LPS:
Lipopolysaccharide. MIA: Monosodium iodoacetate. NMR: Nuclear Magnetic Resonance. TLC: Thin Layer Chromatography. UHPLC-MS: Ultra-High Pressure Liquid
15
Chromatography coupled to Mass Spectrometry. UPLC-ESI-MS: Ultra-performance Liquid Chromatography with Electrospray Ionization coupled to Mass Spectrometry.
UV: Ultraviolet.
Fig. 5. Compounds isolated from Ginkgo biloba (1–3), Echinodorus grandiflorus (4, 5), and Rosmarinus officinalis (6) with anti-arthritic activity.
more effective when compared to the 30 mg/kg dose, and caused a significant decrease in left paw volume, inflammation, nodules,
and joint stiffness in arthritic rats.
Mechanisms of action related to the potential of rosmarinic acid against arthritis have been reported in other studies (Gautam et
al., 2019; Luo et al., 2020; Youn et al., 2003). Youn et al. (2003) observed that the synovial tissue of mice treated with rosmarinic acid
indicated a large reduction in the frequency of cells that express cyclooxygenase-2 (COX-2), an enzyme involved in the synthesis of
pro-inflammatory mediators. At doses of 25 and 50 mg/kg, rosmarinic acid showed a significant decrease in malonaldehyde (MDA)
and TNF-α levels compared to the control group of arthritic rats (Gautam et al., 2019).
16
3.5. Toxicity related to plants used to treat arthritis and osteoarthritis in Brazil
Pterodon emarginatus, popularly known as “sucupira” or “sucupira-branca”, is widely used for the treatment of arthritis in several
Brazilian states, including Mato Grosso (Leitzke, 2012; Ribeiro et al., 2017), Ceará (Pereira et al., 2014), Goiás (Santos et al., 2015),
Bahia (Brito et al., 2015), and São Paulo (Lima, 2017). However, to date, no studies on anti-arthritic activity in animal models or re-
ports of randomized clinical trials with this species have been found. On the other hand, this species requires special attention when
destined for medicinal uses, as cases of intoxication in production animals associated with ingestion of the leaves have been reported
in the Midwest region of Brazil, more specifically in the states of Mato Grosso, Mato Grosso do Sul, and Goiás (Cruz et al., 2012;
Furlan et al., 2012; Sant’Ana et al., 2012; Sant’Ana et al., 2014).
According to Cruz et al. (2012), P. emarginatus is considered a hepatotoxic plant with reports of hepatocellular coagulative necro-
sis observed in cattle. Sant’Ana et al. (2012) also reported lesions in the liver of cattle that ingested P. emarginatus leaves. Among the
histological findings, necrosis and moderate to severe massive hepatocellular degeneration were observed, mainly in the periportal
and intermediate zones. In addition to the leaves, the P. emarginatus seed extract induced depressant and stimulant effects on the Cen-
tral and Autonomic Nervous System (CNS and ANS) in Swiss mice (Fukahori et al., 2015).
Morinda citrifolia is another species widely used for the treatment of arthritis in Brazil, but which has already been reported as
toxic in some studies. According to Müller et al. (2009), the dose of 7.5 mg/kg of the aqueous extract of the fruits of M. citrifolia
caused a 50% reduction in the parturition rate and a 74% decrease in the post-implantation loss rate in Wistar rats. In a study carried
out by Shalan et al. (2017), it was observed that the dose of 2 mg/mL of the aqueous extract of the fruits of M. Citrifolia caused mor-
tality in mice, while the animals treated with 1 mg/kg of the extract showed histological changes in the liver. Poisoning caused by
consumption of this species has also been observed in humans. Yu et al. (2011) reported a case of a previously healthy 14-year-old
boy with acute hepatotoxicity after consuming approximately 91 mg/kg of M. citrifolia juice.
Species of the genus Equisetum, popularly known as “cavalinha”, are traditionally used for the treatment of rheumatic diseases in
Brazil (Cardoso, 2013; Tribess et al., 2015). However, according to Santos et al. (2005), doses of 2 and 5 g/kg of the hydroalcoholic
extract of the stem of Equisetum arvense L. induced mortality in Wistar rats, in addition to causing transient respiratory depression and
high sedation in all treated animals. The ethanol extract of aerial parts of E. arvense at a dose of 120 mg/kg caused mild hepatocellular
necrosis in rats (Badole and Kotwal, 2015).
In a study carried out by Queiroz et al. (2014), it was observed that a dose of 100 mg/kg of the ethanolic extract of the aerial parts
of Equisetum hyemale L. induced changes in the pattern of piloerection in mice during the initial minutes after administration. Al-
though the dose of 100 mg/kg is relatively low for the acute toxicity test, the E. hyemale extract showed effects on piloerection in the
evaluated animals. Thus, higher doses are likely to cause more severe toxic effects. According to the guidelines of the Organization for
Economic Co-operation and Development (OECD) (Acute Toxic Class Method – OECD 425), the recommended dose to assess acute
toxicity is at least 2000 mg/kg (OECD, 2022).
4. Gaps and future prospects

Brazil is known for having a medicinal flora rich in bioactives (Dutra et al., 2016). Our findings indicated a total of 55 cultivated
species traditionally used to treat arthritis and osteoarthritis in the country. Despite advances in the bioprospecting of Brazilian
species (Nogueira et al., 2010; Bolzani et al., 2012; Silva et al., 2022b), many plants mentioned in ethnobotanical surveys still lack sci-
entific investigations that prove their anti-arthritic effects. It was observed that a relatively low number of compounds isolated from
these plants were pharmacologically evaluated in models of induced rheumatic diseases in animals. These studies are important to
elucidate which are the mechanisms of action of natural products involved with anti-arthritic and anti-osteoarthritic activity.
Despite the need to develop new products for the treatment of chronic diseases, it was found that of the 14 species used in random-
ized clinical trials, only products obtained from U. tomentosa and C. sativus were evaluated in the treatment of rheumatoid arthritis
(Mur et al., 2002; Hamidi et al., 2020; Sahebari et al., 2021). For the treatment of patients diagnosed with knee osteoarthritis, 12
species were evaluated in clinical trials for this purpose. These studies indicated that products obtained from cultivated plants used in
Brazil constitute an important source of active molecules for the treatment of rheumatic diseases. In this perspective, it is important to
continue the randomized clinical trials aimed at the development of new safe and effective anti-arthritic herbal medicines.
There is constant concern about the side effects caused by drugs marketed for the treatment of rheumatoid arthritis (Narayan et
al., 2017; Wang et al., 2018; Coirier et al., 2018; Friedman and Cronstein, 2019; Tavakolpour et al., 2019). However, it was found that
some species widely used by traditional communities in Brazil for this purpose have hepatotoxicity and damage to the animals’ repro-
ductive system. Thus, it is important that more studies be carried out to investigate the potential of other species traditionally used in
the treatment of arthritis and osteoarthritis in the country.
5. Conclusion
This is the first study that brings together literature publications on species cultivated in Brazil used in the treatment of arthritis
and osteoarthritis. Of the 55 species traditionally used to treat rheumatic diseases, only 24 have had their anti-arthritic and anti-
osteoarthritic activities scientifically investigated, and 14 have been evaluated in randomized clinical trials. The Asteraceae,
Fabaceae and Lamiaceae families were the most representative in number of species indicated for the treatment of rheumatic dis-
eases. Phenolic compounds such as flavonoids may be directly involved with the anti-arthritic and anti-ostoarthritic activity of the
species reported in this study. The evidence of toxicity of P. emarginatus and M. citrifolia is worrying, since the products obtained from
these plants are widely used for the treatment of arthritis and osteoarthritis in Brazil.
17
The discovery of phytopharmaceuticals from novel plant sources is pivotal in introducing novel therapeutic options that are read-
ily accessible to the general population. The results of this study highlight that plant species cultivated in different regions of Brazil
present bioactive compounds of pharmacological interest, demonstrating their potential for formulating herbal medicines targeted at
treating rheumatic diseases. Additionally, 27 medicinal species cited by traditional Brazilian communities still lack scientific in vitro
and in vivo studies to prove their anti-arthritic and anti-osteoarthritic effects.
CRediT authorship contribution statement

José Jailson Lima Bezerra: Writing – original draft, Validation, Methodology, Investigation, Formal analysis, Data curation,
Conceptualization. Antônio Fernando Morais de Oliveira: Writing – review & editing, Supervision, Project administration, Data
curation.
Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgments
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) – Finance
Code 001. The first author is grateful to the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – Brazil)
(167916/2022-0) and Fundação de Amparo à Ciência e Tecnologia de Pernambuco (FACEPE – Brazil) (BCT-0737-2.10/22). The sec-
ond author is grateful to the CNPq for the research grant (310177/2022-7).
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Exploring The Therapeutic Potential of Brazilian Medicinal Plants For Anti-Arthritic and Anti-Osteoarthritic Applications

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Biocatalysis and Agricultural Biotechnology 56 (2024) 103064

Contents lists available at ScienceDirect

Biocatalysis and Agricultural Biotechnology

Exploring the therapeutic potential of Brazilian medicinal plants

ARTICLE INFO ABSTRACT

2.2. Inclusion and exclusion criteria

2.3. Data screening and categorization of information

2.4. Statistical analysis

Fig. 1. Flow diagram of selection of scientific documents included in this review.

3. Results and discussion

Northeast Ceará (CE) 6 8.69

3.2. Anti-arthritic and anti-osteoarthritic activity of plants cultivated in Brazil

Bark Decoction, oral use Goiás Gonçalves (2016)

Species Plant Extract or fraction Dose Experimental model References

Species Plant Extract or fraction Dose Experimental model References

Species Study design Patients Products Dose Recommendations References

Species Study design Patients Products Dose Recommendations References

Species Plant organ Compounds Type of extract/ Identification Experimental References

4. Gaps and future prospects

CRediT authorship contribution statement

Declaration of competing interest

Pharmaceut. Sci. 119, 112–120. https://doi.org/10.1016/j.ejps.2018.04.010.

de Goiás. Pesqui. Vet. Bras. 32, 485–489. https://doi.org/10.1590/S0100-736X2012000600003.

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