UNIVERSIDADE ESTADUAL PAULISTA
“JÚLIO DE MESQUITA FILHO”
Instituto de Ciência e Tecnologia
Campus de São José dos Campos
SYSTEMATIC REVIEW DOI: https://doi.org/10.4322/bds.2024.e3907
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Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in
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Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Extratos vegetais utilizados no Brasil para tratamento de úlceras orais e mucosite: revisão sistemática
Luiz Evaristo Ricci VOLPATO1 , Patrícia Leão Castillo EUBANK1 , Lorraynne dos Santos LARA1 ,
Géssica Vasconcelos GODINHO1 , Lucas Guimarães ABREU2
1 - Universidade de Cuiabá, Cuiabá, MT, Brazil.
2 - Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
How to cite: Volpato LER, Eubank PLC, Lara LS, Godinho GV, Abreu LG. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review. Braz Dent Sci. 2024;27(1):3907. https://doi.org/10.4322/bds.2024.e3907
ABSTRACT
Objective: To identify and analyze plant extracts used in Brazil for the treatment of oral ulcers and oral mucositis.
Material and Methods: A systematic review was registered in PROSPERO (CRD 42018102184) and performed
following the PRISMA protocol. The databases searched were PubMed, Web of Science, Scopus, Lilacs, Scielo,
the Brazilian Dentistry Library. Manual searches were also performed. Results: Initially, 440 studies were found,
of which 392 were excluded after reading the titles and abstracts. A total of 29 articles were read in full and
11 studies were excluded, resulting in 18 articles included in the systematic review. Nine plant species were
identied in ve clinical trials and 13
in vivo
studies, with
Chamomila recutita
being the most used (33.3% of
the studies).
Chamomila recutita
showed more promising results for analgesic, anti-inammatory, and healing
properties.
Calotropis procera
latex signicantly decreased (p<0.05) inammatory mediators, such as TNF-α and
IL-1β in oral mucositis induced in rats.
Eupatorium laevigatum
showed anti-inammatory activity and analgesic
action on oral ulcers.
Carapa guianensis Aubl
. reduced the severity and painful symptoms of oral mucositis and
exhibited better results compared to the use of low power laser.
Curcuma longa L
accelerated re-epithelialization
and resolution of inammatory processes.
Spondias mombin
reduced oxidative stress and inammation caused
by oral mucositis and helped on healing it. Extracts of
Aloe barbadensis Miller
or
Aloe vera
showed anti-
inammatory action but did not help in the healing process of oral ulcers.
Copaifera reticulata
Ducke oil did
not induce improvement in the healing process, nor did it show an anti-inammatory effect.
Malva sylvestris
did not show an anti-inammatory action on oral lesions in humans or rats. The assessment of methodological
heterogeneity showed the impossibility of performing a meta-analysis. Risk of bias varied from low to high.
Conclusion: The plant species most used and with the best results for the treatment of oral ulcerations and
oral mucositis was
Chamomilla recutita
.
Spondias mombin L
.,
Curcuma longa L
.,
Carapa guianensis
Aubl and
Calotropis procera
showed good results in the treatment of oral mucositis, while
Eupatorium laevigatum
was
efcient in the treatment of ulcers of traumatic origin.
Malva sylvestris
,
Copaifera reticulata
Ducke, and
Aloe
barbadensis
Miller did not exhibit signicant results.
KEYWORDS
Medicinal plants; Mucositis; Oral ulcer; Phytotherapy; Plant extracts; Stomatitis.
RESUMO
Objetivo: Identicar e analisar extratos vegetais utilizados no Brasil para o tratamento de úlceras orais e mucosite
oral. Material e Métodos: Uma revisão sistemática foi registrada no PROSPERO (CRD 42018102184) e realizada
seguindo o protocolo PRISMA. As bases de dados pesquisadas foram PubMed, Web of Science, Scopus, Lilacs, Scielo,
Biblioteca Brasileira de Odontologia. Buscas manuais também foram realizadas. Resultados: Inicialmente, foram
encontrados 440 estudos, dos quais 392 foram excluídos após a leitura dos títulos e resumos. Um total de 29 artigos
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Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
INTRODUCTION
Oral ulcers have a variety of clinical
characteristics and are classified based on the
evolution period (acute or chronic), the number of
lesions (single or multiple), and etiological factors
(local or systemic), such as traumatic ulcers and
recurrent aphthous stomatitis [1]. Oral mucositis
(OM) is a common outcome in patients undergoing
cancer treatment [2], whose probable mechanism
of action is the development of complex biological
events mediated by inammatory cytokines, which
cause ulceration and destruction of the epithelial
barrier [3] and make the underlying connective
tissue unprotected and vulnerable to external
aggression [4] as well as other oral ulcers.
These oral lesions can decrease the patient’s
quality of life, causing pain and discomfort,
leading to the impairment of some functions such
as chewing, swallowing, speaking, and taste [5,6].
OM can become a limiting factor for cancer
treatment and may cause its interruption [7] or
serve as a gateway for the proliferation of bacteria,
fungi, and viruses in an already debilitated
patient [8].
The absence of a standard protocol for the
treatment of OM and oral ulcerations points to
the need for further studies with possible effective
and more accessible interventions [9]. The most
used measures are based on palliative care, such
as good oral hygiene, use of mouthwashes, anti-
inammatories, and low power laser [8,10].
Natural treatment with medicinal plants is
an affordable option for patients who already
use several medications, as it has fewer side
effects and lower cost compared to conventional
medications [11,12]. It is known that plants
have long since been used for various purposes,
including the prevention and treatment of
diseases [13].
Brazil has an extensive territorial area and
biodiversity, with a great variety and quantity of
plant species with medicinal potential [14]. It also
has a good adaptation of plant cultures from
different parts of the world that, when cultivated
in Brazil, can have different properties [15].
Knowledge on plants and natural products
with therapeutic potential is important both
for their historical-cultural value and for
information about their correct indication, use,
and commercialization [16]. Thus, this systematic
review aimed to identify and evaluate herbal
medicines or plant extracts used in Brazil for the
treatment of oral ulcers and mucositis.
MATERIALS AND METHODS
Protocol registration and reporting guidelines
This systematic review followed the
guidelines of the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses,
the PRISMA statement [17]. A protocol was
registered, under the number CRD 42018102184,
foram lidos na íntegra e 11 estudos foram excluídos, resultando em 18 artigos incluídos na revisão sistemática. Nove
espécies vegetais foram identicadas em cinco ensaios clínicos e 13 estudos
in vivo
, sendo a
Chamomila recutita
a mais
utilizada (33,3% dos estudos). A
Chamomila recutita
apresentou resultados mais promissores quanto às propriedades
analgésicas, anti-inamatórias e cicatrizantes. O látex de
Calotropis procera
diminuiu signicativamente (p<0,05)
os mediadores inamatórios, como TNF-α e IL-1β, na mucosite oral induzida em ratos.
Eupatorium laevigatum
apresentou atividade anti-inamatória e ação analgésica em úlceras orais.
Carapa guianensis Aubl.
reduziu a gravidade
e os sintomas dolorosos da mucosite oral e apresentou melhores resultados em comparação com o uso do laser de
baixa potência.
Curcuma longa L
. acelerou a reepitelização e resolução de processos inamatórios.
Spondias mombin
reduziu o estresse oxidativo e a inamação causadas pela mucosite oral e ajudou na sua cicatrização. Extratos de
Aloe
barbadensis Miller
ou
Aloe vera
apresentaram ação anti-inamatória, mas não auxiliaram no processo de cicatrização
de úlceras orais. O óleo de
Copaifera reticulata Ducke
não induziu melhora no processo cicatricial, nem apresentou
efeito anti-inamatório.
Malva sylvestris
não apresentou ação anti-inamatória em lesões orais em humanos ou ratos.
A avaliação da heterogeneidade metodológica mostrou a impossibilidade de realizar uma meta-análise. O risco de viés
variou de baixo a alto. Conclusão: A espécie vegetal mais utilizada e com melhores resultados para o tratamento de
ulcerações orais e mucosite oral foi a
Chamomilla recutita
. S
pondias mombin L., Curcuma longa L., Carapa guianensis
Aubl e Calotropis procera
apresentaram bons resultados no tratamento da mucosite oral, enquanto
Eupatorium
laevigatum
foi eciente no tratamento de úlceras de origem traumática.
Malva sylvestris, Copaifera reticulata Ducke
e
Aloe barbadensis Miller
não apresentaram resultados signicativos.
PALAVRAS-CHAVE
Plantas medicinais; Mucosite; Úlcera oral; Fitoterapia; Extratos vegetais; Estomatite.
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Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
in the International Prospective Register of
Systematic Reviews (PROSPERO).
Denition of the clinical question
The clinical question of the systematic review
was: “What are the most effective medicinal
plants used in Brazil for treatment of oral
ulcerations and mucositis”? A PICO question is
depicted in Table I.
The strategies for the searches performed on
09/17/2022 are presented in Table II.
Randomized or non-randomized clinical
trials as well as animal studies assessing
interventions with plant extracts or herbal
medicines used in Brazil for the treatment of
oral alterations characterized by ulcerations or
oral mucositis were used as inclusion criteria.
Meeting abstracts, qualitative studies, editorials
and expert opinions were excluded.
Article selection and data extraction
The article selection process was carried out
by two reviewers independently. Inter-examiner
agreement was veried by applying the Kappa
index (0.798) after reading 10% of the studies
retrieved in the searches. Divergences were
discussed and resolved by consensus. In the rst
phase, the studies were identied in the databases
following the inclusion criteria applied to titles
and abstracts. In the second phase, the full texts
were obtained and analyzed based on the same
eligibility criteria. The references meeting the
eligibility criteria were included.
The two researchers independently and
qualitatively evaluated each included study using
an evaluation form with data on the following
items: author; year of publication; study design;
characteristics of the participants; oral alteration;
inclusion criteria; medicinal plant, clinical/
macroscopic/ microscopic aspects analyzed and
results.
Risk of bias assessment
The risk of bias was estimated for each
selected study according to the method used.
Clinical trials were evaluated using the tool
for risk of bias assessment of the Cochrane
collaboration (Cochrane Handbook for
Systematic Reviews of Interventions) to judge
the following items: selection bias composed
of random sequence generation and allocation
concealment; performance bias due to blinding
of participants and raters; incomplete outcomes,
selective reporting of results, and other biases
(absence of sample calculation, standard
deviation or confidence interval, inadequate
statistical analysis, and observation period
incompatible with the purpose of the study) [18].
The evaluation of
in vivo
studies carried out in
animals was performed using the SYRCLE tool,
assessing selection bias (sequence generation,
baseline characteristics, allocation concealment),
performance bias (random housing, blinding),
Table I - Description of the PICO strategy used to develop the clinical question
ACRONYM DEFINITION DESCRIPTION
P Participants Cancer patients, healthy patients and animals with induced oral mucositis or oral ulcers due
to mechanical trauma
I Intervention Treatment with medicinal plants in Brazil
C Comparison No treatment / treatment with placebo or anti-inflammatory
O Outcome Clinical and histopathological characteristics of the lesions, reduced incidence of oral lesions,
degree of severity and symptomatology
Table II - Search strategy used in the databases
Databases Keywords combined with Boolean operators
Pubmed/Medline/Lilacs/Web of
science/Scielo/Brazilian Dentistry
Library
(phytotherapy OR “herbal drug” OR “plant extract” OR plant OR “medicinal plant” OR
pharmacognosy OR ethnobotany OR ethnomedicine OR ethnopharmacology OR “flower
essences” OR “natural product”) AND (mucositis OR mucositides OR stomatitis OR
stomatitides OR oral ulcer) AND (Brasil OR Brazil OR Brazilian)
Scopus
(phytotherapy OR “herbal drug” OR “plant extract” OR plant OR “medicinal plant” OR
pharmacognosy OR ethnobotany OR ethnomedicine OR ethnopharmacology OR “flower
essences” OR “natural product”) AND (mucositis OR mucositides OR stomatitis OR
stomatitides OR “oral ulcer”) AND (Brasil OR Brazil OR Brazilian)
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Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
detection bias (random outcome assessment,
blinding), attrition bias, reporting bias, and other
sources of bias [19]. For each item of both tools,
the study could exhibit high risk of bias, low risk
of bias or unclear risk of bias.
Synthesis of results
The evaluation of methodological
heterogeneity showed the impossibility of carrying
out a meta-analysis, since the articles exhibited
different methods and varied characteristics in
relation to the medicinal plants used.
RESULTS
The search resulted in 440 potentially relevant
references. The main results found are described
in the Prisma Flow Diagram (Figure 1). After
evaluating the titles and abstracts, 29 publications
were selected. After the complete assessment of
the 29 articles, literature reviews, an
in vitro
study
and an
in vivo
study with diabetic wounds were
excluded. Thus, 18 articles were included in the
qualitative analysis [3,20-36].
Most articles reported
in vivo
studies
(n = 13, 72.2%) performed with wistar rats or
hamsters [3,25-36] and ve articles were clinical
trials (27.8%) [20-24]. Regarding plant species,
nine different types were tested.
Chamomilla
recutita
was the most used (n = 7, 38.8%) [3,21-
23,25,27,34].
Aloe barbadensis
Miller (n = 2,
11.1%) [29,30],
Copaifera reticulata
Ducke (n = 2,
11.1%) [31,32],
Calotropis procera
(n = 2, 11.1%)
[26,35],
Carapa guianensis
Aubl. (n = 2, 11.1%)
[24,33],
Eupatorium laevigatum
Lam (n = 1, 5.5%)
[20],
Malva sylvestris
(n = 1, 5.5%) [28],
Curcuma
longa
L (n = 1, 5.5%) [34] and
Spondias mombin
(n = 1, 5.5%) [36] were also tested.
A total of 232 patients were evaluated in the
randomized clinical trials. Of these, 112 patients
had been included in studies analyzing the
effectiveness of
Chamomilla recutita
[21-24],
60 patients had been included in studies assessing
Eipatorium laevigatum
Lam [20], and 60 had
been included in studies evaluating
Carapa
guianensis
Aubl [24] (Table III).
The animals used in the
in vivo
studies were
hamsters (n = 473) and rats (n = 390), totaling
Figure 1 - PRISMA Flow Diagram for inclusion of articles in the systematic review.
:
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Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
863 animals. Chamomile extract presented in
ointment and commercialized as Admuc® was
used in three studies [3,25,27].
Aloe barbadensis
Miller [29,37] and
Copaifera reticulata
Ducke
extracts [31,32] were analyzed in two animal
studies. Latex from
Calotropis procera
[26],
Table III - Characteristics of clinical trials included in the systematic review
Authors
(year) Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Pauloetal.
(2000) [20]
60 patients
Oral ulcer
(aphtha) at an
early stage
Eupatorium laevigatum
Lam
Clinical characteristics of
buccal ulcers and Pain
Clinical characteristics of buccal
ulcers
TG:
Eupatorium
laevigatum
Lam CG:
triamcinolone 0.1%
orabase
(
mata-pasto
or
cambará-falso
)Cure: CG: 26.7% and TG: 40%;
Slight improvement:
3 times/day for 5 days
CG: 30% and TG: 36.7%; non-
improvement: CG: 43.4% and TG:
23.3%.
Pain
Alleviated in pain: CG: 33.3% and
TG: 70%
(p=0.01).
Ramos-e-
Silvaetal.
(2006) [21]
34 patients
Oral lesions of
non-specific
cause (aphtha)
Chamomile recutite
(chamomile) Topical
application of AdMuc®
Pain relief assessed VAS
before application (T1),
after 5 minutes (T2),
10 minutes (T3) and 15
minutes (T4).
Treatment efficiency of 82%.
TG: AdMuc® Pain relief after topical
application (VAS) in T1 (113.49),
T2 (75.84), T3 (48.43) and
T4 (36.25) were statistically
significant (p <0.05).
No CG
Bragaetal.
(2015) [22]
40 patients
Oral mucositis
Chamomile recutite
(chamomile) extract
Mouthwash in three
concentrations
Incidence and intensity of
oral mucositis using the
oral toxicity measurement
scale (WHO).
Incidence of mucositis:
CG- Chlorhexidine
0.12% TG2 had 30% incidence of ulcers,
TG3 60%, TG1 70% and CG 90%
(p = 0,01).
TG1 Chamomile 0.5%
TG2 Chamomile 1% Intensity of the mucositis:
TG3 Chamomile 2%
TG2 had mean of 0.7 intensity
of mucositis, TG1 and TG3 mean
of 1.6 each and CG mean of 2.1
(p = 0.01).
Duration of Mucositis:
TG2 had average duration of 1.9
days, TG1 and CG 5.7 days each
and TG3 6.9 days (p = 0.01).
Reisetal.
(2016) [23]
38 patients
Induced oral
mucositis (5-FU
425 mg/m2 and
leucovorin 20
mg/m2)
Chamomile recutite
(chamomile)
Assessment of oral
mucosa 8, 15 and 22
days after chemotherapy.
Occurrence and intensity
of oral mucositis (WHO)
and pain in the mouth
(VAS)
Day 8: Assessment of the oral
mucosa: TG had 0% and CG had
16% ulceration (p =0.10).
TG: Cryotherapy with
chamomile
Infusion (10g of chamomile
flowers prepared in 400 ml
of water)
Pain: TG had 0.6 level of pain
and CG 2.3 (p=0.02).
CG: Cryotherapy with
plain ice
Day 15: Assessment of the oral
mucosa: TG and CG with similar
results.
Pain: TG had 0.9 level of pain
and CG 2.3 (p=0.09).
Day 22: Assessment of the oral
mucosa: TG and CG with similar
results.
Pain: TG and CG with similar
results.
30% of TG patients and 50%
of CG patients developed oral
mucositis at some point during
treatment. TG patients never
developed grade 2 or higher
mucositis.
Soaresetal.
(2021) [24]
60 children
(6-12 years old)
Oral mucositis
in patients
undergoing
chemotherapy
Carapa guianensis Aubl
(andiroba)
OM severity degree
(WHO) and Pain level
(Wong-Baker visual
analogue scale) in days
1 to 9.
Days 1, 2, 5-9: OM severity: TG
and CG with similar results.
TG- andiroba Pain: TG and CG with similar
results.
CG-Laser
Day 3: OM severity: TG and CG
with similar results.
Pain: TG presented 0.7 and CG
1.0 (p = 0.031).
Day 4: OM severity: TG had
fewer lesions than CG
(p =0.003).
Pain: TG presented 0.5 and CG
0.9 (p =0.003).
Notes: CG: Control group; OM: Oral mucositis; TG: Treatment group; VAS: Visual analog scale; WHO: World Health Organization
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Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
orabase from
Malva sylvestris
L. [28], and oil
from
Carapa guianensis
Aubl. [33] were tested
in one study each (Table IV).
Risk of bias assessment
The studies of Paulo et al. [20] and Ramos-
e-Silva et al. [21] exhibited high risk of bias
in the selection of participants and blinding
of participants and/or evaluators. The studies
carried out by Braga et al. [22], Reis et al.
[23] and Soares et al. [24] described, in their
methods, the generation of a random sequence,
concealment of allocation, blinding of participants
and evaluators adequately exhibiting low risk of
bias for these items. Figure 2 presents the risk of
bias assessment for the clinical trials.
Risk of bias assessment in animal studies
showed that all animal samples (rats or hamsters)
were homogeneous with accommodation
under standard conditions. The risk of bias
regarding blinding of trial caregiver and
researcher was unclear in the studies carried
out by Kovalik et al. [28], Coelho et al. [29],
Schmidt et al. [34], Ramos et al. [35], and Sousa
Gomes et al. [36]. The risk of bias was low for
incomplete results, selective reporting selective,
and other sources of bias. The risk of bias was
low for random allocation in all studies, except
for the study of Freitas et al. [26] and Sousa
Gomes et al. [36] (Figure 3).
DISCUSSION
This is the rst systematic review carried out
with medicinal plants used in Brazil for treatment
of oral ulcerations and mucositis. Currently, there
are no established therapeutic protocol for these
conditions, only methods to alleviate pain and
shorten lesion duration [7,8,32,37-39]. Therefore,
the exploration of alternative treatments is
crucial. Plant species have been used because they
have fewer side effects compared to chemical or
synthetic drugs [11,12] and there is a growing
interest in evaluating their therapeutic effects
due to their diverse antioxidant, analgesic, and
anti-inammatory properties [12].
The Brazilian flora is very rich in plant
species with therapeutic properties with active
principles that need to be explored. The country’s
fertile soil and climate allow both native and
imported plant species to thrive [15]. The variety
of species, the knowledge and influence of
different cultural heritages strengthens the use
for phytotherapeutic purposes, prevention and
treatment of diseases, which only contributes to
improving the development of studies with this
approach [40].
Figure 3 - Assessment of the risk of bias in animal studies included in the systematic review.
Figure 2 - Assessment of the risk of bias in clinical trials included in the systematic review.
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Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Table IV - Characteristics of animal studies included in the systematic review
Author
(year)
Number and
type of animals Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Duarteetal.
(2011) [25] 36 wistar rats
TG- 0.04 mL/
day of chamomile
ointment
Mouth ulcer due
to mechanical
trauma
Topical application
of chamomile
extract (AdMuc®)
Histomorphological
analysis: Degree of
inflammation, fibroblast
count, wound size and
epithelialization (3,
7 and 10 days) and
percentage of collagen
fibers (10 days)
TG and CG had similar
results in days 3 and 7.
CG- placebo
Day 10: degree of
inflammation, fibroblast
count, and wound
size: TG and CG had
similar results. TG
had a higher degree
of reepithelialization
than CG (p=0.08). TG
had greater degree of
collagen fiber formation
than CG (p=0.02).
Pavesietal.
(2011) [3] 105 hamsters
TG1- Chamomile
Induced oral
mucositis (5-FU-
60 mg/kg on day
0, and 40 mg/kg
on day 2)
Topical application
of chamomile
extract (AdMuc®)
Weight analysis, clinical
and histopathological
analysis by degree of
mucositis
Weight Analysis: There
were no notable weight
changes in each group
analyzed individually
(p=0.3070), but TG1 and
TG2 weighed significantly
less than the CG
(p=0.0004).
TG2-
betamethasone
corticoid
CG- Control
without treatment
Clinical analysis: There
were no significant
changes in the mucositis
scores over time for
CG (p=0.3742) and TG1
(p=0.6568). However, TG2
which had diminished
severity scores over time
(p=0.0349). Furthermore,
the TG1 group had a
12-fold greater chance of
scoring zero (absence of
mucositis) than the TG2
(p =0.0001).
Histopathological
analysis: In each group
individually were no
significant associations
(CG - p=0.2631; TG1-
p=0.151; TG2 - p=0.0847).
The comparisons
between groups revealed
that the TG1 exhibited
the least degree of
mucositis throughout the
experiment in comparison
to the CG and TG2
groups (p =0.0001).
Notes: 5-FU: 5-Fluorouracil; CG: Control group; CGA:
Carapa guianensis Aubl.
oil
;
CLX: chlorhexidine; CO: Copaiba oil; MPO: myeloperoxidase
test; LP: Laticifer proteins; LPI: Protein fraction I of laticifer proteins; LPII: Protein fraction II of laticifer proteins; LPIII: Protein fraction III of laticifer
proteins; LPII-IAA: Protein fraction II treated with iodoacetamide MT: Mechanical trauma; PG: Placebo Group; TG: Treatment Group; VE: Vitamin E.
This systematic review examined 18 studies
on the impact of plant extracts on oral ulcers or
mucositis caused by cancer treatment. The review
found ve clinical trials [20-24] and 13
in vivo
studies [3,25-36] with nine different plant
species. The major number of
in vivo
studies
than clinical trials is not surprising, as substances
can only be tested on human beings after its
properties and effects are thoroughly understood
in vivo
studies [41].
Chamomilla recutita
was the most frequently
used, appearing in seven studies.
Aloe barbadensis
Miller,
Copaifera reticulata
Ducke,
Calotropis
procera
and
Carapa guianensis
Aubl. were present
in two studies each and
Eupatorium laevigatum
Lam,
Malva sylvestris
,
Curcuma longa
L and
Spondias mombin
in one study each. Only three
plant species were used in clinical trials,
Eupatorium
laevigatum
Lam,
Chamomilla recutita
and
Carapa
guianensis
Aubl. While
Chamomilla recutita
,
Aloe
barbadensis
Miller,
Copaifera reticulata
Ducke,
latex from
Calotropis procera
,
Malva sylvestris
,
Carapa guianensis
Aubl.,
Curcuma longa
L and
Spondias mombin
were studied in
in vivo
studies,
primarily with rats and hamsters.
8
Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Author
(year)
Number and
type of animals Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Freitasetal.
(2012) [26] 90 hamsters
TG1- Normal
Induced oral
mucositis (5FU-60
mg/kg on day 1
and 40 mg/kg
Processed
Calotropis procera
at 0.25, 1, 5 e 25
mg/kg
Macroscopic analysis,
histopathological
analysis,
myeloperoxidase
test (MPO) and
immunohistochemistry
(TNFα, IL-β, iNOS,
COX-2)
Macroscopic analysis:
TG2- MT
on day 2) and
mechanical
trauma
(
Flor de seda
,
algodão de seda
or
queimadeira
)
TG3 had significant
injuries compared to TG1
and TG2 (p<0.001). TG4
had significant lesions
compared to TG5, TG6,
and TG7 (p<0.05). On
D10, TG6 showed less
erythema and no ulcers or
abscesses compared to
TG1 (p<0.001).
TG3- MT/5FU The other groups did
not show significant
statistical differences,
when compared to each
other.
TG4- MT/5FU025
TG5- MT/5FU1 Histopathological
analysis: Both TG5
(p<0.05) and TG6
(p<0.001) significantly
reduced inflammatory
effects, edema,
hemorrhage and
prevented the formation
of ulcers and abscesses
in comparison to TG1.
The other groups did
not show significant
statistical differences.
TG6- MT/5FU5
TG7- MT/5FU25
Myeloperoxidase test
(MPO):
TG5 showed a 71% MPO
activity (p <0.01). The
TG6 demonstrated an
even stronger result,
an 88% of MPO activity
(p<0,001). The other
groups did not show
significant statistical
differences.
Immunohistochemistry:
Only TG1, TG2 and TG6
were evaluated: In the
inflamed conjunctive
tissue, TG6 showed
significant increases
in the expression of
TNF-α (p<0.001), IL-1β
(p<0.001), iNOS (p<0.05),
and COX-2 (p<0.05)
compared to TG1.
In the epithelial tissue,
TG6 only showed a
significant decrease in
the immunostaining of
COX-2 (p<0.05) and
iNOS (p<0.05) compared
to TG1.
Notes: 5-FU: 5-Fluorouracil; CG: Control group; CGA:
Carapa guianensis Aubl.
oil
;
CLX: chlorhexidine; CO: Copaiba oil; MPO: myeloperoxidase
test; LP: Laticifer proteins; LPI: Protein fraction I of laticifer proteins; LPII: Protein fraction II of laticifer proteins; LPIII: Protein fraction III of laticifer
proteins; LPII-IAA: Protein fraction II treated with iodoacetamide MT: Mechanical trauma; PG: Placebo Group; TG: Treatment Group; VE: Vitamin E.
Table IV - Continued...
9
Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Author
(year)
Number and
type of animals Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Curraetal.
(2013) [27] 36 hamsters
TG1- Chamomile
TG2-
Betamethasone
Corticoid
Induced oral
mucositis (5-FU-
60 mg/kg on day
0, and 40 mg/kg
on day 2)
Topical application
of chamomile
extract (AdMuc®)
Distribution and
location of IL-1β
and TNF-α proteins
Immunostaining of IL-1β
and TNF-α and
Distribution and location
of IL-1β and TNF-α
proteins:
CG-Control
Clinical evaluation on
days 0, 5,10 and 14
Both IL-1β and TNF-α
proteins showed a
similar distribution
and localization,
exhibiting a diffuse
pattern throughout the
connective tissue. The
epithelium and adipose
tissue were negative for
both proteins.
Immunostaining of IL-1β
and TNF-α and clinical
evaluation on days 0, 5,10
and 14:
IL-1β: After infusion
with 5-FU, all
groups discovered a
significant increase in
immunolabeling for IL-1β
(p < 0.05). The highest
scores were observed in
the 10-day period in all
groups (p<0.05).
TG1 showed lower levels
of IL-1β D14 in relation
to groups CG and TG3
(p<0.05). TG1 presented a
lower degree of mucositis
than CG and TG2
(p<0.05).
TNF-α: After infusion with
5-FU, all groups showed
a significant increase
in immunolabeling for
TNF-α (p < 0.05) and
the development of
oral mucositis (Days
5–14). However, the
TG1 group exhibited a
unique pattern of protein
expression. This pattern
was characterized by an
initial increase in tissue
levels of TNF-α on Day 5,
followed by a significant
decrease on Day 10. A
subsequent increase was
observed on Day 14
(p = 0.0188).
Kovaliketal.
(2014) [28] 136 rats
TG- Mauve
Mouth ulcer due
to mechanical
trauma
Stems and dried
leaves of Malva
sylvestris L. 20%
in orabase (
malva
cheirosa
or
malva
silvestre
)
Wound healing
area (mm2) for each
experimental time (0 3,
7, 15 and 21 days)
Wound area (macroscopic
and histological) and
percentage of healing:
G2- Orabase
vehicle
No statistical significance
was found between
groups in all periods.
However, wound
protection can mitigate
the impact of physical
damage directly at the
site of injury.
GCLX
CG- Control
Notes: 5-FU: 5-Fluorouracil; CG: Control group; CGA:
Carapa guianensis Aubl.
oil
;
CLX: chlorhexidine; CO: Copaiba oil; MPO: myeloperoxidase
test; LP: Laticifer proteins; LPI: Protein fraction I of laticifer proteins; LPII: Protein fraction II of laticifer proteins; LPIII: Protein fraction III of laticifer
proteins; LPII-IAA: Protein fraction II treated with iodoacetamide MT: Mechanical trauma; PG: Placebo Group; TG: Treatment Group; VE: Vitamin E.
Table IV - Continued...
10
Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Author
(year)
Number and
type of animals Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Coelhoetal.
(2015) [29] 72 rats
TG- Aloe Vera
Mouth ulcer due
to mechanical
trauma
Aloe barbadensis
Miller (
Aloe vera
)
in
0.5% hydroalcoholic
extract 12 / 12h
Clinical analysis of the
area and healing
Clinical analyzes of the
area and wound healing:
There was no statistical
difference between
groups. Histopathological
analysis of
CG- Control
of the wound and
histopathological
analysis of the re-epithelialization and
degree of inflammation:
statistical significance
among groups in all
periods.
PG- Placebo (hydro
alcoholic extract)
reepithelialization
and degree of
inflammation,on days 1,
5, 10, 14
Cubaetal.
(2015) [30] 35 wistar rats
TG1- 70% AV
Mouth ulcer due
to mechanical
trauma
Aloe barbadensis
Miller (
Aloe
vera
)
70%
and
vitamin E gel (VE)
ephynal®400mg
Evaluation on days
5 and 7 to verify:
inflammatory response
by cells and blood
vessels (Absent, mild,
moderate and intense).
Lesion size and weight
loss
Inflammatory response,
lesion size and weight
loss: 5-day period: TG1
and TG2: presented
the intensity of the
inflammatory process
ranged from mild to
moderate. TG1: Three
animals showed lesions
on the tongue. TG2: Two
animals showed lesions
on the tongue. CG: All
animals had moderate
intensity inflammation
and showed lesions
on the tongue, and
the size of the lesions
was statistically larger
compared to the animals
to the TG1 e TG2 groups
(p<0,05). In the 5-day
experimental period,
there was no weight loss
in any animal.
TG2- 400mg VE
CG- hydroxy-
methylcellulose
7-day period: TG1 and
TG2: The inflammation
decreased from moderate
to mild. All animals
showed complete healing
of the lesions. CG: All
animals developed
an intense degree of
inflammation and some
degree of ulceration, and
the size of the lesions
was statistically larger
compared to the TG1 and
TG2 groups (p <0.05). All
animals showed weight
loss, ranging from 50 to
100 g.
Notes: 5-FU: 5-Fluorouracil; CG: Control group; CGA:
Carapa guianensis Aubl.
oil
;
CLX: chlorhexidine; CO: Copaiba oil; MPO: myeloperoxidase
test; LP: Laticifer proteins; LPI: Protein fraction I of laticifer proteins; LPII: Protein fraction II of laticifer proteins; LPIII: Protein fraction III of laticifer
proteins; LPII-IAA: Protein fraction II treated with iodoacetamide MT: Mechanical trauma; PG: Placebo Group; TG: Treatment Group; VE: Vitamin E.
Table IV - Continued...
11
Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Author
(year)
Number and
type of animals Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Teixeiraetal.
(2017) [31] 15 wistar rats
TG- CO
Mouth ulcer due
to mechanical
trauma
Copaífera reticulata
Ducke (Copaiba oil)
Toxicity, qualitative
analyzes: edema,
inflammatory infiltrate,
Immunohistochemical
analysis
Negative acute oral
toxicity test within 48
hours. TG showed less
inflammatory infiltrate
compared to CG (p
<0.05). TG showed
greater anti-inflammatory
action and faster repair
of the injured area. TG
reduced the intensity
of the edema (1.8 ±
0.20) compared to CG
(2.4 ± 0.4) (p <0.05). TG
with reduction of CD68
positive macrophages in
comparison to CG
(p = 0.04).
GCort-
Corticosteroid
dexamethasone
200mg/kg/day
CG-Control
Wagneretal.
(2017) [32] 96 wistar rats
TG- CO
Mouth ulcer due
to mechanical
trauma
Copaífera reticulata
Ducke (Copaiba oil)
Animal weight,
Clinical analysis of
healing process and
histopathological
analysis in days 3, 5, 10
and 14.
Weight Analysis: On days
3 and 5 there was no
significant difference in
the weight of the animals.
GCort lost more weight
than CG (p=0.006) and
PG (p=0.02) after 10
days. GCort lost more
weight than TG (p=0.01)
after 14 days.
GCort-
Corticosteroid
CG-Control
PG-Placebo
Clinical analysis of
healing process: At day
3, 5 and 10, all animals
experienced a similar
percentage of wound
healing. However, at the
14-day analysis, GCort
showed a slower wound
healing process
(p = 0.007).
Histopathological
analysis: Did not show
differences between
groups.
Wanzeleretal.
(2018) [33] 122 hamsters
TG1- CGA (100%)
Induced oral
mucositis (5-FU-
60 mg/kg on
days 0, 5 and 10)
and mechanical
trauma
Carapa guianensis
Aubl.
(
andiroba
)
Cytotoxicity,
genotoxicity,
degree of mucositis,
histopathological
evaluation
Cytotoxicity and
genotoxicity: Andiroba
did not show cytotoxicity,
but genotoxic potential
(p <0.001).
TG2- CGA (10%)
TG3- CGA
(10%refinado)
Degree of mucositis:
TG1 showed a significant
reduction in the degree
of mucositis in relation
to the other groups
(p<0.005).
TG4-
Cyclophosphamide
CG- no treatment
Histopathological
evaluation: TG1 showed
reduced inflammatory
infiltrate in compared
to the group without
treatment during the
histopathological
evaluation (p<0.005).
Notes: 5-FU: 5-Fluorouracil; CG: Control group; CGA:
Carapa guianensis Aubl.
oil
;
CLX: chlorhexidine; CO: Copaiba oil; MPO: myeloperoxidase
test; LP: Laticifer proteins; LPI: Protein fraction I of laticifer proteins; LPII: Protein fraction II of laticifer proteins; LPIII: Protein fraction III of laticifer
proteins; LPII-IAA: Protein fraction II treated with iodoacetamide MT: Mechanical trauma; PG: Placebo Group; TG: Treatment Group; VE: Vitamin E.
Table IV - Continued...
12
Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Author
(year)
Number and
type of animals Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Schmidtetal.
(2019) [34]
62 golden
Syrian
hamsters
CG-Control
Mechanical
trauma Induced
oral mucositis
(5-FU-60 mg/kg
on day 0, and
40 mg/kg
on day 2)
TG1 - Chamomile
extract (AdMuc®)
Clinical and
histopathological
analysis,
Inflammatory process,
immunostaining of
TGF-β1 in the epithelial
lining.
Clinical Analysis: All
animals exhibited Oral
Mucositis (OM) on Day 5.
On Day 8, the TG1 group
showed a milder form
of OM compared to the
CG (p < 0.05) and PG
(p < 0.01) groups. TG2
revealed less severe OM
compared with CG (p <
0.01) and PG (p < 0.001).
No differences were
observed among groups
on Days 10 and 14.
PG-Placebo
TG2 - mucoadhesive
formulation
containing
Curcuma
longa
L. extract
TG1-
Chamomilla
recutita
Histopathological
Analysis: No differences
were observed among
groups on Days 5. At
Day 8, TG1 and TG2
demonstrated accelerated
re-epithelialization in
comparison to CG (p
< 0.001) and PG (p <
0.001). At Days 10 and
14, all groups showed
re-epithelialization
coverage of all of the
wound thickness. The only
statistically significant
difference observed at
day 10 was between PG
and TG2 (p < 0.05).
TG2-
Curcuma
longa
L.
Inflammatory Process:
No differences were
observed among groups
on Day 5. At Day 8,
CG and PG showed
similar scores with
predominance of diffuse
acute inflammation.
TG2 and TG1 revealed
a significant reduction
and chronification of
inflammation process
comparing with CG (p
< 0.05; p < 0.001) and
PG (p < 0.01; p < 0.001).
At Day 10, TG1 and
TG2 still demonstrated
a lower inflammatory
process compared
with the PG (p < 0.05).
At Day 14, all groups
presented resolution and
healing (reduction or
disappearance of chronic
inflammation).
Immunostaining of TGF-
β1: At Day 8, the TG2
exhibited significantly
lower labeling of this
cytokine compared with
PG (p = 0.019) and CG
(p = 0.019). At Days 5, 10
and 14, no difference was
found among groups.
Notes: 5-FU: 5-Fluorouracil; CG: Control group; CGA:
Carapa guianensis Aubl.
oil
;
CLX: chlorhexidine; CO: Copaiba oil; MPO: myeloperoxidase
test; LP: Laticifer proteins; LPI: Protein fraction I of laticifer proteins; LPII: Protein fraction II of laticifer proteins; LPIII: Protein fraction III of laticifer
proteins; LPII-IAA: Protein fraction II treated with iodoacetamide MT: Mechanical trauma; PG: Placebo Group; TG: Treatment Group; VE: Vitamin E.
Table IV - Continued...
13
Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Author
(year)
Number and
type of animals Comparison groups Oral alteration Plant Extract
(popular name) Analyzed variables Results
Ramosetal.
(2020) [35]
64 male Golden
Sirius hamsters
TG-
Calotropis
procera
latex
Mechanical trauma
Induced oral
mucositis (5-FU-60
mg/kg on day 1,
and 40 mg/kg on
day 2)
Calotropis procera
(sodom apple)
Lesion area,
animal weight,
Inflammatory markers,
immunohistochemistry.
Lesion area: The LP and
LPPII-IAA groups were
better and prevented
ulceration of the mucosa.
protein samples (LP,
LPI, LPII, LPIII and
LPII-IAA)
CG-Control Body weight of the
animals: The LP, LPII
and LPII-IAA groups
contributed to avoid the
severe effect of 5-FU in
terms of survival and body
weight gain.
PG-Placebo
Inflammatory markers:
The LPII and LPII-IAA
groups demonstrated a
similar ability to inhibit
key inflammatory markers,
including the recruitment
of inflammatory cells
and the release of pro-
inflammatory cytokines.
Immunohistochemistry: An
inhibitory effect of LPII-IAA
on IL-1β was observed.
Treatments with both
LP and LPII-IAA resulted
in a decrease in ICAM-1
immunolabeling. An
increase in type I collagen
fibers was observed in
the tissues obtained from
animals that underwent
either LP or LPII-IAA
therapy.
Sousa
Gomesetal.
(2020) [36]
30 Golden
Siryan male
hamsters
CG- Control
Mechanical trauma
Induced oral
mucositis (5FU)
Spondias mombin
(
caja)
Macroscopic scores, Macroscopic scores: The
CG and TG5 presented
significantly lower
macroscopic scores
when compared to TG2
(p < 0.05).
TG1- MT
Histopathological and
spectroscopic analyses.
TG2- 5-FU-
60 mg/kg on day 1,
and 40 mg/kg
Histopathological
analyses: TG5 exhibited
almost complete healing
in all animals, areas
of re-epithelialization,
discrete cell infiltration,
absence of hemorrhage,
edema, ulcers, and
abscesses, significantly
lower than TG2 (p < 0.05).
on day 2/MT
TG3- 50mg/kg
S. mombin
Spectroscopic analyses:
TG4- 100mg/kg
S. mombin
TG5 animals were able
to significantly prevent
the reduction of total
glutathione (GSH) levels
compared to the TG2
(p < 0.01).
TG5- 200mg/kg
S. mombin
Malondialdehyde (MDA)
levels were lower in
the CG and TG5 when
compared to that observed
in the TG2 (p < 0.001).
The estimation of
Superoxide dismutase
(SOD) was lower in the
CG, TG1, TG4 and TG5
compared to the TG2
(p < 0.05).
Inflammatory cytokine
IL-1β was significantly
lower in the CG and TG5
(p < 0.05) compared
to TG2. TNF-α was
significantly reduced in the
CG and TG5 (p < 0.0001),
and in the TG1 compared
to TG2 (p < 0.001).
Notes: 5-FU: 5-Fluorouracil; CG: Control group; CGA:
Carapa guianensis Aubl.
oil
;
CLX: chlorhexidine; CO: Copaiba oil; MPO: myeloperoxidase
test; LP: Laticifer proteins; LPI: Protein fraction I of laticifer proteins; LPII: Protein fraction II of laticifer proteins; LPIII: Protein fraction III of laticifer
proteins; LPII-IAA: Protein fraction II treated with iodoacetamide MT: Mechanical trauma; PG: Placebo Group; TG: Treatment Group; VE: Vitamin E.
Table IV - Continued...
14
Braz Dent Sci 2024 Jan/Mar;27 (1): 3907
Volpato LER et al.
Plant extracts used in Brazil f or treatment of oral ulcer s and mucositis: systematic revie w
Volpato LER et al. Plant extracts used in Brazil for treatment of oral ulcers and
mucositis: systematic review
Chamomilla recutita
is native