Taxonomic synopsis of medicinal Lamiales species used in Alta Floresta, Mato Grosso, Brazil: Potentialities for the Unified Health System

This work presents the morphology of 16 medicinal species of Lamiales used in Alta Floresta, Mato Grosso, Brazil, as well comments about phytogeography, popular use in the municipality, the status of the species in the National Policy on Medicinal Plants and Phytotherapeutics, and examples of preclinical trials. The work was performed between March and September 2020, through botanical sample of the Lamiales species presented in the book " Plantas medicinais de Alta Floresta: com contribuição a etnobotânica", obtained in rural communities and urban neighborhoods in the municipality of Alta Floresta, State of Mato Grosso. The morphological study was carried out at the Laboratory of Plant Morphology, located at the University Campus of Alta Floresta, Universidade do Estado de Mato Grosso. In general, the species are native (56%) with wide distributions in Brazil. Most species have glandular trichomes (72%) on the leaves and/or flowers and have been shown to be efficient and/or promising (85.5%) in studies. However, only 37.5% of these studies were conducted by the Ministry of Health. None of the species are offered as a phytotherapeutic by the Unified Health System (SUS), although six are on the last National Report of Medicinal Plants of Interest published by SUS. Based on the information provided, it is evident that these species could be used in studies about new phytotherapeutics for SUS users.

Worldwide, the order comprises 26 families and 23,755 species (Stevens 2001 onwards). In Brazil, it is represented by 18 families and 2,369 species (BFG, 2018;Souza & Lorenzi, 2019;FB, 2020). The representativeness of this taxonomic group can be seen in the book Plantas medicinais no Brasil: nativas e exóticas, which includes morphological, biogeographic and medicinal information about 335 species; 45 species belong to Lamiales, the largest order in number of species (notably those of Lamiaceae with 25 species and Bignoniaceae and Verbenaceae with seven species each), followed by Asterales with 43 species (all in the Asteraceae) (Lorenzi & Matos, 2008). The book Plantas Medicinais de Alta Floresta: com contribuição à Etnobotânica contains information about the ethnobotany of 82 species used by residents of the municipality Alta Floresta, in the northern part of Mato Grosso State (MT), including 16 Lamiales species (of which six are in Lamiaceae) and nine Asterales species (all in the Asteraceae) (Fernandes, 2002). Additionally, in Vale do Juruena in northern Mato Grosso, Bieski et al. (2015) conducted an ethnobotanical study of medicinal plants in seven municipalities and found that 40 Lamiales species (12% of the species studied) are used by the population to treat diseases, including 22 Lamiaceae species.
Lamiales species stand out among the medicinal plants in Brazil due to the high number of native and exotic species, the dependence on them to treat diseases of minor or medium complexity, and their chemical compounds with proven pharmacological efficacy. Among the chemical compounds are the following: cornosides that exhibit hypotensive action; flavones that exhibit capillary permeability, antioxidant, anti-inflammatory, antitumor and hormonal activity ; caffeic acid with antimicrobial activity (Fu, et al., 2010); and phenylethanoid glycosides that have inhibitory effects on neuroinflammation, such as that associated with Alzheimer's and Parkinson's disease (Nan, et al., 2013), anti-inflammatory, antioxidant, antibacterial and antivirus activity, cytotoxic, immunomodulatory, enzyme inhibiting effects, and pharmacokinetic properties (Xue & Yang, 2016).
Even with the proven pharmacological efficacy of Lamiales chemical compounds, the group has been poorly explored in relation to the production of phytotherapeutic medicines that are destined for Brazil's Unified Health System (Sistema Único de Saúde or SUS). Of a total of 12 species, only Mentha piperita Linnaeus and Plantago ovata Forsskål are listed as sources of phytotherapeutics in the National Report of Essential Medicines (Relação Nacional de Medicamentos Essenciais) (Brasil, yards. In the rural areas, collections were made in the Central, São Bento and Guadalupe communities, from known properties. Additionally, one herbarium specimen (at HERBAM) and two images of specimens (at K, CEN) were used.
The entire plant or fertile branches were collected, photographed and processed using standard techniques for specimen herborization (Fidalgo & Bononi, 1989). Identifications were checked using taxonomic works, the spelling of scientific names and authors follows IPNI (2020), and the Angiosperm Phylogeny Group classification system was used (Stevens, 2021;APG, 2016). The geographic distribution in Brazil is based on BFG (2018), FB (2020) and REFLORA (2020).
The specimens are in the Herbário da Amazônia Meridional (HERBAM) at the Universidade do Estado de Mato Grosso, Campus de Alta Floresta. The morphological descriptions were made in the Plant Morphology Laboratory, at HERBAM, using a stereomicroscope; the terminology was adapted from Radford et al. (1974) and Barroso et al. (1999). The reproductive structures of Mentha pulegium Linnaeus and Rosmarinus officinalis Linnaeus were described based on Franco and Afonso (1972) and Harley (1972). Literature was used to verify the medicinal uses in Alta Floresta (Fernandes, 2002), status of the species in the National Policy on Medicinal Plants and Phytotherapeutics, preclinical trials coordinated by the Ministry of Health (Brasil, 2006a(Brasil, , 2006b(Brasil, , 2006cBrasil, 2009;Brasil, 2016;Brasil, 2019; and examples of independent pharmacological trials.

Results and Discussion
This work describes the morphology of 16 medicinal Lamiales species used in the municipality of Alta Floresta (MT), notably Lamiaceae (6 spp.), Bignoniaceae (4 spp.) and Plantaginaceae (3 spp.), followed by Verbenaceae (2 spp.) and Acanthaceae (1 sp.). For each species, the following is provided: a morphological diagnosis, with diagnostic characteristics related to habit, leaves, inflorescences, flowers, fruits and seeds; phytogeographic information; medicinal uses in Alta Floresta; information about pharmacological trials; and the status in the National Policy on Medicinal Plants and Phytotherapeutics (NPMPP).
A decoction of the inner bark is used to bathe wounds and is ingested to treat throat infections and to purify blood (Fernandes, 2002). The species is not of interest to SUS and is not in the Brazilian Pharmacopeia (Brasil, 2009;Brasil, 2019).

Fernandes 1708 (HERBAM), C.R.A. Soares et al. 1834 (HERBAM).
This species is native from Belize to Bolivia and Brazil (Gentry, 1992). In Brazil, it occurs in the North (AC, AM, AP, PA, RO, RR), Northeast (MA) and Central-West regions (MT), in the Amazon biome (BFG, 2018). In the municipality of Alta Floresta (MT), it was collected in areas of seasonal semideciduous forest.

Marsypianthes chamaedrys
The species is native to Central and South America and, in Brazil, occurs in all the regions, states and biomes, except the Pampa (Hashimoto & Ferreira, 2020). In the municipality of Alta Floresta (MT), it was collected in rural yards and is often found in urban yards.
An infusion of the leaves is used to treat intestinal colic, diarrhea, nausea and as a dewormer (Fernandes, 2002). It is not on the list of interest by SUS or in the Brazilian Pharmacopeia (Brasil, 2009;Brasil, 2019). In an in vitro study, 100g of macerated leaves and inflorescences, as well as an infusion (2.5%), exhibited anti-inflammatory and anticoagulant mechanisms under the effect of Botrops atrox venom; in the future, this species could contribute to treating snake bites (Magalhães, et al., 2011).

R.F. Vieira 77 (photo K!).
This species is native to Europe, the Mediterranean, Northern Iran and Ethiopia and introduced in most other countries, especially those with a temperate climate (Harley, 1972). In Brazil, fertile specimens have been recorded in yards in the Northeast (BA, CE, RN), Central-West (DF, MS), Southeast (ES, MG, RJ, SP) and South regions (PR, SC, RS) (REFLORA, 2020). In the municipality of Alta Floresta (MT), it was collected in a yard but was not fertile. According to residents, the species never flowers and there are no specimens of it at HERBAM.
An infusion of the leaves is used to treat respiratory problems, menstruation, nausea, intestinal colic, intestinal gas, and for burping and intestinal colic of newborn babies (Fernandes, 2002). It is a species of interest to SUS (Brasil, 2009) but is not in the Brazilian Pharmacopeia (BRASIL, 2019). The essential oil of the species (70.66% pulegone, 11.21% neomenthol and 2.63% menthone) exhibits antioxidant activity and inhibits the enzyme butyrylcholinesterase, making it a candidate for therapies for cancer and Alzheimer's patients (Cheraif, et al., 2020).   An infusion of the leaves is used to treat intestinal gas and respiratory problems, such as a cough, and as a diuretic and to help with digestion, while an infusion of the entire plant is used to treat high blood pressure and the seeds and roots are used to prepare an expectorant syrup (Fernandes, 2002). It is not a plant of interest to SUS and is not in the Brazilian Pharmacopeia (Brasil, 2009;Brasil, 2019). However, an experiment conducted in vitro suggests that a leaf infusion of the species is a potential source of antihyperglycemic agents and rosmarinic acid and methyl rosmarinate decreased glucose (Ruiz-Vargas, et al., 2019). Andrews, Bot. Repos. 9: t. 594. 1809. Lamiaceae. Common name: boldo.
The macerated leaves are used to treat liver problems, indigestion, food toxicity and hangovers (Fernandes, 2002). It was added to the list of interest by SUS in 1986 and is on the last SUS list (Brasil, 2006c;Brasil, 2009) but is not part of the Brazilian Pharmacopeia (Brasil, 2019). In preclinical studies (Process nº 18545/87), an extract (0.1 to 1.0g/kg) resulted in decreased motility, drowsiness, ptosis and contortions, with normal data for subacute and chronic toxicity, but there is evidence that acute toxicity can cause abdominal contortions and decreased motility (Brasil, 2006c).  Inflorescences verticillastriform on the side branches, peduncle and pedicels tomentose, stellate trichomes present; flowers zygomorphic; calyx 5-7 mm long, campanulate, tomentose to glabrescent, green to purplish; corolla 10-12 mm long, light blue, rarely pink or white, 2 upper lobes concave, 2 lateral lobes and lower lobe cochleariform; stamens 2. Fruits nutlets.
This species is native to the Mediterranean, Portugal and Spain and cultivated in other countries (Franco & Afonso, 1972  An infusion of the leaves is used to treat the nervous system, heart, menstruation and rheumatic pain (Fernandes, 2002). The species is not of interest in studies by SUS (Brasil, 2009) but a protocol to extract the volatile oil is in the Brazilian Pharmacopeia (Brasil, 2019). Data show that an aqueous extract exhibits significant in vitro antioxidant capacity that is attributed to the presence of phenolic compounds in its composition; when administered to rats at a concentration of 50mg/kg, it was efficient at mitigating oxidative stress caused by experimental diabetes (Silva, et al., 2011).  Herbs, 25-60 cm tall. Leaves opposite, simple, sessile, 3-9 × 0.3-0.5 cm, narrow-lanceolate, base sessile, apex acuminate, adaxial and abaxial surfaces with dense, stipitate glandular trichomes with a small head, margin sparsely serrate.

Voucher: J.M. Fernandes 1738 (HERBAM).
This species is endemic to Brazil, where it is native to the Northeast Region (CE, PB, PE, RN), in the Caatinga biome, and cultivated in the other regions (Souza & Giulietti, 2009;BFG, 2018). In the municipality of Alta Floresta (MT), it was only collected on a rural property.
An infusion of the leaves is used to regulate menstruation and intestinal gas, as a sedative and for rheumatic pain, while a decoction of the entire plant is used to treat scabies and itches (Fernandes, 2002). It is not on the list of interest by SUS or in the Brazilian Pharmacopeia (Brasil, 2009;Brasil, 2019). No in vitro or preclinical studies were found for this species.
However, according to Vanitha et al. (2014), in a study of an alcohol extract of the entire plant 33 types of phytochemicals were found, which might have therapeutic potential.
An infusion of the leaves and stems and a decoction of the stems are used to treat respiratory problems (e.g., bronchitis), fever, hemorrhoids and earaches, and to expel phlegm (Fernandes, 2002). The species was added to the list of interest by SUS in 1986 (BRASIL, 2006c) but is not part of the Brazilian Pharmacopeia (Brasil, 2019). There is little information related to pharmacological studies of this species, but an extract of the plant reduced sorbitol dehydrogenase (SDH) activity and decreased glycemia and glycosylated hemoglobin in diabetic rats (Latha & Pari, 2004).  An infusion of the leaves is used to treat stomach problems, intestinal gas and nervousness (Fernandes, 2002). It was added to the lists of interest by SUS in 1986(BRASIL, 2006c. Preclinical studies (Technical Advice nº 012/87, Process nº 456/85) found the following for the species: a lack of significant activity at the central nervous system level; lack of hypnotic and anxiolytic activity; and, at elevated doses (200mg/kg), clear toxic effects were observed, suggesting this species should not be used for therapeutic purposes (Brasil, 2006c).  Subshrubs, 0.60-1.2 m tall. Leaves opposite, simple, sessile, blades 2.5-6.5 × 1.4-2.9 cm, ovate, apex acute, base attenuate, adaxial and abaxial surfaces villous to sericeous, sparse glands present at the base of the abaxial surface, margin crenate-serrate. Inflorescences spikes, terminal, rachis 10-19 cm long; flowers zygomorphic, pentamerous; calyx 4.3-5 × 1 mm, green-vinaceous, sparsely sericeous to sparsely villous, glands 3-6, embedded in the rachis, upper lip lobe 0.2-0.3 mm long, greenish, 4 lobes on lower lip 0.5-0.8 mm long, vinaceous; corolla 7-7.3 mm long, hypocrateriform, glabrous externally, tube white, lobes lilac, 2 upper lobes 2 × 2-3 mm, 2 lateral lobes and lower lobe 1.4-1.7 × 1.3-2 mm; fertile stamens 2, basal, 1.8-2 mm long; ovary 1.2-1.4 mm long. Fruits schizocarps, mericarps 3.5-4 x 1.3-1.6 mm long, outer surface reticulate, This species is native from Central American and the Caribbean to South America, until Argentina, and is widely naturalized in all tropical and subtropical regions of the world (Atkins, 2005). In Brazil, Alagoas, Piauí and Rio Grande do Norte (Northeast Region) are the only states where it does not occur; it is found in the Amazon, Caatinga, Cerrado, Atlantic Forest, Pampa and Pantanal biomes (BFG, 2018). In the municipality of Alta Floresta (MT), it was collected in rural yards and an anthropic area. This species is used as a stimulant, febrifuge and diuretic, to sweat, and to treat urinary problems, chest, stomach and liver pain, constipation and hepatitis (Fernandes, 2002). It was added to the list of interest by SUS in 1986 but is not in the Brazilian Pharmacopeia (Brasil, 2006c;Brasil, 2019). Preclinical research (Process nº 08443/88) coordinated by SUS showed pharmacological effects, central antialgic and antiedematogenic activity, but no antispasmodic activity (Brasil, 2006c). It is not among the phytotherapeutics medicines offered by SUS .

Conclusion
Most of the Lamiales species in this study are native to and have a wide distribution in Brazil that, combined with popular knowledge, can facilitate preclinical and clinical trials.
During the morphological study of the fresh samples, glandular trichomes on the leaves and/or flowers were observed on almost all of the species, which are an important source of secondary compounds and indicative of possible new phytotherapeutics. It is sometimes difficult to observe these structures on dried specimens. Thus, when conducting morphological and/or taxonomic studies of herbarium specimens, it is suggested to rehydrate leaves and other structures so glandular trichomes can be observed.
Due to the relevance of Lamiales species in Brazil and popular medicine, as well as in the examples of the trials presented in this work, the Ministry of Health has consistent justifications to intensify its National Policy on Medicinal Plants and Phytotherapeutics, with the goal of increasing its phytotherapeutic options in the National Report of Essential Medicines provided to SUS users that seek non-conventional treatments.
Additionally, the importance of taxonomic works to medicinal plant studies is evident, since they help with identification and understanding morphology that are the basis for interdisciplinary studies that search for new phytotherapeutics. New works with the same profile are needed, as way to show and draw the attention of the Ministry of Health on the potential of brazilian biodiversity.