Guaco

Guaco (Mikania glomerata Spreng. / Mikania laevigata Sch. Bip.): A Comprehensive Reference

1. Identity and Botanical Classification

Botanical Names and Taxonomy

"Guaco" is the common name applied to two closely related species: Mikania glomerata Spreng. and Mikania laevigata Sch. Bip. ex Baker — important medicinal plants native to South America, particularly Brazil. The genus Mikania Willd. is the largest genus of the tribe Eupatorieae (Asteraceae family), comprising approximately 450 species. Many of these species are found in South American countries, with its two major diversity centres in the highlands of south-eastern Brazil and the eastern foothills of the Andes from Bolivia to Colombia, as well as tropical regions of Asia and Africa.

Mikania glomerata is a perennial vine from the Asteraceae family, primarily found in tropical and subtropical regions. The two guaco species differ morphologically in leaf form, which is ovate to lanceolate-hastate in M. glomerata and ovate-lanceolate in M. laevigata. The morphoanatomical characteristics of the leaves, petioles, and stems are highly similar, which presents a significant challenge in differentiating them.

Both species are endemic to South America, with distribution in the Atlantic Forest biome between Brazil, Argentina, and Paraguay, and have great macro- and microscopic similarity, sharing the same habitat. Mikania glomerata and Mikania laevigata, both popularly called guaco, are used without distinction in Brazilian traditional medicine for respiratory diseases.

Common Names and Official Status

Mikania glomerata is popularly known as "guaco," which became official in the first Brazilian Pharmacopoeia because of its therapeutic properties as a bronchodilator, antiallergic, and antiasthmatic agent. Due to the therapeutic properties attributed to these species, both were included in the official Brazilian Pharmacopoeia, and because of their similarity, they are hardly differentiated.

In 2007, M. glomerata leaf syrup was included in the Reference List of Complementary Medicines and Supplements of the Brazilian Pharmaceutical Assistance and is used primarily as a bronchodilator and expectorant. In Brazil, guaco extracts are used as medicinal products authorized by the National Health Surveillance Agency (ANVISA). The phytotherapic products of guaco have the largest number of registrations at ANVISA, being sold freely in pharmacies in the country and distributed by some municipalities to the population.

Plant Parts Used and Preparation Forms

Guaco preparations are sourced from the leaves of the plant, with extraction typically involving ethanol or hydroalcoholic methods to produce standardized extracts rich in coumarins, sesquiterpenes, diterpenes, and flavonoids. The tinctures of its leaves are used in the preparation of syrups and oral solutions for the treatment of respiratory diseases, acting as an anti-inflammatory, balsamic, and expectorant. In Brazil, the leaves of both species are widely used in folk medicine, mainly in the form of infusions to treat colds, flu, and respiratory problems. Decoctions are also employed in traditional external applications. A decoction of the leaves is employed externally for neuralgia, rheumatic pain, eczema, pruritus, and wounds.

2. Traditional and Historical Use

Indigenous and Rainforest Traditions

Mikania laevigata and M. glomerata, popularly known as "guaco," have a long history of use. Brazilian Indigenous peoples have an ancient tradition of using guaco for snakebites. These indigenous peoples prepared a tea with the leaves, taking it orally as well as applying the leaves or stem juice directly onto the snakebite.

Brazilian Indigenous peoples traditionally use guaco to treat snakebites, arthritis, and various inflammatory conditions such as rheumatism, enteritis, ulcers, and fever. In folk medicine, their leaves have ample use due to their balsamic, antiophidic, appetite stimulant, antispasmodic, expectorant, and antimalarial properties, among others.

Brazilian Ethno-medicine and Fitoterapia

Guaco has been used in Brazilian traditional medicine (fitoterapia) for centuries to treat respiratory conditions and inflammation, and is officially recognized in Brazilian pharmacopeias as a phytotherapeutic agent. In current herbal medicine in Brazil, guaco is used as an effective natural bronchodilator, expectorant, and cough suppressant employed for all types of upper respiratory problems including bronchitis, pleurisy, colds, flu, coughs, and asthma. In Brazil, this plant has been widely used, even as commercial preparations.

Guaco is also popular in Brazil as an anti-inflammatory, antispasmodic, and pain-reliever for rheumatism, arthritis, intestinal inflammation, and ulcers. Ethnopharmacological studies of the Mikania genus showed pharmacological properties such as tonic, depurative, antipyretic, and appetite stimulant, and as a treatment for influenza.

Due to their important effects, pharmaceutical preparations including syrup and oral solutions are freely distributed through various government phytotherapy programs and thus widely used by the population. This plant and its syrup are commercialized and distributed for free by Brazilian government health programmes to treat respiratory complaints such as asthma, bronchitis, and cough.

3. Key Chemical Constituents and Active Compounds

Primary Phytochemical Classes

The main chemical groups present in Mikania glomerata are: coumarins and derivatives, sesquiterpenes, sesquiterpene lactones, diterpenes, phytosterols/terpenoids, and flavonoids. The constituents of the species M. glomerata have been specifically identified as coumarin, lupeol acetate, o-hydroxycinnamic acid, kaurenoic acid, cinnamoylgrandifloric acid, and stigmasterol.

Coumarins

The biological activity of M. glomerata extracts is due, in significant part, to the presence of coumarins — a large family of phenolic substances made of fused benzene and α-pyrone rings. Coumarin (1,2-benzopyran), dihydrocoumarin, and O-coumaric acid have been identified in extracts of M. glomerata and M. laevigata. Coumarin (1,2-benzopyrone) has been quantified at approximately 0.1–0.5% dry weight in leaves and is the principal marker compound used for standardization of commercial preparations.

The most characteristic class of compounds in the Mikania genus are the coumarins and derivatives, frequently responsible for pharmacological activity. A wide variety of biological activities is assigned to these compounds, including antimicrobial, antiviral, anti-inflammatory, antispasmodic, antitumoral, anticoagulant, bronchodilator, and antioxidant.

An important inter-species distinction regarding coumarin has been established by chemical analysis: one study found 17.81% of coumarin in M. laevigata but did not detect coumarin in the ethanolic extract of M. glomerata, detecting it only in the ethyl acetate fraction of M. glomerata at a relatively low percentage (1.43%). Thus, the percentage of compounds in both species shows great variation, as does the quality of compounds, depending on the geographical origin of the plants. As a consequence, coumarin is not considered a valid chemical marker for M. glomerata. Additionally, M. glomerata exhibits higher concentrations of chlorogenic and dicaffeoylquinic acids.

Caffeic Acid Derivatives

Caffeic acid derivatives are present at approximately 0.3–1.2% dry weight, including chlorogenic acid and dicaffeoylquinic acid isomers. These phenolic compounds distinguish the two principal guaco species chemically and may contribute independently to the plant's anti-inflammatory and antioxidant profile.

Flavonoids

Flavonoids — including kaempferol, quercetin, and luteolin glycosides — are present at approximately 0.5–2.0% dry weight total.

Diterpenes: ent-Kaurenoic Acid

Many of the pharmacological activities of M. glomerata have been attributed to its phytochemical composition, which is primarily composed of diterpenes, such as ent-kaurenoic acid (KA). Kaurenoic acid (KA) has demonstrated many pharmacological activities, including antioxidant, anti-inflammatory, leishmanicide, antimicrobial, antimalarial, and cytotoxic properties. Lupeol has anti-inflammatory activity, and kaurenoic acid is a potential antimicrobial and hypotensive compound.

Other Identified Constituents

Among the further chemical constituents of Mikania glomerata leaves identified by high-resolution gas chromatography-mass spectrometry are lupeol and lupeol acetate. Terpenes including friedelan-3β-ol (friedelanol), lupeol, and β-sitosterol are identified in leaf extracts. Alkaloids are absent or present only in trace amounts.

Seasonality and variations in cultivation conditions of medicinal plants may result in different concentrations of active components, affecting the safety, quality, and efficiency expected of herbal medicines. During the flowering period, there is an increased concentration of compounds in the plants; for guaco, this period extends from August to December.

4. Established Mechanisms of Action

Bronchodilation and Smooth Muscle Relaxation

Coumarin appears to be partially responsible for the bronchodilator activity of the plant through relaxation of smooth muscle. The mechanism of bronchodilation has been investigated in tissue preparations: studies in isolated tissue suggested that the inhibitory effect of M. glomerata was not dependent on inhibition of muscarinic or histaminergic receptors, activation of β2-adrenoceptors, release of nitric oxide and/or prostanoids, or activation of K+ channels, indicating a distinct, not fully elucidated mechanism of smooth muscle relaxation.

Anti-inflammatory Pathways

The coumarins were correlated with most of the activities reported for guaco species, including those associated with popular use, such as antimicrobial, anti-inflammatory, bronchodilator, and antiulcerogenic. Preclinical work has shown that guaco preparations can inhibit specific inflammatory cascades: the subcutaneous injection of 100 mg/kg of the dichloromethane fraction significantly reduced plasma exudation, leukocyte infiltration, and platelet-activating factor (PAF). Because pre-treatment did not alter pleurisy induced by histamine, serotonin, or carrageenan, the fraction was considered effective only for inhibiting immunologic inflammation, and not the acute inflammatory response caused by other agents.

Antiophidic (Anti-venom) Activity

The antiophidic effect of coumarin present in M. glomerata was tested against the venom of Bothrops jararaca snake, and the animal survival rate was evaluated, resulting in 40% survival in animals that received treatment compared to 0% in the control group. Maiorano (2005) observed the antiophidic activity of M. glomerata root extracts that reduced the hemorrhage zone stimulated by the intradermal injection of Bothrops venom by 80% in rats.

Anxiolytic / GABAergic Activity

A standardized ethanol extract of M. glomerata leaves demonstrated anxiolytic effects in animal models that may be mediated by the GABAergic system. It was able to increase GABA levels and reduce glutamate and aspartate concentrations in the mouse hippocampus, which can directly and/or indirectly contribute to its anxiolytic effect. More studies are needed before this finding can be meaningfully translated to clinical populations.

5. Scientific Evidence by Area of Use

5.1 Respiratory System: Bronchodilation, Expectorant, Antiasthmatic

Evidence level: Preclinical (animal/ex vivo); one relevant human tissue study; no controlled clinical efficacy trials identified.

The effects of aqueous extracts and hydro-alcoholic extract (HAE), and of a dichloromethane fraction obtained from the HAE of Mikania glomerata leaves on isolated respiratory and vascular smooth muscle have been investigated. Aqueous extracts and HAE induced a significant inhibition of histamine-induced contractions in the isolated guinea-pig trachea. HAE extract induced a concentration-dependent relaxation on guinea-pig trachea pre-contracted with histamine (IC50 0.34 mg/mL), acetylcholine (IC50 0.72 mg/mL), or K+ (IC50 1.41 mg/mL), and on isolated human bronchi pre-contracted with K+ (IC50 0.34 mg/mL).

The dichloromethane fraction induced a concentration-dependent relaxation in guinea-pig trachea pre-contracted with K+ (IC50 0.017 mg/mL). This ex vivo study is notable because it demonstrated relaxation of isolated human bronchial tissue, providing a mechanistic basis for the traditional respiratory use. However, it is not a clinical trial measuring patient outcomes.

There is also pre-clinical evidence of the anti-inflammatory, anti-allergy, and bronchodilation activities of these species. The evidence gap map for M. glomerata shows evidence for 33 biological activities, with most of this evidence presenting a moderate-to-high risk of bias. In addition, there is a gap in the evidence from clinical trials.

5.2 Anti-inflammatory Activity

Evidence level: Primarily preclinical (in vitro and rodent models); strong mechanistic signal; no controlled human efficacy trials.

The anti-inflammatory activity of M. laevigata has been the most extensively studied property, with a total of nine investigations conducted. This species did not exhibit anti-inflammatory activity in primary cultures of dystrophic skeletal muscle cells; however, eight studies confirmed the presence of this activity. One study evaluated this activity in vitro using a screening kit to demonstrate activity against cyclooxygenase-1 and 5-lipoxygenase. Six studies in vivo demonstrated the extract's impact on intraperitoneal inflammation.

The most extensively researched activity for both species is their anti-inflammatory properties, which have been associated with their efficacy in treating bronchoconstriction and their popular uses as an antiophidic agent.

5.3 Antiulcer Activity

Evidence level: Preclinical only.

Antiulcerogenic activity of a crude hydroalcoholic extract and coumarin isolated from Mikania laevigata Schultz Bip. has been reported in Phytomedicine, 2005. Preclinical data from rodent models support the anti-ulcerogenic property, which has been attributed principally to coumarin content. No human clinical trials on this endpoint have been identified.

5.4 Antimicrobial Activity

Evidence level: Preclinical (in vitro); evidence is preliminary and fraction-dependent.

The hexane fraction (with kaurenoic acid as a major compound) from both species of Mikania was found to be the most effective against crude extract and ethyl acetate fractions in inhibiting growth and cell adherence to a glass surface of mutans streptococci. Another study found that ethanolic and dichloromethane extracts did not show antibacterial activity, detected only in the hexane extract of M. glomerata. The results from both studies suggested that the biologically active compounds were present mostly in the hexane fraction.

Time-kill and anti-biofilm activity assays conducted for ent-kaurenoic acid (KA) at concentrations between 3.12 and 12.5 µg/mL exhibited bactericidal activity between 6 and 72 hours of incubation and 50% inhibition of biofilm formation for Porphyromonas gingivalis, Propionibacterium acnes, Prevotella nigrescens, P. melaninogenica, and Aggregatibacter actinomycetemcomitans. KA combined with chlorhexidine dichlorohydrate (CHD) had an additive effect against P. gingivalis compared to CHD alone. It was concluded that M. glomerata extract and its major compound ent-kaurenoic acid showed in vitro antibacterial activity, with the latter being a potential biofilm inhibitory agent.

5.5 Antiophidic (Antivenom) Activity

Evidence level: Animal models; no human clinical data.

Although serotherapy is available, many rural communities lack access to antivenoms and alternatively use plants with antiophidic activity known in popular culture, including some species of the genus Mikania. Animal studies (detailed in the Mechanisms of Action section above) demonstrated meaningful survival benefits. The activities of coumarins are described as including antisnake venom among other properties. These findings remain at the preclinical stage.

5.6 Anxiolytic / Neurochemical Effects

Evidence level: Animal models only.

A standardized ethanol extract of M. glomerata leaves demonstrated anxiolytic effects in animals, possibly mediated by the GABAergic system, and was able to increase GABA levels and reduce glutamate and aspartate concentrations in the mouse hippocampus. Although more studies are needed, the extract could represent an interesting therapeutic strategy in the treatment of anxiety. There are currently no human trials evaluating this effect.

5.7 Antioxidant Activity

Evidence level: In vitro; limited preclinical data.

The compounds present in the extracts of the leaves of guaco species, including coumarins, terpenes, kaurenoic acid, aldehydes, and organic esters, have been associated with a range of pharmacological activities. Coumarin in particular has been associated with antioxidant activities. Antioxidant activity has been confirmed in vitro but has not been the subject of controlled human studies.

5.8 Other Reported Preclinical Activities

Integrative reviews of the guaco literature describe diverse therapeutic properties, including antiasthmatic, tonic, antipyretic, expectorant, appetite stimulant, anti-influenza, antirheumatic, antiallergic, antifungal, and anthelmintic activity. Texts also indicate performance on duodenal and stomach ulcers and infectious diseases such as tonsillitis and oropharyngeal inflammation. The gap map illustrates the lack of evidence to support the biological activity of these species for some popular uses, such as their use as expectorants, antipyretics, for arthritis, rheumatism, neuralgia, and as an antisyphilitic.

Overall Evidence Assessment

A total of 57 studies (31 assessed only M. glomerata, 17 assessed only M. laevigata, and 9 assessed both species) evaluating 38 different biological activities demonstrated that preclinical studies reported 23 biological activities for M. glomerata and 24 for M. laevigata. Despite promising preclinical evidence, the translation into clinical application remains limited. Challenges such as low oral bioavailability, individual variations in hepatic metabolism mediated by CYP2A6, and reports of hepatotoxicity limit the clinical advancement of new formulations. Coumarins still require well-designed clinical trials to more robustly validate their therapeutic applications. There is a clear need for further studies to evaluate the activity of these species for these purposes, mainly through clinical studies.

6. Dosage Forms and Dosages Reported in Studies

Both species are marketed as tinctures and used in the preparation of syrups and oral solutions for the treatment of respiratory diseases.

There are no clinical trials established for efficacy at defined doses; the major clinical study to date focused specifically on safety evaluation rather than dose-finding for therapeutic effect. In that Phase I safety study: participants (n = 19) were randomly allocated to one of two arms. Group 1 received 15 mL of M. glomerata oral solution twice daily for 7 days and then 30 mL twice daily for 7 days. Group 2 received M. laevigata oral solution in the same manner. After 14 days, participants went through a washout period of 7 days before crossover to the other group.

A multi-ingredient clinical study also recorded guaco dosing: the clinical trial of Saratosse®, a phytomedicine syrup composed of several medicinal plants including Mikania glomerata, gave 26 adult volunteers an oral dose of 15 mL for 28 consecutive days, four times a day.

Commercial preparations are standardized to coumarin as the marker compound, though, as noted, coumarin is a more reliable marker for M. laevigata than for M. glomerata.

7. Safety Considerations and Interactions

Phase I Clinical Safety Trial

Although M. glomerata and M. laevigata leaves are used interchangeably in Brazilian ethno-medicine, mainly for the treatment of respiratory diseases, no clinical trial had evaluated the safety of these species at different doses until the first Phase I trial. The study was designed to evaluate the safety of two oral solutions from each species, across two weeks of use and two doses, in a randomized, open-label, multiple-dose, two-arm design. Adverse events, clinical parameters, and blood markers were monitored at baseline (T0) and at the end of each week of the study, which was concluded after six weeks. A clinical trial was conducted to assess the safety of both species. The results indicated that neither posed any significant risk.

Coumarin and Hepatotoxicity

Coumarin has been used as an effective treatment for primary lymphoedema; however, its clinical use is limited in several countries due to the possible occurrence of hepatotoxicity, mainly in the form of mild to moderate transaminase elevation. Only a few cases of severe hepatotoxicity have been described in the literature, with no reported cases of liver failure. Coumarin-induced hepatotoxicity is restricted to a small subset of patients, probably due to the activation in these individuals of alternative metabolic pathways involving specific CYP450 isoforms. This coumarin-related hepatotoxicity concern applies principally to M. laevigata preparations, which contain significantly higher coumarin concentrations.

Toxicity of Isolated Constituents

Dihydrocoumarin administered to groups of rodents led to carcinogenic activity, ulcers, forestomach inflammation, parathyroid gland hyperplasia, and increased nephropathy in preclinical toxicology studies. Kaurenoic acid has been shown to kill sea urchin embryos and to cause hemolysis in mouse and human erythrocytes in laboratory studies; the clinical relevance of these findings at doses present in traditional preparations has not been fully established.

Anticoagulant Considerations

The activities of coumarins described in the guaco literature include anticoagulant activity. Because coumarin (the simple benzopyrone present in guaco) is a structural precursor class of anticoagulant drugs (though it does not itself have direct anticoagulant activity equivalent to warfarin-class drugs), there is potential for pharmacokinetic or pharmacodynamic interactions with anticoagulant therapy that warrants attention in patients using such medications.

Gestation and Reproductive Safety

A study analyzed the toxic effects of Mikania glomerata administration during the gestational period of hypertensive rats, in which groups of pregnant Wistar rats received treatments with guaco extract (1 to 2 mL). Reproductive performance, morphological parameters, and fetal-placental histology were assessed. Medicinal plants have potential toxic effects not yet fully discovered and may have unproven interactions with other medications. The use of drugs during pregnancy is vigorously studied, yet there are few studies of herbal medicines in pregnant women.

Quality Control and Species Confusion

Seasonality and variations in cultivation conditions of medicinal plants may result in different concentrations of active components, affecting the safety, quality, and efficiency expected of herbal medicines. The great macro- and microscopic similarity of the two species makes it difficult to distinguish between them, leading to the marketing and use of the two species interchangeably. Differences in composition between species were always greater than variations due to seasonality or treatments within the same species, indicating that they should not be used without distinction.

Earlier Limitations of Human Safety Data

Guaco syrup has been commercialized and distributed for free by Brazilian government health programmes to treat respiratory complaints such as asthma, bronchitis, and cough; although this clinical practice has been described as harmless and safe, neither the assessment of the toxicity of guaco syrup used by humans, nor its efficacy or mechanisms of action, had been investigated properly prior to the first Phase I trial.

8. Body Systems and Health Areas of Association

• Respiratory system: Guaco preparations are used in traditional Brazilian medicine, mainly to address respiratory conditions affecting the upper airways. Specific conditions associated historically and in preclinical research include asthma, bronchitis, coughs, and colds.
• Immune/inflammatory system: The most extensively researched activity for both species is anti-inflammatory properties, associated with their efficacy in treating bronchoconstriction and antiophidic use.
• Gastrointestinal system: Guaco has been associated with anti-ulcerogenic activity in preclinical research, with both hydroalcoholic extracts and isolated coumarin showing effects in rodent ulcer models.
• Musculoskeletal system: Brazilian Indigenous peoples traditionally use guaco to treat arthritis and inflammatory conditions such as rheumatism.
• Central nervous system: Preclinical animal data suggest anxiolytic effects possibly mediated by the GABAergic system.
• Integumentary system: A decoction of the leaves is employed externally for neuralgia, rheumatic pain, eczema, pruritus, and wounds.
• Cardiovascular / anticoagulant: Coumarin content is associated with anticoagulant and vasodilatory properties in preclinical studies.
• Anti-infective (venoms, microbes): Antiophidic and in vitro antimicrobial activities have been documented preclinically.

References

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