Abstract

Guarana is native to the Amazonian region of Brazil and, widely used in liquid preparations due to its stimulating effect, along with other therapeutic properties. Its chemical components, methylxanthines and condensed tannins, exhibiting a marked biological activity, may be found in commercially available powdered guarana brands at varying levels, possibly due to their provenance and drying processes. However, the chemical standardization of its extract maintains the same quantified content of active substances on each and every lot of extract produced, thus asssuring their quality and therapeutic efficacy. Consumption of guarana by the population should be controlled, since there is controversy as to its dosage and association with allopathic drugs, the interactions of which may result in increasing the therapeutic effect, reducing efficacy or even bringing about adverse reactions. However, the use of guarana in adequate concentrations may contribute to achieve therapeutic properties with less toxicity on account of it being some natural antioxidants source and considered one of the most important new substances directly used as effective medicinal agents.

1. Introduction

Paullinia cupana Kunth originates from the Amazon Basin, belongs to family Sapindaceae and is consumed on a global scale ¹. Historical data reveal that guaraná was already known by the Maués, Andirás and Marabitanas tribes of Amazonia, before the arrival of the Europeans, due to its stimulating ², antidepressant ³ and diuretic ⁴ activities.

Large amounts of methylxanthines, including caffeine, theophylline and theobromine, in addition to saponins, polyphenols, and especially condensed tannins, are responsible for the benefits brought on to the population on account of being chemical substances bearing bioactive properties ⁵.

Therefore, the biologic activities of guarana possess therapeutic indications, to be investigated in the prevention treatment of diseases, with promising perspectives for producing novel phyto drugs.

2. Chemical Characteristics

Guarana seeds (Figure 1), source: Rebelo/INPA-Brazil, contain a high concentration of bioactive components, described in 1669, when their daily use by the indigenous peoples of the Amazon region, was observed.

Among the main chemical constituents of guarana, methylxanthines, I- Caffeine (1,3,7-trimethylxanthine), II- Theophylline (1,3-dimethylxanthine) and III- Theobromine (3,7-dimethylxanthine) (Figure 2 & Figure 3) ⁹⁰ and condensed tannins, are composed of interconnected monomeric units, the main ones of which being proanthocyanidin: catechin and epicatechin (flavan-3-ol), due to their antioxidant effect in the protection of atherosclerotic cardiovascular diseases and the process of carcinogenesis ^{6, 7, 8, 9}. Phytochemical composition includes: xanthine: caffeine (1,3,7-trimethylxanthine) (2 to 7.5%), theobromine (0.02 to 0.03%) and theophylline (0.25%). In the essential oil, cyclic sesquiterpenes and cyclic monoterpenes were identified. Minerals were also identified: calcium (0.1%), phosphorus (0.3%), potassium (0.3%), magnesium (0.08%), iron (4.3 mg); flavonoids: catechol and epicatechol; tannins (8.5 to 25%) ^{2, 9, 10, 11, 12, 13, 14, 15}.

3. Biological Activity

Several studies on the medicinal properties of guarana seeds have been carried out, especially in the last three decades, demonstrating the potential of the biological activities concentrated in guarana with its exceptional content of methylxanthines and proanthocyanidins ¹¹. Thus, the isolated substances have already been analyzed according to the studies described below (Table 1).

4. Bioactive Compound Contents

In the scientific literature, the data on the concentration of guarana powder are conflicting, depending on the region of planting and techniques used for its cultivation and drying processes. Studies have verified different levels of caffeine in marketed powdered Guarana brands, being outside the pharmacopoeia quality specifications. The caffeine content in the samples presented a great variability, in the range of 9.52 to 36.71 mg / g of powder. Due to this variation, the consumers of this product are liable to ingest uncontrolled doses, which may cause a health damage ⁴⁴. This demonstrates the need to implement quantitative techniques in the physical-chemical quality control of plant raw materials, in addition to the need to qualify suppliers by emphasizing the control in acquisition, storage and handling ⁴⁵.

Under this context, studies will provide better definitions, showing guarana to bear a higher caffeine content than that of coffee seeds (7.59 mg caffeine / gram of guarana powder), verified in the studies ⁴⁴, in threefold higher quantity, with a mean caffeine concentration of 20.68 mg / g (caffeine / gram of powder), and this difference can reach up to fourfold ⁴⁶.

Technological alternatives are necessary in order to consume guarana since it tastes bitter and irritates the gastrointestinal tract. Short-term medicinal effects are commonly considered to result from caffeine and associated alkaloids high content as well as considerable amounts of tannins ^{4, 47}. Thus, future research may show that various saponins also play an important role in pharmacology of the drug, particularly with regard to its long-term influence as a general and prophylactic toner.

Studies have noted that five minutes after consumption, caffeine can be detected throughout the human body, reaching its peak action after 30 minutes and lasting from four to six hours. Excessive consumption of caffeine-rich foods can cause unpleasant symptoms such as irritability, headaches, insomnia, diarrhea and tachycardia. Guarana should not be consumed by individuals, with a history of heart disease, hypertension, sensitive to caffeine use, and with gastrointestinal disorders (irritable bowel syndrome, colitis, diarrhea, gastritis). Eating more than 400mg per day can lead to so-called "caffeinism" the most common symptoms of which have shown to be anxiety, restlessness, irritability, tremors, appetite loss, muscle tension, insomnia, and heart palpitations. The safe dose of guarana powder has not been defined as of yet ^{44, 48, 49, 50}.

Conversely, effects can be described as increased alertness and reduced fatigue associated with improved performance of activities ^{3, 18, 27, 44, 51}.

Studies have shown guarana concentration to be of critical importance for the cytotoxic activity of the compounds present in guarana. Low guarana concentrations have been shown to be harmless, whereas higher ones could be cytotoxic ^{33, 52, 53}.

As to phenols, they are not considered to be toxic in normal amounts and conditions, except for polymeric phenols called tannins, which have the ability to complex and precipitate proteins from aqueous solutions ⁵⁴. When oxidized, tannins turn into quinones, which form covalent bonds with some functional groups of the proteins, mainly the cysteine and lysine ε-amino sulfide groups ⁵⁵.

More specifically, tannins are high molecular weight compounds, containing enough phenolic hydroxyl groups, to allow the formation of stable cross-links with proteins ⁵⁶. They are present in a larger quantity in the foods normally consumed, in the composition of the dietary fiber fraction of different foods and may be considered indigestible or partially digestible ^{54, 56, 57, 58, 59}.

Experimental evidence confirms previous observations that polyphenolic compounds significantly inhibit iron absorption, but the negative effect of tannin on iron absorption can be effectively prevented by simultaneous administration of ascorbic acid ^{60, 61}.

However, no effect of tannins on calcium absorption was observed in rats ⁶². For the authors, the explanation of the results may be due to the fact that tannins preferentially bind to the iron leaving the calcium free. With respect to calcium homeostasis, data compiled in a review indicate that caffeine is not detrimental to bone metabolism of individuals whose calcium intake is adequate to their daily metabolic needs ⁶³.

Thus, moderate consumption of guarana (maximum 4.6mg/kg body weight/day) in healthy adults of reproductive age is not associated with adverse effects ^{64, 65, 66}. Therefore, it is important to carefully instruct the use of guarana to the population with prescription and guidelines ^{44, 67, 68, 69}.

5. Drug Interactions

The use of caffeine in the form of drugs, as for instance, in anti-flu drugs, and of a lot it in the composition of a variety of dietary supplements, is mainly used because of its high content ^{12, 70, 71}.

Guarana potentiates the action of analgesics, antidepressant activity, and, consumed with anticoagulants can lead to inhibition of platelet aggregation, thus increasing the risk of bleeding ⁶⁸.

Drug interactions are pharmacological responses, in which the effects of one or more medicinal products are altered by their concomitant administration. These interactions are both observed with synthesized chemicals (allopathic drugs), and those present in plants being used in home preparations and herbal medicines ⁷².

However, interactions with guarana may result in its therapeutic effect potentiation, efficacy reduction or the appearance of adverse reactions ^{72, 73, 74}.

6. Use of Guarana in Allopathy

As a medicinal plant guarana holds an essential content of caffeine makes part of the pharmacopoeia of Brazil, ⁷⁵ and several European countries, Mexico and the United States. "Guarana” is used in migraines as a sedative and tranquilizer, has shown to be an excellent in the convalescence of serious diseases; inestimable cardiovascular, exerting a generalized tonic action in the senile evolution. It regulates the cardiac energy, combats and prevents the passive congestions so peculiar and frequent in the aged “organs" ⁷⁶. Thus, treating the therapeutic value of this Sapindácea reveals that daily consumption has a neurostimulating effect ⁷⁷. Guarana is one of the most important and advantageous medicines of modern therapy, on account of properties. Its therapeutic value, evidenced in studies and trials, is increasing and, represents an important role of worldwide repercussion, in medicine ⁷⁸. The compendia and pharmacological catalogs clearly describe numerous and vast uses of guarana in the various formulas.

It can be observed that the therapeutic knowledge of guarana is ancient, and it was observed that in the Upper Amazon, the general use of chewing small fragments of guarana paste, can prevent one from feeling thirsty, hungry, and even physically and mentally fatigued, and able to work longer hours. And that the use of the guaraná paste this way leaves a bitter taste in the mouth, which can be sweetened by the ingestion of water ⁷⁹.

A specified study has found guarana to act as a physiological functions stimulant and an excellent intestinal regulator ⁸⁰. Aiming at the development of its culture and use, they report its action as an aphrodisiac to be the most important one ^{4, 47}.

Due to being a source of bioactive substances with multifaceted activity, guarana is used in therapeutics to treat human diseases as well as to rise its effectiveness in acting as stimulants ^{20, 32, 81}.

The interest in its consumption is due to its high content of caffeine and tannins ³⁵, with antioxidant action in the promotion, prevention and recovery of health, in addition to other biological properties ⁸². Thus, caffeine appears to have an effect on the control of the metastasis process ⁸³ and the catechins associated with other derivative tannins present in guarana, such as epicatechin, ent-epicatechin and procyanidins B1, B2, B3, B4, A2 and C1 ⁵, have been contributing to the control of in vivo melanoma growth by reducing cell proliferation and increasing cell death through apoptosis, in addition to antiaging activity, and verified in this Amazonian fruit ³⁴.

The studies on the antibacterial activity of guarana could justify some ethnopharmacological uses, such as against diarrhea and dysentery, since they demonstrate the strong activity of this plant against some pathogens of the digestive tract ¹².

According to studies, the alcoholic extracts presented a higher antimicrobial activity against all the tested microorganisms than that of the aqueous extract in vitro, when found in three fungi transmitted by foods: Aspergillus niger, Trichoderma viride and Penicillium cyclopium and in three bacteria harmful to health: Escherichia coli, Pseudomonas fluorescens and Bacillus cereus ¹⁴. However, the authors observed that in the aqueous extract, they presented higher amounts of caffeine and catechins, conferring greater antioxidant activity.

Due to the ongoing emergence of antibiotic-resistant strains, there is a continuing demand for new antibiotics. In many developing countries, about 80% of available medicines come from medicinal plants, and in developed countries plants are the raw material for processes that synthesize pure chemical derivatives ⁸⁴.

Among the therapeutic effects of guarana, it it comes to cotribute in a beneficial and effective way when included in the development of new drugs in intermediate and final pharmaceutical forms, since it minimized side effects ⁸⁵, when administered correctly, and is more more cost effective since it can be obtained from natural sources and does not need to be industrialized ^{86, 87, 88}.

Complexes containing caffeine and catechins (and their dimers) may be responsible for antiplatelet aggregating activity in guarana seeds and may offer health benefits by lowering the risk of thrombosis and cardiovascular disease ⁸⁹.

For decades, the phenolic compounds of guarana have been of interest for studies, due to their phytochemicals bearing beneficial effects on human health, able to stabilize free radicals, increasing antioxidant activity, among other biological and pharmacological effects. Therefore, recent studies have verified that guarana catechins are bioavailable and contribute to reduce the oxidative stress of clinically healthy individuals by the direct antioxidant action of the absorbed photochemistry and the positive regulation of enzymes, thus reinforcing the published research on the benefits to human health with the use of guarana ³⁴.

7. Summary

The therapeutic properties of guarana are attributable to more than one potentially bioactive component. These include the relatively high levels of saponins, tannins, and caffeine contained in guarana extracts. The perspective of association with single or multiple vitamins and minerals deserves to be investigated in order to make part of new drugs. Thus, the relationship between the concentration of guarana bioactive compounds and their antioxidant capacity is associated with the therapy of diseases and beneficial effects for health. The study of the presence and concentration of these compounds in guaraná should be expanded, in order to allow a better evaluation of their effects, allowing a broader understanding that aims to contribute in several aspects regarding their use, such as: chemical composition, quality control, kind of extraction, therapeutic value, posology, pharmacological potential and association with allopathic drugs.

Acknowledgements

The authors are grateful to the Federal University of Amazonas.

Conflict of Interest

The authors declare no conflict of interest.

References