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History of medicinal plant use

The use of medicinal plants for their therapeutic capabilities is an age old tradition which continues to evolve with scientific research and new discoveries [9]. Generally, there is a strong association between medicinal plants and the local area within which they exist and this has resulted in several plant-based medicinal systems such as the Ayurvedic and Unani from India, the Chinese and Tibetan originating from other regions of Asia, the Native American and the Amazonian systems from North and South America, respectively; as well as others from Africa and the Caribbean [10].

According to the WHO, about 70 percent of the global population is dependent on plants to supply their primary health care needs. Approximately 35,000 to 70,000 (14 to 28%) of the 250,000 plant species have been manipulated for their healing properties and to date [10-13], only about fifty major drugs have been developed from tropical plants [14]. This could possibly be attributed to the fact that of the 250,000 species of higher plants worldwide, only about 17% have been scientifically researched for their medical efficacy [15].

The chemical and biological diversity of plants represent a possible limitless renewable source for the use in the development of new pharmaceuticals. China and North America have similar numbers of flowering plants (35,000). However, of these, only about 5000 are utilized in traditional Chinese medicine, whereas, Native Americans used 2564 medicinal plants [15,16]. Herbal medicine in North America is potentially representative of a diverse source of phytopharmaceuticals, but a large number of plants remain unknown and little screening of medicinal plants in that region have been done [17]. The same observations have been made regarding the flora that exists in Jamaica and nearby countries. For the most part, many of the medicinal plants that have been used traditionally for the treatment of various conditions have remained unexplored or untapped.

Presently, a number of practitioners of “conventional” medicine are amenable to recommending herbs, herbal products, or Complementary and Alternative Medicine (CAM) therapy to their patients for the effective treatment of certain diseases [18]. Previous studies indicated that approximately 40% of adults and 11% of children utilize CAM Therapy (CAMT). The adult users were comprised of 43.1% whites and 25.5% blacks [19,20]. In addition, CAM and herbal medicines are more popular amongst people with higher education and income levels and particularly more noticeable in younger patients with breast cancer [21,22].

Research has shown that eighty-nine plant-derived drugs currently being utilised worldwide, were discovered by studying traditional herbal use [15,23]. For instance, the effectiveness of foxglove (Digitalis purpurea) was discovered from traditional European herbal medicine in the 18^th century by William Withering, for treating dropsy [10]. The plant was also found to reduce retention of fluid. Subsequently, more than thirty cardiac glycosides including digitoxin and digoxin were separated from dried foxglove leaves [23]. Another herb referred to as the snakeroot plant (Rauvolfia serpentine) was traditionally used for treating insomnia in India, but in 1949, the alkaloid reserpine was isolated and is presently used for treating high blood pressure [23]. Another useful drug, artemisinin, used to treat malaria was extracted from the wormseed plant (Artemisia annua) based on Chinese traditional use of the plant [24]. In the U.S.A., ethnobotanical studies have resulted in the discovery of alkaloids from the Madagascar periwinkle (Catharanthus roseus), which is used in treating Hodgkin’s disease and leukemia in children. Additionally, the anti-cancer compound taxol, was found in the bark of the Pacific yew tree (Taxus brevifolia), and subsequently approved for use in 1992 by the Food and Drug Administration (FDA).

The identification of plants with compounds for possible use in modern medicine is intricately interwoven in unearthing and understanding the traditional knowledge and use of various medicinal plant systems. Research shows that the Native Americans and Chinese used plants from the same family and genus, in their respective traditional medicine systems [10]. For example, Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius) were used as adaptogenic agents [16,25]. American licorice (Glycyrrhiza lepidota) and Asian licorice (Glycyrrhiza glabra) were utilized similarly for the treatment of asthma in both traditional medicine systems [16,17]. There is currently a plethora of medicinal plants being investigated for their ameliorative properties and well known amongst these plants, is Petiveria alliacea.

In light of the popular practice of using medicinal plants, herbs and herbal medicine for the treatment of various ailments [9], the research thrust in modern therapeutics and the increasing worldwide demand for natural products, the focus of this systematic review is to evaluate the traditional and medicinal uses of Petiveria alliacea through emphasis on treatment evidence and promising reports in the literature.

Distribution and description of Petiveria alliacea

Petiveria alliacea L. belongs to the Phytolaccaceae family which is considered to be the most primitive family of the Caryophyllales [26]. There are about 17 genera and 120 pan-tropical species in this group which are often found throughout North and South America [27,28]. The family is comprised mainly of shrubs and herbs and very few trees. Alliacea is the sole species within the Petiveria genus [29]. The plant is native to Florida and the Lower Rio Grande Valley of Texas in the United States [30], tropical areas of Central and South America and the Caribbean [31]. Introduced populations exist in Benin and Nigeria in Africa [32].

Petiveria alliacea is known by a wide range of common names based on where it grows. In the Dominican Republic, Puerto Rico and Brazil, it is referred to as anamu or guinea hen weed; whereas, in Guatemala it is known as apacin. In Peru, other areas of Latin America, Trinidad and Jamaica, the common names are mucura, guine, mapurite and guinea hen weed, respectively. The plant is also commonly referred to as apacina, apazote de zorro, aposin, ave, aveterinaryte, calauchin, chasser vermine, congo root, douvant-douvant, emeruaiuma, garlic weed, guinea hen weed, guine, guinea, guinea hen leaf, gully root, herbe aux poules, hierba de las gallinitas, huevo de gato, kojo root, kuan, kudjuruk, lemtewei, lemuru, mal pouri, mapurit, mapurite, mucuracaa, mucura, mucuracáa, ocano, payche, pipi, tipi, verbena hedionda, verveine puante and zorrillo [33].

The plant is often described as a weed-like, deeply rooted, erect herb or sub-herbaceous perennial that grows to a height of about 1 m. The stems of the plant are thin, angular and hairy to glabrous. The stipules are 1.5-2 mm and linear [34]. The leaves are alternate, simple, entire and oblong to elliptic, acute to acuminate at the tip and range in size from 5-20 cm x 2-8 cm. The inflorescence can be terminal or axillary, slender with nodding raceme between 10 - 40 cm long and sometimes branched. The bracts are usually 1.5-2.5 mm long. The flowers are bisexual, 4-merous and zygomorphic. Generally, the length of the pedicel ranges from 2-3 mm; whereas, the sepals are 3-4 mm long, free, oblong to rounded and greenish or white to pink in colour. There are no petals present. There are 4-8 irregularly inserted stamens and the filament is about 2 mm long. The 4 hooked ovaries is superior, oblong, shortly hairy and single-celled with a lateral, sessile stigma. The fruit is a narrow, oblong achene, about 6-8 mm long. It is striated, apex 2-lobed, with recurved hooks and has a single seed [34].

Properties

All parts of the P. alliacea plant appear to be useful and to date several biologically active compounds have been isolated. Most prominent among these constituents are sulphur compounds (similar to allicin, found in garlic and onion), flavonoids, triterpenes, steroids, saponins, polyphenols, fredelinol, pinitol and allantoin [35]. Crude extracts of P. alliacea have been shown to exhibit various neuropharmacological benefits including cognitive enhancing activity, as well as anxiolytic, antidepressant, antinociceptive and anti-seizure properties [36]. Pentane extracts of the roots have revealed the presence of several volatile constituents such as benzaldehyde (48.3%), dibenzyl-disulfide (23.3%), dibenzyl-trisulfide (9.4%) and stilbene (8.1%). Whereas, benzaldehyde (54.8%), benzylthiol (20.3%) and dibenzyl-disulfide (18.0%) have been found in the inflorescences. Compounds isolated from extracts (water, methanol, ethanol) of the entire plant include dibenzyl-trisulfide, benzaldehyde, the benzopyran astilbin, and coumarin which, based on in vitro studies, have retarded the growth of leukaemia cells and several other strains of cancerous tumour cells. Based on in vivo and in vitro studies, water extracts appeared to enhance lymphocyte, interferon and interleukin production. Conversely, toxic responses to leukaemia, lymphoma and several other cancer cell lines were noticed. Elevations in the phagocytotic index of human granulocytes was observed with leaf and stem extracts of hexane and cyclohexane, and may have been due to the presence of the immunomodulatory constituent Dibenzyl-Trisulfide (DTS) [37]. Additionally, a protective effect on the blood cells of mice infected with the pathogenic bacterium Listeria monocytogenes was detected when treated with a crude (whole plant) water extract [38]. On examination of the root extracts, significant anti-inflammatory effects in rats and mice using various models, as well as a significant pain-relieving effect in rats was noticed. Inhibitory actions of Cyclooxygenase-1 (COX-1) were also documented with some of the plant extracts [32]. Methanol extracts of the seeds induced contractions of the uterus in rat models. Other studies, using ethanolic, aqueous and chloroform fractions of leaf extracts, resulted in adverse effects on intestinal motility and secretion, as well as antihistamine activity in vitro. An initial test of leaf and stem powder extracts yielded significantly decreased levels of blood sugar in mice [32].

Many clinical reports and studies confirm that the extracts of the aerial parts and roots of P. alliacea have significant broad-spectrum antimicrobial properties (in vitro and in vivo) against numerous strains of bacteria, viruses, protozoa, fungi and yeast. The crude water and alcohol extracts perform similarly. A total of eighteen (18) organosulfur compounds from the roots have been tested for their antibacterial and antifungal activities. The most active compounds were shown to be the thiosulfinates, trisulfides and benzylsulfinic acid. The benzyl-containing thiosulfinates had the broadest spectrum of antimicrobial activity. Antibacterial and antifungal activities were also observed with fresh root extracts which contain (Z)- thiobenzaldehyde S-oxide. Acaricidal activity against Boophilus microplus was documented when an extract of the leaf and dibenzyltrisulfide from the roots, were applied topically. The activity was noticeably higher than commercial acaricides including dimethoate, lindane and carbaryl [32].

Dibenzyl-trisulfide also had a toxic effect on the adult sweet potato weevil (Cylas formicarius elegantulus) and adult coffee borer beetle (Hypothenemus hampei) [32]. Antifeedant activity of leaf extracts was documented against the grasshopper Zonocerus variegatus, and an allelopathic effect on germinating seeds was also observed. Dibenzyl-trisulfide was generally inactive on Bacillus subtilis and had little inhibitory effect on Cladosporium cucumerinum. However, when DTS was transformed to methyl-benzyl-sulfonic anhydride it was found to be effective in preventing the growth of Bacillus subtilis, Pseudomonas fluorescens and Cladosporium cucumerinum. In vitro studies of the growth of seeds of several crops revealed that methanol and dichloromethanol leaf extracts had an allelopathic effect. Seeds sown in the soil were not affected. Additionally, Petiveria alliacea has been shown to accumulate nitrates and has caused nitrate poisoning in cattle [32]. Hence, it is not encouraged as feeding material for animals.

Traditional uses and application

Traditional uses of P. alliacea as a medicinal plant date back to the Mayan era where it was commonly used to bolster the immune system and treat respiratory ailments including symptoms associated with the cold and influenza [39]. Various conditions including nervous spasms, paralysis, hysteria, asthma, whooping cough, pneumonia, bronchitis, hoarseness, fevers, headaches, influenza, cystitis, venereal diseases and menstrual complaints have been treated when the plant is taken internally [40]. External applications include treatment for ear-aches, fever and headaches [40]. Additionally, it is believed that vapours from the plant can stimulate movement in the limbs of paralyzed individuals. The roots have been used to treat toothaches, as well as induce abortions [41]. Macerated leaves are generally applied to the belly to induce contractions in case of difficult delivery [42]. The liquid from the leaves is instilled as nose or eye drops to cure headache, and as nose drops to cure sinusitis [42]. A bath or vapour bath with a leaf decoction is taken in case of oedema [42]. A leaf decoction is applied to abscesses, and is used as an analgesic against muscular pain and to treat skin diseases [42]. An infusion of pounded bark is consumed for treatment of colic, rheumatism, cancer, syphilis, colds, fever, bronchitis and asthma. Colombians coat their teeth and prevent caries by chewing the leaves [42]. In general, slight variations in the use of the plant may be observed depending on where it grows.

Petiveria alliacea has medicinal and ritual significance in southern Florida, Central America and the Caribbean, especially in the Santería religion. The entire plant, leaves and roots are often used in decoctions to calm the nerves, control diarrhoea, lower fever, stimulate the uterus, and relax spasms. The plant is also used in the treatment of hysteria, paralysis, bronchial problems (asthma, whooping cough, pneumonia, and bronchitis), hoarseness, influenza, cystitis, venereal disease, menstrual conditions and abortion. Headaches are cured by binding fresh leaves around the head and earaches are alleviated by juicing the leaves and applying directly to the ear [43].

In Brazil, P. alliacea is used as an antispasmodic agent, diuretic, menstrual and sweat promoter and stimulant. Natural health practitioners also use it for the treatment of arthritis, malaria, oedema, poor memory and rheumatism. It is also used as a topical analgesic and anti-inflammatory for skin conditions. In Central America, the herb is either used to provide relief during childbirth or to promote abortions. Decoctions of the leaves are ingested to alleviate digestive problems, fever and flatulence. Additionally, in major areas of Central and South America, it is used as a natural remedy for treating coughs, influenza, colds, pulmonary and respiratory infections, treatment of cancer and to support the immune system. Historically, the Caribs in Guatemala were known to crush the plant root (which is believed to be more potent than the leaves) and inhale it as treatment for sinusitis; whereas, the Ese’Ejas Indians in the Peruvian Amazon prepared a leaf infusion for alleviating flu and cold symptoms. It is also often used in herbal baths in the Amazon forests. The Garifuna natives in Nicaragua also use an infusion or decoction for coughs, cold, pains and aches and in the performance of specific rituals. In India, some indigenous groups make a paste from the leaves and use it externally for rheumatic pain, headache, and other types of pain. The paste is also used as an insecticide.

In South West Nigeria, P. alliacea has been used by traditional healers for the management of sickle cell disease. Laboratory studies further validated this use when extracts of the plant at concentrations of 1.0 and 0.1 mg/ml were shown to exhibit significant anti-sickling activity [44].

Medicinal application in the treatment of chronic illnesses

Published studies on P. alliacea indicate that the plant has a broad range of anti-leukemic, anti-tumour and anti-cancer properties against several types of cancer cells (including liver, brain, breast and prostate). Additionally, the entire plant is a pungent herb that is believed to be abortifacient, antiseptic, antispasmodic, diuretic and febrifuge. It is perceived to calm the nerves, control diarrhoea and stimulate the uterus [40].

Hernández, et al. validated the biological activity of P. alliacea using metastatic breast adenocarcinoma model (4T1) [43]. In vitro results revealed that a plant fraction induced apoptosis of 4T1 cells, caused activation of caspase-3, DNA fragmentation (without mitochondria membrane depolarization), and decreased growth capacity of cell colony. The fraction also resulted in changes in the expression of glycolytic enzymes which caused a decrease in glucose uptake and lactate production. Additionally there was enhanced regression of breast primary tumour in BALB/c mice transplanted with GFP-tagged 4T1 cells.

In a study conducted by Urueña, et al. it was revealed that a fraction of P. alliacea used multiple molecular targets to exert its antitumor activities against human (K562, A375) and mouse (Mel Rel) tumour cells [45]. Observations also indicated that the fraction exerted G2 cell cycle arrest, induced actin cytoskeleton reorganization, affected cell morphology, caused DNA fragmentation and decreased clonogenicity.

Petiveria alliacea was previously identified (at the University of Illinois at Chicago) as one of only 34 plants (out of 1,400) with active properties specifically against cancer [33]. Several phytochemicals in P. alliacea like astilbin and dibenzyl trisulphide have been documented to directly kill cancer cells [46]. Williams, et al. demonstrated that DTS and its derivatives exhibited potent anti-proliferation/cytotoxic activity on a wide range of cancer cell lines [47]. The research further showed that the compounds in P. alliacea were able to target the cancerous cells, leaving healthy, normal cells unharmed. In addition, other substances in the herb stimulate the body’s natural defences.

The plant has also been verified to have immunostimulant properties [48]. It stimulates the immune system to increase its production of lymphocytes and natural disease-destroying cells. At the same time, it increases the production of interferon and interleukins which are produced naturally by the immune system in fighting cancers and infections.

It is commonly perceived that infection plays a major role in many cancers. P. alliacea is widely used in folk medicine for treating infections. Many clinical reports and studies document that the plant shows broad-spectrum antimicrobial properties against numerous strains of bacteria, viruses, fungi, and yeast. Ruffa, et al. revealed that extracts of P. alliacea inhibited the replication of the bovine diarrhoea virus; (test model for hepatitis C virus) [49]. The antimicrobial properties of the plant have been documented by Cuban scientists who conducted in vitro studies of extracts against numerous pathogens, including Escherichia coli, Staphylococcus, Pseudomonas and Shigella [50]. Crude water extracts of the plant, outperformed the alcohol extracts. The antimicrobial activity was attributed to the presence of phenolic [51,52], and sulphur compounds [53], which were previously found to display antimicrobial action. A German group documented good activity against several bacteria, Mycobacterium tuberculosis, several strains of fungi and Candida. Anamu’s antifungal properties were documented by one research group in 1991, and again by a separate research group in 2001. Its antimicrobial activity was further demonstrated by researchers from Guatemala and Austria who, in separate studies in 1998, confirmed its activity in vitro and in vivo studies against several strains of protozoa, bacteria, and fungi.

Its traditional use as a remedy for arthritis and rheumatism has been validated by clinical research that confirms its pain relieving and anti-inflammatory effect. Researchers in Sweden demonstrated its COX-1 inhibitory properties (cyclooxogenase-1 inhibitors are a new class of popular and profitable arthritis drugs). Petiveria alliacea extracts have been found to relieve pain and inflammation even when applied topically to the skin. Oluwa, et al. in their study on the “Chemical Constituents and Anti-inflammatory Activity of Essential Oil of Petiveria alliacea L.” revealed that phytol was the major constituent of the essential oil of P. alliaceae from Nigeria [54]. Furthermore, the potent anti-inflammatory activity of the essential oil may be attributed to its high content of citronellol, (Z,Z)-α-farnesol and phytol.

There is little scientific data available on the use of P. alliacea for treating diabetes; however, it had been shown in mice to decrease blood sugar levels by over 60 per cent. The inhibitory effects of the leaf extracts of Petiveria alliacea L. on alpha-amylase enzyme was researched and the findings revealed that leaf extracts of Petiveria alliacea showed alpha-amylase inhibitory properties with higher activities than the control drug, acarbose [55]. There by suggesting that the plant contains phytochemicals that could effectively reduce post-prandial glucose levels in diabetics. This strengthens herbal medical practice in Cuba where P. alliacea has long been used to help in the treatment of diabetes. However, Christie, et al. evaluated the effect of aerial parts of the plant in normoglycaemic and diabetic rats for hypoglycaemic activity and discovered that the aqueous extract of P. alliacea had no hypoglycaemic effect in diabetic rats, but showed hyperglycaemic activity in normoglycaemic rats [56]. Given the variations in research findings, the implications for the use of the plant in ethno-traditional medicine is important and needs further investigation.

The anti-viral activity of P. alliacea was previously demonstrated with bovine viral diarrhea virus [49]. Recently, Lowe, et al. investigated the anti HIV-1 activity of Petiveria alliacea and its metabolites [57], and the results suggest that P. alliacea may have therapeutic potential against HIV-1, although additional work is required to demonstrate the extent of its activity.

In South America, P. alliacea is being used for its immune stimulant and anticancerous properties as a support aid for cancer and leukemia patients. In the United States, P. alliacea is now available in capsules and tablets under various labels. It is also being incorporated in several formulations for its antimicrobial properties against bacteria, viruses, yeast, and fungi, as well as in other formulations that support the immune system.

Adverse effects of Petiveria alliacea

Petiveria alliacea has been found to have several adverse effects. Notably, studies have demonstrated that use of the plant could stimulate contractions of the uterus which may result in miscarriage. Therefore, pregnant women and those trying to conceive should avoid its use. Additionally, low concentrations of a blood thinner known as coumadin has been found in the plant. Hence, its use may result in thinning of the blood and should not be taken by persons with pre-existing blood conditions such as hemophilia or those on blood thinning medications such as warfarin. Animal studies have also shown that P. alliacea has a hypoglycemic effect, so individuals with hypoglycemia or diabetes should avoid its use. In vitro and in vivo studies of Petiveria alliacea extracts on behavioural stress in animal models revealed a pro-oxidant effect which resulted in inhibition of the antioxidant level and increased methemoglobin levels in human plasma [35], which may have important implications for anxiety-like behaviour.