Agave Americana)

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Agave (Agave americana)

Article in Journal of Herbal Pharmacotherapy · November 2006 DOI: 10.1300/J157v06n02_09

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Agave (Agave americana)

Dana A. Hackman, Nicole Giese, John S. Markowitz, Adam McLean, Steven G. Ottariano, Chris Tonelli, Wendy Weissner, Shannon Welch & Catherine Ulbricht

To cite this article: Dana A. Hackman, Nicole Giese, John S. Markowitz, Adam McLean, Steven G. Ottariano, Chris Tonelli, Wendy Weissner, Shannon Welch & Catherine Ulbricht (2006) Agave (Agave americana), Journal of Herbal Pharmacotherapy, 6:2, 101-122, DOI: 10.1080/ J157v06n02_09 To link to this article: http://dx.doi.org/10.1080/J157v06n02_09

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Download by: [University of Florida] Date: 22 May 2017, At: 11:43 NATURAL STANDARD REVIEW

Catherine Ulbricht, PharmD, MBA(C), Column Editor

Agave (Agave americana): An Evidence-Based Systematic Review by the Natural Standard Research

Collaboration Dana A. Hackman, BS Nicole Giese, MS John S. Markowitz, PharmD Adam McLean, MPharm Steven G. Ottariano, RPh Chris Tonelli, MA Wendy Weissner, BA Shannon Welch, PharmD Catherine Ulbricht, PharmD for the Natural Standard Research Collaboration

Dana A. Hackman is affiliated with Northeastern University. Nicole Giese is affiliated with Natural Standard Research Collaboration. John S. Markowitz is affiliated with University of South Carolina. Adam McLean is affiliated with University of Nottingham. Steven G. Ottariano is affiliated with VA Medical Center. Chris Tonelli is affiliated with Emmanuel College. Wendy Weissner is affiliated with Natural Standard Research Collaboration. Shannon Welch is affiliated with Northeastern University. Catherine Ulbricht is affiliated with Massachusetts General Hospital. Blinded Peer Review: Natural Standard Editorial Board. Natural Standard Review (www.naturalstandard.com) Copyright ©2005. Re- printed with permission. Journal of Herbal Pharmacotherapy, Vol. 6(2) 2006 Available online at http://jhp.haworthpress.com doi:10.1300/J157v06n02_09 101 102 JOURNAL OF HERBAL PHARMACOTHERAPY

ABSTRACT. An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

KEYWORDS. Folkloric precedent, history, pharmacology, toxicology, dosing, Agave, Agave americana

SYSTEMATIC AGGREGATION, ANALYSIS, AND REVIEW OF THE LITERATURE

Search Strategy

To prepare each Natural Standard Review, electronic searches are conducted in nine databases, including AMED, CANCERLIT, CIN- AHL, CISCOM, the Cochrane Library, EMBASE, HerbMed, Interna- tional Pharmaceutical Abstracts, Medline, and NAPRALERT. Search terms include the common name(s), scientific name(s), and all listed synonyms for each topic. Hand searches are conducted of 20 additional journals (not indexed in common databases), and of bibliographies from 50 selected secondary references. No restrictions are placed on language or quality of publications. Researchers in the field of complementary and alternative medicine (CAM) are consulted for access to additional references or ongoing research.

Selection Criteria

All literature is collected pertaining to efficacy in humans (regardless of study design, quality, or language), dosing, precautions, adverse effects, use in pregnancy/lactation, interactions, alteration of laboratory Natural Standard Review 103 assays, and mechanism of action (in vitro, animal research, human data). Standardized inclusion/exclusion criteria are utilized for selection.

Data Analysis

Data extraction and analysis are performed by healthcare profession- als conducting clinical work and/or research at academic centers, using standardized instruments that pertain to each review section (defining inclusion/exclusion criteria and analytic techniques, including validat- ed measures of study quality). Data are verified by a second reviewer.

Review Process

Blinded review of reviews is conducted by multidisciplinary research-clinical faculty at major academic centers with expertise inepi- demiology and biostatistics, pharmacology, toxicology, complementary and alternative medicine (CAM) research, and clinical practice. In cases of editorial disagreement, a three-member panel of the Editorial Board addresses conflicts, and consults experts when applicable. Authors of studies are contacted when clarification is required.

Update Process

Natural Standard regularly monitors scientific literature and industry warnings. When clinically relevant new data emerge, best efforts are made to update content immediately. In addition, regular updates with renewed searches occur every 3-18 months, variable by topic.

Synonyms/Common Names/Related Substances

• Agavaceae, Agave abortiva, Agave abrupta, Agave acicularis, Agave acklinicola, Agave affinis, Agave ajoensis, Agave aktites, Agave albescens, Agave albomarginata, Agave angustiarum, Agave angustifolia, Agave angustissima, Agave anomala, Agave antillarum, Agave antillarum var. grammontensis, Agave applanata, Agave arizonica, Agave arubensis, Agave aspera, Agave asperrima, Agave attenuata, Agave aurea, Agave avellanidens, Agave bahamana, Agave bakeri, Agave banlan, Agave barbadensis, Agave baxteri, Agave bergeri, Agave bernhardi, Agave boldinghiana, Agave bollii, Agave botterii, Agave bouchei, Agave bourgaei, Agave bovicornuta, Agave braceana, Agave 104 JOURNAL OF HERBAL PHARMACOTHERAPY

brachystachys, Agave bracteosa, Agave brandegeei, Agave brauniana, Agave breedlovei, Agave brevipetala, Agave breviscapa, Agave brevispina, Agave brittonia, Agave bromeliaefolia, Agave brunnea, Agave bulbifera, Agave cacozela, Agave cajalbanensis, Agave calderoni, Agave calodonta, Agave campanulata, Agave cantala, Agave capensis, Agave carchariodonta, Agave caribaea, Agave caribiicola, Agave carminis, Agave caroli-schmidtii, Agave celsii, Agave cernua, Agave cerulata, Agave chiapensis, Agave chihuahuana, Agave chinensis, Agave chisosensis, Agave chloracantha, Agave chrysantha, Agave chrysoglossa, Agave coccinea, Agave cocui, Agave coespitosa, Agave colimana, Agave collina, Agave colorata, Agave compacta, Agave complicata, Agave compluviata, Agave concinna, Agave congesta, Agave conjuncta, Agave connochaetodon, Agave consociata, Agave convallis, Agave corderoyi, Agave costaricana, Agave cucullata, Agave cundinamarcensis, Agave cupreata, Agave dasyliriodes, Agave datylio, Agave davilloni, Agave de-meesteriana, Agave dealbata, Agave deamiana, Agave debilis, Agave decaisneana, Agave decipiens, Agave delamateri, Agave densiflora, Agave dentiens, Agave deserti, Agave desmettiana, Agave diacantha, Agave difformis, Agave disceptata, Agave disjuncta, Agave dissimulans, Agave donnell-smithii, Agave durangensis, Agave dussiana, Agave eborispina, Agave eduardi, Agave eggersiana, Agave ehrenbergii, Agave eichlami, Agave ekmani, Agave elizae, Agave ellemeetiana, Agave endlichiana, Agave engelmanni, Agave entea, Agave erosa, Agave evadens, Agave excelsa, Agave expansa, Agave expatriata, Agave falcata, Agave felgeri, Agave felina, Agave fenzliana, Agave ferdinandi-regis, Agave filifera, Agave flaccida, Agave flaccifolia, Agave flavovirens, Agave flexispina, Agave fortiflora, Agave fourcroydes, Agave fragrantissima, Agave franceschiana, Agave franzosini, Agave friderici, Agave funifera, Agave funkiana, Agave galeottei, Agave garciae-mendozae, Agave geminiflora, Agave gentryi, Agave ghiesbrechtii, Agave glabra, Agave glaucescens, Agave goeppertiana, Agave glomeruliflora, Agave gracilipes, Agave gracilis, Agave grandibracteata, Agave granulosa, Agave grenadina, Agave grijalvensis, Agave grisea, Agave guadalajarana, Agave guatemalensis, Agave guedeneyri, Agave guiengola, Agave gutierreziana, Agave guttata, Agave gypsophila, Agave hanburii, Agave harrisii, Agave hartmani, Agave haseloffii, Natural Standard Review 105

Agave hauniensis, Agave havardiana, Agave haynaldi, Agave henriquesii, Agave hexapetala, Agave hiemiflora, Agave hookeri, Agave horizontalis, Agave horrida, Agave houghii, Agave huachucaensis, Agave huehueteca, Agave humboldtiana, Agave hurteri, Agave impressa, Agave inaequidens, Agave inaguensis, Agave indagatorum, Agave ingens, Agave inopinabilis, Agave integrifolia, Agave intermixta, Agave intrepida, Agave isthmensis, Agave jaiboli, Agave jarucoensis, Agave karatto, Agave kellermaniana, Agave kerchovei, Agave kewensis, Agave kirchneriana, Agave lagunae, Agave langlassei, Agave laticincta, Agave latifolia, Agave laurentiana, Agave laxa, Agave laxifolia, Agavelecheguilla, Agave lemairei, Agave lempana, Agave lespinassei, Agave lindleyi, Agave littaeaoides, Agave longipes, Agave longisepala, Agave lophantha, Agave lurida, Agave macrantha, Agave macroacantha, Agave macroculmis, Agave maculata, Agave madagascariensis, Agave mapisaga, Agave margaritae, Agave marginata, Agave marmorata, Agave martiana, Agave maximiliana, Agave maximowicziana, Agave mayoensis, Agave mckelveyana, Agave medio-picta, Agave medioxima, Agave megalacantha, Agave melanacantha, Agave melliflua, Agave mexicana, Agave micracantha, Agave millspaughii, Agave minarum, Agave mirabilis, Agave missionum, Agave mitis, Agave monostachya, Agave montana, Agave montserratensis, Agave moranii, Agave morrisii, Agave muilmanni, Agave mulfordiana, Agave multifilifera, Agave multiflora, Agave multilineata, Agave murpheyi, Agave oaxacensis, Agave nashii, Agave nayaritensis, Agave neglecta, Agave nelsoni, Agave nevadensis, Agave nevidis, Agave newberyi, Agave nickelsi, Agave nissoni, Agave nizandensis, Agave noli-tangere, Agave obducta, Agave oblongata, Agave obscura, Agave ocahui, Agave offoyana, Agave oligophylla, Agave oliverana, Agave opacidens, Agave orcuttiana, Agave ornithobroma, Agave oroensis, Agave ovatifolia, Agave oweni, Agave pachyacantha, Agave pachycentra, Agave pacifica, Agave pallida, Agave palmaris, Agave palmeri, Agave pampaniniana, Agave panamana, Agave papyriocarpa, Agave parryi, Agave parvidentata, Agave parviflora, Agave patonii, Agave paucifolia, Agave paupera, Agave pavoliniana, Agave peacockii, Agave pedrosana, Agave pedunculifera, Agave pelona, Agave perplexans, Agave pes-mulae, Agave petiolata, Agave petrophila, Agave phillipsiana, Agave picta, Agave planera, Agave 106 JOURNAL OF HERBAL PHARMACOTHERAPY

polianthiflora, Agave polianthoides, Agave portoricensis, Agave potatorum, Agave potosina, Agave potrerana, Agave prainiana, Agave promontorii, Agave prostrata, Agave protamericana, Agave protuberans, Agave pruinosa, Agave pseudotequilana, Agave pugioniformis, Agave pulcherrima, Agave pulchra, Agave pumila, Agave punctata, Agave purpurea, Agave purpusorum, Agave pygmae, Agave quadrata, Agave quiotifera, Agave ragusae, Agave rasconensis, Agave regia, Agave revoluta, Agave rhodacantha, Agave rigida, Agave roezliana, Agave rudis, Agave rupicola, Agave rutteniae, Agave rzedowskiana, Agave salmdyckii, Agave salmiana, Agave samalana, Agave sartorii, Agave scaphoidea, Agave scaposa, Agave scheuermaniana, Agave schildigera, Agave schneideriana, Agave schottii,Agave scolymus, Agave sebastiana, Agave seemanniana, Agave serrulata, Agave sessiliflora, Agave shafer, Agave shawii, Agave shrevei, Agave sicaefolia, Agave simony, Agave sisalana, Agave sleviniana, Agave smithiana, Agave sobolifera, Agave sobria, Agave sordida, Agave striata, Agave stricta, Agave stringens, Agave subinermis, Agave subsimplex, Agave subtilis, Agave subzonata, Agave sullivani, Agave tecta, Agave tenuifolia, Agave tenuispina, Agave teopiscana, Agave tequilana, Agave terraccianoi, Agave theometel, Agave thomasae, Agave thomsoniana, Agave tigrina, Agave titanota, Agave todaroi, Agave toneliana, Agave tortispina, Agave toumeyana, Agave troubetskoyana, Agave tubulata, Agave underwoodii, Agave unguiculata, Agave utahensis, Agave van-grolae, Agave vandervinneni, Agave ventum-versa, Agave vernae, Agave verschaffeltii, Agave vestita, Agave vicina, Agave victoriae-reginae, Agave vilmoriniana, Agave viridissima, Agave vivipara, Agave vizcainoensis, Agave wallisii, Agave warelliana, Agave washingtonensis, Agave watsoni, Agave weberi, Agave weingartii, Agave wendtii, Agave wercklei, Agave wiesenbergensis, Agave wightii, Agave wildingii, Agave winteriana, Agave wislizeni, Agave wocomahi, Agave woodrowi, Agave wrightii, Agave xylonacantha, Agave yaquiana, Agave yuccaefolia, Agave zapupe, Agave zebra, Agave zonata, Agave zuccarinii, American aloe, Arizona agave, Arizona century plant, bald agave, blue agave, Cantala, century plant, Chisos mountain century plant, coastal agave, corita, cow’s horn agave, desert agave, desert century plant, dragon tree agave, drunkard agave, dwarf century plant, dwarf octopus agave, eggers’ century plant, Natural Standard Review 107

chisos agave, false sisal, foxtail agave, golden flowered agave, golden flower century plant, hardy century plant, Havard’s century plant, henequen, hohokam agave, ixtle de jaumave, leather agave, Lecheguilla, little princess agave, maguey, Maguey bandeado, Maguey chato, Maguey del Bravo, Maguey de Desierto, Maguey de Havard, Maguey de la India, Maguey de montaña, Maguey de pastizal, Maguey de Sisal, Maguey de tlalcoyote, Maguey diente de tiburn, Maguey Henequen, Maguey lechuguilla, Maguey liso, Maguey mezortillo, Maguey pajarito, Maguey primavera, Maguey spero, Maguey sbari, Mckelvey Agave, McKelvey’s century plant, Mescal ceniza, Mescalito, Mexican Sisal, Mezcal azul tequilero, Mezcal yapavai, Murphey Agave, Murphey’s century plant, Octopus Agave, Palmer Agave,

Palmer century plant, Palmer’s century plant, Parry Agave, Parry’s Agave, Puerto Rico century plant, Pulque, Queen Victo- ria’s Agave, Rough Century Plant, Smallflower agave, smallflower century Plant, Schott Agave, Schott’s Century Plant, Sisal, Sisal Hemp, Shindagger, Smooth Agave, Squid Agave, St. Croix agave, Slimfoot century plant, Swan’s Neck Agave, Tequila, Te- quila Agave, Thorncrest century plant, Thread-leaf agave, Toumey agave, Toumey’s century plant, Utah agave, Weber agave, Weber blue agave, Weber’s century plant, wild century plant.

CLINICAL BOTTOMLINE/EFFECTIVENESS

Brief Background

• Agaves are succulent plants from the family Agavaceae, which in- cludes Beschorneria, Furcraea, Hesperaloe, Manfreda, Polianthes, Prochnyanthes and Yucca. Agave plants are common in the Amer- ican southwest, Mexico, central and tropical South America, the Mediterranean and some parts of India. Plants in the Agavaceae family are recognizable by their distinctive rosettes, which are composed of thick, hard, rigid leaves often with marginal teeth and usually with a sharp terminal spine and flower spikes. There are over 200 known species of Agave; many produce musky odors that attract bats serve to pollinate them, while others produce sweet odors to attract insects (1). 108 JOURNAL OF HERBAL PHARMACOTHERAPY

• Agave americana is also known as the American aloe, although it is not related to the true aloes. The leaves of the agave plant yield fibers suitable for textile production. The native people in Mexico used the agave spikes to make pens, nails and needles. Agave sisalana, the source of sisal fiber, is cultivated in plantations in Af- rica and Asia. The flowering stem can be dried or roasted and eaten; the seeds can be ground into flour to make bread or used as a thick- ener for soups. A sweet liquid (sap) called agua miel (honey water) gathers in the plant if the stem is cut before flowering. This sap is collected over a period of about two months, and can then be fermented to produce the alcoholic beverage pulque (octili), which Na- tive Americans use in religious ceremonies. Further distillation creates Mescal (mezcal). A form of tequila is made when Mescal is produced from the Blue Agave (Agave tequilana) plant within the Tequila region of Mexico. This is the most important economic use of agave, worth millions of dollars to the Mexican economy. Mescal is often sold with the caterpillar of the agave moth in the bottle. • Agave is also useful as a sugar alternative because with a 90% fructose, it has a low glycemic index. Steroid hormone precursors are obtained from the leaves. Pulque prepared from Agave species was a food item studied intensively for nutrition potential among traditional and indigenous peoples, and is an example of how local food-based strategies can be used to ensure micronutrient nutrition. Traditional food strategies could be used not only for alleviat- ing malnutrition, but also for developing locally relevant programs for stemming the nutrition transition and preventing chronic dis- ease, particularly among indigenous and traditional peoples who re- tain knowledge of using food species in their local ecosystems (2). Scientific Evidence for Common/Studied Uses • Insufficient available evidence. Historical or Theoretical Uses Which Lack Sufficient Evidence

Antibacterial, bruises, constipation, diabetes, diuretic, dysentery, flat- ulence, hair-restorer, hemolytic activities, indigestion, insulin resistance, jaundice, laxative, nutritional supplement, parasites, steroid source, swell- ing, Syndrome X. Natural Standard Review 109

Expert Opinion and Folkloric Precedent

• Pulque is depicted in Native American stone carvings as early as 200 AD. According to pre-Columbian records, a Toltec noble named Papantzin found out how to extract agua miel from the maguey plant and the Aztecs consumed it at religious ceremonies. Brief Safety Summary • Likely Safe: When consumed in amounts usually found in foods and beverages. • Likely Unsafe: When used during pregnancy due to possible contraceptive effects (3).

DOSING/TOXICOLOGY

General • Recommended doses are based on those most commonly used in available trials, or on historical practice. However, with natural products it is often not clear what the optimal doses are to balance efficacy and safety. Preparation of products may vary from manufacturer to manufacturer, and from batch to batch within one manufacturer. Because it is often not clear what are the active com- ponents of a product, standardization may not be possible, and the clinical effects of different brands may not be comparable. Standardization • There is no known standardization for agave. Adult Dosing (18 years and older): Oral • Insufficient available data. Topical • Insufficient available data. Parenteral (Intravenous/Intramuscular) • Insufficient available data. 110 JOURNAL OF HERBAL PHARMACOTHERAPY

Pediatric Dosing (younger than 18 years)

• Insufficient evidence to recommend.

Toxicology

• Over the years, high cirrhosis mortality rates have been reported in Mexico City and in the surrounding states (Hidalgo, Tlaxcala, Puebla and the State of Mexico); conversely, well-defined areas, such as the northern states, have shown a considerably lower mortality rate (4).

PRECAUTIONS/CONTRAINDICATIONS

Allergy

People who have allergies to Agavaceae family should be cautious in using Agave.

Adverse Effects/Post-Market Surveillance

• General: The stiff, erect leaves of some Agave plants are tipped with sharp needles, which can cause injury upon contact. There is one case report of a terminal spine of the agave plant being extracted from a patient’s spinal cord (5). Systemic signs including cutaneous lesions are common; treatment with oral antihistamines and topical saline compresses resulted in subsidence of the systemic symptoms within 24 hours and regression of cutaneous manifestations in 7-10 days (6; 7). • Dermatologic: There are reports of acute irritant contact dermatitis from Agave americana (8; 9; 10). Twelve cases of contact dermatitis provoked by Agave americana have been described: 10 with systemic signs and symptoms and 8 with abnormal laboratory re- sults. Oral antihistamines and topical saline compresses were administered and resulted in subsidence of the systemic symptoms within 24 hours of hospitalization and regression of cutaneous manifestations in 7-10 days. Needle-like calcium oxalate crystals, raphides, are found abundantly in all tissues of Agave tequilana.In tequila distilleries, five-sixth of the workers who handle the agave stems have experienced contact dermatitis, whereas only one-third Natural Standard Review 111

of workers in agave plantations who harvest agave plants, com- plain of irritation (11). • Both vesiculopapular and leukocytoclastic vasculitis purpuric contact dermatitis have been reported resulting from direct exposure to sap propelled by a chainsaw. The sap contains calcium oxalate crystals, acrid oils, saponins, and other compounds, and the oxalic acid crystals, which are recognized systemic toxins, were suspected as the cause. When these crystals are embedded in the skin with resulting oxalism, they may result in vascular damage (12). Previous case reports have also noted a papulovesicular eruption consistent with an irritant contact dermatitis. In a case of Agave-induced purpura in an otherwise healthy patient, histopathology was consistent with an evolving leukocytoclastic vasculitis (13). There are

reports of irritant contact dermatitis from Agave americana when used incorrectly as a hair-restorer (14). • Hepatic: Over the years, high cirrhosis mortality rates have been reported in Mexico City and in the surrounding states (Hidalgo, Tlaxcala, Puebla and the State of Mexico); conversely, well-defined areas, such as the northern states, have shown a considerably lower mortality rate. High alcohol intake and other environmental characteristics could explain this striking difference; however, there are no significant correlations. Further epidemiological studies still need to be done to determine the etiologic role of pulque consumption as well as of the other risk factors. Nonetheless, the current data stress the need to implement public health programs to reduce alcohol consumption, especially pulque, and to minimize the impact of these risk factors in high mortality areas (4). • Hematologic: Although saponins have been found to protect against visceral leishmaniasis in CB hamsters and Balb/c mice, some kinds of saponins, especially steroidic saponins found in Agave sisalana, have high hemolytic activity, and are thus potentially toxic (15). • Other: Calcium oxalate crystals, found in prickly pear and agave, may have caused microwear of human teeth, as seen in archaic hunter-gatherers in the lower Pecos region of west Texas The calcium oxalate phytoliths are harder than enamel (16). Significant increases in homocysteine levels and a tendency to increase blood glucose concentration and to decrease insulin sensitivity were found in healthy, non-obese young men who consumed 30 mL of tequila daily for 30 days (17). 112 JOURNAL OF HERBAL PHARMACOTHERAPY

Precautions/Warnings/Contraindications

• Avoid in patients with known allergies to plants in the Agavaceae family. • Use cautiously in patients trying to conceive due to possible contraceptive effects (3).

Pregnancy and Lactation

• Women from rural areas of the central plateau of Mexico drink a mild alcoholic beverage called pulque as a galactogogue. Pulque is believed to stimulate milk production in lactating women. The relatively small amount of ethanol taken in by infants through milk is unlikely to have harmful effects (18). However, pulque intake dur-

ing lactation may have adverse influences on postnatal growth in some Mexican populations (19). • Contraceptive: Anordin and dinordin, prepared with steroids derived from the sisal plants Agave sisilana and Agave americana have been used for their antifertility effects. These agents, whose antifertility properties have been confirmed by scientists in Sweden and the United States, constitute a new family of contraceptives with the great advantage of having to be taken only once or twice a month instead of the 20 times per month necessary with the ordinary pill (3).

INTERACTIONS

Agave/Drug Interactions

• Steroids: Steroid hormone precursors are obtained from the leaves (2) so there is a possible compound effect. • Contraceptives: Anordin and dinordin, prepared with steroids derived from the sisal plants Agave sisilana and Agave americana have been used for their antifertility effects. These agents, whose antifertility properties have been confirmed by scientists in Sweden and the United States, constitute a new family of contraceptives with the great advantage of having to be taken only once or twice a month instead of the 20 times per month necessary with the ordinary pill (3). Natural Standard Review 113

• Drugs That Alter Blood Sugar Levels: A tendency to increase blood glucose concentration and to decrease insulin sensitivity was found in healthy, non-obese young men who consumed 30 mL of tequila daily for 30 days (17). Agave/Herb/Supplement Interactions • Steroids: Steroid hormone precursors are obtained from the leaves (2) so there is a possible compound effect. • Blood Sugar Altering Herbs and Supplements: A tendency to increase blood glucose concentration and to decrease insulin sensitivity was found in healthy, non-obese young men who consumed 30 mL of tequila daily for 30 days (17).

Agave/Food Interactions • Insufficient available evidence. Agave/Lab Interactions • Homocysteine: Significant increases in homocysteine levels have been found (17). • Blood Sugar Levels: A tendency to increase blood sugar levels and to decrease insulin sensitivity were found in healthy, non- obese young men who consumed 30 mL of tequila daily for 30 days (17).

MECHANISM OF ACTION

Pharmacology • Steroidal Effects: Steroid hormone precursors are obtained from the leaves of agave plants. A new steroidal saponin was isolated from the leaves of Agave attenuata. Its structure was established as (3beta, beta, 25S)-spirostan-3-yl-O-beta-D-glucopyranosyl-(1—> 2)- beta-D-glucopyranosyl-(1—>2)-O-[beta-D-glucopyranosyl- (1—>3)] -beta-D-glucopyranosyl-(1—>4)-beta-D-galactopyranoside. (20). • A new steroidal glycoside, agaveside D, isolated from the fruits of Agave cantala was characterized as 3 beta-(alpha-L-rhamnopyranosyl-(1—>2), beta-D-glycopyranosyl-(1—>3)-beta-D- glucopyranosyl[beta-D-xylopyransoyl-(1—>4) -alpha-L-rhamno- 114 JOURNAL OF HERBAL PHARMACOTHERAPY

pyranosyl-(1—>2)]-beta-D-glucopyranosyl)-25R-5 alpha- spirostane on the basis of chemical degradation and spectrometry (21). • The structures of one new monodesmosidic spirostanoside and one new bisdesmosidic furanostanol glycoside isolated from leaves of Agave lophantha Schiede have been determined by means of spectroscopic and chemical methods as (25R)-5 beta- spirostan-3 beta-ol-3-O-(beta-D-apiofuranosyl(1—>4)beta-D-glucopyranosyl (1—>3)[beta-D-glucopyranosyl(1—>2)] beta-D-galactopyranoside) and 26-O-beta-D-glucopyranosyl(25R)-5 beta-furost- 20(22)-ene-3 beta, 26-diol-3-O-(beta-D-xylopyranosyl(1—>3)- [beta-D-glucopyranosyl(1—>2)] beta-D-galactopyranoside), respectively. The 1H and 13C NMR resonances of the two compounds were assigned by NMR (1H, 13C, HOHAHA, 1H-1H COSY, HMQC, HMBC, NOE difference) studies. The pharmacological activities of the saponin containing fraction are discussed (22). • Crude extracts of Agave americana contain two utero-active compounds. One of these, tentatively named Fraction B, has been purified to chromatographic homogeneity. Its pharmacological actions are similar to those of acetylcholine. However its chromatographic and electrophoretic mobilities are different. Some chemical properties of fraction B are compatible with the structure of an acyl de- rivative of choline different from acetylcholine (23). • Steroid sapogenins are constituents of Agave utahensis var. nevadensis, A. lophantha A. parasana (24) and A. sisalana (25). • From the leaves of Agave lecheguilla Torrey, two steroidal sapogenin diols have been isolated. Mass spectra, infra-red and nuclear mag- netic resonance (NMR) data of these two compounds showed them to be (25R)-spirost-5-ene-2 alpha, 3 beta-diol (yuccagenin) and (25R)-5 beta-spirostane-3 beta, 6 alpha-diol. The latter is a new compound to which the trivial name ruizgenin has been given (26). • Barbourgenin is a steroidal sapogenin from Agave sisalana leaves (27). • A new steroidal saponin was isolated from the leaves of Agave attenuata Salm-Dyck. Its structure was established as (3beta, 5beta, 22alpha, 25S)-26-(beta-D-glucopyranosyloxy)-22-meth- oxyfurostan-3-yl-O-beta-D-glucopyranosyl-(1—>2)-beta-D-glucopyranosyl-(1—>2)-O-[beta-D-glucopyranosyl-(1—>3)]-beta- D-glucopyranosyl-(1—>4)-beta-D-galactopyranoside. The structural identification was performed using detailed analyses of 1H and 13C NMR spectra including 2D NMR spectroscopic techni- Natural Standard Review 115

ques (COSY, HETCOR and COLOC) and chemical conversions. The hemolytic potential of the steroidal saponin was evaluated and the anti-inflammatory activity was performed using the capillary permeability assay (28). • A new steroidal saponin was isolated from the leaves of Agave shrevei Gentry. Its structure was established as 26-(beta-D-glucopyranosyloxy)-22-methoxy-3-(O-beta-D-glucopyranosyl-(1—>2) O-[O-beta-D-glucopyranosyl-(1—>4)-O-[O-beta-D-glucopyranosyl-(1—>6)]-O-beta-D-glucopyranosyl(1—>4)-beta-D-galactopyr- anosyl]oxy)-(3beta, 5alpha, 25 R)-furostane. The structural identification was performed using detailed analyses of 1H and 13C NMR spectra including 2D NMR spectroscopic techniques (COSY, HETCOR, and COLOC) and chemical conversions. The steroidal saponin showed absence of haemolytic effects in the in vitro assay, but demonstrated a significant inhibition of the capillary permeability activity (29). • In a previous paper, the isolation and structure determination of three new steroidal saponins, dongnosides C (3), D (2) and E (1) from the dried fermented residues of leaf-juices of Agave sisalana forma Dong No. 1 was reported. In a continuing study on this plant, two additional new major steroidal saponins, named dongnosides B (4) and A (5), were obtained. Their structures were characterized, respectively, as tigogenin 3-O-alpha-L-rhamonpyranosyl-(1—>4)-beta-D-glucopyranosyl-(1—>2)-[beta-D-glucopyranosyl-(1—>3)]-beta-D-glucopyranosyl-(1—>4)-beta-D-galactopyranoside and 3-O-alpha-L -rhamnopyranosyl-(1—>4)-beta-D-glucopyranosyl-(1—>2)-[beta- D-xylopyranosyl-(1—>3)-beta-D-glucopyranosyl-(1—>3)]-beta-D- glucopyranosyl-(1—>4)-beta-D-galactopyranoside on the basis of chemical and physicochemical evidence (30). • A new protease was isolated from an extract of leaves of Agave americana variegata. The protease (EC 3.4.-) was purified 565- fold with a yield of 39.5%. The 43.8 mg enzyme had a specific activity of 0.44 units/mg. According to electrophoretic, ultracen- trifugal and other physical characterizations the enzyme was homo- geneous. The enzyme had an MR of 57000, a S20,W-value of 4.37 S, a D20, W-value of 6.8-7.0 - 10(-7) cm2secϪ1,aStokesradiusof 3.18 nm, a partial specific volume of 0.735 cm3gϪ1, a frictional ra- tion of 1.25, a molecular absorbancy index at 280 nm of 5.773- 10(4), an isoelectric point of 5.25 and contained 8-10% carbohy- drate. Agave protease could hydrolyze a variety of protein sub- strates although it did have a restricted specificity. It is not a 116 JOURNAL OF HERBAL PHARMACOTHERAPY

sulphhydryl protease but seems to be an alkaline “serine” protease with an optimum pH of 7.8-8.0 Agave protease had marked esterol- ytic activity and with Cbz-Tyr-ONp had an apparent Michaelis con- stant of 0.0345 -10(-3) M and a V of 1.24 mol substrate/mol enzyme per sec. The enzyme did not need metal ions for optimal activity, monovalent cations did not influence its kinetic parameters, but it was inhibited by cobalt, pC1HgBzO- and TosPheCH2C1. With re- spect to its primary specificity, as well as its pH-dependence there was a resemblance with chymotrypsin, although the rate of hydrolysis of Agave protease is much lower (31). • A new bisdesmosidic spirostanol saponin, along with three known saponins, were isolated from Agave americana (Agavaceae). The structure of the new saponin was elucidated as (25R)-3 beta, 6 alpha-dihydroxy-5 alpha-spirostan-12-one 3,6-di-O-beta-D-gluco- pyranoside. Among the isolated saponins, hecogenin tetraglycoside showed cytotoxic activity against HL-60 human promyelocytic leu- kemia cells with an IC50 value of 4.3 µg/mL (32). • Sterols, steroidal sapogenins, steroidal alkaloids and alkaloidal amines derived from plant sources provide the starting materials for steroid production. Hecogenin (IV), a saponin (Agave sislana), was manufactured to cortisone by the process of Spensley et al. (33). • The bacterial diversity in pulque, a traditional Mexican alcoholic fermented beverage, was studied in 16S rDNA clone libraries from three pulque samples. Identity of 16S rDNA sequenced clones showed that bacterial diversity present among pulque samples is dominated by Lactobacillus species (80.97%). Seventy-eight clones exhibited less than 95% of relatedness to NCBI database se- quences, which may indicate the presence of new species in pulque samples (34). • Antibacterial: Kassu et al. determined the botanical identity, cytotoxicity, and antibacterial properties of the commonly used toothbrush sticks in Ethiopia (35). The study was performed by purchasing the commonly used toothbrush sticks from street mar- kets in various towns of Ethiopia. Voucher specimens were collected and their botanical identity was determined following floral keys. The toothbrush sticks were ground in a mill and soaked in absolute methanol for 24 hours and filtered. The crude methanol extracts were used to test their antibacterial activity by impregnat- ing into filter paper discs and placing on test plates of Staphylococ- cus aureus and Bacillus cerues. Their lethality to brine shrimp (Artemia salina) was performed following standard procedures. Natural Standard Review 117

Crude methanol extracts of only Agave sisalana, Birbira and Hypericum revolutum test concentrations up to 500 µg/ml showed weak toxicity to brine shrimp. All the extracts showed antibacterial activity against Staphylococcus aureus and Bacillus cereus by agar diffusion method. Davidson et al. discussed the wound treatment practices of the Aztecs are discussed (36). The use of concen- trated maguey sap (Agave ssp.) was widespread and has persisted in folk medicine due to its effectiveness. A possible reason may be that it is effective. Laboratory analysis of maguey syrup indicates that its utilization as a remedy by ancient and modern Mesoamer- icans could contribute to the healing process of aerobic wound infections. Both pyogenic and enteric bacteria appear to be suscep- tible to maguey syrup. The traditional addition of salt to the rem-

edy seems to enhance the effectiveness of the material in inhibiting the growth of one of the major causes of pyogenic infective pro- cesses, Staphylococcus aureus. This finding is additional proof of the effectiveness of pre-Hispanic medicine, and of the skills of pre-Hispanic physicians. • Anti-Inflammatory: Agave intermixta Trel. and Cissus sicyoides L. are two tropical plants originating from the Dominican Republic that have shown anti-inflammatory effects from both oral (300 and 500 mg/kg (p.o)) and topical (2 and 5 mg/mouse ear) application in in vivo models(37) Agave extract was able to reduce edema by 50% compared with the control group. No lethal effects were produced after oral administration of the extracts. In homogenated tissue samples from the inflamed areas, a distinct decrease in the level of myeloperoxidase enzyme was noted (37). • In lyophilized extracts of Agave americana L. (Agavaceae)administered by the intraperitoneal route at doses equivalent to 200 and 300 mg/kg of fresh plant starting material, showed good anti- inflammatory activity. Doses of genins (total steroidal sapogenins, hecogenin and tigogenin) equivalent to the amount in the lyophilized extracts produced an anti-edentatous effect which was much stronger and more efficacious than that obtained with an intraperitoneal administration of 5 mg/kg of indomethacin or dexametha- sone 21-phosphate at a dose equivalent to the molar content of hecogenin administered. At the doses used to evaluate the anti-inflammatory activity, the genins did not have any harmful effect on the gastric mucous membranes. Lesions occurred when signifi- cantly higher doses of hecogenin were given, but gastric damage 118 JOURNAL OF HERBAL PHARMACOTHERAPY

was still less than that caused by the drugs used for comparative purposes (38). • Antitumor: Antitumor agents have been extracted from Agave schottii (Amaryllidaceae) (39). • Cytotoxic: A new chlorogenin hexasaccharide (1) was isolated from leaves of Agave fourcroydes (Agavaceae). The structure of the new saponin was elucidated as chlorogenin 3-O-[alpha-L-rhamnopyranosyl-(1—>4)-beta-D-glucopyranosyl-(1—>3)-[beta-D-glucopyranosyl-(1—>3)-beta-D-glucopyranosyl-(1—>2)]-beta-D-glucopyranos yl-(1—>4)-beta-D-galactopyranoside] (1) by spectroscopic analysis and the result of acidic hydrolysis. The new saponin (1) as well as known hexasaccharides (3 and 5) isolated here showed cytotoxicity against HeLa cells, and (1) exhibited a cell cycle inhibitory effect at the G2/M stage at the concentration of 7.5 and 10 µg/mL (40). • The cytostatic activities of Agave intermixta L. (Agavaceae) and Cissus sicyoides L. (Vitaceae) have been determined. In the antimi- totic assay, Agave intermixta L. showed complete inhibition of cell division at 24 h of treatment. Both species showed a moderate cytostatic activity against HEp-2 cells, Cissus sicyoides L. being the most active species (41). Cytotoxic saponins can be obtained from Agave (42). • Other: Agave americana is a cactus growing abundantly in Mex- ico. Its cooked stem (“quiote”) yields by mastication a sweet juice, which is swallowed while the fibers (“bagazo”) are spit out. This may account for the rarity of bezoars from this origin (43). • Contraceptive: Anordin and dinordin, prepared with steroids derived from the sisal plants Agave sisilana and Agave americana have been used for their antifertility effects. These agents, whose antifertility properties have been confirmed by scientists in Sweden and the United States, constitute a new family of contraceptives with the great advantage of having to be taken only once or twice a month instead of the 20 times per month necessary with the ordinary pill (3). Pharmacodynamics/Kinetics • Clearance Rate in Blood and Milk: One study assessed the quantity of ethanol consumed in pulque, a mildly alcoholic beverage from the maguey cactus, and its clearance rate in the blood and milk of 11 rural women in the state of Mexico. They divided lactating mothers into two groups: one ingested a single dose of pulque Natural Standard Review 119

0.21 Ϯ 0.08 g/kg of body weight (group A) and one ingested 0.44 Ϯ 0.11 g/kg (group B). Maximal concentration of ethanol was reached in milk at 60 minutes and almost equaled that in plasma. Both groups showed a similar clearance pattern regardless of the volume of pulque ingested. Clearance rates between groups were different: ethanol concentration in milk at 60 min were 8.4 Ϯ 3.0 mg/dL for group A and 26.2 Ϯ 7.0 mg/dL, for group B. Two hours later ethanol levels were 3.6 Ϯ 3.4 mg/dL and 23.3 Ϯ 9.4 mg/dL respectively, for the two groups. Clearance rates were slower in mothers showing the highest concentration of ethanol in milk. The present data demonstrate that there is no differential elimination of ethanol in maternal blood and milk following ingestion of a moderate amount of pulque during lactation. The amount of ethanol re- ceived by infants through milk is relatively low and therefore it is unlikely to have harmful effects on them. Pulque consumption adds about 350 kcal/day to the customary dietary intake of these lactating women (18).

HISTORY

EVIDENCE TABLE

• No available studies qualify for inclusion in the evidence table.

PRODUCTS STUDIED

Brands Used in Clinical Trials • NA Brands Shown to Contain Claimed Ingredients Through Third-Party Testing • Consumerlab.com (October 2005): NA • Consumer Reports (October 2005): NA 120 JOURNAL OF HERBAL PHARMACOTHERAPY

• NSF (October 2005): NA • USP (October 2005): NA

AUTHOR/UPDATE INFORMATION

• Last Updated: May 2006.

REFERENCES

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