Marys Medicine

Pii: s0378-8741(99)00085-9

Journal of Ethnopharmacology 68 (1999) 3 – 37 Aloe vera leaf gel: a review update T. Reynolds a,*, A.C. Dweck b a Jodrell Laboratory, Royal Botanic Gardens, Kew, Richmond, Surrey, UK b Dweck Data, 8 Merrifield Road, Ford, Salisbury, Wiltshire, UK Received 20 April 1999; accepted 20 May 1999 Research since the 1986 review has largely upheld the therapeutic claims made in the earlier papers and indeed extended them into other areas. Treatment of inflammation is still the key effect for most types of healing but it isnow realized that this is a complex process and that many of its constituent processes may be addressed in differentways by different gel components. A common theme running though much recent research is the immunomodulatoryproperties of the gel polysaccharides, especially the acetylated mannans from Aloe 6era, which are now a proprietarysubstance covered by many patents. There have also been, however, persistent reports of active glycoprotein fractionsfrom both Aloe 6era and Aloe arborescens. There are also cautionary investigations warning of possible allergic effectson some patients. Reports also describe antidiabetic, anticancer and antibiotic activities, so we may expect to see awidening use of aloe gel. Several reputable suppliers produce a stabilized aloe gel for use as itself or in formulationsand there may be moves towards isolating and eventually providing verified active ingredients in dosable quantities 1999 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Aloe 6era gel; Active polysaccharides; Therapeutic properties lay and Reynolds, 1986) popular interest and useof the gel have increased dramatically. In this Aloes have been used therapeutically, certainly country it is now a familiar ingredient in a range since Roman times and perhaps long before of healthcare and cosmetic products widely avail- able and advertised in shops. The preserved but 1984), different properties being ascribed to the otherwise untreated gel is also sold as a therapeu- inner, colourless, leaf gel and to the exudate from tic agent in its own right as are various concen- the outer layers. During the 12 years since the last trated, diluted and otherwise modified products.
major review of Aloe 6era (L.) Burm.f. gel (Grind- This need has been met by a number of whole-salers who get their supplies from plantations in * Corresponding author.
Texas, Florida and Venezuela while new ones are 0378-8741/99/$ - see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved.
T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 being proposed for Israel, Queensland and East own, 1987; Fox, 1990; Marshall, 1990; Briggs, Africa (Jamieson, 1984). This commercial activity 1995) and may account for much of its effect.
has been accompanied by an upsurge of both More speculative is the presence of salicylates, by clinical and chemical research which is reaching implication having an aspirin-like effect (Robson more closely towards the active ingredients and et al., 1982; Klein and Penneys, 1988; Marshall, their biological activity. There is now less said 1990; Shelton, 1991; Canigueral and Vila, 1993), about doubts as to the efficacy of the material, although the differences between natural salicy- although there are some warnings of allergic side lates and aspirin, a synthetic product, were effects (Klein and Penneys, 1988; Briggs, 1995).
pointed out (Frumkin, 1989). Another simple sub- Harmful reactions to aloe gel treatment are stance, magnesium lactate, is said to inhibit the recorded infrequently (Hunter and Frumkin, production of histamine by histidine decarboxy- 1991; Schmidt and Greenspoon, 1993) but need to lase and is claimed as a gel constituent (Rubel, be taken seriously. There is still confusion be- 1983; Natow, 1986; Marshall, 1990; Shelton, tween the leaf exudate and the gel, Morsy and 1991; Canigueral and Vila, 1993). Inhibition of Ovanoviski (1983), Natow (1986) and Duke pain-producing substances such as bradykinin or (1985) where a great number of folk medicine uses thromboxane is often claimed (Rubel, 1983; Na- are described and Ahmad et al. (1993). However tow, 1986; Danof, 1987; Fox, 1990; Marshall, many commentators clearly distinguish between 1990; Shelton, 1991; Canigueral and Vila, 1993).
the two parts (Watson, 1983; McKeown, 1987; On a more sophisticated level, action on the im- Capasso et al., 1998) and describe in some detail mune system has been postulated and to some how the gel is prepared (McAnalley, 1988, 1990; extent tested (Rubel, 1983; Schechter, 1994; Agarwala, 1997). At one time there was much Griggs, 1996). A recent, very interesting book discussion about the relative efficiency of ‘decol- (Davis, 1997), dwells at some length on the im- orized' and ‘colorized', i.e. with exudate compo- munomodulatory properties of the gel poysaccha- nents, gels (Danof, 1987; Agarwala, 1997). There rides and presents a viewpoint complementary to is also a feeling that some of the variable results the present review. Polysaccharides are another reported in the literature may be due to treatment group of gel constituents to which activity has of the gel subsequent to harvest (Fox, 1990; Mar- been ascribed, particularly in immunomodulatory shall, 1990; Briggs, 1995; Agarwala, 1997).
reactions and one, acemannan, has reached pro- A number of reviews have appeared in recent prietary status (Schechter, 1994; McAnalley, 1988, years covering various aspects of aloe gel use, as 1990; Agarwala, 1997). There has been much in- well as much commercial literature. Exaggerated terest recently in the biological activity of polysac- claims are still being made and although doubts charides, which is greater and more diverse than as to the substance's efficacy are more muted, previously realized. Although the substances are there is still room for the caution which has been varied and widespread in plants some are well voiced (Hecht, 1981; Marshall, 1990). The empha- known as entities, albeit often with uncertain sis is changing towards definition of the active structures (Franz, 1989; Tizard et al., 1989; constituent or constituents so that they can be McAuliffe and Hindsgaul, 1997). Also often men- used accurately in formulations (Reynolds, 1998).
tioned are the antibacterial, antifungal and even There has been a greater willingness to investi- antiviral properties demonstrated by the gel gate reasons for the recorded variability in cura- (Klein and Penneys, 1988; Marshall, 1990; Ahmad tive properties.
et al., 1993), while anti-oxidant effects are becom- Reasons presented for aloe gel efficacy are still ing of interest. Although A. 6era gel is the only varied perhaps because there are in fact several one being used commercially, there is the possibil- different healing activities operating (Capasso et ity of discovering useful properties among the al., 1998). The action of aloe gel as a moisturizing other 300 or more species (Newton, 1987).
agent is still a popular concept (Meadows, 1980; In this update the trend to be emphasized is Watson, 1983; Natow, 1986; Danof, 1987; McKe- away from the more naive arbitrary use of the leaf T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 gel (Reynolds 1996) and towards a quest for ety of criteria (Cera et al., 1980, 1982; Robson et deeper, more precise understanding of its con- al., 1982) and therapeutic benefits were recorded.
stituents and the varied biological activities which This type of test system was returned to later they may or may not display (Reynolds 1996).
(Heggers et al., 1993) with similar positive results.
A study, with good replication, of healing after a precise skin hole punch demonstrated the anti- 2. Test systems and clinical trials1
inflammatory properties of the gel leading tomore rapid healing (Davis et al., 1987a) A differ- 2.1. Burns and incisions ent approach was taken whereby the subjects(mice) were fed aloe gel for some time before hole For testing the efficacy of aloe gel or its various punch wounding and compared with those treated components on inflammation a number of tests topically after wounding (Davis et al., 1989c).
have been used, usually in relation to some sort of Both methods produced healing. A further varia- deliberate wounding. These need to be distin- tion was the treatment of punch wounds on mice guished from clinical trials where the injuries al- or rats made diabetic by streptozotocin and there- fore more slow to heal. Again healing by aloe gel systematically by a number of putative therapeu- was demonstrated (Davis et al., 1988; Davis and tic agents. The earliest experimentation related to Maro, 1989). A return to wounding by precision skin burns and arose in relation to clinical obser- burns using a hot metal plate with adequate repli- vations, going back to the 1930s (Grindlay and cation again demonstrated positive healing activ- Reynolds, 1986). It was often inconclusive due to ity (Rodriguez-Bigas et al., 1988). This technique inadequate controls and replication and an impre- was further elaborated to produce first, second or cise correlation of cause and effect. One of the third degree burns by precisely timed exposures to most detailed and accurate of these clinical trials the hot metal plate (Bunyapraphatsara et al., took place in 1957 with use of aloe gel against controlled thermal and radiation burns on rats Two special examples of burns are sunburn and and rabbits compared with clinical studies on frostbite and these have been used experimentally.
human patients (Ashley et al., 1957). This failed Thus, precise UVB burns were produced with a to demonstrate any healing properties of the gel.
light pen but were unaffected by aloe gel (Crowell In contrast another careful study but with far et al., 1989). In a later trial to test the effect of the fewer replicates gave a positive result (Rovatti and gel on UV-induced immune suppression a bank of Brennan, 1959). Another approach a little later, UV lights were used (Strickland et al., 1994).
was to measure the tensile strength of the healing Frostbite was produced by exposing rabbit ears to of a precise incision wound, post mortem (Goff ethanol and solid carbon dioxide (Heggers et al., and Levenstein, 1964). An undescribed aloe ‘ex- 1993; Miller and Koltai, 1995) and was relieved tract' speeded healing but had no effect on the by application of aloe gel.
final result. A similar wound tensile strength testwas used later to compare the effects of steroids 2.2. Irritating compounds producing oedema and aloe gel on inflammation and healing (Daviset al., 1994b), and later of antibacterial agents Experimental production of swelling, caused by (Heggers et al., 1995). Then in the early 1980s fluid accumulation in a tissue (Oedema) initiated both precise experimental scald burns as well as by irritating compounds has been used as an previous injuries were again compared by a vari- inflammatory model with the mouse ear or rathind paw as subjects. Croton oil, a powerfulirritant, was applied to the right ear with the left 1 The authors wish to make it clear that neither they nor remaining as control. Inflammation was measured anyone else at RBG, Kew is in any way envolved in vertebrate by weighing a tissue punch sample and was shown experimentation, which is only described here as part of thereview. Ethical approval is not implied.
to decrease after topical application of aloe gel T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 (Davis et al., 1987b; 1989a,b). A subsequent trial 2.5. In 6itro studies demonstrated an even greater decrease when thegel was combined with a corticosteroid (Davis et A number of experiments have been carried out al., 1991, 1994b). This trial was accompanied by a in which the effects of components of Aloe leaf on similar one where mustard as the initiating agent various biochemical or microbiological systems, was injected into a rat paw, subsequent swelling relevant to the four inflammation responses and being measured volumetrically and fluid with- to wound healing, have been studied. Enzymes in drawn to determine leucocyte infiltration. In this aloe gel destroying the nonapeptide bradykinin case aloe gel, with or without steroids was injected which causes vasodilatation and pain production, previously rather than being applied topically.
were the subject of one such investigation, al- This study had followed some more or less similar though angiotensin-converting-enzyme received ones, where a variety of irritants, gelatine, albu- less attention. Prostaglandins were another obvi- min, dextran, carrageenan and kaolin had been ous subject and their presence in Aloe was used (Davis et al., 1989a) and the inflammation claimed, as well as a complex lipid inhibiting successfully treated with aloe gel, orally or arachidonic acid oxidation. On the other hand production of the vasodilator histamine from his-tidine was said to be inhibited by the gel. Effects 2.3. The air pouch of aloe gel on separate components of woundhealing in tissue culture have been made, notably A modification of these models involving fibroblast proliferation (Brasher et al., 1969; oedema was developed in which air was injected Danof and McAnalley, 1983) and growth of new under the skin to form a cavity, a simulated blood capillaries (Lee et al., 1995). The involve- synovium, to which irritants and therapeutic ment of immunological effects has been recog- agents could be added. This was taken to be analogous to the joint cavity, containing synovial formation and activity (Imanishi and Suzuki, fluids which becomes inflamed during arthritis.
1984). Alongside these studies of in vitro systems Such an air pouch was produced on the backs of there were also many attempts to analyse the anaesthetized mice, irritated with carrageenan and plant material and to identify the active fraction treated with A. 6era gel solution (Davis et al., or fractions.
1992). Healing effect was measured histologicallyby counting the number of mast cells in the cavityfluid, decreased by aloe gel treatment and by 3. Treatment of inflammation
examining pouch wall vascularity, also decreasedby the gel.
Inflammation is a tissue reaction by the body to 2.4. Adju6ant arthritis injury and typically follows burns or other skininsults. It is classically characterized by swelling An important extension of experiments on le- (tumor), pain (dolor), redness (rubor) and heat sions caused by applied irritants is the deliberate (calor) as well as loss of function (Macpherson, production of a condition resembling arthritis in 1992). It is thus a complex process and investiga- an animal model, usually rat. This can then be tions into the therapeutic properties of the gel followed by treatment with putative therapeutic should take account of its effects on these various agents to suppress either the inflammation or symptoms. In addition, the gel may have more immunologic consequences. The irritating agent than one active constituent, which may be ad- used was a suspension of heat-killed Mycobac- dressing different parts of the healing process.
terium butyricum in mineral oil which produced Failure to take all this into account may be inflammation directly in the injected paw and also responsible for ambiguities which may have arisen in the other paw by an immunologic pathway in the past about the efficacy of the gel. Although (Saito et al., 1982).
inflammatory processes are a natural response to T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 injury and may hinder healing it may also be The first, the academic, analytical approach, seeks undesirable to suppress them in an unstructured to dissect the processes and reveal the individual way before their purpose is accomplished. Leuco- biochemical and physiological reactions, while the cytes accompanied by fluid accumulate in the second, the clinical approach, puts the various damaged tissues producing the swelling, these processes back together and studies their interac- movements being the result of increased capillary tions. The second can only be ultimately success- permeability. Pain is a complex reaction following ful when the first is well known. In the best, the release of short peptides and prostaglandins.
recent, precise experimentation, care has been The redness and heat are caused by vasodilatation taken to separate the inner parenchyma of the which reduces blood pressure and increases circu- aloe leaf completely from the outer layers rich in lation, although this gradually slows. Inflamma- phenolics, both experimentally and conceptually.
tion can be either caused, or intensified by However in some trials this separation has not invasion with micro-organisms. As well as in been complete and two preparations were deliber- wounds, inflammation is involved in conditions ately made and tested, one decolorized and the such as arthritis. Continuing research into inflam- other containing anthraquinones from the outer mation has shown that it is a complex process layers (Davis et al., 1989). These substances were involving many biochemical pathways and a vari- to some degree toxic and reduced for instance ety of agents and mediators (summarized in Davis suppression of polymorphonuclear lymphocyte et al., 1989a). In particular these authors distin- infiltration (Davis et al., 1986b). They also greatly guish three components, reduced the healing of croton oil-induced inflam- 1. Vasoactive substances; agents causing dilation mation (Davis et al., 1989b, 1991). A component of blood vessels and opening of junctions be- extracted from whole Aloe barbadensis (sic) leaves tween cells of the ultimate capillaries, pro- and probably originating from the exudate rather duced by altering contractile elements in than the gel was characterized as a cinnamic acid endothelial cells. These factors include vasoac- ester of aloesin and shown to reduce croton oil-in- duced inflammation (Hutter et al., 1996). A low molecular weight component claimed to be ex- 2. Chemotactic factors; these agents cause in- tracted from the gel but probably also of exudate creased cell motility, especially of white blood origin, was shown to have cytotoxic effects similar cells (leucocytes) into stressed areas. These in- to barbaloin (Avila et al., 1997). This raises the clude several proteins and peptides.
possibility of both irritating and healing agents in 3. Degradative enzymes; these are hydrolytic en- the exudate as well as the gel. Even this compari- zymes breaking down tissue components.
son is not strictly accurate as it is not clear how Proteases in particular participate in inflam- the anthraquinone-free gel is made and if other matory states causing chemotactic factors to substances are removed, or not, at the same time.
be released. It was also shown that aloe gel Mannose-6-phosphate was shown to have anti- contained both an inhibitory system and a inflammatory activity and this was said to resem- stimulatory system that influenced both infl- ble the known activity of acetylated mannan, a gel ammatory and immune responses (Davis et al., component (Davis et al., 1994a).
Two aspects of inflammation reduction follow- The healing effects of A. 6era gel are therefore ing aloe gel treatment by injection in rats were ob- now being seen as more complex than previously served (Davis et al., 1986a,b, 1987c). Mustard in- realized (Ho¨rmann and Korting, 1994). It now duced oedema of the paw was reduced by between appears that several activities are operating each 445 and 70% while infiltration of polymorphonu- with its own part to play in the overall therapy.
clear lymphocytes into a skin blister was reduced These activities may well reflect the presence of by 58%. Two other substances, RNA and vitamin several different active agents in the gel. There C synergized with the gel in inhibiting oedema.
seems to be a need for two types of investigation.
Similarly mouse ear inflammation induced with T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 croton oil was reduced by up to 67% following detailed study of healing of a surgical cut which topically applied aloe gel (Davis et al., 1987b). In showed that ‘A. 6era extract in an ointment base' another study these workers tested the action of speeded repair but did not alter the ultimate result topical or injected aloe gel against inflammation (Goff and Levenstein, 1964). Perhaps aloe gel produced by a variety of agents which were con- removes delaying effects rather than accelerating sidered to induce different types of inflammation healing as such. The use of aloe gel to heal (Davis et al., 1989a). Thus the gel relieved the wounds is the classic use of the material and one inflammatory effects of kaolin, carrageenan (an of the first explanations of its efficacy was its high algal polysaccharide), albumin, gelatin, mustard water content which kept the wound moist and and croton oil which were said to act either by increased epithelial cell migration (Morton, 1961; promoting prostaglandin synthesis or by increas- Erazo et al., 1985), although even this has been ing infiltration of leucocytes. Elsewhere, aqueous questioned (Roberts and Travis, 1995). Indeed the or chloroform extracts of the gel reduced a car- beneficial effects on oral wounds where moisture rageenan-induced inflammation and migration of is abundant, indicates that other factors operate neutrophils (Vazquez et al., 1996). Aloe gel was (Sudworth, 1997). A report of effective aloe gel less effective against inflammatory agents which healing of pressure sores recorded rapid granula- produced allergic reactions through the action of tion (Cuzzell, 1986), an effect also noted with bioactive amines such as histamine, even if their various incision wounds in rats and attributed to synthesis might be inhibited by magnesium lac- more rapid maturation of collagen (Udupa et al., tate. In other ways aloe gel was found to show immunomodulatory properties (t'Hart et al., In a more detailed study, a skin punch wound 1988) so the full picture is still not clear. Another healed more rapidly when treated with ‘decol- aspect is the use of the gel as a vehicle for orized' gel than with ‘colorized' gel (Davis et al., application of other active substances to which it 1986). These observations were made on the 7th may additionally impart its own activity (Davis et day after wounding a mouse or rat skin which al., 1989c).
was said to be optimal for recording healing.
Treatment by daily injection of the gel reduced 3.1. Wound healing wound diameter, increased skin circulation andseemed to reduce scarring (Davis et al., 1987a, If inflammation is a complex process, then 1989a). Acute inflammation was also inhibited.
wound healing is much more so and the interven- The colour mentioned is due to anthraquinones tion of aloe gel is likely to be multifaceted. A from the aloe leaf exudate but details of their wound to the skin may pierce two layers, the removal (‘decolorized' gel) were not given. Else- epidermis and dermis as well as damaging ap- where, trials using cultures of human endothelial pendages. A temporary repair is effected by fibrin cells or fibroblasts demonstrated cytotoxicity in clot which is then invaded by a variety of cells, gel samples contaminated with leaf exudate some of which produce the inflammatory response (Danof and McAnalley, 1983). In contrast, cyto- and which eventually carry out a permanent re- toxicity was shown to be reduced in neutrophils pair (Martin, 1997). It may well be that the repair treated witha low molecular weight fraction of is not perfect in that scar tissue is produced and gel, probably exudate-derived, although this was appendages do not regenerate. The epidermis is not stated, following inhibition of release of reac- repaired in three phases, migration of cells, prolif- tive oxygen species (t'Hart et al., 1990). In a eration and maturation, while new connective tis- further study, ‘A. 6era' (sic), presumably the gel, sue is found in the dermis (Davis et al., 1987a). As was administered orally over two months or ap- well as repair of structure there is an urgency to plied to the wounded skin in a cream. Both avoid microbiological entry which can retard treatments improved wound healing. It was sug- wound contraction (Hayward et al., 1992). In- gested that one of the factors, out of several, creased speed of repair was seen in an early enhanced by aloe gel was increased oxygen access T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 as a result of increased blood supply. (Davis et al., powers of acemannan on wounds in elderly or 1989b). In another trial using topical application, obese rats also attributed to macrophage stimula- stimulation of fibroblast activity and collagen pro- tion (Tizard et al., 1994). Total regeneration of liferation was demonstrated (Thompson 1991).
the skin also requires that ‘difficult' cells such as Angiogenesis, the growth of new blood capillaries, neurons are replaced. Proliferation of neuron-like is a necessary part of tissue regeneration and cells and also perhaps cell adhesion, in a culture vascularity of burn tissue of a guinea pig was of rat adrenal cells was stimulated by gel prepara- shown to be reestablished by topical application tions (Bouthet et al., 1995).
of aloe gel (Heggers et al., 1992). A low molecular Following the idea that there were factors with weight component of freeze-dried aloe gel was different types of activity in the gel an attempt shown to stimulate blood vessel formation in a was made to separate anti-inflammatory and wound healing components (Davis et al., 1991c).
methanol-soluble fraction of the gel was shown to A precipitate formed by treatment with 50% stimulate proliferation of artery endothelial cells aqueous ethanol seemed to have most of the in an in vitro assay and to induce them to invade wound healing activity observed in the raw gel a collagen substrate (Lee et al., 1998). Activation when used against punch wounds in mouse skin.
of matrix proteinases, which allow penetration, The supernatant contained anti-inflammatory ac- was thought to be involved. Tissue survival fol- tivity which was attributed to glycoprotein. Else- lowing arterial damage in a rabbit ear, which where, significant wound healing was produced by mimicked drug abuse damage, was maintained by mannose-6-phosphate (Davis et al., 1994a) Heal- topical aloe gel application (Heggers et al., 1993).
ing of an incision wound by aloe gel was found to Healing of an experimental excision wound was be accompanied by higher levels of hyaluronic promoted by topically applied aloe preparation acid and dermatan sulphate produced more and this was enhanced when the gel was combined rapidly. This was suggested to stimulate collagen with a nitric oxide inhibitor (Heggers et al., 1997).
synthesis and fibroblast activity (Chithra et al., Subsequent work showed that another impor- 1998a). There was also increased activity of b-glu- tant impediment to wound healing, microbiologi- curonidase and N-acetyl glucosaminidase which cal activity, infection, was also addressed by aloe was said to increase carbohydrate turnover in the gel treatment (Heggers et al., 1995). Here, cuts to wound matrix. Fibroblast proliferation in vitro rat skin were more rapidly healed by topical and in vivo was observed after treatment with the applications of aloe gel compared with an un- acetylated mannan fraction carrisyn™ (McAnal- treated control or by applications of potential anti-microbials. Many antibiotic agents are more wounded diabetic rats treated orally and topically toxic to fibroblasts than to bacteria and seem to with aloe gel was later demonstrated (Chithra et retard the healing process (Lineaweaver et al., al., 1998b). The collagen formed had a higher 1985). The gel was thought to contain a growth degree of crosslinking indicating enhanced levels factor which enhanced the breaking strength of of type III (Chithra et al., 1998c). There were also wounds. Only buffered sodium hypochlorite solu- higher levels of protein and DNA. In another test tion (0.025%) had therapeutic effects similar to on surgical cuts in mice, hydrocortisone given by aloe gel (Heggers et al., 1996). Macrophages play injection, while reducing inflammation, hindered a considerable part in controlling microorganisms wound healing but when ‘A. 6era' (presumably and it was shown that young active macrophages the gel) was included then wound suppression was accelerated the rate of wound healing in aged rats, compared with rates where senescent cells in these (Davis, et al., 1994b). Healing and control of animals were left alone to act. Activation of acute inflammation, distinct from chronic inflam- macrophages by acemannan, an aloe gel polysac- mation, was observed following gel treatment of charide, was claimed (Maxwell et al., 1996). This excision and incision wounds in rats (Udupa et followed previous observations on the healing T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 Widespread acclamation of the healing powers possible and the third where both epidermis and of aloe gel is not however universal. Some older dermis are irreversibly damaged (Bunyapraphat- studies were unable to demonstrate any curative sara et al., 1996a). Like wound healing it is one of properties (Ashley et al., 1957; Gjerstad, 1969; the classic subjects for aloe gel treatment (Ashley Ship, 1977; Spoerke and Elkins, 1980; Kaufman et al., 1957; Rovatti and Brennan, 1959; Cera et et al., 1988) and more recently a trial with surgical al., 1982), although as for wound healing some wounds in human patients even suggested that studies demonstrate little benefit (Heck et al., healing was delayed (Schmidt and Greenspoon, 1981). In a large, double-blind trial using 194 1993). No effects of aloe gel on re-epithelization patients with radiation burns, no difference to a or wound contraction of excision wounds in pigs placebo was observed (Williams et al., 1996).
was observed (Watcher and Wheeland, 1989). No However other samples of the preparation used in healing properties at all were observed with this trial (Fruit of the Earth) were found else- corneal punch wounds (Green et al., 1996), in where to have no mucopolysaccharide content contrast to earlier positive observations with (Ross et al., 1997). The existence of diverse com- corneal flash burns (Lawrence, 1984). Elsewhere it ponents of a burn and the diverse components of was found that acemannan had an equal, not aloe gel which might be healing the burn, were better, healing and bactericidal effect on shave soon recognized (Robson et al., 1982). Here the biopsy wounds as the antibiotic bacitracin® gel was said to possess an anaesthetic effect, a (Phillips et al., 1995). The two lines of conflicting bactericidal action and an anti-thromboxane ef- evidence may be explained by the fragility of the fect. Recognizing the possible multifarious activi- active ingredients as it appears from several ac- ties of Aloe constituents, a series of tests of aloe counts that the treatment of the gel after harvest- gel on heat burns, electrical burns and frostbite in ing is crucial for activity. Effects may also vary guinea pigs, rabbits and in clinical studies with with the type and location of wound. Using a humans demonstrated a therapeutic potential proprietary aloe dressing on pad wounds of dogs across the wide variety of soft tissue injuries (Heg- it was concluded that healing processes during the gers et al., 1993). The gel was shown to penetrate first 7 days were speeded, an advantage to a tissue, relieve pain, reduce inflammation and in- wound exposed to weight bearing, although the crease blood supply by inhibiting the synthesis of end result was the same as that with antibiotic thromboxane A , a potent vasoconstrictor. Hot- treatment alone (Swaim et al., 1992).
plate burns to guinea pig skin healed morequickly after topical aloe gel application and in- 3.2. Burn healing terestingly, the bacterial count was reduced by60% (Rodriguez-Bigas et al., 1988; Kivett, 1989).
Burn healing can be regarded as a special type A recent study demonstrated healing activity to- of wound healing and most of the skin reactions wards gamma-radiation burns but only if applied are the same. It has been pointed out however quickly, when it produced more rapid healing that conditions for healing would differ according than controls but only because peak reaction lev- to the depth of the burn wound and that several els were reduced (Roberts and Travis, 1995). Here factors can interfere with the healing process it was speculated that aloe gel affected the induc- (Kaufman et al., 1989) Thus three zones have tion of the skin reaction but not the later healing been recognized in a burn, an inner zone (coagu- phases. In a similar trial using mice, differences lation zone) where cell damage is irreversible, a were seen in the effect on first, second and third middle zone (statis zone) where damage is severe degree burns. Gel preparations delayed the infl- and an outer zone (hyperemic zone) where recov- ammatory response and speeded the recovery time ery is likely. In addition there are three degrees of for first and second degree burns and epithelial- burns, the first in which the epidermis only is ization was rapid. Third degree burns proved damaged, the second where some dermal damage also occurs but where epithelial regeneration is 1996a). A synergism was noted between the gel T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 and the cream base used. Elsewhere, partial 3.4. Adju6ant arthritis thickness burns were observed to heal morerapidly when treated with aloe gel, compared One very troublesome instance of inflammation with vaseline, both growth of epithelial cells is rheumatoid arthritis where the joints become and organization of fibro-vascular and colla- inflamed and a complex syndrome of pathological gen tissue being stimulated (Visuthikosol et al., effects appears. An experimental model set up to probe this disorder is the so called adjuvantarthritis produced by injection of a substance 3.3. Frostbite which unspecifically intensifies the immune re-sponse without itself being antigenic. In one ex- Direct and indirect cellular injury arising from perimental design the adjuvant is injected into the frostbite can be regarded as a type of burn right hand paw of a rat where it soon produces (Heggers et al., 1990), although the stages inflammation, whereas later inflammation in the described differ. One classification distinguished left hand paw is held to be an immunologic four degrees, the first with numbness and ery- phenomenon. A whole leaf extract from A.
thema, the second where oedema and blisters africana (sic), strictly A. ferox Mill. or a hybrid, occur and thromboxane is released, the third but probably in fact A. 6era, was injected and where damage extends to the subdermis and decreased inflammation (48%) in the right paw the fourth with full tissue thickness damage.
also inhibiting the immunological response (72%) (McCauley et al., 1990). Another classification in the left paw (Hanley et al., 1982). It was recognized four phases, the first (pre-freeze speculated without experimental evidence that phase) with chill but no ice crystal formation, the second (freeze – thaw phase) with ice forma- prostaglandin synthesis. In another test A. 6era tion, The third (vascular stasis phase) with extract, described as a 5% leaf homogenate, (also plasma leakage and the fourth (ischemic phase) called A. africana in parts of the text) together with thrombosis, blood loss and even gangrene with ascorbic acid and RNA was applied topically (Miller and Koltai, 1995). Thromboxane is a in a hydrophilic cream base, again produced re- duction of both immediate inflammation (39%) (McCauley et al., 1983; Miller and Koltai, 1995) and subsequent arthritis (45%) (Davis et al., and has been implicated in frostbite injuries 1985). The gel itself, included in this mixture (Heggers et al., 1987) It was suggested that produced 45% regession (Davis, 1988). A further the main function of aloe gel in healing frostbite study attempting to pinpoint active ingredients is the reduction of thromboxane levels (Raine found that injected aqueous suspensions of an- et al., 1980) and has been used clinically on this thraquinone, anthracene, cinnamic acid or an- assumption to treat the more severe blisters where thranilic acid inhibited inflammation to various there was structural damage (McCauley et al., extents (Davis et al., 1986), while anthraquinone 1983). Topical application of A. 6era cream (sic) and cinnamic acid had some effect on the immune enhanced tissue survival of frost-bitten rabbit ear.
In an accompanying clinical trial with humans, Another experimental model attempting to sim- 68% of the aloe-treated patients achieved full ulate the synovial cavity in a joint, where inflam- healing, while only 33% of those receiving other matory reactions occur and produce arthritis is treatments were fully healed. In the first group 7% the ‘synovial pouch' where air is injected under required amputation, compared with 33% in the the skin to form a cavity. The walls of the cavity second group (Heggers et al., 1990). In another are said to resemble the synovial membrane and trial with rabbit ears, 24% survived from those the action of carrageenan on this is said to resem- treated with A. 6era cream while only 6% of ble arthritic inflammation (Davis et al., 1992).
the untreated ears survived (Miller and Koltai, Subsequent injection of aloe gel reduces this infl- ammation rapidly and then induces fibroblast T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 growth. The number of mast cells migrating from the steroids cholesterol, campestrol and b-sitos- surrounding connective tissue was also reduced.
terol were all found in whole leaf extracts of A.
6era (Waller et al., 1978, Ando and Yamaguchi, 3.5. Bradykinin 1990) while b-sitosterol was isolated from A. ar-borescens leaves (Yamamoto et al., 1986) and In studying the effect of aloe gel on skin lesions, found to have anti-inflammatory prpoerties in one line of research that has been pursued follows common with some of the exudate compounds the part played by the nonapeptide bradykinin in (Yamamoto et al., 1991). Lupeol and b-sitosterol the inflammatory process. A peptidase, bradyki- were again isolated from A. 6era leaves, accompa- nase, active in breaking down bradykinin to inac- nied by b-sitosterol-3-glucoside and its 6%-palmi- tive units was isolated from A. arborescens Mill.
tate (Kinoshita et al., 1996). Lupeol, campestrol leaves (Fujita et al., 1976) and shown subse- and b-sitosterol were found to be significantly quently to be a carboxypeptidase (Fujita et al., anti-inflammatory in wounded mice (Davis et al., 1979) and then a serine carboxypeptidase (Ito et 1994b). Other, unknown factors in the gel pro- al., 1993). In a separate study with the same moted healing which would have been hindered species, a glycoprotein with carboxypeptidase ac- by the sterols alone. Another analysis of the lipid tivity was isolated (Yagi et al., 1987a). Aloe ar- fraction of A. 6era leaves revealed various com- borescens is much used in Japan in a way similar mon substances, including cholesterol and also a to A. 6era, although in these studies it appears range of more complex polar lipids (Afzal et al., that the whole leaf was used in the preparation 1991). Among the fatty acids, of which the chief rather than the isolated gel. A high molecular was g-linolenic acid (42% of total fatty acids), weight, water-soluble fraction was separated so it they determined arachidonic acid (3% of total could be assumed that this probably came from the gel. However, in yet another study a car- prostaglandins. This compound in turn is pro- boxypeptidase was prepared from the ‘leaf skin' duced in reactions involving phosphatidyl choline and partially purified (Obata et al., 1993). This and phosphatidyl ethanolamine and these were latter preparation alleviated pain after a burn and each found in A. 6era at levels around 12% of the inhibited the acceleration of vascular permeabil- polar lipids. Although they did not detect ity. These effects were attributed to the hydrolysis prostaglandins as such, they demonstrated the of bradykinin and angiotensin I. It was also presence of cyclo-oxygenase by the production of shown that intravenous dosing before the burn prostanoids from radioactive arachidonic acid was more effective than dosing after the burn.
added to homogenized leaf tissue.
Some of these latter authors had previously iso- The possible presence of prostaglandins and lated a bradykinase from yet another species, A.
their effects on platelet activity in wounded tissue saponaria (Aiton) Haw., this time from the gel is complex. It depends on the molecular species alone (Yagi et al., 1982).
present and other biochemical factors in the tissue(Venton et al., 1991). Some prostaglandins areessential for normal processes in the skin such as 4. Steroids and prostaglandins
cell function and integrity, while others, notablythromboxane A can have devastating Because of the effect of various prostaglandins effects on the cells (Heggers and Robson 1983, in either stimulating or inhibiting aggregation of 1985). The level of thromboxane B2 in guinea pig platelets in relation to wound healing it would burns was reduced by topical application of aloe clearly be of interest to seek interactions between gel (Robson et al., 1982). Other studies have these compounds and aloe gel components or suggested that unspecified substances in aloe gel even presence of the compounds themselves.
inhibited arachidonic acid oxidation (Penneys, Steroids are another obvious group of active com- 1982) and thereby reduced inflammation. Against pounds of interest. The triterpenoid lupeol and this, another study claimed that aloin, a com- T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 pound from Aloe leaf exudate, and a common gel outside agents, both harmful and beneficial and it contaminant, stimulated prostaglandin synthesis is among the latter that aloe constituents may (Capasso et al., 1983). The presence or absence of play a part.
this compound perhaps explains the apparent High molecular weight substances prepared contradiction between the results of Afzal et al., from A. arborescens extracts were shown to pre- (1991) and Penneys, (1982). From a different as- cipitate serum proteins from a range of animals pect it was suggested that aloe exudate an- (Fujita et al., 1978a) and described as lectins. Two fractions were purified and both characterized as inhibitors to enzymes involved in the synthesis of glycoproteins but with differing biological activi- thromboxane A , a potent vasoconstrictor (Heg- ties. One, P2, with a molecular weight of approxi- gers and Robson, 1985). An aqueous extract from mately 18 000 Da, had some haemagglutinating aloe gel inhibited the production of prostaglandin activity, precipitated serum proteins and also E2 from arachidonic acid in vitro and sterols were detected in the extract as well as ‘anthragly- lymphocytes. The other, S1, with a molecular cosides' (sic) (Vazquez et al., 1996). Inhibition of weight of approximately 24 000 Da showed much thromboxane production and consequent vaso- stronger haemagglutinating activity against ery- constriction, was said to be useful in frostbite throcytes but no other biological properties treatment where restriction of circulation is a (Suzuki et al., 1979a). The S1 fraction was named problem (Raine et al., 1980; McCauley et al., Aloctin B but its properties remain relatively un- 1990). A glycoprotein component of the gel, known. The P2 fraction, named Aloctin A, was Aloctin A, was shown to inhibit prostaglandin E2 shown to agglutinate tumour cells but to show no production but over a relatively long incubation cytotoxicity (Suzuki et al., 1979b) and to inhibit time (Ohuchi et al., 1984), in contrast to drugs the growth of fibrosarcoma in vivo but not in such as aspirin, so perhaps the anti-inflammatory vitro (Imanishi et al., 1981). It was also shown to factor needs to be sought elsewhere. It is evident inhibit chemically induced arthritis (Saito et al., that there is much complexity both in the dam- 1982) and to inhibit uptake of foreign erythro- aged tissues and the plant extracts and that pre- cytes by activated rat macrophages (Ohuchi et al., cise mechanisms and pathways have yet to be determined in the field of prostaglandins and their It was then shown that aloctin A injected intra- interaction with platelets.
venously into mice, stimulated the cytotoxicity ofharvested spleen cells and peritoneal exudate cellstowards tumour cells in vitro, under somewhat 5. Interaction with macromolecules: the immune
limited conditions (Imanishi and Suzuki, 1984).
Evidence points to an apparent stimulation ofhost activity against tumour cells and also ele- The interactions of large molecules in biological vated levels of plasma proteins (Imanishi and systems play an important part in many life pro- Suzuki, 1986). Lymphokine production as a result cesses. Both polysaccharides and glycoproteins of T cell stimulation by aloctin A was increased are involved in such activities, especially in con- (Imanishi, 1993). It was then confirmed that the nection with the immune system. Some glyco- proteins of non-immune origin, termed lectins, lymphokine activated and that there was the specifically bind to cells causing agglutination, or promise that these cells would be sensitized to precipitate macromolecules with specific sugar tumour antigens (Imanishi et al., 1986). Aloctin A structures. The immune system itself is very much had no direct cytotoxic effect on tumour cells more complex, having at its centre the reaction of themselves. Later, a range of pharmacological a host's antibodies with invasive antigens. The activities was described for aloctin A (Saito, many reactions surrounding this and contributing 1993). These included suppression of tumour to it are susceptible to interference by certain growth, not apparently directly but by stimulating T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 host response, increase in macrophage levels and ponent. The high molecular weight fraction, per- activity and also reduction of gastric lesions and haps polysaccharide, was shown to deplete ulcers. A third glycoprotein from A. arborescens, complement components while the low molecular molecular weight 40 000 Da, was shown to agglu- weight fraction interfered with processes in acti- tinate sheep erythrocytes and to stimulate DNA vated polymorphonuclear leukocytes which led to synthesis in cell cultures (Yagi et al., 1985). Yet the production of oxygen free radicals (t'Hart et another lectin fraction from A. arborescens, desig- al., 1988) and subsequent cytotoxicity (t'Hart et nated ATF1011,distinct from the Aloctins, was al., 1990). The high molecular weight fraction was shown to activate helper T cells by binding to the further separated by gel filtration into two cell surface (Yoshimoto et al., 1987). On the other polysaccharide components, B1 (320 000 Da) and hand, phagocytosis of yeast cells by neutrophils B2 (200 000 Da), largely composed of mannose from human asthmatics was stimulated by both (t'Hart et al., 1989). Both substances show anti- glycoprotein and polysaccharide fractions of complement activity at the C3 activation step.
whole leaves of A. arborescens (Shida et al., 1985), Elsewhere a proprietary substance isolated from while activity was also shown by a mixture of the gel and called acemannan (Carrisyn™) by proline and cysteine from the low molecular Carrington Laboratories, Texas was described as weight fraction (Yagi et al., 1987c). This in turn an acetylated polymannan at the 1987 meeting of contrasts with yet other findings which strongly the American Society of Clinical Pathologists and ascribe enhancement of phagocytosis to a polysac- reported to stimulate the immune system (Mc- charide gel component, acemannan, described be- Daniel and McAnalley, 1987). It may be that the low (McDaniel et al., 1987).
whole range of activities described for this sub- With another species, A. 6ahombe(sic), it was stance (Table 3) relate to immunological proper- shown that mice inoculated with a leaf prepara- ties. Acemannan was shown to stimulate antigenic tion were protected from infection by Klebsiella responses of human lymphocytes as well as the pneumoniae apparently by stimulation of the im- mitogenic response (Womble and Helderman, mune system (Solar et al., 1979). However, they 1988) but not to be mitogenic itself. The reaction appear to have obtained their active fraction from seemed to be specific for acemannan compared the leaf exudate which with other workers occurs with other polysaccharides and the effect specific as a contaminant to the gel as ‘colorized' gel. A for the stimulated generation of T cells (Womble fraction separated on Sephadex G50 was shown and Helderman 1992). Acemannan injected sub- to protect mice against infection by a range of bacteria and fungi (Brossat et al., 1981). The same pressed) stimulated the formation of all types of fraction, now characterized as containing a gluco- leucocytes (Egger et al., 1996b), from both spleen mannan of molecular weight above 30 000 Da and bone marrow, although responses in the two suppressed growth, in vivo, of one type of tumour locations were different and depended on the dose in mice, but not of others (Ralamboranto et al., rate (Egger et al., 1996a). Mouse macrophages in 1982). Later, cell division in lymphocytes in cul- monolayer culture were stimulated by acemannan ture was shown to be stimulated (Ralamboranto to show an enhanced respiratory burst and in- et al., 1987). A commercial aloe product (ALVA) creased phagocytosis (Stuart et al., 1997). This was presented as an immunostimulant, augment- was reflected clinically by an observed increase in ing the production of tumour necrosis factor leucocyte count in horses suffering from lethargy (Michel et al., 1989).
syndrome, associated with persistant leucopaenia The therapeutic properties of A. 6era are of (Green, 1996). Acemannan injected into mice or course of prime interest and studies similar to added to murine macrophage cultures stimulated those on A. arborescens have been made on that the synthesis of a variety of immunologicaly ac- plant. Using a membrane filter a high molecular tive interleukins (Merriam et al., 1996). Involve- weight compound of aloe gel above 10 000 Da was separated from a low molecular weight com- observations of the induction of programmed cell T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 death (apoptosis) of macrophages in culture in the A. 6era gel was found to contain 12 polypeptides presence of IFNg (Ramamoorthy and Tizard, by the same method (Bouthet et al., 1996). Lectin activity was determined only for the unseparated One feature of acemannan-induced macro- material and shown as haemagglutination which phages in a chicken bone marrow cell culture was was glucosamine specific.
an increase in nitric oxide production said tocontribute to cytotoxicity (Karaca et al., 1995). Inmouse macrophage cultures, nitric oxide synthase 6. Effects on gastrointestinal function and ulcers
levels were increased by transcriptional activationof the appropriate gene caused by acemannan Aloe gel is offered commercially for oral con- (Ramamoorthy et al., 1996). In contrast it was sumption and many claims are made for benefits shown in vivo that nitric oxide inhibitors en- in various internal inflammatory conditions. A hanced wound healing by limiting generation of series of trials on human patients indicated a tonic oxygen radicals, while addition of aloe gel also effect on the intestinal tract with a reduced transit enhanced the process (Heggers et al., 1997).
time. Also the bacterial flora appeared to benefit, The active gel constituents just described were with a reduction in the presence of yeasts and a found to be polysaccharides free of any polypep- reduction in pH. Bowel putrefaction was reduced tide chains. Other work with A. 6era went back to the idea of active glycoproteins, lectins. Partially (Bland, 1985). Preadministration of a water ex- purified fractions prepared by differential step- tract of whole A. 6era leaves to rats, reversed the wise centrifugation from whole leaves of A. 6era inhibition by blood ethanol of alcohol dehydroge- and A. saponaria were shown to agglutinate hu- nase and aldehyde dehydrogenase activities. It man or canine erythrocytes and to stimulate im- also reversed the increase of lactate/pyruvate ratio mune reactions against human, canine and which could decrease NAD supply. Thus ethanol baboon sera (Winters et al., 1981) These fractions levels in the blood were decreased but not uptake were also shown to stimulate cell division of (Sakai et al., 1989).
lymphocytes (blastogenesis) and that lectin-like An early trial with human patients found oral haemagglutination was associated with terminal administration of aloe gel effective in the treat- D-mannose (Winters, 1991). Subsequently other ment of peptic ulcers (Blitz et al., 1963) although gel fractions were found to suppress cell growth the mode of action could not be determined.
(Winters, 1992). Separation by gel filtration en- However, these observations were contradicted abled these activities to be measured more accu- later using experimentally induced gastric and rately and suggested that activity resided at the duodenal ulcers in rats where both the exudate glucose and mannose sites of the glycoprotein and the gel were found to be ineffective (Parmar (Winters, 1993). They resembled the A. arbores- et al., 1986). However, other workers claimed that cens lectins in many of their properties. Further a component from Cape Aloe exudate named aloe separation by polyacrylamide gel electrophoresis ulcin, suppressed ulcer growth and L-histidine revealed the presence of 23 distinct polypeptides decarboxylase in rats (Yamamoto, 1970, 1973), in whole leaf preparations, of which 13 occurred while another, cruel, experiment where ulcers were in the gel (Winters and Bouthet, 1995). Of these, induced in rats by severe stress, showed that aloe 19 showed lectin activity towards specific antibod- gel, administered in advance, had a prophylactic ies against five known lectins in an immuno-blot effect and was also curative if given as a treatment assay. Most showed the presence of mannose and (Galal et al., 1975) A lectin fraction (glycoprotein) glucose in the polysaccharide moiety and a few from A. arborescens, Aloctin A, was active against the presence of galactose and N-acetylgalac- gastric lesions in rats (Saito et al., 1989),while tosamine. In the same study five major polypep- another high molecular weight fraction, not con- tides were found in whole leaf preparations from taining glycoprotein, was very effective in healing A. saponaria. A commercial sample of lyophilized mechanically and chemically induced ulcers but T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 not those induced by stress (Teradaira et al., (Koo, 1994) and in fact seemed to cause an in- 1993). This fraction contained substances with crease. Elsewhere, no effect was found using nor- molecular weights between 5000 and 50 000 Da, mal rats (Herlihy et al., 1998b). The question with which were considered to both suppress peptic all these studies is what Aloe leaf constituents are ulcers and heal chronic gastric ulcers.
being tested. It is sometimes not clear how rigor- Oral ulcers (aphthous stomatitis) are trouble- ous is the separation of the mucilaginous gel and some because of the difficulty of applying and the exudate anthraquinones. Polysaccharide frac- retaining a therapeutic agent. A clinical trial with tions from water extracts of whole leaves of A.
the polysaccharide Acemannan accelerated heal- 6era, A ferox Mill., A. perryi Baker, A. africana ing time and reduced pain without the side effects Mill. and A. arborescens were found to lower attributed to other agents (Plemons et al., 1994).
blood glucose levels in normal mice (Hikino et al.,1986). Two polysaccharides were separated fromA. arborescens extract and described as Arboran 7. Anti-diabetic activity
A (molecular weight 12 000 Da, 17% O-acetylgroups, 2.5% peptides) and Arboran B (molecular Diabetes mellitus is a disorder of carbohydrate weight 57 000 Da, 5% O-acetyl groups, 10% pep- metabolism characterized by lowered insulin se- tides). Both lowered blood glucose levels in al- cretion. It is a syndrome with both hereditary and loxan-induced diabetic mice. On the other hand a environmental factors and has been classified into ‘bitter principle' separated from crystalline (sic) a number of types or groups, among which are aloes, presumed to be from A. 6era, produced the insulin-dependent and non-insulin dependent significant lowering of fasting blood glucose levels types. It is evident that causes, symptoms and when injected into alloxan-treated mice, both in a treatments are varied and need to be carefully few hours and after several days (Ajabnoor, distinguished. An early clinical trial in India 1990). A more detailed study using leaf skin and where over 3000 ‘mildly' diabetic patients were pulp preparations as well as those from the whole fed with bread incorporating aloe gel, demon- leaves of A. arborescens, showed that the effects strated a reduction in blood sugar levels in over were more complex than previously thought 90% of the cases (Agarwal, 1985). A survey of (Beppu et al., 1993). By using acetone precipita- patients in Texas showed that 17% of those of tion to prepare the active fraction they aimed to Mexican origin used A. 6era in an unspecified eliminate anthraquinone material which previous way, presumably with satisfaction (Noel et al., workers might have included. They found that 1997). Dried aloe exudate has been used in Arabia preparations from both the outer regions of the in diabetes treatment. Administration to non-in- leaf and the inner gel caused a decrease in blood sulin dependent human patients in a small trial glucose level in mice. With gel components, per- resulted in a sustained lowering of blood sugar haps glycoproteins, this rapid fall in glucose was levels (Ghannam et al., 1986). A similar effect was followed by a rise when treatment was discontin- achieved on mice, made diabetic with alloxan ued. There was also a significant rise in insulin treatment (Ajabnoor, 1990). Again, a number of level. The leaf skin preparation also lowered diabetic patients in Thailand were treated orally blood glucose and in artificially induced diabetic with ‘A. 6era juice', to their benefit. Blood sugar animals normal insulin production was resumed.
and triglyceride levels fell during the treatment High levels of carboxypeptidases were found in period (Yongchaiyudha et al., 1996). In parallel this fraction.
trials, patients that failed to respond to other Decreased wound healing associated with dia- anti-diabetic medication responded to the aloe betes is a likely subject for aloe gel treatment. It treatment in a similar way (Bunyapraphatsara et was demonstrated that in rats an A. 6era gel al., 1996b). On the other hand an A. 6era gel preparation injected subcutaneously promoted di- preparation was found to be ineffective in lower- abetic wound healing, reduced abnormal sensitiv- ing blood glucose levels of alloxan-treated rats ity to pain and reduced oedema induced by T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 mustard (Davis et al., 1988). In a following study, man leukemia cells in culture was observed (Gri- both A. 6era gel and surprisingly, gibberellic acid, maudo et al., 1997).
were reported as having almost equal inflamma- Activity has been claimed for two fractions tion-reducing properties in chemically induced di- from aloes, glycoproteins (lectins) and polysac- abetic mice (Davis and Maro, 1989). In a later charides. Lectin-like substances (sic) from leaves trial both excision and incision wounds in chemi- of A. 6era and A. saponaria and a commercial cally induced diabetic rats healed more rapidly aloe gel were shown to have haemoagglutinating after both oral or topical applications of aloe gel.
properties and fresh preparations also promoted Collagen and hexosamine levels were higher dur- growth of normal human cells in culture but ing the early part of healing (Chithra et al., inhibited tumour cell growth (Winters et al., 1981). The commercial aloe gel showed an unspe- It would seem that at least two processes are cific cytotoxicity. Interestingly another commer- being described in these reports. The first results cial aloe gel had previously showed cytotoxicity in lowering of blood glucose levels and involves (Brasher et al., 1969). Two glycoproteins, aloctin either a leaf exudate component or a glycoprotein A and aloctin B were separated from A. arbores- and the second results in wound healing, recalling cens. The first one which is smaller (molecular the classic effects of gel polysaccharides.
weight 7500) is water soluble. Thus growth of aninduced fibrosarcoma in mice was inhibited byaloctin A perhaps by an immunologic route, as 8. Anti-cancer activity
cytotoxicity was not observed (Imanishi et al.,1981). The level of a mouse serum protein named Agents active against neoplasms are much hemopexin was shown to increase during develop- sought after and aloe preparations are of course ment of some tumours, implying a defensive re- obvious candidates. An early report claimed anti- sponse. Injection of aloctin A also produced a tumour activity in an ethanol-precipitated frac- serum protein increase for a short period and this tion, alomicin, from ‘Cape Aloe' here described as was correlated with anti-tumour activity (Ishiguro A. ferox, A. 6era and A. africana (sic) (Soeda, et al., 1984). Another glycoprotein, ATF1011, 1969). A large epidemiologic survey of lung can- from A. arborescens, distinct from the aloctins cer and smoking in Japan suggested that ingestion was shown to augment anti-tumour immunity in of aloe ‘juice', presumably the gel, prevented (sic) mice by T-cell activation but not by direct cyto- pulmonary carcinogenesis and was said to prevent toxicity (Yoshimoto et al., 1987).
(sic) stomach and colon cancer. Whether it was A polysaccharide, ‘aloe mannan', molecular claimed to also suppress cancers already estab- weight 15 000 Da, isolated from A. arborescens lished was not clear (Sakai, 1989).
inhibited growth of an implanted sarcoma in mice Whole freeze-dried leaves of A. arborescens (Yagi et al., 1977). Later another polysaccharide were fed to rats subsequently challenged with fraction, molecular weight above 30 000 Da from either of two carcinogens, an undefined pyrolysis A. 6ahombe (sic) was shown to reduce the growth product (the initiative stage) or diethyl ni- of an induced fibrosarcoma in mice, perhaps by trosamine (the promotion stage), acting on the stimulation of phagocyte activity (Ralamboranto liver. The initiation stage was somewhat de- et al., 1982). Similar effects of the commercial pressed, while there was a significant reduction in polysaccharide fraction Acemannan™, an acety- tumour promotion (Tsuda et al., 1993). In 1995, a lated mannan from A. 6era, against tumour Japanese patent was filed claiming mutagenesis growth were later noted. Growth of a murine inhibition by aloe-emodin from A. arborescens sarcoma implanted in mice, showed regression (Inahata and Nakasugi, 1995). A much earlier after acemannan treatment (Peng et al., 1991), paper had described antileukemic activity by aloe probably through an immune attack. Injection of emodin from Rhamnus frangula L. (Kupchan and mice with acemannan inhibited the growth of Karim, 1976) and later cytotoxicity against hu- murine sarcoma cells implanted subsequently and T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 decreased mortality by about 40% (Merriam et 9. Microbiological effects
al., 1996). Elsewhere, activation of macrophages There has been interest over the years in the was again reported (Zhang and Tizard, 1996).
effects of aloes on microorganisms, with conflict- Clinical observations on acemannan-treated ani- ing results. Infection hinders wound healing and it mals suggested that soft tissue sarcomas initially may be that part of the efficacy of aloe gel lies in increased in size but that this was followed by its antibiotic properties (Cera et al., 1980). Re- fibrous encapsulation, invasion by lymphocytes ports of positive antibacterial effects are shown in and necrosis (Harris et al., 1991). In another Table 1. An early test on the action of a large number of plant extracts against growth of My- growth was again observed, followed by necrosis cobacterium tuberculosis in tube cultures, showed (King et al., 1995).
positive activity for water and ethanol extracts of In a very recent study, carcinogenesis by A. chinensis (sic) but not A. barbadensis (synonym DNA adduct formation was shown to be inhib- for A. 6era) (Gottshall et al., 1949) which is odd ited by a polysaccharide-rich aloe gel fraction in as the former is held to be merely a synonym, at an in vitro rat hepatocyte model (Kim and Lee, best a variety, of the latter (Reynolds, 1966).
Similar results were found with leaf ‘sap' from Table 1A selection of microorganisms inhibited by aloe gel preparations Bacillus subtilis Whole leaf (A., littoralis) Escherichia coli Candida albicans phagocyte culture Exudate (4 species) a References: GP., George and Pandalai, 1949; G., Gottshall et al., 1949; L., Lorenzetti et al., 1964; S., Soeda et al., 1966; B., Bruce, 1967; H., Heggers et al., 1979; Hk., Heck et al., 1981; R., Robson et al., 1982; L., Levin et al., 1988; S., Stuart et al., 1997.
T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 several Aloe species where barbaloin, however, failed to demonstrate antibacterial activity, espe- was said to be the most active component (Dopp, cially in deep wounds which became so heavily 1953). A later, very careful study, with Staphylo- infected that death eventually ensued (Bun- coccus aureus and Escherichia coli in both agar yapraphatsara et al., 1996b). In a trial with inci- plate and liquid broth cultures failed to show any sion wounds in rats, aloe gel was compared with activity in either the gel or the outer leaf layers standard antimicrobials and was found to speed (Fly and Kiem, 1963). A vehement rebuttal of this wound healing, while the antimicrobials had an was made the following year, reporting inhibition initial retardant effect (Heggers et al., 1995). It of bacterial growth by very fresh or freeze-dried may be that antibiotic factors are released by the Aloe ‘juice', presumably the exudate (Lorenzetti et healing tissues in response to aloe treatment.
al., 1964). Various anthraquinones were found to Antifungal activity has received less attention.
be inactive but the main such compound in the exudate, barbaloin, an anthrone-C-glucoside, was against Trichophyton spp. (Soeda et al., 1966) by not tested. Shortly afterwards other workers re- A. ferox ‘juice'. More detailed work demonstrated ported antibacterial activity in various Aloe weak inhibitory activity against spore germination preparations (Soeda et al., 1966; Bruce, 1967; and hyphae growth of T. mentagrophytes by high Heggers et al., 1979; Robson et al., 1982). In a molecular weight components of A. arborescens clinical trial, aloe gel used to treat burns, con- leaves (Fujita et al., 1978b). In subsequent work trolled bacterial growth which was otherwise an antifungal low molecular weight fraction was present in the untreated controls (Heck et al., described, which almost certainly contained bar- 1981) and similar results were achieved in experi- baloin (Kawai et al., 1998). At the same time mental trials (Rodriguez-Bigas et al., 1988; Kivett, inflammation of guinea pig paws infected with T.
1989), although the relevance of casual microor- mentagraphytes was reduced by treatment with a ganisms was challenged (Kaufman et al., 1989).
whole leaf homogenate. Growth of the yeast Can- There remained a divergence of opinion as to the dida albicans was also somewhat inhibited by A.
active agent, on the one hand said to be in the ferox ‘juice' (Soeda et al., 1966) or by a processed ‘anthraquinonic' fraction (Bruce, 1967, 1975; An- A. 6era gel preparation (Heggers et al., 1979).
ton and Haag-Berrurier, 1980), on the other to Later, extracellular killing of Candida by aceman- reside in the gel (Heggers et al., 1979). The former nan-stimulated macrophages was demonstrated view was supported by the demonstration of activ- (Stuart et al., 1997).
ity against Bacillus subtilis in ethanol extracts of Anti-viral activity would be more remarkable the leaf (Levin et al., 1988). It was suggested here that controversial data could be due to beneficial munodeficient virus type 1 (HIV-1), which would nutrients present in some aloe preparations.
arouse topical interest. Indeed, aloe gel was in- There are two useful related outcomes if an- cluded in nutritional supplements used in a clini- tibacterial activity of Aloe can be confirmed.
cal trial with acquired immunodeficient syndrome Firstly there is the obvious general antibiotic ac- (AIDS) patients, where it was said to be beneficial, tivity against pathogens exemplified in the very without specific effects being recorded, rather, first paper quoted (Gottshall et al., 1949) and nutritional supplementation was emphasized as secondly there is activity against bacteria which being very important (Pulse and Uhlig, 1990). A may be hindering the wound healing process and polysaccharide fraction from aloe gel, the acety- contributing to inflammation (Heggers et al., lated mannan acemannan, had previously been 1995). A report of clinical cases suggested that the used to treat AIDS patients. A 71% reduction gel was bactericidal towards Pseudomonas aerugi- in symptoms was recorded, perhaps due to nosa (Cera et al., 1980). In a much later study, stimulation of the immune system (McDaniel acemannan prevented adhesion of P. aeruginosa et al., 1987), although some patients seemed to human lung epithelial cells in monolayer cul- to show no response (McDaniel et al., 1988). A ture (Azghani et al., 1995). However, some studies further clinical study using cats infected with fe- T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 line leukemia, a normally fatal disease showed, Another aloe component, aloe emodin, was again, a 71% survival rate over 12 weeks (Sheets shown to disrupt the coating of enveloped viruses et al., 1991) probably through immunostimula- such as herpes and influenza virus A, while show- tion. Acemannan used as an adjuvant to New- ing no cytotoxicity to the host cells (Sydiskis et castle disease virus and infectious bursal disease al., 1991). In a clinical trial genital herpes was virus antigens in chick, increased virus titre with treated by either an ethanolic extract of freeze no toxic side effects (Chinnah et al., 1992). A dried leaves made up as a cream or the raw gel, similar effect was shown with acemannan as an both applied topically. Significant healing was adjuvant for turkey herpes virus vaccine to con- achieved but it was not clear if this was a direct trol Marek's disease in both laboratory and field action on the virus or some host mediated re- trials with chickens (Nordgren et al., 1992). Injec- sponse (Syed et al., 1996a). Fractions from aloe tion with acemannan reduced immunosupression gel containing lectins were also shown to directly inhibit proliferation of cytomegalovirus in cell macrophage stimulation (Sharma et al., 1994). In culture, perhaps by interfering with protein syn- a similar trial acemannan was successfully used as thesis (Saoo et al., 1996).
an antigen adjuvant against polyomavirus in avariety of birds again with the mildest of sideeffects (Ritchie et al., 1994). Acemannan also 10. Various activities
showed antiviral activity in vitro against measles, 10.1. Radiation effects on skin herpes, feline rhinotracheitis and HIV in mono-layer culture (McAnalley et al., 1988). In a trial The modern awakening of interest in aloe gel using cats suffering from feline immunodeficiency resulted from treatment of X-ray burns, so it was virus, sepsis was decreased and lymphocyte count natural to extend these observations to other increased together with an extension of survival forms of radiation. Topical applications of gel rates, following injection with acemannan (Yates were found not to alter the development of either et al., 1992). Infectivity of HIV-1, herpes simplex erythema or increased blood flow in human skin and Newcastle disease viruses and virus-induced exposed to UVB radiation (Crowell et al., 1989).
cell fusion in two cultured target cell lines was A detailed study of the interactions of UVB and reduced in the presence of acemannan (Kemp et aloe gel on mouse skin demonstrated that the gel al., 1990). Again, in human lymphocyte cultures prevents immune suppression by UV. This was infected with HIV-1, acemannan increased cell shown where UV suppressed the immune reaction viability and reduced viral load, perhaps by in- to either fluorescein or Candida infection but the effect was reversed by gel application. No suns- (Kahlon et al., 1991a). Other effects included creen activity was found but the effects of expo- inhibition of virus-induced cell fusion and sup- sure were less deleterious following gel application pression of virus release. Acemannan acted syner- up to 48 h after exposure. The gel restored the gistically with azidothymidine, enabling lower activity of various epidermal cells reduced by UV doses of this agent to be used effectively (Kahlon exposure (Strickland et al., 1994). A much briefer et al., 1991b). It may well be that many of the study on photo-ageing of skin indicated that antibiotic and also indeed antitumour effects are treatment of skin with aloe extracts increased the brought about by stimulation of natural killer cell soluble collagen level (Danof, 1993 quoting Sta- activity (Marshall and Druck, 1993), an effect chow et al., 1984). A later study demonstrated also observed with the lectin, Aloctin A (Imanishi that acetylated mannan from Aloe increased colla- and Suzuki, 1984). In another trial with advanced gen biosynthesis perhaps through macrophage HIV patients treated with acemannan, no increase stimulation (Lindblad and Thul, 1994). Elsewhere, in CD4 cells or viral burden could be demon- a gel component of between 500 and 1000 Da strated (Montaner et al., 1996).
recovered the supression of Langerhans cell acces- T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 sory cell function induced by UVB radiation (Lee although local pain was experienced at first, at- et al., 1997). Damage by free radicals has often tributed to improved circulation (El-Zawahry et been invoked to explain radiation effects and it is al., 1973). In a study of burns it was suggested that the nature of the healing process depended (Sabeh et al., 1993) and superoxidase dismutase on the type of damage, which in turn depended (Sabeh et al., 1996) activities have been reported on the depth of the wound and that aloe gel could from A. 6era gel.
impair some wound healing by not fulfilling allthe healing requirements (Kaufman et al., 1988).
10.2. Cholesterol le6els This multiplicity of factors in the healing ofwounds was emphasized in clinical trials where In a small trial with monkeys it was found that facial skin was deliberately abraded (Fulton, orally administered aloe gel lowered total choles- 1990). Here aloe gel-treated zones healed more terol by 61% and also that proportion in the high rapidly and completely than untreated zones al- density lipoprotein (HDL) increased (Dixit and though again burning sensations were sometimes Joshi, 1983).
noted. In a quite separate case application of aloegel resulted in a severe burning sensation, fol- 10.3. Hormone le6els lowed by long term erythema (Hunter andFrumkin, 1991). With a different type of wound, In a trial with rats, ingestion of aloe gel lowered those following Caesarean delivery, treatment plasma levels of calcitonin and parathyroid hor- with a proprietary gel fraction delayed healing mone (Herlihy et al., 1998b).
and was discontinued (Schmidt and Greenspoon,1993).
10.4. Psoriasis A controlled toxicological evaluation of ace- mannan administered by injection into mice, rats In a large clinical trial, an A. 6era extract, and dogs failed to identify any adverse effects but compared with a placebo, significantly cured a there was an increase in circulating leucocyte large number of patients (Syed et al., 1996b).
count probably as a result of stimulation of theimmune system. There was also a concentrationof macrophages in lungs, liver and spleen (Fogle- 11. Deleterious effects
man et al., 1992b). Elsewhere macrophages inculture were shown to be stimulated by aceman- In contrast to clinical reports of no useful activ- nan (Zhang and Tizard, 1996). A study of inges- ity with aloe gel, there were also a few cautionary tion by rats of a diet containing up to 1% aloe gel accounts of harmful effects. An early report of a showed no adverse effects on growth or patholog- single case of an eczema appearing after topical ical effects. (Herlihy et al., 1998a).
and internal application of A. 6era gel (Morrow et A factor which may or may not be relevent to al., 1980) was followed by another on A. arbores- the preceding remarks is the presence of exudate cens gel with a hypersensitive patient (Shoji, 1982) phenolic substances, notably anthrone C-gly- and then with a young child (Nakamura and cosides, in the gel as contaminants. It has been Kotajima, 1984). On the other hand a patch test shown that the yellow leaf exudate killed fibrob- trial on 20 human subjects exposed to UV radia- lasts in cell culture, whereas the clear gel stimu- tion showed only a persistent skin pigmentation lated cell growth (Danof, 1987). Elsewhere we (Dominguez-Soto, 1992). The effect of an allergic have the concept of ‘colorized' and ‘decol- dermatitis arising in regions remote from the area orized'gels (Davis et al., 1986a), where the former of application was again described, in some detail had much less healing capacity. The decolorized (Hogan, 1988), where it hindered the treatment of gel reduced wound swelling caused by infiltration chronic leg ulcers. In another study of this intran- of polymorphonuclear leucocytes to a greater ex- sigent lesion, healing with the gel was successful, tent than colorized gel (Davis et al., 1986b), as T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 well as reducing wound diameter more quickly 12.2. Gel compounds (Davis et al., 1987a). Similar studies had com-pared a gel fresh from the plant and dialysed to Few Aloe species have been examined for gel remove low molecular weight components with a constituents. Up to 1986 polysaccharides had ‘commercial stabilized' gel. Cytotoxic effects of been extracted and described from A. arborescens, the ‘commercial sample' were observed but as- A. 6ahombe (sic), A. plicatilis (L.)Mill. and A. 6era cribed to substances introduced during processing (Grindlay and Reynolds, 1986) and A. saponaria (Winters et al., 1981). Some commercial samples and A. 6anballenii Pillans (Gowda, 1980). Later, were found to contain ‘yellow sap' and were A. ferox was added to the list (Mabusela et al., cytotoxic in fibroblast cell cultures (Danof and 1990). In this species, arabinogalactans and rham- McAnalley, 1983). Later studies on a low molecu- nogalacturonans were conspicuous whereas gluco- lar weight fraction ( B10 000 Da) from whole A.
mannans, common in other aloes, were less so.
6era leaves showed that this had a disruptive Work on the components of A. 6era gel has of effect on monolayer cell cultures and inhibited course continued. A study of the rheology of the neutrophils from releasing bactericidal reactive gel suggested that glucomannans in aloes were oxygen species (Avila et al., 1997). Aloe emodin rarely found in most other plants and had plastic and aloin (barbaloin) had a similar effect.
properties akin to those of human body fluids(Yaron 1991). In order to maintain the viscosityon storage, addition of other natural polysaccha- 12. Aloe gel constituents
rides was beneficial (Yaron et al., 1992; Yaron,1993). Table 2 summarises the types of polysac- During all these discussions on the pharmaceu- charide so far reported from the seven species tical properties of aloes a clear distinction should examined. They are largely glucomannans of vari- be made between substances in the colourless, ous compositions, some acetylated and some not, tasteless parenchyma cells, the aloe gel and sub- although polymers of other hexoses occur, nota- stances in the bitter exudate from cells associated bly those in A. ferox. Galactose and galacturonic with vascular bundles in the outer green rind of acid polymers are frequently found. It should be the leaf (Agarwala, 1997). As mentioned above, noted that observations by different investigators this distinction has sometimes been clouded by reveal differing polysaccharide structures, espe- using extracts of the whole leaf or allowing, dur- cially with A. 6era on which most work was done.
ing preparation of the gel, exudate compounds to An acetylated mannan became available commer- infiltrate. The concept of colorized and decol- cially and was known as acemannan or Car- orized gels described above, leads to confusion in risyn™ (McDaniel et al., 1987). Its existence was ascribing activities to individual components.
announced at a conference in 1987 but minimal There may indeed be synergies which would not details of extraction, purification and characteri- appear if the fractions were kept separate. In view zation given, although much more information of the complexities inherent in aloe pharmacology was released in subsequent patents (McAnalley, it might be better to be as rigorous as possible in 1988, 1990). It is an acetylated mannan prepared separation, at least initially, and only combine from A. 6era gel with a range of interesting bio- factors at later stages of the investigation.
logical activities (Table 3) and appears to consist 12.1. Exudate compounds of three chemical entities. Recently NMR studieshave been reported and used as a means of qual- These are largely phenolic in nature and were ity control of the gel (Diehl and Teichmu¨ller, reviewed some time ago (Reynolds, 1985). Many 1998). It may be chemically related to the ‘aloe of the exudates from around 300 species have mannan' isolated somewhat earlier from A. ar- been examined chromatographically and about 80 borescens (Yagi et al., 1977). It was followed in main constituents distinguished. Of these many 1988 by another only partially described mannan species (OS2) also only described at a conference Table 2Polysaccharides from aloe leaf gel Hexose composition Glc:Man:GlcA = 19:19:1 Gowda et al. (1979) Acetylated glucomannan Acetylated glucomannan Gal:GalA:Rha = 1:20:1 Mandal and Das (1980a) Mandal and Das (1980b) Mandal et al. (1983) Glc:Gal:Man = 2:1:2 Haq and Hannan (1981) Galactoglucoarabinoman- 320 000 Gal:Glc:Arab:Man = 4:3:1:89 t'Hart et al. (1989) Galactoglucoarabinoman- 200 000 Gal:Glc:Arab:Man = 2:1:1:22 Acetylated mannan Man:Ac = 16:5 (approx.) Manna and McAnalley (1993) Yagi et al. (1977) Acetylated mannan Yagi et al. (1986) Acetylated mannan Table 2 (Continued) Hexose composition Glc:Rha:Gal = 0.3:0.3:1 Hikino et al. (1986) Acetylated gluco- Wozniewski et al. (1990) Acetylated gluco- Aloe plicatilis Acetylated gluco- Paulsen et al. (1978) Acetylated gluco- Radjabi et al. (1983) Vilkas and Radjabi Nassab(1986) Radjabi-Nassab et al. (1984) Acetylated gluco- Vilkas and Radjabi Nassab Aloe ferox Arab:Rha:Gal = 1.2:0.6:1 1 “4, 1“5 Mabusela et al. (1990) Arab:Rha:GalA = 0.7:0.6:1 1 “4 Xyl:Rha:GalA = 1:6:1 Aloe saponaria1) Glc:Gal:Man = 1:0.25:1.25 Acetylated mannan Acetylated mannan Yagi et al. (1984) Acetylated gluco- Glu:Gal:Mann = 1:0.5:1 Acetylated mannan T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 (Eberendu et al., 1988). Apart from technical A selection of references to biological activity of Acemannan inconsistencies it appears that the range of carbo- hydrate types may relate to plants of different Inhibition of bacterial adhesion to Azghani et al.
geographical origin or possible varieties or even Adjuvant to virus Chinnah et al.
Most of the polysaccharide preparations men- tioned above contain very little or no nitrogen.
Stimulation of macrophage formation Egger et al.
(1996a) However a fraction from A. arborescens gel was Lack of toxic reactions Fogleman et al.
shown to be a glycoprotein, appearing as a single electrophoretic band (Yagi et al., 1986), while two Lack of oral toxicity Fogleman et al.
glycoprotein fractions were separated by differen- Stimulation of leucocyte production tial precipitation (Kodym, 1991). Haemaggluti- Necrosis of canine and feline tumours Harris et al.
nating activity typical of lectins was found in fractions from the gels of A. 6era, A. saponaria Supression of virus replication in vitro Kahlon et al.
and A. chinensis (sic) (Winters, 1993).
More recently the polypeptide composition of Kahlon et al.
(1991b) gel proteins from Aloe species has been deter- Modifdication of glycosylation of viral mined by sodium dodecyl sulphate polyacry- lamide gel electrophoresis (SDS-PAGE) which Regression of fibrosarcomas King et al. (1995) disrupts oligomeric proteins and sorts the resul- Stimulation of collagen synthesis Lindblad andThul (1994) tant polypeptides according to molecular size Anti-viral activity in cell cultures McAnalley et al.
(Winters and Yang, 1996). It was shown that A.
saponaria, A. 6era and A. arborescens had five McDaniel et al.
major polypeptides in common with molecular weights 15 000, 46 000, 65 – 66 000, 71 000 and 76 – Stimulation of natural killer cell 77 000 Da. The species had totals of 11, 12 and nine major polypeptides, respectively.
Induction of cytokines Marshall et al.
Various biological activities have been ascribed to Aloe proteins, mentioned elsewhere in this re- Adjuvant to herpes vaccine Nordgren et al.
(1992) view. Lectin activity is prominent among the gly- Regression of murine sarcoma Peng et al. (1991) coproteins and two entities, Aloctin A and Healing of oral ulcers Plemons et al.
Aloctin B were isolated from A. arborescens (Suzuki et al., 1979a; Saito, 1993). Aloctin A had Adjuvant to virus antigen Ritchie et al.
(1994) a molecular weight of 18 000 Da and was made up Healing of radiation burns of two subunits of 7500 and 10 500 Da with a carbohydrate content of 18%. Aloctin B was Clinical stabilization of feline leukemia Sheets et al.
24 000 Da with two subunits of 12 000 Da each Stimulation of phagocytosis Stuart et al.
and a carbohydrate content of 50%. A different glycoprotein, designated ATF191, was subse- Tizard et al.
quently prepared from the same species (Yoshi- moto et al., 1987), while later another lectin, Induction of cytokines Tizard et al.
molecular weight 35 000 Da, was prepared from Stimulation of lymphocyte response to the outer layers of the leaf (Koike et al., 1995).
An aloe preparation which healed exicsional Relief of feline AIDS Yates et al.
wounds in rats was shown to contain a high molecular weight polypeptide (Heggers et al., Stimulation of macrophages Zhang andTizard (1996) 1996). Recently a glycoprotein (Pg21-2b) with cellproliferation-promoting activity has been reported T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 from A. 6era gel (Yagi et al., 1997). It has a chosen (Yamoto, 1983). It may be that irrigation molecular weight of 29 000 Da and consisted of affects gel composition so that leaves from well two subunits. Other protein fractions showed irrigated plants have less polysaccharide than growth inhibiting activity which seemed however drier plants (Yaron, 1993). It was also claimed to be associated with phenolic contaminants.
however that plant grown hydroponically had a A variety of simple substances have been found higher carbohydrate content (Pierce, 1983). There from time to time in aloe gel (Grindlay and are still other factors operating because a careful Reynolds, 1986) although there is always the analysis of plants from many origins showed great problem of complete separation from leaf exudate variation in leaf size, pH, fibre content, calcium components (Agarwala, 1997). A recent, seem- and magnesium contents and certain HPLC peaks ingly careful, study reported the presence of (Wang and Strong, 1993). Finally a continuing aluminium, boron, barium, calcium, iron, magne- problem is the presence of anthraquinone deriva- sium, manganese, sodium, phosphorus, silicon tives (‘aloin') derived from the mesophyll exudate.
and strontium (Yamaguchi et al., 1993). Among Methods for addressing all these problems are set the organic material was b-sitosterol, reported out in detail in two US Patents (McAnalley 1988, frequently before and large number of long chain hydrocarbons and esters which are more typicalof industrial contaminants.
14. Commercial production
13. Gel preparation
Use of aloe gel and preparations containing it has become widespread and consequently a large It would seem that many of the inconsistent industry has developed, mostly in Texas and Flor- clinical results obtained for therapeutic efficacy of ida. One of the earliest producers was Carrington aloe gel result from the history of the sample after removal from the leaf, or even growing conditions about.html) which used the expertise of staff from of the plant (Yaron, 1993). In the commercial Texas A. and M. University and grows its plants literature there are claims and counter-claims as in Costa Rica. Among a range of products to the superiority of one or another process. This the preparation named Acemannan or Carrisyn™ was supposedly finalised in a report from the was much studied. An associated firm, Mannat- United Aloe Technologists Association (Morsy et al., 1983) and was reviewed more recently (Agar- inc.com/) produced a similar mannose-based wala, 1997). Heat during pasteurization is one of mucopolysaccharide from A. 6era, marketed as the stresses imposed on the gel and there are Manapol® by a Carrington subsidiary, Caraloe advantages in using high temperatures for short (http://www.aloevera.com/) backed by HPLC val- times preferably with the addition of an antioxi- idation. Dr Madis Laboratories of New Jersey is dant such as ascorbic acid (Ashleye, 1983). Muco- another firm that was early in the field, supplying polysaccharide integrity during storage was found both the fresh gel and derived products. In view to be preserved by the addition of other natural of the many claims made by aloe producers and polysaccharides which act synergistically (Yaron, the variable results achieved, the International 1991, 1993; Yaron et al., 1992). An HPLC analy- Aloe Science Council (http://www2.iasc.org/iasc/ sis using size exclusion chromatography, of a articles.html) was set up in 1981 by the Trade number of commercial ‘aloe' products revealed to try to establish standards. One major supp- widely differing levels of mucopolysaccharides (Ross et al., 1997). These processes are also im- www.aloecorp.com/aloecorp.htm) with estates in portant when the gel is intended for internal use Texas and Mexico. They support a wide range of research activities and supply products in the (Gorloff, 1983) and additives must be carefully form of the gel either in the raw form, concen- T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 trated or freeze or spray-dried. Another well es- ity was not always clear. Since then much more tablished (1973) firm is Terry Laboratories (http:// experimental work has been carried out and a www terrylabs.com/index.htm) who are major picture of biological activity properties is emerg- suppliers of gel to many multinational companies ing. One feature that is becoming clear is that the and are major supporters of aloe research and systems undergoing healing contain several inter- quality control. Dr Madis Laboratories Inc.offers acting factors, each of which may be affected by the gel either as a purified extract or in a more than one component of the raw gel. It may be that some of the inconsistencies reported are pany UK (Forever Living Products) (http:// caused by unknown variation in any of these www.aloevera.co.uk/home.htm) are active in sell- ing the gel and derived products by franchise, It certainly seems that one feature, immunos- using aloes grown in Texas. Many firms concen- timulation, is frequently appearing as a major trate the gel by either mild air drying or freeze contributory factor. This is associated with the presence in the gel of polysaccharides. These sub- stances occur in all plants, often as storage carbo- hydrates such as starch or inulin or structural CRH International Inc (http://www.aloealoe.com/ carbohydrates such as cellulose while others have raw.html) and Valley Aloe Vera Inc (http:// a more limited distribution. Many of these spe- www.quikpage.com/valleyaloe). This is by no cialized polysaccharides of unknown function in means a complete list, there are many other pro- the plant have been found to be physiologically ducers, large and small, some of which have pages active in animals and subjects for new therapies on World Wide Web.
(Franz, 1989; Tizard et al., 1989; McAuliffe and An information site ‘The Aloe 6era studies or- Hindsgaul, 1997). Mucopolysaccharides also oc- cur in saliva and it is fascinating to speculate if some interesting hints, although its botany is a the supposed therapeutic powers of dogs, licking little quaint. A similar site has been set up by wounds, is due to these substances. In Aloe an ‘Miracle of Aloe' (http://www.miracleofaloe.com/ acetylated glucomannan was found the be biologi- cally active, so much so that it was named ace- Laboratories' (http://www.primenet.comp hidden/ mannan (Carrysin™). If the presence of acetyl hayward.html). Although these informative sites groups is necessary for activity, one wonders if make very positive, often triumphalist statements this is because they cover a number of hydrophilic in favour of the efficacy of aloe gel for a variety of hydroxyl groups and thus make the molecule ills, they do not make the extravagant claims more able to cross hydrophobic barriers in the which are a feature of some promotional litera- cell. It may also be that some of these ester bonds ture, even if their scientific descriptions are some- are particularly labile, accounting for differences times a little garbled.
of reported efficacy of different preparations. Noinvestigations appear to have been made into thisor into the possibility of using other residues to cover hydroxyl groups, except for methylation,described in an American patent (Farkas, 1967) The literature covered by the previous review and this was to confer stability to the polymer (Grindlay and Reynolds, 1986) contained many chain. It should also be noted however that active case reports and more or less anecdotal accounts glycoproteins have also been demonstrated in aloe of the healing powers of A. 6era gel, especially for gel and may well play some part in therapeutic skin lesions but extended by some to a host of activity, either immunologically as lectins or as other complaints (Bloomfield, 1985). Laboratory proteases such as anti-bradykinins.
studies indicated that there was indeed in vitro There seems to be ever-decreasing doubt that activity present but the relevance to in vivo activ- aloe gel has genuine therapeutic properties, cer- T. Reynolds, A.C. Dweck / Journal of Ethnopharmacology 68 (1999) 3 – 37 tainly for healing of skin lesions and perhaps for domonas aeruginosa to human lung epithelial cells. Glyco- many other conditions. It is also clear that the biology 5, 39 – 44.
Beppu, H., Nagamura, Y., Fujita, K., 1993. Hypoglycemic subject is by no means closed and much needs to and anti-diabetic effects of Aloe arborescens Miller var.
be discovered, both as to the active ingredients natalensis Berger. Phytotherapy Research 7, S37 – S42.
and their biological effects. These ingredients, act- Bland, J., 1985. Effect of orally consumed Aloe vera juice on ing alone or in concert, include at least polysac- gastrointestinal function in normal humans. Preventive charides, glycoproteins, perhaps prostaglandins, Medicine 14, 152 – 154.
small molecules such as magnesium lactate, Blitz, J., Smith, J.W., Gerard, J.R., 1963. Aloe vera gel in peptic ulcer therapy: preliminary report. Journal of the infiltrating exudate phenolics and even, simplest American Osteopathic Association 62, 731 – 735.
of all, water.
Bloomfield, F., 1985. Miracle Plants: Aloe Vera. Century, Bouthet, C.F., Schirf, V.R., Winters, W.D., 1995. Stimulation of neuron like cell growth by aloe substances. Phytother- apy Research 9, 185 – 188.
Bouthet, C.F., Schirf, V.R., Winters, W.D., 1996. Semi-purifi- The authors would like to thank Professors cation and characterization of haemagglutinin substance M.D. Bennett and Monique Simmonds for their from Aloe barbadensis Miller. Phytotherapy Research 10, encouragement and support and Dr N.C. Veitch for critically reviewing the manuscript.
Brasher, W.J., Zimmermann, E.R., Collings, C.K., 1969. The effects of prednisolone, indomethacin, and Aloe 6era gel ontissue culture cells. Oral Surgery, Oral Medicine and OralPathology 27, 122 – 128.
Briggs, C., 1995. Herbal medicine: Aloe. Canadian Pharma- ceutical Journal 128, 48 – 50.
Afzal, M., Ali, M., Hassan, R.A.H., Sweedan, N., Dhami, Brossat, J.Y., Ledeaut, J.Y., Ralamboranto, L., Rakotovao, M.S.I., 1991. Identification of some prostanoids in Aloe L.H., Solar, S., Gueguen, A., Coulanges, P., 1981. Im- vera extracts. Planta Medica 57, 38 – 40.
munostimulating properties of an extract isolated from Agarwal, O.P., 1985. Prevention of atheromatous heart dis- Aloe vahombe. 2. Archives Institut Pasteur Madagascar ease. Angiology 36, 485 – 492.
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Agarwala, O.P., 1997. Whole leaf aloe gel vs.standard aloe gel.
Bruce, W.G.G., 1967. Investigations of antibacterial activity in Drug and Cosmetics Industry February, 22 – 28.
the Aloe. South African Medical Journal 41, 984.
Ahmad, S., Kalhoro, M.A., Kapadia, Z., Badar, Y., 1993.
Bruce, W.G.G., 1975. Medicinal properties in the Aloe. Ex- Aloe' a biologically active and potential medicinal plant.
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