Healing Powers of Aloes: Pharmacology and Therapeutic Applications

2015

Constipation

Aloe latex possesses laxative properties and has been used traditionally to treat constipation. The old practice of using aloe as a laxative drug is based on its content of anthraquinones like barbaloin, which is metabolised to the laxative aloe-emodin, isobarbaloin and chrysophanic acid. The term ‘aloe’ (or ‘aloin’) refers to a crystalline, concentrated form of the dried aloe latex. In addition, aloe latex contains large amounts of a resinous material. Following oral administration the stomach is quickly reached and the time required for passage into the intestine is determined by stomach content and gastric emptying rate. Glycosides are probably chemically stable in the stomach (pH 1–3) and the sugar moiety prevents their absorption into the upper part of the gastrointestinal tract and subsequent detoxification in the liver, which protects them from breakdown in the intestine before they reach their site of action in the colon and rectum. Once they have reached the large intestine the glycosides behave like pro-drugs, liberating the aglycones (aloe-emodin, rhein-emodin, chyrosophanol, etc.) that act as the laxatives.

The metabolism takes place in the colon, where bacterial glycosidases are able to cleave the C-glycosidic bond of glycosides. Their transformation into the active aglycones is carried out by the Eubacterium species of the human intestinal flora. Aloe-emodin is metabolised quickly; therefore its bioavailability is low, perhaps <10%, and the half-life is approximately 48–50 hours. Aloe-emodin and rhein are poorly absorbed. In spite of this, rhein has been recovered in urine, in breast milk, in brown fat, muscle, bones and the gonads, although in very low concentrations. In human volunteers, aloe was as active as aloin. Since aloe contains only about 20% aloin, it looks as though the latter is five times more active than aloes. This means that solubility or resorption differences as influenced by accompanying substances can always play a role. It is also important to remember that the resins in aloes are as active as anthraquinones (); like aloe, the resins require the presence of bile acids in order to act. Aglycones like aloe-emodin and rhein act syner-gistically, evoking secretory and motility changes in the gut.

Although there is no doubt that aloe exerts its action on the colonic mucosa, its mechanism of action is still unclear. It is believed that aloe, or its active ingredient aloe-emodin-9-anthrone, acts by disturbing the equilibrium between the absorption of water from the intestinal lumen via active sodium transport and the secretion of water into the lumen by a prostaglandin-dependent mechanism. Other probable mechanisms could be an increased mucosal permeability of the epithelial cells of the colon, a rise of the level of cAMP in the enterocytes and a stimulation of nerve endings. Platelet-activating factor (PAF) could also contribute to the laxative effect, as aloe-emodin stimulates the release of PAF in human ileal and colonic mucosa.

Furthermore, aloe, in contrast to other antraquinones drugs (cascara and senna), inhibits calcium-dependent nitric oxide synthase (NOS) activity in the rat colon, aloin being the active ingredient responsible of this activity. Taken in doses of 0.25 mg, aloe causes laxative action after 6–12 hours with loose bowel movements accompanied by abdominal pain. Among the anthraquinone drugs, aloe possesses the most potent action () and has an effect persisting over several days. Excessive doses may cause gas and cramps.

These adverse effects, occurring after an overdosage, have reduced its use as a laxative in recent years in some countries while in others it is still widely used. Aloe is also occa-sionally used in association with coleretic and cholagogue drugs to solve atonic constipation, some cases of acute constipation, dyschesia and before endoscopy of the gastrointestinal tract. Aloe is not advisable for treating spastic constipation, constipation associated with proctitis or haemorrhoids, in the presence of chronic renal disease and for many other conditions. Although no clinical evidence seems to have been published, the use of aloe is discouraged to women during menstruation, lactation or in pregnancy. It has been shown that rhein, an active metabolite of aloe-emodin, passes into the breast milk but a laxative effect has not been noted in nursing infants. In addition, although it had been considered abortifacient in folk medicine, no experimental or clinic evidence for an abortifacient action is found in the literature on aloe. Aloe activity is increased when administered with small quantities of soap or alkaline salts. Aloe latex is available in a wide variety of forms, including red and white powders, tablets, capsules, or similar products; it contains standardised amounts of active components along with appropriate directions for use. The use of non-standardised preparations must be avoided because the pharmacological effect could be unpredictable. The laxative aloe is regulated as a drug by the FDA and similar Associations. For the German Commission E, aloe must not be used for more than one or two weeks in self-treatment of constipation. Aloe is commonly available in Italy in combination with: cascara sagrada (Grani di Vals R), rhubarb, Gentian (Puntualax R); licorice, senna, cascara (Puntuale R).

Wound healing properties

Aloe gel is a mucilagenous substance which is 98.5% water. The mucilage contains predominantly polysaccharides which are partially acetylated glucomannans. Aloe gel has been mainly used for the treatment of minor burns, both thermal and from the sun and other skin conditions.

It is incorporated in ointments, creams and lotions and other preparations for external use. Aloe gel is also included in many cosmetics for its emollient properties and anti-ageing effects on the skin. Several studies have shown that activity of aloe gel varies and that it is attributed to changes in the gel composition during growth or after harvest. On the other hand there is a general agreement that aloe gel used in a fresh state, not from storage, is more able to show therapeutic properties. This variation seems due in part to the instability of its important active ingredients, acemannan and anthraquinone glycosides. It is also important to detect the adulteration of commercial aloe gel powder, as the content of commercial maltodextrin, by HPLC and TLC analysis.

Aloe gel comes in a variety of forms, such as a pure gel in a natural or decolourised state, or as a liquid concentrate (10- to 40-fold), either natural or decolourised. Aloe gel can be concentrated and dried to produce spray and freeze-dried powders. There are also formulations like Aloe vera oil, separated pulp and preparations labelled ‘Aloe vera extracts’ which may be highly diluted or ‘reconstituted Aloe vera’, meaning that the product has been prepared from powder or liquid concentrate.

In recent years some interesting studies and reviews have been published and several mechanisms of action for the wound healing properties of aloe gel have been suggested. Aloe gel may simply act as a protective barrier and increase capillary perfusion after local application. It may also influence the wound healing process by enhancing collagen turnover in the wound tissue. Aloe gel also has impressive topical demulcent properties when applied directly to broken or unbroken skin. However, most of the therapeutic uses of aloe gel can be justified by its anti-inflammatory, immunomodulating and anti-bacterial activities.

Anti-inflammatory activity

The anti-inflammatory activity of aloe gel has been extensively studied in an attempt to find the responsible components and their mechanism of action. For this purpose several models of inflammation (adjuvant arthritis and hind-paw oedema in rats, ear swelling in mice and rabbits, synovial pouch and burn in mice, rats and guinea-pigs) and phlogogen (carrageenan, kaolin, albumin, dextran, gelatin, mustard, croton oil, streptozocin, etc.) have been used. Aloe gel contains small amounts of salicylic acid. Other components, such as emodin, emolin and barbaloin, are converted to salicylic acid, perhaps explaining in part the anti-inflammatory activity of aloe gel.

The anti-inflammatory activity of aloe gel could be due to the inhibition of prostanoids. Alternative mechanisms are inhibition of polymorphonuclear (PMN) leucocyte infiltration, inhibition of histamine formation by magnesium lactate, or destruction of bradykininase or inhibition of bradykinin activity. However, it has been observed that the vehicles used in commercial aloe gel preparations (mineral oil, petrolatum and aquaphor) may inhibit prostanoid production themselves. Some observations suggest that the presence of small amounts of anthraquinones are necessary for the absorption of aloe gel given orally and may enhance its anti-inflammatory effect. One study in support of this hypothesis found that an aloe gel containing anthraquinone was more effective than an anthraquinone-free gel. On the contrary, another study found that the decolourised (i.e. without anthraquinones) aloe gel is more potent as an anti-inflammatory agent than the colourised form. However, the same authors also noted that PMN leukocyte infiltration and inflammation are decreased by both colourised and decolourised aloe gel. Therefore the role of anthraquinones on skin ailment management is still confused and further studies are required to clarify the capacity of aloe gel (acemannan) to interact with integrins, heterodimeric cell surface receptors. Integrins play a role in inflammation, permitting inflammatory cells to leave the bloodstream and enter damaged tissues. Lastly, aloe gel and hydrocortisone seem to inhibit the inflammatory process in an additive, dose-dependent manner when given concurrently.

Immunomodulatory action

Aloe gel may also directly stimulate the immune system through its active ingredient acemannan. This polysaccharide increases lymphocyte response to alloantigen; it activates macrophages to produce nitric oxide and cytokines (interleukins 1 and 6, interferon, tumor necrosis factor); it enhances phagocytosis (); and, it increases the number of circulating monocytes and macrophages. Aloe gel also causes a local activation of complement at the level of C3. Recently Qiu et al. (2000) have developed a process to activate and stabilise aloe polysaccharide. Modified aloe polysaccharide (MAP) prevents ultraviolet (UV) irradiation-induced immune suppression as determined by contact hypersensitivity response in mice. MAP also inhibits UV irradiation-induced TNF (tumour necrosis factor) release from human epidermoid carcinoma cells. All these results indicate that MAP can be used to reduce the risk of sunlight-related human skin cancer.

Antibacterial activity

Aloe gel (and acemannan) has been shown to have antibacterial activity against Streptococcus species, Enterobacter cloacae, Citrobacter species, Serratia marcescens, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and other bacteria. Aloe gel also accelerates the rate of healing, decreases the production of prostanoids and inhibits infection by Pseudomonas aeruginosa.

Clinical studies

The first case report on the use of aloe gel for wound healing was published in 1935. Roentgen dermatitis developed by a woman for depilatory purposes, treated with aloe gel, showed rapid relief. Since then, there are other reports dealing with successful medicinal applications of aloe gel, in roetgen dermatitis, ulcers and telangiectasis, palmar eczema and pruritus vulvae, finger abrasions and thermal burns. However, the literature on skin ailment management is not always positive because in some cases the researcher does not use the fresh drug and standardised preparations. In this way for many years little interest was paid by researchers and clinicians to the medicinal properties of aloe gel. The fact that the active components were little known has also contributed to the concealment of the therapeutic use of aloe gel.

Vogler and Ernst systematically reviewed the evidence for and against aloe gel clinical effectiveness. Only controlled clinical trials on aloe gel were included in their study. They found two controlled clinical trials related to the topical application of aloe gel for healing wounds and two for the prevention of radiation-induced skin burns. The results of this study indicate that the topical application of aloe gel is not an effective preventative for radiation-induced injuries. Furthermore, whether or not it promotes wound healing is unclear. The essential extractable information from these studies is provided below.

The effects of two different dressings for wound-healing management on full-faced dermabrasion patients was documented by Fulton. He divided the abraded faces of 18 patients suffering from acne vulgaris in half. One side was treated with a standard polyethylene oxide gel wound dressing, while the other side was treated with a polyethylene oxide dressing saturated with aloe gel. He reported that aloe gel reduced oedema, exudate and crusting in two to four days. Reepithelialization was complete to 90% on the aloe side compared with 40–50% on the control side after five days. Overall, wound healing was approximately 72 hours faster at the aloe side. The time interval required for wound healing in a 40-women gynaecological surgery was evaluated by Schmith and Greenspoon in an open-label study. The authors found that the mean healing time in the conventional care group was significantly shorter than in the aloe gel group (53 versus 83 days). Two randomised clinical trials were reported in one publication by Williams et al.. A total of 194 women receiving radiation therapy were treated with aloe gel or placebo gel, twice per day, by self-administration. The severity of the dermatitis was scored weekly during the ten-weeks treatment period both by the patients and by their healthcare providers. No differences between the placebo and the treatment group were noted.

Some clinicians participating in this trial felt that there were fewer skin problems than normally expected. Thus, it was speculated that the inert carrier gel might have had some beneficial effects. A second randomised clinical trial was therefore performed with 108 women. The only difference compared with the first study was that the control group now received no topical therapy at all. The trial was therefore not blinded. Again, the results did not suggest any benefit of the aloe gel in terms of prevention of radiation-induced dermatitis.

Psoriasis

Anthrones have long been used in medicine as antipsoriatic agents. Their mode of action is not known exactly, although many biological molecules and cell types have been identified as potential targets of anthrones. The antipsoriatic activity of anthrones is probably multimodal: inhibition of the oxygen consumption of cells; a reduction in size of the intracellular spaces and a decrease in ribosomes and mitochondria; interaction with DNA; inhibition of various enzyme systems associated with cell proliferation and inflammation and a redox reaction resulting in mitochondrial damage and destruction of membrane lipids in the psoriatic epidermis, have all been noted. All these mechanisms may in part retard the increased cell division found in the psoriatic epidermis. Syed et al. randomised 60 patients with mild to moderate chronic psoriasis to receive either an aloe gel or placebo cream. The cream was self-applied three times per day for four weeks. Patients were subsequently followed up for 12 months. The cure rate in the aloe gel group was 83% and only 7% in the placebo group.

Viral diseases

Anthraquinone derivatives have been shown to inhibit several viruses in vitro, including herpes simplex of type 1 and type 2, varicella-zoster, pseudo-rabies and influenza. Acemannan is another compound of aloe extract that has been reported to have antiviral activity and to play a role as an adjuvant treatment in HIV/AIDS. This polymannan increases in vitro the production and function of cytotoxic T cells in a dose-dependent manner. Acemannan in combination with the antiviral agent azidothymidine protected the cells from rapid HIV-1 replication, which causes premature cell death. The combination of acemannan and acyclovir also inhibited HIV-1 replication. The mechanism of action of acemannan’s antiviral activity is the inhibition of glycosylation of viral glycoproteins. Therefore, aloe extract is considered as a possible therapy for AIDS, alone or in association with azidothymidine. It is also able to reduce the dosage of antiviral treatment up to 90%, consequently reducing the side-effects of azidothymidine.

Dianthrones and other anthraquinone derivatives, including rhein and emodin, have antiviral activity against human cytomegalovirus. However, it is unlikely that systemic antiviral effects would follow from the ingestion of these compounds, due to their low bioavailability. Two randomised clinical trials, conducted by the same research group indicate that topical application of aloe vera might be effective against the first episodes of genital herpes. In the first study, they divided 120 men into three parallel groups. Each group was treated three times daily for two weeks with placebo, aloe gel or aloe cream. The numbers of cured patients were 7.5%, 45% and 70%, respectively. In addition, aloe gel cream showed a shorter mean duration (4.8 days) of healing than aloe gel (7 days) and placebo (14 days). Of the 49 patients healed at the end of this trial period, six had a relapse after 21 months of follow-up. In the second study, 60 men were randomly divided into two groups (placebo versus aloe gel). The authors reported that the aloe gel cream group had both significantly shorter healing time (4.9 days versus 12 days) and a higher number of cured patients (66.7% versus 6.7%) compared with the placebo group. Of the 22 healed patients, three showed recurrence after 15 months.

Diabetes

Hypoglycaemic action has been studied in an animal (mouse) model of diabetes and in humans. The mechanism of action for this effect has yet to be determined. It has been hypothesised that aloe may stimulate the release, or synthesis, of insulin from the β-cell of the Isles of Langerhans. Another study has shown that a formula containing aloe vera and a small number of natural agents (Nigella sativa L., Boswella carterii Birdw., Commiphora myrrha Engl. and Ferula assa-foetida L.) inhibits gluconeogenesis and lowers blood sugar in an animal model.

Two controlled clinical trials suggest that oral administration of aloe gel might be a useful adjunct for lowering blood glucose in patients with diabetes. Yongchaiyudha et al. divided 72 women without drug therapy into two groups. They received one tablespoon of aloe gel or placebo for 42 days. Blood glucose levels subsequently decreased from 250 mg to 141 mg percentage in the experimental group, while controls showed no significant changes. In addition, cholesterol, serum triglycerides, weight and appetite were also monitored. With the exception of triglyceride levels, which fell significantly in the actively treated group, these variables remained unalterated in both groups. This study was neither randomised nor blinded to patient or investigators. The same research team investigated the effects of aloe gel in combination with a standard oral antidiabetic therapy. All diabetic patients admitted to this study received 5mg oral glibenclamide, twice daily. In addition, for the duration of the trial (42 days) they were given either aloe gel or placebo as above. The results show similar decreases in blood glucose and serum triglyceride levels in the actively treated group, as described in the first trial. The same methodological drawbacks apply as to the previous study.

Hyperlipidaemia

Sixty patients with hyperlipidaemia who had not responded to dietary interventions received either 10 ml or 20 ml aloe gel or placebo daily for a period of 12 weeks. Blood lipid levels were measured before treatment and after 4, 8 and 12 weeks. Total serum cholesterol decreased by 15.4% and 15.5%, triglycerides by 25.2% and 31.9%, LDL by 18.9% and 18.2%, respectively, in the two groups receiving different doses of aloe gel.

Gastric ulcer

Aloe gel had a prophylactic effect and was also curative if given as a treatment for stress-induced gastric ulceration in rats. A lectin fraction (glycoprotein) from Aloe arborescens, aloctin A, had an anti-ulcer effect in rats, while another high molecular weight fraction, not containing glycoprotein, was very effective in healing ulcers induced by mechanical or chemical stimuli but not those induced by stress. This fraction contained substances with molecular weights between 5,000 and 50,000 Daltons, which were considered to both suppress peptic ulcers and to heal chronic gastric ulcers. In addition, a component from Cape Aloe, named aloe ulcin, suppressed ulcer growth and L-histidine decarboxylase in rats. An early clinical study found that oral administration of aloe gel was effective in the treatment of peptic ulcer.

Cancer

The whole leaf extract of aloe (=aloe extract) combines aloe gel with aloe latex and aloe epidermis. Aloe extract contains, among other substances, immunomodulatory, mild anti-inflammatory and antitumor mucopolysaccharides, acemannan being the most notable. Mucopolysaccharides are normally produced by the human body until puberty, after which, these substances must be introduced from outside sources. Their deficiency could produce drastic degenerative diseases. Acemannan is able to increase antibody-dependent cellular cytotoxicity and stimulate the proliferation of thymic cells. Acemannan is also effective in the treatment of fibrosarcoma in dogs, cat and mice, in that the survival rate is increased. In addition, polysaccharides from Aloe barbadensis, Lentinus edulis and others (Ganoderma lucidum, Coriolus versicolor) have demonstrated anti-genotoxic and antitumor promoting activities in in vitro models. The antitumor effect of acemannan may be due to stimulation of the production of tumor necrosis factor (TNF), interleukin-1 and interferon by macro-phages; acemannan is also able to abrogate viral infections in both animals and men. From the few reports available, it appears that large doses of polysaccharides are necessary to produce immunostimulating and antitumor effects. To achieve excessive amounts of acemannan and consequently of aloe preparation, aloe has been combined with other substances. Aloe vera in combination with squalene and vitamins A and E has been demonstrated to have chemopreventive and curative properties in the prevention and treatment of mouse skin tumors. Aloe vera with vitamin supplementation has been found to be able to reduce the severity of chemical hepatocarcinogenesis in rats.

Aloe extract also contains aloctins, substances which possess many biological activities such as mitogenic activity for lymphocytes, binding of human 22-macroglobulin, and complement activation via the alternative pathway. In addition, aloctin A is considered a promising candidate as an immunomodulator. This substance administered to mice inhibits growth of methylcholanthrene-induced fibrosarcoma and the results have been attributed to the immunomodulatory effect of aloctin A, not to its cytotoxicity.

Anti-inflammatory, immunomodulating and antitumor agents also include anthra-quinones. Aloe-emodin is active against P-388 leukemia in mice and selectively inhibits human neuroectodermal tumor cell growth in tissue cultures and in animal models. Aloe-emodin does not inhibit the proliferation of normal fibroblasts nor that of hemopoietic progenitor cells. The cyto-toxicity mechanism consists of the induction of apoptosis, whereas the selectivity against neuroectodermal tumor cells is due to a specific energy-dependent pathway of compound incorporation. Aloe-emodin is toxic against neuroectodermal tumors with no evidence of acute or chronic toxicity: therefore it shows a favourable therapeutic index. However, others have investigated aloe-emodin as a cytotoxic agent on several tumor cell lines but no significant activity was found. A stimulatory effect of aloe-emodin on urokinase secretion and colorectal carcinoma cell growth has also been described. Antitumor effects are also exhibited by diethylhexylphthalate (DEHP), isolated from Aloe vera but probably as a contaminant. DEHP is a plasticizer and has a potent antileukaemic effect in human cells and anti-mutagenic activity in the Salmonella mutation assay. The presence of all these principles might be enough to explain the prophylactic and possible therapeutic effect of aloe extract and its antitumour activity against leukopenia caused by exposure to cobalt 60, sarcoma-180 and Elhrich ascites.

Experimental studies have also reported antimetastatic activity of aloe gel in rats and mice. The importance of platelet aggregation in metastasis is now more widely accepted. Several studies have shown that migrating cells from some cancers induce platelet aggregation by modifying the balance between prostacyclin (PGI2) and thromboxane (TXA2). PGI2 inhibits platelet aggregation while TXA2 enhances aggregation. Tumors promote platelet aggregation by stimulating the production of TXA2 and/or inhibiting the production of PGI2. Aloe gel inhibits metastasis by decreasing TXA2 and TXB2 production in vitro () and this could be one of the mechanisms of antimetastatic activity of aloe. Several natural agents that inhibit kinin production or degrade kinins may inhibit kinin-induced angiogenesis. These agents include aloe gel. Aloe gel and glycoproteins isolated from Aloe arborescens and A. saponaria degrade bradykinin in vitro and inhibit the formation of histamine in vitro. Aloe gel has also demonstrated antiangiogenic activity in vivo in the synovial pouch model in mice. Other studies have shown aloe extract to have an inhibitory effect when used against preneoplastic hepatocellular lesions in rats and a regression of the pleural tumor in rats has been demonstrated by aloe latex. Antitumor effects of aloe may also depend on the ability to augment tumor specific immunity. All these findings have encouraged cancer treatment in humans with a preparation as follows: aloe (five years old-fresh leaf ), 300 g; honey 500 g; 2 tablespoons of gin, vodka or whisky. The mixture can be left for ten days in a jar, filtered and taken (1 tablespoon one or two times a day for 14 days), or mixed in a blender and then taken as above. Honey increases the palatability of the preparation and could enhance the effect of aloe for its content of caffeic acid phenethyl ester (CAPE), a potent chemopreventive agent useful in combating diseases with a strong inflammatory component, including various types of cancer. A recent clinical study has also shown that concomitant administration of aloe and melatonin enhances the therapeutic result of melatonin given alone in patients with advanced solid tumors such as lung cancer, gastrointestinal cancer, breast cancer or brain glioblastoma, for whom no effective standard anticancer therapies are available. It may be worthwhile to combine melatonin with immunostimulant drug such as aloe, since these may all act together to increase interleukin-2 activity. It has been also demonstrated that aloe latex enhances the activity of 6-fluorouracil and cyclophosphamide. However, until well-designed clinical trials on aloe are conducted, it will not be possible to determine the anticancer activity of the drug with certainty.

Miscellaneous

There is evidence showing the efficacy of aloe extract in chronic bronchial asthmatic patients. The effect of aloe extract seems due to the formation of some prostanoids during dark storage of aloe extract at 4°–30 °C, for a period of three to ten days. Some studies also report the effectiveness of aloe gel in increasing the rate of healing after dental procedures. The efficacy of a new bioadhesive patch with aloe gel for the treatment of mouth ulcers has recently been evaluated. The results of this study underline the good efficacy and compliance of the patch for the treatment of the aphtous stomatitis. On the contrary, a study carried out to evaluate the effectiveness of a medicine containing aloe, silicon dioxide and allantoin on aphthous stomatites indicated a lack of effect of the gel on aphthous ulcers. Rojas et al. have studied the antiparasitic action of an aqueous extract of Aloe barbadensis against an in vitro culture of Trichonomas vaginalis. The extract inhibited the growth of T. vaginalis suggesting its potential use in womens’ disturbances. Studies also show that topical and oral administration of aloe preparations in patients with chronic venous leg ulcers may aid healing. It has been also inferred that aloe reduces the growth rate of urinary calcium crystals that contribute to the formation of kidney stones. Aloe is considered as a ‘panacea’ in veterinary medicine although its real efficacy has been questioned. Aloe has been used as a purge for cattle and aloe gel has been used in the treatment of ringworm, allergies, abscesses, fungal infections and different types of inflammation. Its use has also been reported to be beneficial in the treatment of thermal burns in dogs. Its successful use in an extensively burned monkey has also been referred. However, in the absence of larger research studies we must be prudent against generalisations of these therapeutic treatments.