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The first case report on the use of aloe gel for wound healing was published in 1935 (Collins and Collins, 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 (Wright, 1936; Loveman, 1937), palmar eczema and pruritus vulvae (Crewe, 1937), finger abrasions (Barnes, 1947) and thermal burns

(Crewe, 1939). However, the literature on skin ailment management is not always positive (Kaufman etal, 1988; Ashley etal., 1957; Watcher and Wheeland, 1989; Schmidt and Greenspoon, 1993) 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 (1999) 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 (1990). 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 (1993) 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 etal. (1996). 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 (Williams etal, 1996). 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 (Verhaeren, 1980; Anton and Haag Berrurier, 1980; Friedman, 1980; Muller, 1996). All these mechanisms may in part retard the increased cell division found in the psoriatic epidermis. Syed etal. (1996a) 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 (Sydiskis etal, 1991). 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 (Kahlon etal, 1991a). 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 (AZT) protected the cells from rapid HIV-1 replication, which causes premature cell death (Kahlon etal, 1991b). 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 (Kahlon etal, 1991b). Therefore, aloe extract is considered as a possible therapy for AIDS, alone or in association with AZT. It is also able to reduce the dosage of antiviral treatment up to 90%, consequently reducing the side-effects of AZT (Werbach and Murray, 1994).

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 (Syed etal., 1996b; Syed etal., 1997) indicate that topical application of aloe vera might be effective against the first episodes of genital herpes. In the first study (Syed etal., 1996b), 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 (Syed etal., 1997), 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 (Ajabnoor, 1990) and in humans (Ghannam etal, 1986). 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 P-cell of the Isles of Langerhans (Ajabnoor, 1990). 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 (Al-Awadi etal, 1991).

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 etal., 1996; Bunyapraphatsara etal., 1996). Yongchaiyudha etal. (1996) 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 250mg 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 (Bunyapraphatsara etal., 1996). All diabetic patients admitted to this study received 5 mg 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 (Nassif etal, 1993). 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 (Galal etal., 1975; Parmar etal., 1986). A lectin fraction (glycoprotein) from Aloe arborescens, aloctin A, had an anti-ulcer effect in rats (Saito etal, 1989), 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 (Teradaira etal., 1993). This fraction contained substances with molecular weights between 5,000 and 50,000Daltons, 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 (Yamamoto, 1973). An early clinical study found that oral administration of aloe gel was effective in the treatment of peptic ulcer (Blitz etal., 1963).

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 (Manna and McAnalley, 1993; Peng etal, 1991; Harris etal, 1991; Gribel and Pashinki, 1986; Ralamboranto etal, 1982). In addition, polysaccharides from A. barbadensis, Lentinus edulis and others (Ganoderma lucidum, Coriolus versicolor) have demonstrated anti-genotoxic and antitumor promoting activities in in vitro models (Kim etal, 1999). The antitumor effect of acemannan may be due to stimulation of the production of tumor necrosis factor (TNF), interleukin-1 and interferon by macrophages; acemannan is also able to abrogate viral infections in both animals and men (Womble and Helderman, 1988). 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 (Shamaan etal, 1998).

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 (Suzuki etal., 1979). 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 (Imanishi etal, 1981).

Anti-inflammatory, immunomodulating and antitumor agents also include anthra-quinones. Aloe-emodin is active against P-388 leukemia in mice (Kupchan and Karim, 1976) and selectively inhibits human neuroectodermal tumor cell growth in tissue cultures and in animal models (Pecere etal, 2000). 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 (Grimaudo etal., 1997). A stimulatory effect of aloe-emodin on urokinase secretion and colorectal carcinoma cell growth has also been described (Schorkhuber etal, 1998). Antitumor effects are also exhibited by diethylhexylphthalate (DEHP), isolated from A. vera but probably as a contaminant. DEHP is a plasticizer and has a potent antileukaemic effect in human cells (Lee etal, 2000) and anti-mutagenic activity in the Salmonella mutation assay (Lee etal, 2000). 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 (Arendarevslii, 1977; Yagi etal, 1977).

Experimental studies have also reported antimetastatic activity of aloe gel in rats and mice (Gribel and Pashinskii, 1986). 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 (Klein and Penneys, 1988) 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 (Klein and Penneys, 1988). Aloe gel and glycoproteins isolated from A. 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 (Davis etal, 1992). Other studies have shown aloe extract to have an inhibitory effect when used against preneoplastic hepato-cellular lesions in rats (Tsuda etal., 1993) and a regression of the pleural tumor in rats has been demonstrated by aloe latex (Corsi etal, 1998). Antitumor effects of aloe may also depend on the ability to augment tumor specific immunity (Yoshimoto etal, 1987). All these findings have encouraged cancer treatment in humans with a preparation as follows: aloe (five years old-fresh leaf), 300g; 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 (Frenkel etal., 1993). 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 (Lissoni etal, 1998). 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 (Gribel and Pashinski, 1986). 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 (Afzal etal, 1991). Some studies also report the effectiveness of aloe gel in increasing the rate of healing after dental procedures (Bovik, 1966; Payne, 1970). 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 (Andriani etal., 2000). 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

(Garnick etal., 1998). Rojas etal. (1995) have studied the antiparasitic action of an aqueous extract of A. 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 (Atherton, 1998). It has been also inferred that aloe reduces the growth rate of urinary calcium crystals that contribute to the formation of kidney stones (Marti, 1995). Aloe is considered as a 'panacea' in veterinary medicine although its real efficacy has been questioned (Anderson, 1983). Aloe has been used as a purge for cattle (Crellin and Philpott, 1990) and aloe gel has been used in the treatment of ringworm, allergies, abscesses, fungal infections and different types of inflammation (Northway, 1975). Its use has also been reported to be beneficial in the treatment of thermal burns in dogs (Cera etal., 1980). 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.

ADVERSE EFFECTS, TOXICITY, DRUG INTERACTION Aloe latex (laxative use)

Aloe latex may cause abdominal complaints, meteorism, flatulence, cramps and abdominal pain, just like other laxative drugs such as senna, rhubarb, etc., which are digested by colon microflora (Newall etal., 1996). However, because constipation is often associated with abdominal discomfort, the causative role of aloe is not always apparent. Other side-effects include hemorrhoid congestion and coloration of the urine which becomes orange if the pH is acidic, or reddish purple if the pH is alkaline. This is caused by the renal excretion of the hydroxyanthracene derivatives (Boon and Smith, 1999). An overdosage may cause nephritis, vomiting, bloody diarrhoea with mucus and hemorrhagic gastritis (Canigueral and Vila, 1993). Prolonged use or overdosage may result in watery diarrhoea leading to electrolyte imbalance (Figure 9.4). The increased intestinal loss of K+ can lead to hypokalemia, while Na+ loss can result in secondary hyperaldosteronism. This can exacerbate renal K+ excretion, leading to further reduction of colonic motility. This situation results in fatigue, muscular weakness, weight loss, mental disturbances, steatorrhoea, electrocardiographic abnormalities and kidney dysfunction (Figure 9.4) (for ref. see Capasso and Gaginella, 1997).

Hypokalemia, which results from K+ loss, may potentiate the action of digoxin, a cardiac glycoside. Drugs like thiazide diuretics, corticosteroids and licorice may exacerbate hypokalemia (Dalton and Cupp, 2000). Table 9.4 lists other possible interactions regarding both aloe latex and aloe gel. Damage to surface epithelium and an impairment of function following damage to the autonomic nervous system may also develop (Muller-Lissner, 1993). These changes, however, have not been clearly demonstrated in animals and humans.

The abuse of aloe has been associated with melanosis coli, which consists of a mahogany to dark brown coloration of the intestinal mucosa that begins at the ileocolonic junction and may extend to the rectum (Koskela etal., 1989; Gobel, 1978; Steer and Colin-Jones, 1975; Wittoesch etal, 1958). The morphological basis of melanosis is a pigment, probably lipofuscin, within macrophages of the large intestinal mucosa (Figure 9.5). A correlation between the intake of laxative and melanosis is accepted now

Laxative Abuse Kidney
Figure 9.4 Metabolic consequence of laxative abuse (From Capasso and Gaginella, 1997).

but there is no indication that melanosis has any pathophysiological consequences. On the other hand the intestinal mucosa recovers its usual coloration 4—12 months after the intake of the laxative has stopped (Boon and Smith, 1999).

Habituation has not been proved for aloe. Indeed studies in rats suggest that long-term aloe treatment (three to six months) does not induce tolerance in the sense of a reduced laxative effect (Capasso, personal communication).

Anthraquinone derivatives have shown genotoxicity in Salmonella assay (Brown and Brown, 1976; Mori etal., 1985; Westendorf etal., 1990; Muller etal., 1996) but the clinical relevance of this experimental result is still not clear. On the other hand, due to the artificial nature of these methods many flavonoids (quercetin, galangin, kaempferol) and antioxidants, including vitamin C, have produced genotoxic effects under these conditions (Mascolo etal, 1998).

In recent years the risk of colon cancer has been found to be related to constipation and to use of anthraquinone laxatives (Siegers, 1992; Sonnenberg and Muller, 1993) but epidemiological studies are in disagreement. Jacobs and White (1998), in a recent study, reported that when the colon cancer risks for constipation and laxatives were adjusted for each other, the association with laxatives disappeared, whereas the association with constipation remained strong. Other retrospective data related to laxative use

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