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Scientific studies on the pharmacological properties of Aloe vera

Healing and anti-inflammatory activity 

Some substances are slightly responsible for the anti-inflammatory and healing activity of Aloe vera, were the conclusions reached by animal studies or in vitro tests.

What mechanisms of action of Aloe vera have anti-inflammatory and healing effects? 

 

In anexperiment, in vitro  acemanan (a polysaccharide abundant in Aloe vera gel) stimulated macrophages murine(from the RAW 264.7 strain) to release interleukin-6, tumor necrosis factor-α and nitric oxide. Acemanan combined with interferon-γ, triggered a synergistic action potentiating the healing and anti-inflammatory effects

In another study, in vitro, acemanan, in concentrations of 2 to 16mg / mL, significantly increased the proliferation of fibroblasts gingivaland stimulated the secretion of keratinocyte growth factor - 1 (KGF-1), of vascular growth factor endothelial (VEGF) and type I collagen. All of these substances are directly linked to healing. They play important roles, namely in tissue re-epithelialization, formation of blood vessels and formation of connective tissue. 

It is suggested, as a possible mechanism of action, the binding of mannose-6-phosphate to receptors present in fibroblasts, thus influencing the healing process. 

The proteins and glycoproteins extracted from the Aloe vera gel also showed anti-inflammatory activity in vitro. In what way? They significantly reduced the enzymes COX-2 and lipoxygenase in a way comparable to non-steroidal anti-inflammatory drugs such as diclofenac and nimesulide. When tested on animals, they were able to accelerate healing and increase cell proliferation. Aloin and aloe-emodin, tested in vitro, demonstrated anti-inflammatory effects, comparable to that of quercetin and Campeferol. 

 

In humans, the results on the healing effect of Aloe vera are conflicting. Studies report that the use of Aloe vera gel increased the healing time in surgical wounds when compared to identical treatment that did not include the gel. However, recently, a randomized, double-blind, placebo-controlled study, in which patients undergoing surgery (open hemorrhoidectomy and) who applied the cream containing Aloe vera had less postoperative pain (pain) complaints, improved healing and lower consumption of painkillers when compared to the placebo group. Why? These conflicting results can be partially explained, considering the hydrophilic character of the active components present in Aloe vera. These cross the skin barriers with great difficulty. It is known that the synergy of Aloe vera gel with ultrasound, microcurrents or in the form of liposomes accelerates healing and decreases inflammation by favoring the penetration of assets into the tissue. 

The effect of treating burns with Aloe vera, too, has been tested. A comparison was made between 1% silver sulfadiazine (commonly used treatment) and a cream containing 0.5% Aloe vera, in 30 individuals with second degree burns. 

 

The cream containing Aloe vera promoted the healing and reepithelization of the skin more effectively, in less than 16 days. The wounds treated with the cream containing silver sulfadiazine took an average of 19 days to heal. In the case of sunburn, the same effectiveness could not be proven. According to a randomized, double-blind study, the cream containing 70% Aloe vera did not have a protective effect or aid in the treatment of sunburn in 20 tested volunteers. 
 

Antineoplastic activity 

Aloe vera has been shown to haveantineoplastic activity for some types of cancer. 

What underlies this capacity? It is assumed that alloin, aloe-emodin and acemanan are partially responsible. There are several suggested mechanisms for the cytotoxic effect caused by Aloe vera. They all depend on the dose used and the type of tumor. One of the hypotheses is closely linked to the reduction in the proportion of cells in the mitotic phase (due to the induction of apoptosis, caused by anthraquinones). Other hypotheses suggested, for this antiproliferative effect, are related to disturbances in the cell cycle and differentiation, stimulation of the immune system and high antioxidant activity. A recent study in rats used a solution made with bee honey and Aloe vera. There was a progressive decrease in the size of the tumor when compared to the control group.

In another study, the application, in rats, of topical and / or oral Aloe vera promoted a decrease in the amount of tumors and an increase in the time of their appearance. 

Another preliminary study used a different species of the genus Aloe - Aloe arborescens - and used chemotherapy in 240 patients with cancer undergoing metastasis. It was possible to evidence a higher rate of tumor survival and regression, in addition to relief of fatigue and asthenia, when compared with the control group. 

Another preliminary study, carried out in patients withneoplasia advanced, demonstrated greater stabilization of the disease and increased survival time in the group treated with the combination of Aloe vera and the hormone melatonin. 

The results available so far, although scarce, are encouraging, however, well-conducted clinical studies with a larger number of patients are necessary to verify their real effectiveness. 

 

In the treatment of psoriasis 

In the treatment of psoriasis, Aloe vera showed clinical efficacy demonstrated in a randomized, double-blind, placebo controlled study involving 60 patients suffering from psoriasis, from mild to moderate degree. Patients were divided into a control group and a placebo. A hydrophilic cream containing 0.5% Aloe vera extract or a similar cream without the active ingredient was applied three times a day to the lesions. At the end of the four weeks of treatment, 83% of patients who used the cream with Aloe vera were considered cured against only 6% of the placebo group. Treatment with Aloe vera cream was well tolerated, with no adverse effects, and patients improved or had complete lesion resolution. Another randomized, double-blind study was carried out, which evaluated the effectiveness of an Aloe vera cream with a different composition, containing 0.1% triamcinolone acetonide, in eighty patients with psoriasis, from light to moderate level. They observed that the cream containing Aloe vera, was more effective in improving clinical symptoms than conventional treatment, however, both were similar in improving the patient's quality of life. 

 

In the treatment of dermatitis and mucositis by radiation 

The first report of the use of Aloe vera for the treatment of dermatitis caused by radiation was made by Collins & Collins (1935). The patient who suffered from severe dermatitis on the left side of the face was instructed to apply the fresh leaf gel topically to the affected area. Twenty-four hours later, it reported improvement in the itching and burning sensation and about a month after the daily use of the gel there was complete cure. 

 

Another report was made by Loveman (1936), where two patients with dermatitis and severe hand ulcerations, caused by radiation, were treated with fresh Aloe vera leaf gel for varying periods of time. Both patients had complete healing of dermatitis and ulcers. Due to these reports, Aloe vera has been indicated for the treatment of radiation dermatitis, although there is no established treatment protocol. 

Two phase III clinical studies have been done in cancer patients treated with radiation therapy. In both, it was not possible to evidence the effectiveness of Aloe vera gel in relieving dermatitis (Williams, 1996; Merchant, 2007). According to Su et al. (2004) Aloe vera did not show a statistically significant benefit in improving the degree of mucositis or in tolerance to radiotherapy when compared to the control group, in the treatment of radiation-induced mucositis, in a double-blind, randomized, controlled placebo study in 58 patients with head and neck cancer. Puataweepong et al. (2009) conducted a study similar to that made by Su et al. and reported that the incidence of severe mucositis was lower in the group treated with Aloe vera gel than in the control group. Such difference in results is explained by the authors: the preparation made with fresh gel from the leaves of Aloe vera in well controlled conditions, preserved a greater number of active substances. 

 

In the treatment of hyperglycemia and dyslipidemia 

The hypoglycemic activity of Aloe vera has been verified in animals through studies such as that carried out by Tanaka et al. (2006). A strain of rats with metabolic disorders similar to those caused by type 2 diabetes, such as hyperglycemia, obesity and insulin resistance were treated orally with 25 µg / animal / day of Aloe vera gel (in concentrations of 20, 30 and 50 mg / mL) and 1 µg / animal / day of 5 different phytosterols isolated from this species (lophenol, 24-methyl-lophenol, 24-ethyl-lophenol, cycloartanol and 24-methylene-cliartanol). The authors reported that the test group, after 33 days of treatment, obtained a significant reduction (p <0.05 for the concentrations of 20 and 30 mg / mL and p <0.005 for the dose of 50 mg / mL) in fasting glucose levels and they also did not lose weight, a symptom presented by the animals in the control group, since they, due to the high glycemia rate, lose a large amount of glucose in the urine. In other studies, performed on rats with type 1 Diabetes, induced by streptozotocin, the authors were able to verify antioxidant activity, reduction of plasma glucose to normal levels and histological tests performed on the pancreas, liver, kidney and intestines were able to demonstrate the protective effect of Aloe vera gel. when compared to the control group (Rajasekaran et al., 2005; Noor et al., 2008). In humans, Ngo et al. (2010) recently published a review article on the use of Aloe vera for the treatment of Diabetes and dyslipidemia. The authors verified the existence of 8 clinical studies with 5285 patients in total and came to the conclusion that there is evidence of benefit from the use of Aloe vera in reducing glucose and cholesterol

 

Other uses described in the literature 

The use of syrup containing 50% Aloe vera gel provided clinical improvement and functional respiratory indicators in patients with bronchial asthma, without significant side effects. Control group patients reduced the use of othermedications antiasthmatic and it was shown that nebulization of Aloe vera extract protected the patient from bronchial hyperreactivity caused by carbacoline (Rivas et al., 2004). 

Aloe vera also appears to be effective in the treatment of conjunctivitis, according to an exploratory descriptive study published by Guerra et al. (2008) where twenty-six patients reported pain control, decreased redness and healing after 3 days of treatment when using the ophthalmic gel. 

In the treatment of oral lichen planus, the topical application of A. vera promoted an improvement in the patients' quality of life, although there was no significant difference in pain reduction when compared to placebo (SalazarSanchez et al., 2010). In another randomized, double-blind, placebo-controlled study Choonhakarn et al. (2008) reported that the Aloe vera gel caused clinical and symptomatic improvement of the oral lichen planus when compared to the placebo group. In the vulvar lichen planus, the local application of Aloe vera gel resulted in the improvement of lesions in 82% of the treated group compared to 4% of the placebo group (Rajar et al., 2008). 

In a randomized, double-blind, placebo-controlled study using an oral solution containing Aloe vera gel, it was possible to verify clinical and histological improvement in patients with active ulcerative colitis more frequently than when compared to the control group (Langmead et al 2004). 

Aloe vera has a broad antimicrobial spectrum acting on fungi, viruses and Gram positive and Gram negative bacteria. Studies have identified some compounds with bactericidal or bacteriostatic action in Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Helicobacter pylori, Salmonella typhi, Bacillus cereus, Candida albicans, Shigella flexneri, Streptococcus pyogenes, Mycobacterium tuberculosis, among others. Pyrocatechol, cinnamic acid, ascorbic acid and p-cumaric acid are some of the compounds identified that are likely to act synergistically (Puerto et al., 2001; Ferro et al. 2003; Tamura et al., 2009; Lawrence et al., 2009; Gupta et al. 2010; Das et al., 2011). The activity of Aloe vera against genital herpes was verified in two double-blind, placebo controlled studies. The studies involved about 180 patients in total and the hydrophilic cream containing 0.5% Aloe vera extract was the one with the highest cure rate when compared to the Aloe vera gel or the placebo (Syed et al. 1996b; Syed et al. 1997). 

An oral solution prepared with Aloe vera gel increased theby more than three times bioavailability of vitamins C and E in tests performed on normal humans, leaving room for their use in vitamin supplements (Vinson et al., 2005). 

 

Another study reports a decrease in wrinkles and increased expression of type 1 collagen in a group of women over 45 years of age who took an oral ingestion of a solution made of powdered Aloe vera gel dissolved in distilled water. These results, however, are limited since there was no control group (Cho et al. 2009). 

Due to its moisturizing power, theindustry cosmetics and personal hygiene makes extensive use of Aloe vera gel in several types of formulations, such as creams, shampoos and soaps. In some countries it is incorporated in shaving creams with the objective of helping the healing of cuts (Eshun & He, 2004). 

According to a study published by Dal'Belo et al. (2006) thepower moisturizing of Aloe vera gel on the skin is probably due to a humectant mechanism. The application of the formulation containing the gel significantly increased the water content of the stratum corneum, without causing occlusion or changes in the skin barriers. 

The gel of this plant is also added in several toothpastes under the claim of having anti-plaque and anti-gingivitis effect, despite the lack of data in the literature to confirm this information. In order to verify the effectiveness of Aloe vera in these cases, Oliveira et al. (2008) tested the anti-plaque and anti-gingivitis effects of commercial cream containing Aloe vera in 30 patients and found no significant differences when compared to the control group. With the use of mouthwash at a concentration of 50%, Villalobos et al. (2008) observed a decrease in plaque and gingivitis when compared to a placebo group. These discrepant results can perhaps be explained by the higher concentration of A. vera present in the mouthwash. Another study conducted by Lee et al. (2004) verified by means of in vitro tests the inhibitory effect of commercial toothpaste containing A. vera gel on A. viscosus, C. albicans, S. mutans and S. sanguis, which are some of the microorganisms most involved with oral diseases. The results of this study, however, may have suffered interference from other substances with antimicrobial activity present in the analyzed toothpaste. 

 

Contraindications and side effects 

Due to the presence of anthraquinones, its oral use during pregnancy is not recommended, since its stimulatory effect in the large intestine can cause reflexes in the uterine muscles inducing abortion. 

Anthraquinones also cause, when in excess, severe diarrhea, colic, nausea and consequently loss of electrolytes which results in cardiac and neuromuscular dysfunction, especially if the patient already uses cardiac, diuretic or anti-arrhythmic glycosides (Baretta et al. , 2009; WHO, 1999). Chronic use can also result in damage to the neuromuscular apparatus and the formation of a “colon of laxatives”, in addition to causing chronic kidney damage (Wagner & Wiesenauer, 2006). Currently, there are cases in the literature of acute hepatitis caused by oral consumption of Aloe vera. The first report was made in Germany, by Rabe et al. (2005) who reported the case of a 57-year-old woman who, after taking tablets with 500 mg of Aloe vera extract for four weeks, presented symptoms such as jaundice, itching and abdominal pain. Through laboratory tests, it was possible to verify abnormal levels of alanine aminotransferase (1480 U / L - normal: <22 U / L), aspartate aminotransferase (711 U / L - normal: <15 U / L) and liver biopsy revealed hepatitis severe acute. One week after the suspension of the tablets the patient became asymptomatic and the levels of alanine aminotransferase slowly returned to normal. In 2007, Bottenberg et al. reported a case similar to that of Rabe et al. where a 73 year old patient complained of nausea, fatigue, weight loss and other symptoms. Laboratory tests and liver biopsy indicated acute hepatitis and only after being specifically asked about the use of herbal medicines did she admit that for the past 5 years she had been consuming capsules containing 500 mg of Aloe vera every 2 or 3 days to treat cold. Levels of bilirubin, alanine aminotransferase and aspartate aminotransferase returned to normal after a few months of capsule suspension. More recently, three other cases have been reported by Yang et al. (2010) involving the consumption of preparations containing Aloe vera and toxic liver disorders. Interestingly, Chandan et al. (2007) report hepatoprotective effect of aqueous extract of Aloe vera against damage caused by carbon tetrachloride in rats. The levels of alanine aminotransferase, aspartate aminotransferase, bilirubin and other biochemical parameters analyzed were restored without signs of toxicity at doses of up to 2g / kg rat. The authors suggest that this hepatoprotective effect of the aqueous extract is due to the presence of antioxidants that prevent glutathione depletion and protect against lipid peroxidation. Ozsoy et al. (2009) identified the presence of several natural antioxidants, such as flavonoids, ascorbic acid, β-carotene and α-tocopherol, in aqueous extract of Aloe vera leaf. Antioxidant activity of the aqueous extract was not observed when using the leaf gel. According to a study published by Holanda et al. (2009) oral consumption of Aloe vera extract caused greater uptake of sodium pertechnetate, a radiopharmaceutical used in diagnostic imaging, in the blood, femur, kidneys, liver, stomach, testicles and thyroid in tested rats, which can result in incorrect diagnoses or misinterpretation of image results. The study also reported increased levels of alanine aminotransferase and aspartate aminotransferase and decreased cholesterol, glucose and triglycerides when compared to a control group. There are reports in the literature of contact dermatitis and a burning sensation caused by the topical use of Aloe vera gel. These reactions are probably due to the presence of anthraquinone residues in the gel used (Horgan, 1988; WHO, 1999). The marketing of juices or other foods containing Aloe vera was recently banned by ANVISA (2011) due to the lack of scientific evidence to prove its safety and due to reports of adverse reactions.


 

CONCLUSION

Numerous biological activities have been attributed to Aloe vera over the years, and this is probably due to the combination of the various assets in its composition. The result of the bibliographic research revealed that this species is effective in the treatment of psoriasis, genital herpes, hyperglycemia and in burns. 

Antineoplastic, antimicrobial, anti-inflammatory and immunomodulatory activities have also been demonstrated by in vitro and in vivo studies. In wound healing the results are conflicting, and this may be related to the hydrophilic character of the active components that face difficulties to cross the barriers imposed by the skin (Takahashi, 2009). It may also be due to differences in the way of extracting the active ingredients or in the storage methods used by researchers. In the treatment of radiation dermatitis, in sunburn or as sunscreen, the plant's gel has not shown effectiveness. 

Regarding its toxicity, cases of acute hepatitis have been reported and some symptoms such as colic, nausea and diarrhea have also been observed with the consumption of oral preparations containing Aloe vera. 

It is essential to standardize the use of Aloe vera, with the objective of better conserving its chemical characteristics and defining the best form of its application. 

It is evident the enormous range of activities that this species has, being necessary, however, controlled studies with a larger number of participants, in order to define a dose and a safe way for its use.

 

in: Pharmacological properties of Aloe vera (L.) Burm. f. FREITAS, VS1 *; RODRIGUES, RAF 2.3; GASPI, FOG2 1 Postgraduate course in the Herbal Medicine Specialization Course at Fundação Hermínio Ometto - UNIARARAS