Aloe Vera

The aloe plant?/strong>Aloe
barbadanis Miller (syn. Aloe vera [L.] N.L. Burm.)—in the
family Liliaceae is the most researched and used of the more than 300 species
of aloe. Aloe has been used medicinally for several thousands of years in many
cultures—from ancient Egypt, Greece, and Rome to China and India. The plant has
many common names and is often referred to as aloe vera, burn plant, first-aid
plant, or medicine plant. Its name is most likely derived from the Arabic word
Alloeh, meaning “shining bitter substance.?Aloes are thought to have originated
in tropical Africa but are now cultivated in warm climate areas of Asia,
Europe, and America. Aloe has been extensively cultivated in the Caribbean
islands and in Mexico since the early 1800s. In the U.S., it is grown
commercially in the Rio Grande valley of Texas, southern California, and
Florida. Aloe plants can withstand high temperatures and long periods of
drought, due to their ability to store water in their succulent leaves. On the
other hand, they are very sensitive to freezing temperatures, which can damage
or kill the plants.Chemical Composition and Active
Constituents

The aloe plant is the source of two herbal preparations: aloe
gel (AG) and aloe latex. Aloe gel is often called “aloe vera?and refers to the
clear gel or mucilaginous substance produced by parenchymal cells located in
the central region of the leaf. Diluted aloe gel is commonly referred to as
“aloe vera extract.?The gel is composed mainly of water (99%) and mono- and
polysaccharides (25% of the dry weight of the gel). The most prominent
monosaccharide in AG is mannose-6-phosphate, and the most common
polysaccharides are called gluco-mannans (beta-(1,4) acetylated mannan).1 They are long-chain sugars containing
glucose and mannose. A prominent gluco-mannan named acemannan has been isolated
and is being marketed as Carrisyn. Recently a glycoprotein with antiallergic
properties, called alprogen, was isolated from AG.2 In addition, a novel anti-inflammatory
compound, C-glucosyl chromone, has recently been isolated from AG.3

Commercially, aloe gel is claimed to be “stabilized?to preserve its
activity during long-term storage. Whether stabilized gel has the same
pharmacological activity as the fresh gel is controversial.

Pericyclic tubular cells beneath the outer leaf epidermis produce a
bitter yellow substance known as aloe latex, commonly referred to as “aloe
juice?or “aloe.?This substance is usually dried and used as a potent stimulant
laxative. Aloe latex contains a series of glycosides known as anthraquinones,
the most prominent being aloin A and B.7 It should be noted that aloe gel is
often contaminated with aloe latex during its isolation. This could explain the
abdominal cramps, diarrhea, and laxative effects sometimes seen with certain
aloe gel preparations.

Medicinal Uses and
Pharmacology

Wound Healing: Aloe gel has long been used both externally and
internally for its beneficial effects in the wound-healing process. It is most
often included in topical formulations (ointment, cream, or lotion), but
evidence also supports its effectiveness when taken orally. At least part of
AG’s beneficial effect on the skin likely is due to its moisturizing effect.
Also, it may leave a protective layer on the skin after drying, possibly
providing some protection to the wound.

Both topical and oral AG have been shown to significantly stimulate
collagen synthesis in experimental dermal wounds in rats.8 Aloe gel not only increased collagen
content of the wound but also changed collagen composition (more type III). In
addition, it increased the degree of collagen crosslinking. In an earlier
study, the investigators also demonstrated an increased synthesis of hyaluronic
acid and dermatan sulphate in the granulation tissue of a healing wound
following oral or topical AG treatment.9 Both studies support an earlier trial
demonstrating that both oral (100 mg/kg/day) and topical (25% AG) treatment
(two months) of biopsy punch wounds in mice resulted in a significant (50%?3%)
reduction in wound diameter.10 Similar beneficial effects of topical AG have
been demonstrated in a skin-wound rat model. Aloe gel treatment accelerated
wound contraction and increased the breaking strength of resulting scar tissue,
due to increased collagen content and degree of crosslinking.11

In order to identify which constituents of AG are responsible for
wound-healing effects, Davis and colleagues tested the effects of
mannose-6-phosphate in a mouse-wound model system.12 An oral dose of 300 mg/kg resulted in
significant wound healing, similar to that seen with AG. However, not all
animal studies have shown positive results. In one study, various topical
agents were tested for their effects on wound contraction and rate of
re-epithelialization in full-thickness excisions in a porcine mode; AG failed
to show any beneficial effects.13

AG studies in humans are more limited, and the results generally are
not as positive as those from the aforementioned animal studies. In one
positive study, AG (when added to a polyethylene oxide gel wound dressing) was
shown to accelerate wound healing following full-face dermabrasion.14 By day six, re-epithelialization was
complete at the AG-treated sites. However, soon after this study a report
emerged of four patients who experienced severe burning sensations and
dermatitis upon application of topical aloe gel following dermabrasion.15

An acemannan-containing gel (Carrisyn Gel Wound Dressing) was recently
shown to be no more effective than a standard saline gauze dressing in the
treatment of pressure ulcers.16 In another study, a similar AG dermal wound gel was
actually shown to significantly delay wound healing in surgical wounds
following cesarean delivery or laparotomy.17

Effects on Burns: Several animal studies and a clinical trial have
assessed the effectiveness of AG in the treatment of skin burns. One study
looked at full-thickness burns in guinea pigs.18 Aloe gel promoted complete healing of
burn wounds within 30 days, compared to 50 days in the control group. In
contrast, a similar study in guinea pigs published the same year showed that AG
was less effective in treating second-degree burns when compared to standard 1%
silver sulfadiazine cream.19
Wound re-epithelialization, wound contraction, and formation of granulation
tissue occurred more slowly in the AG-treated animals. In another study, AG was
found ineffective in treating hydrofluoric-acid induced burns in rats.20 In a human study, 27 patients with
partial thickness burn wounds were treated with topical AG or a standard
Vaseline gauze.21
The average healing time was 18.19 days in the Vaseline-gauze treated wounds
and 11.89 days in the AG-treated wounds. Histological examination showed early
epithelialization in the AG-treated skin areas.

Effects on Skin Exposure to UV and Gamma Radiation: Some of the first
scientific studies on the effectiveness of AG were performed during the 1930s
and involved protection of the skin against radiation damage. For the most
part, these studies were inconclusive. Interestingly, recent evidence has
supported a protective benefit of AG against several forms of radiation damage
to the skin. An acemannan-containing topical gel was demonstrated to reduce
skin damage following exposure to gamma radiation in mice.22 The results were best in animals who
received the gel treatment for at least two weeks beginning immediately after
irradiation. A protective effect also was documented in mouse skin exposed to
soft x-irradiation.23
Investigators found that an antioxidant protein, metallothionein, was induced
in the skin and liver within 24 hrs of AG administration. Following x-ray
exposure, AG was found to scavenge hydroxyl radicals and prevent suppression of
superoxide dismutase and glutathione peroxidase in the skin.

Several additional studies in mice and in epidermal cell culture have
demonstrated an immunomodulatory effect of AG in protecting skin cells from the
damaging effects of UVB radiation. UVB radiation is known to suppress the
ability of Langerhans cells in the epidermis to support antibody primed T-cell
mitogenesis. In one study, aloe gel prevented this UVB-mediated suppression
within the first 24 hrs of irradiation in murine epidermal cell culture.24 Immunomodulatory activity was found to
reside in a number of low molecular weight compounds present in AG. A more
recent study reports the isolation of these small immunomodulatory substances
from AG.25
Topical application of these compounds prevented UVB-induced immune suppression
in mouse skin. Further work in this area has confirmed these observations and
has demonstrated how AG-derived immunoprotective factors likely work.
Presumably, UV-induced suppression of delayed type hypersensitivity is
prevented by reducing the production and release of skin keratinocyte derived immunosuppressive
cytokines, such as interleukin-10 (IL-10).26Another study
demonstrated that AG’s prevention of UV-induced immune suppression did not
involve prevention of UV-induced DNA damage or an acceleration of the repair of DNA.27

The anthraquinone aloin, which is present in aloe latex, has been
shown to inactivate various enveloped viruses, such as herpes simplex.

Treatment of Frostbite and Psoriasis: Several animal studies support
the clinical use of AG in treating frostbite tissue damage. Heggars and
associates utilized an experimental rabbit ear model to demonstrate the
effectiveness of AG, as well as that of several inhibitors of arachidonic acid
metabolism (e.g., aspirin and methylprednisolone).28 In control animals, no tissue survival
was seen. In contrast, AG treatment resulted in 28.2% tissue survival compared
to 22.5% and 12.5% with aspirin and steroid, respectively. The investigators
concluded that the progressive dermal ischemia occurring during frostbite could
be reduced by inhibiting the production of prostaglandins and thromboxanes from
arachidonic acid. A more recent study supports these observations. Systemic
pentoxifylline and topical AG cream were both found to improve tissue survival
in the frostbitten ears of New Zealand rabbits.29 Using both agents together further
increased tissue survival.A recent double-blind, placebo-controlled study in 60 psoriasis
patients evaluated the efficacy of treatment with topical AG.30 PG extract (0.5% in a hydrophilic
cream) was administered three times daily for five consecutive days each week
for 16 weeks. At the end of the study AG had significantly reduced lesions,
decreased erythema, and lowered PASI (psoriasis area and severity index) scores
in 25 out of the 30 patients in the treatment group. In comparison, two out of
30 patients in the placebo group improved.

Anti-inflammatory Effects: Several animal studies have been undertaken
since 1989, clearly demonstrating the anti-inflammatory activity of AG. One
study found that an aqueous extract of AG decreased carrageenan-induced edema
in a rat hind-paw.31
Further, the AG extract reduced prostaglandin E2 production from [14C]
arachidonic acid via inhibition of cyclooxygenase. In a series of experiments
conducted from 1989?994, Davis and colleagues demonstrated the
anti-inflammatory action of oral and topical AG preparations in various animal
models of inflammation. In their earliest study they reported a 47% reduction
in swelling in the croton oil-induced edema assay in rats after topical administration
of AG.32 In a
later study they demonstrated an anti-inflammatory response to AG in an
inflamed synovial pouch model in rats.33 AG reduced the vascularity and
swelling in the inflamed pouch by 50%. The investigators also noted a 48%
reduction in the number of mast cells in the synovial fluid of the pouch. Also
of interest, they found an increased number of fibroblasts following treatment
with aloe gel. C-glucosyl chromone is the anti-inflammatory compound recently isolated
from AG extracts.3
The substance was shown to be similar in potency to hydrocortisone when tested
in a mouse ear bioassay.

Effects on the Immune System: Many claims have been made throughout the
years regarding AG’s ability to support and enhance the immune system.
Experimental evidence is now accumulating documenting immune-stimulating
constituents present in AG. One of the first studies in the early 1980s
demonstrated that a partially purified AG extract from Aloe vahombe acted as a
nonspecific immunostimulant, protecting mice against infection from various
bacteria and fungi.34
The AG extract had to be administered two days before exposure of the mice to
the pathogenic agent to be effective. Later in the 1980s, acemannan isolated
from AG was shown to increase the response of lymphocytes to antigens in an in
vitro study.35
This helped explain the many reports of acemannan’s apparent antiviral effect.
In later studies, a highly purified form of acemannan derived from AG
stimulated the synthesis and release of interleukin-1 (IL-1) and tumor necrosis
factor from peritoneal macrophages in mice that had previously been implanted
with murine sarcoma cells.36
These cytokines in turn initiated an immune attack on the sarcoma cells that
resulted in necrosis and regression of the cancerous cells. These effects
resulted in an increased survival of the sarcoma-implanted mice. In another
study, acemannan stimulated the production of nitric oxide in cultures of
chicken macrophages.37
Still another study demonstrated that several low molecular weight compounds
isolated from AG are capable of inhibiting the release of reactive oxygen free
radicals from activated human neutrophils.38 This inhibition does not appear to
affect the phagocytic activity of neutrophils but may protect tissues from
excessive oxidative damage from free radicals.

Early this year, a study was published reporting the isolation and
partial purification of an antiallergic compound called alprogen from AG
extracts. Alprogen was shown to inhibit the antigen/antibody-mediated release of
histamine and leukotriene from mast cells.2 The postulated mechanism of this effect
was via inhibition of Ca2+
influx into mast cells.

Antiviral and Antitumor Activity: Most of the reported antiviral and
antitumor effects of AG likely are due indirectly to the stimulation of the
immune system, as discussed previously. However, one study reports that
anthraquinones, which are present in aloe latex, have direct virucidal effects.
The anthraquinone aloin was shown to inactivate various enveloped viruses, such
as herpes simplex, varicella-zoster, and influenza. Although anthraquinones
only appear in AG as a contaminant,39 low concentrations present in some
preparations could have significant antiviral activity.

Several recent studies have demonstrated direct inhibitory effects of
AG on both tumor initiation and promotion. A polysaccharide fraction of AG
inhibited the binding of benzopyrene to primary rat hepatocytes and thus
prevented the formation of potentially cancer-initiating benzopyrene-DNA
adducts.40
This effect was also demonstrated in vivo, where adduct formation was reduced
in various organs. A follow-up study published in 1999 by the same
investigators showed that several other plant-derived polysaccharides were also
able to block benzopyrene-DNA adducts.41 They also reported in this study an
induction of glutathione S-transferase and an inhibition of the tumor-promoting
effects of phorbol myristic acetate by AG. These two studies suggest a possible
benefit of using aloe gel in cancer chemoprevention.

Laxative Effects of Aloe Latex: Anthraquinones present in aloe latex
function as potent stimulant laxatives. Aloe latex is typically sold as an
incapsulated dried powder. The substance is still listed in the U.S.
Pharmacopoeia and is recognized by the FDA, as well as in several other
European countries, as an effective laxative. Studies in rats have shown that
aloe latex increases intestinal water content, stimulates mucus secretion, and
increases intestinal peristalsis.42 Long-term use of the substance could
result in electrolyte imbalances, especially depletion of potassium salts.

Toxicity and Adverse
Reactions

Aside from occasional allergic skin reactions in a small number of
people, AG used topically has few if any side effects. Several patients who
applied AG topically following dermabrasion reported burning sensations and
development of dermatitis on the face.15 Because of possible contamination by
anthraquinones, oral AG may cause symptoms of abdominal cramps and diarrhea.
There have also been several reports of AG lowering plasma glucose levels in
laboratory animals and in humans.43,44 It was postulated in one study that this
hypoglycemic effect was mediated through the stimulation and release of insulin
from the beta-cells of the pancreas.44 Therefore, caution should be exercised
when using oral AG in patients with diabetes.