Aloes – Aloes folii succus siccatus (Aloe barbadensis Mill. and Aloe (various species, mainly Aloe ferox Mill. and its hybrids))
|Latin name of the genus:||Aloes folii succus siccatus|
|Latin name of herbal substance:||Aloe barbadensis mill. and aloe (various species|
|Botanical name of plant:||Aloes|
|English common name of herbal substance:||Mainly aloe ferox mill. and its hybrids)|
Latin name of the genus: Aloes folii succus siccatus
Botanical name of plant: Aloe barbadensis Mill. and Aloe (various species, mainly Aloe ferox Mill. and its hybrids)
English common name of herbal substance: Aloes
This assessment report reviews the scientific data available for the dried juice of the leaves of Aloe vera (L.) Burm. f., known also as Aloe barbadensis Miller, (barbados aloes), or of Aloe ferox Miller and its hybrids (cape aloes), primarily the clinical data.
SupersededBarbados aloes consists of the concentrated and dried juice of the leaves of Aloe barbadensis Miller. It contains not less than 28% of hydroxyanthracene derivatives, expressed as barbaloin (C21H22O9; M
The word “Aloe” in pharmacopoeias and formularies means a herbal substance derived from the dried leaf juice. This has always created confusion due to the fact that the leaves are the source of two products “aloe dried juice” and “aloe gel”, which are quite different in their chemical composition and their therapeutic properties.
The plant material of interest here is aloe dried juice, which is prepared by cutting transversely the leaf near the base and taking it inclined so that the juice contained in the specialised pericyclic cells and
sometimes in the adjacent parenchyma flow out in about 6 h. The juice is allow to ry with or
418.4) and calculated with reference to the dried herbal substance. The material complies with the European Pharmacopoeia monograph “Aloes, Barbados” (ref. 0/2005:0257).
Cape aloes consists of the concentrated and dried juice of the leaves of various species of Aloe, mainly Aloe ferox Miller and its hybrids. It contains not less than 18% hydroxyanthracene derivatives, expressed as barbaloin (C21H22O9; Mr 418.4) and calculated with reference to the dried herbal substance. The material complies with the European Pharmacopoeia monograph “Aloes, cape” (ref. 01/2005:0258).
The constituents with known therapeutic activity of barbados aloes are
mixture of aloin A (10S,1’S) and aloin B (10R,1’S), named barbaloin and their
and a mixture of
The constituents with known therapeutic activity of cape aloes are
There are also small quantities in both aloes of the aglyka,
II.1.2 Absorption, metabolism and excretion
Aloins A and B, hydroxyaloins and the aloinosides A and B are not absorbed in the upper gut. In humans, they pass into the colon unmodified aft r oral ing stion. Human int stinal flora are able to break down
It is not known to what xt nt aloe-
After oral administration of 4.5 mg/kg
The E COP monograph mentioned an unpublished research report of a human pharmacokinetic study in 6 healthy volunteers (ref. 39 in 3). After oral administration of aloes (equivalent to 16.4 mg of hydroxyanthracene derivates) for 7 days,
The absorbed rhein anthrone is glucuronidised in the liver. One part of the glucuronides is excreted via the urine and cause the yellow or redbrown discolouration of the urine. The other part is excreted via the bile (61).
II.1.3 Progress of action
Aloes acts within 6 to 12 hours due to the time taken for transport to the colon and metabolisation into
the active compounds.
II.2.1 Mode of action
• Laxative effect
Constipation is said to be present when passed stools are of hard consist ncy and wh n vacuation of faeces is too difficult, too infrequent and irregular. The physiological range for fr qu ncy of bow l movements is wide, extending from three times daily to once every 2 to 3 ays. In the pathog n sis of
constipation the colon plays a key role because this is where the contents of the gut r main for 24 – 48 hours. During this period the liquid contents from the small intestine are converted into faeces by absorption of water and electrolytes in response to the action of bacteria. These functions are dependent on the interplay of peristaltic process s which mix the cont nts and the normal coordination of the anorectal muscles during defaecation. A disturbance involving any of these in ividual areas may lead to constipation. In this context, functional disturbanc s are far more common than those of
an organic origin. In addition, asse ment is probl matic b cause the symptoms are perceived
differently by the individuals affected (16, 17), due to diff r nt conc pts of what normal bowel habits are.
Aloe dried juice belongs to the stimulant laxatives.
Ishii Y et al. 1990 (13) investigated the mechani m of action of
pretreatment with lo ramide com l t ly pr v nted the increase of paracellular permeability induced
Hoenig J et al. 1992 (18, 19) studied the influence of 23 anthraquinones and anthrones on the reg latory vol me decrease (RVD) which is effected in Ehrlichs ascites tumor cells by activation of Cl– channels. They showed that the inhibition of the
Ishii Y et al. 1994 (20) measured simultaneously in the same rat charcoal transport, as an indicator of the degree of peristalsis, and water content in th large intestine after intracaecal administration of barbaloin. Charcoal transport was significantly accelerated at both 3.5 and 6.5 h after the administration of barbaloin. At 6.5 h, diarrhoea instead of normal faeces was observed. Moreover, at 1 h before the acceleration of charcoal transport, a marked increase in water content of the large intestine was observed: It appeared that the increase in water content of the large intestine induced by barbaloin preceded the stimulation of peristalsis, attended by diarrhoea. The authors therefore
suggested that the increase in water content is a more important factor than the stimulation of peristalsis in the diarrhoea induced by barbaloin.
Results of investigations of Capasso F et al. 1983 (27) in rat isolated colon suggest that the laxative properties of aloin and
Supersededand calcium ionophore A23187 on plat l
The exact mechanism of action is still unknown. Besides a direct influence of the motility leading to a reduced transit time, an influence on secretion processes by two concomitant mechanisms is assumed namely inhibition of absorption of water and electrolytes
methyl ester) reduced the diarrhoea induced by aloe (20 g/kg)) 9 h aft r its oral administration. The increase in faecal water excretion was al o reduc d.
stomach, ileum or colon mucosa. Aloe- modin (100 µg/ml) stimulated a small release of PAF in ileum and colon mucosa. Rh in had no ff ct.
Izzo AA et al. 1998 (85) reviewed the key features of the involvement of NO and PAF in the action of laxatives. PAF is a phospholipid mediator of inflammation and stimulates anion secretion in animals and in isolated preparations of human colon. NO, synthesised from the amino acid
Longo R 2002 (86) referred in his monograph “Aloe today” (part four) to recent investigations that produced a better explanation of the mechanism of th action of stimulus on the colon. The inhibition of
Recapitulating, biological factors such as PAF and NO may play a role on the action of the stimulus on the colon, but it should be considered that the investigations mentioned above are only experimental ones.
Koch A 1995 (28) evaluated the laxative effect of aloin in experiments on herself. Neither a dose of 20 mg aloin nor an increase to 60 mg aloin caused a laxative effect. Aloin was found in the faeces. The author also studied the use of aloe as a laxative in 3 patients given 50 mg aloin in a gelatine capsule in the evening at 8 p.m. Test person A (female) fed upon vegetable and animal products, test person E (female) predominantly fed upon fish and meat and test person H (male) was a vegetarian. Test person A experienced soft stools once at day 1 and 2 and normal stools at day 3. Test person E
Superexperienced soft stools at day 1 for foursededtimes. Test person H experienced soft stools once at day 1, 2
and 3. These different results corresponded to the cleavage of aloin and appearance of
Kopp H 1979 (29) tested in an open study
total of 18 cholecystectomised patients or patients with gallstones, in comparison with a plac bo (physiological saline solution) as to its choleretic properties and tol rability.
This investigation of a combination p oduct of eve al agents cannot exactly show the contribution of aloe to the observed effects.
• Other eff cts
There are many exp rim ntal inv stigations, which study several effects of different ingredients of aloe. The part of the plant, from which the ingredients were isolated, has not always been defined exactly. Investigations of the g l or of substances isolated from the gel are not mentioned in the assessment re ort.
¾ Antitumour effect
Grima do S et al. 1997 (21) studied the antitumour effects of 5 purified compounds from the plant
Aloe vera on h man K562 leukaemia cells and on the multidrug resistant (MDR) variant cell line, K562/R. The glycosides aloin A and B, aloesin and aloeresin were devoid of antitumour activity up to 200 µM concentrations. Only the aglycon
Fenig E et al. 2004 (67) conducted a study to determinate if members of the anthraquinone family could be used as adjuncts to increase the growth inhibiting effect of anticancer agents in Merkel cell carcinoma (MCC). An adherent variant of MCC was derived from a previously established MCC cell line suspension. Emodin and
Chen HC et al. 2004 (68) evaluated the chemopreventive role of
Lee HZ et al. 2001 (69), 2003 (70), and 2005 (71) demonstrated that
significant change in the expression of lung cancer cell
In investigations using the contact hypersensitivity response Yagi A t al. 2003 (22) show a
preventive effect of aloesin, isolated from Aloe species, on the
Staphylococcus aureus, Streptococcus pyogenes, Coryn bact rium x rose and Salmonella paratyphi.
Another investigation by Liu M et al. 1996 (24) how d pot nt antibact rial activity of
¾ Antifungal effect
Shamim S et al. 2004 (25) valuat d the activity of Aloe barbadensis Miller and two other plants (Allium sativum L. and Solanum nig um L.) against some common fungal species associated with superficial mycos s. The thanol and aqu ous xt acts of these plants were tested to establish the
antimycological ff cts against d rmatophyt s, saprophytes, and Candida species isolated from
infected hos italis d ati nts. The in vitro antifungal activity was established by observing and measuring the zon s of inhibition form d on selective nutrient media. Zones of inhibition were categorised as very high
Chronic se or ab se of aloe dried juice preparations may lead to hypokalaemia. This hypokalaemia
and the increased loss of potassium may increase the activity of cardiac glycosides and interfere with the action of antiarrythmic agents (interaction with antiarrhythmic medicinal products, which induce reversion to sin rhythm, e.g. quinidine) and medicinal products inducing
Chung JH et al. 1996 (26) investigated the influence of aloe on the ethanol metabolism in rats based on reports indicating that an extract of aloe enhances ethanol metabolism. Aloe contains aloin, a C- glycoside of anthraquinone. Quinones in general have a functional role in elevating the ethanol metabolism rate in vivo. Upon oral administration of aloin (300 mg/kg) 12 h before ethanol administration, the area under the curve of blood ethanol significantly decreased by 40%, while the
slope of elimination and rate of disappearance from the body increased by 60% and 64%, respectively.
Based on these results, the authors concluded that aloin could be the substance in aloe that promotes ethanol metabolism in vivo.
Lee A et al. 2004 (66) described a patient with massive intraoperative bleeding after oral consumption of Aloe vera tablets. A
Supersededpsyllium and 13 on placebo successfully completed the study. The initial dose was 1 capsules per day, taken with water at bedtime, and increasing to 3 capsules per day depending on the response. The
impairs platelet aggregation, and prolongs bleeding. Although the vascularity and size of the haemangioma were the most important factors for the massive intraoperative blood loss, the authors concluded that concomitant use of sevoflurane and Aloe vera played a contributory role and that this adverse event was possible as a result of the sevoflurane and Aloe vera interaction.
The information given in the publication is insufficient. The Aloe vera preparation may not be comparable to the aloe preparations assessed in this report.
clinical investigations with other
The German Commission E monograph (1) indicat a daily do of 20 – 30 mg hydroxyanthracene derivatives calculated as aloin but recommends that the pharmac utical form must allow lower
dosages than the usual daily dose.
The ESCOP monograph (3) and the WHO monog aph (4) r comm nd 10 – 30 mg hydroxyanthracene derivates.
This dosage recommendation is also given in con ide ation of the toxicological data, which were evaluated and led to pharmacovigilance actions in Ge many for
Through the individual product info mation ( specially the package leaflet), patients should be informed that the corr ct individual dose is the smallest equired to produce a comfortable
It is normally suffici nt to take an
Odes HS et al. 1991 (30) evaluated the effect of a laxative preparation, composed of celandine, Aloe vera and psylli m in patients with chronic constipation i.e. requiring laxative treatment for at least 2 years. The aloe preparation in this combination product derived from the leaves of Socotrine Aloes and also contained barbaloin and other anthraquinone derivatives. Capsules of 500 mg were made up to contain the active ingredients celandine, aloe vera and psyllium in the ratio 6:3:1. Thirty five men and women were randomised to receive capsules containing
these had simple constipation, and the others suffered from irritabl bowel syndrome with
constipation. Organic causes for constipation were excluded. Nineteen patients on
patients kept a daily diary card during the basal and treatment periods and recorded: date, number of capsules taken, number of bowel actions, stool consistency, abdominal pain and distension, heartburn, other medications and fibre supplements taken to relieve constipation, medicinal products taken for
other conditions, and fluid intake. Symptoms of the last 2 weeks of the treatment period were compared to those in the
Supolder than 2 yearsersededof age should incr ase th ir intake of dietary fibre (increased consumption of a variety of fruits, v g tabl s, c r al and oth r grain product) to an amount equal or greater than their
demonstrated no changes. Subjects on
This investigation of a combination product of three herbal substances cannot establish the contribution of aloe to the observed effects. Furthermore, the herbal substance is “Socotrine Alo s”, which does not correspond to barbados aloes and cape aloes described in this ass ssm nt r port and derives from a different species. This species however contains also barbaloin and oth r anthraquinone derivatives (31).
In the absence of clinical studies, the postulated laxative effect of barba os aloes and cape aloes is mainly based on pharmacological data, experts’ opinions and clinical experiences. Clinical and pharmacological data obtained on other
The other effects mentioned in chapter II.2.1 have b n pr dominantly inv stigated in experimental studies. Adequate clinical trials are not available.
age plus 5 g (e.g. 8 g/day at age 3) (32). Change in nutrition should be accompanied with behaviour modification, e.g. incr as d hysical x rcise. There are no systematic clinical data available, which evaluate the use of aloe dried juice as a laxative in children.
According to the ESCOP and WHO monographs, the use in children under 10 years of age cannot be recommended.
According to the “Note for guidance on clinical investigation of medicinal products in the paediatric pop lation” (CPMP/ICH/2711/99) of 27 July 2000, the age limit between “children” and “adolescents” is set to “12 years of age”.
III.3.2 Use during pregnancy and lactation
There are no recent investigations available.
In theory, it is possible that reflex stimulation might occur, involving not only the colon but also uterine muscles and then might lead to the development of hyperaemia in the pelvic region and to miscarriage as a result of neuromuscular stimulation of uterine muscles. Especially high doses shall lead to metrorrhagia, and miscarriage (7).
Animal experiments demonstrated that placental passage of rhein is small.
No teratogenic or foetotoxic effects were seen in rats after oral treatment with aloe extract (up to 1000 mg/kg) or aloin A (up to 200 mg/kg) (4). The pregnant rats were treated between the 10th and 13th day of the gestational period. A caesarean section was done on the 21st day post conception.
SupMorimoto I. et al.erseded1982 (76) reported the results of the Ames test and the
mutagenic activity in Salmonella typhimurium strains
Brown JP 1980 (77) reported that barbaloin, a
Marquardt et al. 1987 (cited in the unpublished report of Brusick DJ 1994 (78)) conduct d a more thorough evaluation of
In 1992 Cytotest Cell Research GmbH & Co. conducted a s ri s of g n tic tests using a batch of commercial
A mammalian cell assay for gene mutation conducted in V79 cells showed no evidence of mutagenicity with aloe extract in concent ations up to 1,000 µg/ml without S9 mix and up to 5,000 µg/ml with S9 mix.
Brown JP and Dietrich PS 1979 (79) reported that
witho t 9 activation, 14 (100 µg) with S9 activation; 12 (250 µg) without S9 activation, 15 (250 µg) with 9 activation.
Westendorf J et al. 1990 (33) reported on the genotoxicity of
Heidemann A et al. 1996 (34) undertook in vitro and in vivo experiments to clarify the genotoxic potential of the hydroxyanthraquinone
risk for man might be unlikely.
Lee KH et al. 2000 (36) isolated
chromatography. The identity of DEHP was confirmed using an authentic sample. As the inv stigators used the entire leaves, it is not possible to give evidence whether the juice contains this ingr i nt or not.
Shiota K 1985 (35) reported that
and PO or IP doses of MEHP, although high dos s were abortifaci nt and l thal to pregnant females.
The difference in metabolism, dispo ition, or xcr tion by th route of administration may be
responsible for the difference in DEHP teratogenicity. Since IP inj ction of DEHP was not teratogenic, it is unlikely that metabolism outside the ga trointe tinal tract conv rts DEHP to any teratogenic
metabolites. DEHP was not mutagenic in the Am ’ almon lla/microsome test using hepatic
preparations. Although MEHP is a p incipal metabolite of DEHP and is several times more toxic than DEHP to adult mice, it seems that MEHP and its metabolites are not teratogenic in ICR mice.
The European Union classifi d DEHP as toxic to ep oduction category 2 in the Directive 2003/36/EC
of the European Parliam nt and the Council of 26 May 2003 (73). Category 2 includes substances, which should be r gard d as if th y impair f tility in humans or as if they cause developmental
toxicity to humans bas d on suffici nt vid nce or other relevant information. DEHP has to be
declared with the symbols R60 (may impair f rtility) and R61 (may cause harm to the unborn child).
The ‘Scientific Pan l on Food Additiv s, Flavourings, Processing Aids and Materials in contact with food (AFC)’ assessed DEHP for use in the manufacture of food contact materials, on a request from the Commission and ado ted an o inion on 23 June 2005 (74). Previously, a Tolerable Daily Intake (TDI) of 0.05 mg/kg bw was set by the Scientific Committee for Food (SCF), based on the endpoint of
peroxisome roliferation in rodent liver. There was then a scientific consensus that liver peroxisome
proliferation in rodents is not relevant for human risk assessment. Th critical effects of DEHP relate to reprod ction.
Testic lar effects have been observed in several repeated dose toxicity studies in rats, mice, and ferrets. Minor effects were observed in hamsters, and in the available studies marmosets were not sensitive to DEHP. No studies on testicular effects in rabbits are available.
113 mg/kg bw/day, respectively.
From a multigeneration reproductive study in which DEHP was administered to rats in the diet (Wolfe GW and Layton KA 2003), a NOAEL of 4.8 mg/kg bw/day for testicular toxicity and developmental toxicity can be derived.
Based on the current literature on DEHP testicular toxicity, the Panel allocated a TDI of 0.05 mg/kg bw, based on a NOAEL of 5 mg/kg bw/day, and making use of an uncertainty factor of 100.
The EU Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) had prescribed in 1998 the same value for the TDI (75).
SupersededThe Britisch Pharmaceutical Codex 1911 (40) mentions aloe as a purgative. Because the action of aloe on the large intestine induces some pelvic congestion, it is therefore employed as an
Because the data are insufficient and the results of available investigations are not consistent, use during pregnancy cannot be recommended. Furthermore other actions like behavioural mo ification, dietary changes and use of bulk forming agents should be the first actions taken during pregnancy to treat constipation.
Use during lactation is not recommended as there are insufficient data on the xcr tion of m tabolit s
in breast milk, too. Investigations with a “standardised senna laxative” (Agiolax®), which also contains Plantago ovata seeds/husks as bulk substances, showed that small amounts of active m tabolit s
(rhein) are excreted in breast milk. No laxative effect in breast fed babi s has b n r port d (37).
The risk caused by DEHP following the administration of aloe ried juice pr parations cannot be assessed. No clear evidence exists that these aloe preparations contain this substance at all, and, if any, in which amount. Children below the age of 12 years, pregnant and
although it seems to be likely that aloe gel or imilar preparations and not aloe dried juice were externally used.
Because of this lack of information, this epo t cove all traditional indications reported for “aloe” altogether.
Aloe has a long history as a m dicine and skin ca e aid. For over 6,000 years aloe was used for a wide range of ailments. The anci nt Egyptians us d aloe to heal battle wounds and cure infections. The early Greeks used it for r li ving blist rs, burns and leg ulcers as well as bowel and stomach disorders.
Legend it that Aristotle rsuad d Al xand r the Great to conquer the Isle of Socroto to secure enough aloe vera to heal his soldi rs’ wounds. In England aloe was already used in the 10th century. In the 12th century aloe was brought to Germany by Albertus Magnus (38).
Diosk rides (39) already mentioned aloe in his materia medica
emmenagogue in amenorrhoea, generally with iron. The recommended dose is 1 to 3 decigrams (2 to 5 grains).
In the Dispensatory of the United States of America 1918 (41) aloe is mentioned as a cathartic (purgative). It is also described that it was formerly almost universally believed that aloe possessed emmenagogue properties and it was accordingly largely used in the treatment of various forms of amenorrhea, but that it is extremely doubtful whether aloe exercises any action upon the pelvic organs which is not attributable to its cathartic effects.
In his “Manual of Materia Medica and Pharmacology”, Culbreth 1927 (42) mentions as indications constipation, atonic dyspepsia, jaundice,
Hager 1927 (43) mentions the use as an appetising agent in low doses (0.05 – 0.1 g) and as a cathartic in higher doses (0.2 – 1.0 g). The use in menstruation, pregnancy and bleeding haemorrhoids is not
supported by experimental or clinical data: tr atm nt of s borrho ic d rmatitis, peptic ulcers, tuberculosis, fungal infections, and for reduction of blood ugar l v ls. The r ferences given are not original sources and date from 1991 and 1995.
Besides the use as a laxative, the use as an emmenagogue and the external use for wounds and abscess are described in most references mentioned above, however the preparations used are not well defined. But, as already m ntion d in the Disp nsato y of the United States of America 1918, it is extremely doubtful whether aloe x rcis any action upon the pelvic organs which is not attributable to its cathartic effects. Th re are no plausible pha macological data for this indication, nor for haemoptysis, jaundice or gout etc.
Concerning the ext rnal us , the r f r nc s do not describe exactly the preparations used. Furthermore, the ossible risks as d scrib d in chapter IV Safety have to be taken into account.
As mentioned in chapter III.3 Clinical studies in special populations, toxicological data from in vitro investigations (33) indicate that the hydroxyanthraquinones, emodin and
The genotoxic actions reported for certain constituents of aloe species indicate a carcinogenic potential for certain hydroxyanthraquinones. There are a very few investigations in animals which do not, however, so far permit adequate assessment.
The occurrence of intestinal tumours in rats has been reported by Mori H et al. 1985 (46) following the dietary administration of chrysazin
animals of the control group. Some of the hyperplastic lesions were difficult to distinguish from true neoplasms. Similar hyperplastic lesions were also recognised together with the carcinomas in rats (s above 46).
Danthron and 8 other hydroxyanthraquinone w re comparativ ly inv stigated by Wölfle D et al. 1990 (48) for activities associated with tumour promotion, uch as timulation of cell proliferation and enhancement of malignant t ansfo mation. The in vivo tr atm nt of primary rat hepatocytes with danthron,
methylcholanthrene. The r sults of th se in vit o studies suggest that hydroxyanthraquinones, possessing 2 hydroxy groups in
In a model of dim thylhydrazin
The aim of the study of Schörkhuber M et al. 1998 (50) was to demonstrate the effect of the 1,8- dihydroxyanthraquinone
Both cell numbers and DNA synthesis were increased. In contrast to SW480 carcinoma cells, VACO235 cells were also sensitive to sennoside and bisacodyl. No effects of DHA were observed in normal colorectal epithelial cells. The biological effects were preceeded by specific phosphorylation of cellular proteins with molecular weights of 110, 78, 63, 57 kDa, indicating the specific induction of a cellular signalling cascade by the laxatives.
In 2001 the National Toxicology Program (NTP) of the U.S. Department of Health and Human Services published a technical report on toxicology and carcinogenesis studies of emodin (107).
Groups of 5 male and 5 female rats were fed diets containing 0, 600, 2,000, 5,500, 17,000, or 50,000 ppm emodin. This corresponds in males to average daily doses of approximat ly 50, 170, 480, 1,400, or 3,700 mg emodin/kg bw and in females to 50, 160, 460, 1,250, or 2,000 mg/kg bw. Thr f male
corresponds to average daily doses of approximately 50, 100, 190, 400, or 800 mg/kg in males and 60, 130, 240, 500, or 1,100 mg/kg in females. Relative kidney weights of male mice exposed to 1,250 ppm or greater, relative lung weights of males exposed to 625 ppm or greater, and relative liver weights of female mice exposed to 625 ppm or greater were increased. The incidences and severities of nephropathy were increased in males and female exposed to 1,250 ppm or greater. The incidences of renal tubule pigmentation were significantly increased in males exposed to 1,250 ppm or greater.
Groups of 65 male and 65 female rats were fed diets containing 0, 280, 830, or 2,500 ppm emodin (equivalent to average daily doses of approximately 110, 320, or 1,000 mg/kg in males and 120, 370, or 1,100 mg/kg in females).
Three Zymbal’s gland carcinomas were observed in female rats exposed to 2,500 ppm. This incidence exceeded the range observed for current historical controls and was considered an equivocal finding. At the 6- and
containing 0, 312, 625, or 1,250 ppm emodin (equivalent to average daily dos s of approximat ly 30, 60, or 120 mg/kg). Low incidences of renal tubule adenoma and carcinoma occurr d in xpos d male mice; these incidences included one carcinoma each in the 312 and 625 ppm groups. R nal tubule neoplasms are rare in male mice, and their presence in these groups sugg st a possible association with emodin exposure. At the
Emodin was mutag nic in Salmon lla typhimu ium st ain TA100 in the presence of S9 activation; no mutagenicity was d t ct d in st ain TA98, with or without S9. Chromosomal aberrations were induced in cultured Chinese hamst r ovary c lls tr at d with emodin, with and without S9. Three separate in vivo micronucleus t sts w re rform d with modin. A male rate bone marrow micronucleus test, with emodin administ r d by 3 intrap riton al injections, gave negative results. Results of acute- exposure (intra eriton al inj ction) micronucleus tests in bone marrow and peripheral blood erythrocytes of male and female mice were negative. In a peripheral blood micronucleus test on mice from the
Concl sion by the “National Toxicology Program’s Board of Scientific Counselors’ Technical Reports
• In view of conflicting results on genotoxicity, it was noted the first pass effect and need for metabolic activation suggesting a metabolite as the genotoxic form. The metabolite 2- hydroxyemodin acts as the genotoxin (88).
IV.1.2 Clinical Data
Siegers CP et al. 1993 (51) reported about a retrospective study of 3,049 patients, who underwent diagnostic colorectal endoscopy. The incidence of pseudomelanosis coli was 3.13% in patients without pathological changes. In those with colorectal adenomas, the incidence increased to 8.64% (p<0.01), and in those with colorectal carcinomas it was 3.29%. This lower rate was probably caused by incomplete documentation of pseudomelanosis coli in those with carcinoma. In a prospective study of
1,095 patients, the incidence of pseudomelanosis coli was 6.9% for patients with no abnormality seen Supersededon endoscopy, 9.8% (p=0.068) for patients with adenomas and 18.6% for patients with colorectal carcinomas. From these data a relative risk of 3.04 (1.18, 4.9; 95% confidence interval) can be
calculated for colorectal cancer as a result of chronic anthranoid laxative abuse.
Kune GA et al. 1988 (52) and Kune GA 1993 (53) reported about the “M lbourne Color ctal Canc r Study”. Commercial laxative use as a risk factor in colorectal cancer was inv stigat as one part of this large population based epidemiological study of colorectal incid nc , a tiology and survival. Commercial laxative use was similar in 685 colorectal cancer patients and 723 ag /s x match d community based controls. Also, when laxatives were subdivided into various groups containing anthraquinones, phenolphthalein, mineral salts and others, previous laxative intake was similar between cases and controls. Previous use of anthraquinone laxativ s and of ph nolphthal in containing laxatives was not associated with the risk of colorectal cancer. Furthermore the results of this study suggest that chronic constipation, diarrhoea, and the frequency and consistency of bowel motions are unlikely to be etiologic factors in the d v lopm nt of color ctal cancer. They indicate that
it is the diet and not the constipation that is associat with the risk of
Additionally, a highly statistically significant association (p=0.02) with the risk of colorectal cancer was found in those who reported constipation and al o had a high fat intake.
In a retrospective study a cohort of 2,277 patients was d fin d by colonoscopy. Among other factors
Nusko G et al. 1993 (54) tested whether in the pati nts laxative use or the ndoscopically diagnosed presence of melanosis coli we e isk facto elated to colorectal neoplasm. In comparison to patients
taking no laxatives there was no significant inc ea e in colorectal cancer rate either in laxatives users or in patients with melanosis coli. Howeve , the e was a tati tically significant association between the occurrence of color ctal ad nomas and laxative use (relative risk of all patients exposed to laxatives = 1.72; of pati nts xpos d to laxativ s without melanosis coli = 1.47). The relative risk of adenoma developm nt in pati nts with m lanosis coli was 2.19. Taking into account that polyps can be diagnosed in the dark mucosa of m lanosis coli patients more easily, the authors concluded that even this relative risk of 2.19 s ms to be r lat d to a generally enhanced risk of laxative intake rather than to a s ecial group of
Sonnenberg A et al 1993 (55) erformed a
Loew D et al. 1994 (56) conducted a comparative study involving 423 patients with colorectal neoplasms and 522 patients with benign proctologic disorders who were regular users of laxatives for bowel regulation. A pseudomelanosis coli (PMC) test was used as an indicator of exposure to
and the control groups (4.2%) (p≤0.197).
Jacobs EJ et White E 1998 (90) examined the associations of colon cancer with constipation and use of commercial laxatives in a
Supersededlevels of homocysteine, folate and cobalamine in a
associated with increased risk of colon cancer. When adjusted for constipation, commercial laxative use was no longer associated with increased risk (RR = 0.3, 95%CI =
Nusko G et al. 2000 (57) performed a prospective case control study at the University of Erlangen to investigate the risk of
adenomatous polyp, and 238 patients (controls) with no colorectal neoplasm who had b n r f rr for
total colonoscopy were studied. The use of anthranoid preparations was ass ss d by standardis d interview, and endoscopically visible or microscopic melanosis coli was studi d by histopathological
logistic regression analysis the odds ratio for adenomas was 0.84 (95% CI
Willems M et al. 2003 (58) described a ca e of m lano is coli, which occurr d in a
Roberts MC et al. 2003 (91) conduct d a
increased risk of cancer, and cardiovascular and neurological diseases. The homocysteine level depends on the supply of folate and cobalamine, which constipation and/or laxative treatment might compromise. The study was based on biochemical tests in 341 females and 183 males aged 82 years and older. The concentrations of homocysteine (plasma), folate, cobalamine and urea (serum) were measured in subjects with and without ongoing treatment with laxative products. Values were adjusted for age, gender and frailty, as well as for clinical diagnoses and medicinal product therapies known to affect homocysteine levels. Homocysteine levels were increased and those of folate reduced in aged subjects on laxatives. Homocysteine remained elevated after adjusting for frailty and various neurological disorders. There was no significant effect on homocysteine and folate in constipated subjects without laxatives.
Jae Sik Joo et al. 1998 (62) investigated changes occurring on barium enema in patients ingesting stimulant laxatives. The study consisted of two parts. In part 1, a retrospective review of consecutive barium enemas performed on two groups of patients with chronic constipation (group 1, stimulant laxative use (n=29); group 2, no stimulant laxative use (n=26)) was presented to a radiologist who was blinded to the patient group. A data sheet containing classic descriptions of cathartic colon (historic term for the anatomic alteration of the colon secondary to chronic stimulant laxative use) was
Superseded daily for 12 weeks and aloin was orally administered up to 60 mg/kg daily for 20 weeks (3).
completed for each study. Chronic stimulant laxative use was defined as stimulant laxative ingestion more than three times per week for 1 year or longer. To confirm the findings of the retrospective study, 18 consecutive patients, who were chronic stimulant laxative users underwent barium enema examination, and data sheets for cathartic colon were completed by another ra iologist (part 2). Colonic redundancy (group 1, 34.5%; group 2, 19.2%) and dilatation (group 1, 44.8%; group 2, 23.1%) were frequent radiographic findings in both patient groups and w re not significantly iff r nt in the two groups. Loss of haustral folds, however, was a common finding in group 1 (27.6%) but was not seen in group 2 (p<0.005). Loss of haustral markings occurred in 15 (40.5%) of the total stimulant laxative users in the two parts of the study and was seen in the left colon of 6 (40%) pati nts, in the right colon of 2 (13.3%) patients, in the transverse colon of 5 (33.3%) pati nts, and in the ntire colon of 2 (13.3%) patients. Loss of haustra was seen in patients chronically ing sting bisacodyl, phenolphthalein, senna, and casanthranol. The authors conclu ed that
results in anatomic changes in the colon characterised by loss of haustral fol s, a fin ing that suggest neuronal injury or damage to colonic longitudinal musculature caused by these agents.
Because of the possible genotoxic or tumourigenic ri k in xp rim ntal inv stigations and the results of Siegers 1993, pharmacovigilance actions for
Germany in 1996: the daily dose and the duration of admini tration w re limited and children, pregnant women and nursing mothe s we e exclud d f om the application of aloe containing laxatives.
The results of the most recent studies a e incon i tent and the que tion of a possible carcinogenic risk of
laxatives. This finding disappears 6 – 12 months after stopping chronic laxative administration.
Regardless of whether a definitive causal relationship can be demonstrated between the use of anthraquinone laxatives and colonic pathology, these agents should not be recommended for chronic or
Aloe preparations should not be used by patients with known hypersensitivity to aloe.
The German Health Authority has received one report of an adverse event concerning a combination preparation of aloe, senna, curcuma, and mandrake root. Half an hour after ingestion the patient developed an urticaria and an angiooedema. An allergy test showed a positive result for aloe.
There are several publications available dealing with allergic reactions. Most of all these reactions were caused by local application and the aloe preparations used are not exactly specified.
Supersededor the administration of bulk forming agents.
Ernst E 2000 (63) reported that remedies which can cause dermatological
Anliker MD et al. 20002 (64) describe a case of an anaphylactic shock due to local application of “aloe vera leaves”.
Schempp CM et al. 2002 (65) categorise “aloe” as sensitising plant in cosm tics.
Furthermore, like all
IV.4 Special warnings and precautions for use
The following warnings and precautions for use are r comm nd d:
Patients taking cardiac glycosides, antiarrhythmic m dicinal products, m dicinal products inducing
It cannot be assessed definitely if a longer than a brief period of treatment with stimulant laxatives leads to dependence req iring increasing quantities of the medicinal product, to an atonic colon with impaired f nction and to aggravation of the constipation.
The only study comparing the morphology of the autonomous nervous system of constipated patients taking anthraquinones (aloe) to that of an appropriate control group of constipated patients without laxative intake (Riecken EO et al. 1990 (99)) did not support the hypothesis that anthraquinone- containing laxatives are able to provoke relevant degenerative changes in the colonic nerve tissue. But this investigation was conducted in 11 matched pairs only.
gastrointestinal symptoms and passage of liquid stools, in particular in patients with irritable colon. However, these symptoms may also occur gen rally as a cons qu nce of in ivi ual overdosage. In such cases dose reduction is necessary. The corr ct individual ose is the smallest required to produce a comfortable
As mentioned above hypersensitive reactions may occur.
Chronic use may lead to diso de s in water equilib ium and l ctrolyte m tabolism, and may result in albuminuria and haematuria.
Furthermore, use over a long pe iod may lead to pigmentation of the intestinal mucosa (pseudomelanosis coli), which usually c d s when the patient stops taking the preparation (see chapter IV.1.3 Conclusion).
Luyckx VA et al. 2002 (72) r ort d a case of a
The ca sality cannot be assessed definitely.
The German Health A thority has received one report of an adverse event concerning a mono- preparation (a Mexican aloe extract). A
Like for all
adrenocorticosteroids are being taken at the same time.
Superss bstances for
Treatment should be supportive with generous amounts of fluid. Electrolytes, especially potassium, should be monitored. This is especially important in the elderly.
Furthermore chronic ingestion of overdoses of
Beuers U et al. 1991 (101) reported a case of toxic hepatitis related to abuse of s nna glycosi s in a
Vanderperren B et al. 2005 (102) reported a case of a
The c rrent level of evidence1 of the available scientific data for “the short term use of occasional constipation” can be identified as level IV becaus
The conditions determined in the pharmacovigilance actions for
1 As referred to in the HMPC ‘Guideline on the assessment of clinical safety and efficacy in the preparation of Community herbal monographs for
The use in children under 12 years of age is contraindicated and use during pregnancy and lactation is not recommended.
Besides the use as a laxative, the use as an emmenagogue and the external use for wounds and abscess
are described in most references mentioned above. But as already mentioned in the Dispensatory of Supersededthe United States of America 1918, it is extremely doubtful whether aloe exercises any action upon the pelvic organs which is not attributable to its cathartic effects. There are no plausible pharmacological
data for this indication, nor for haemoptysis, jaundice or gout etc. Furthermore, the preparations used are not described exactly, even for the external use
In view of existing possible risks, such traditional uses cannot be recomm nd and r f rr to in the ‘Community list of herbal substances, preparations and combinations th of for use tra itional h rbal medicinal products’. This is in accordance with the German pharmacovigilance actions for anthranoid- containing laxatives.