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

I.INTRODUCTION

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 anthrone-10-C-glycosides viz. a

mixture of aloin A (10S,1’S) and aloin B (10R,1’S), named barbaloin and their 6’-0-p- Supersededcoumaroylesters, a mixture of 7-hydroxyaloins A (10S) and B (10R) and their 6’-0-p-coumaroylesters

and a mixture of 8-0-methyl-7-hydroxyaloins A (10S) and B (10R) and their 6’-0-cinnamoylesters.

The constituents with known therapeutic activity of cape aloes are 10-C-glycosides viz. a mixture of aloins A (10S) and B (10R), named barbaloin, and 5-hydroxyaloin A (10S) b si s 10-C-11-0- diglycosides viz. aloinosides A and B (11-0-α-L-rhamnosides of aloins A an B).

There are also small quantities in both aloes of the aglyka, aloe-emodin and chrysophanol, and 2- alkylchromones named aloeresins (4, 7).

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 O-glycosides easily but only to some xtent C-glycosi s of most anthranoi s. A strictly anaerobic, Eubacterium sp. BAR, was isolated from human fa ces as one of the intestinal bacteria capable of metabolising barbaloin to aloe-emodin anthrone (8, 9). Barbaloin was transformed to aloe- emodin anthrone in the faeces from gnotobiotic rats mono-a ociat d with the Eubacterium sp. BAR, but not in faeces from conventional rats or the gnotobiotic rats mono-associated with Peptostreptococcus intermedius, a human inte tinal anaerobe capable of reducing sennidins to rhein anthrone. Only in gnotobiotic ats mono-a ociated with the Eubacterium sp. BAR administration of barbaloin causes severe diarrhea. The faecal water content was ignificantly increased (10). In contrast Ishii Y et al. showed that aloe-emodin-9-anth one was produced in the rat large intestine (11, 12). Aloe-emodin-9-anthrone is the main active m tabolite, which acts specifically on the colon (13).

It is not known to what xt nt aloe- modin-9-anth one is absorbed. In the case of senna, animal experiments with radio-lab l d h in anth one administered directly into the caecum demonstrated absorption < 10% (14).

After oral administration of 4.5 mg/kg 14C-aloe- modin to rats 20 – 30% of the dose was excreted in urine and the rest in fa c . Aloe- modin was quickly metabolised to rhein, to an unknown metabolite and to conjugates of all three. In the plasma about 10% of 14C-activity was identified as free aloe- emodin. Maximum lasma values were reached 1.5 – 3 h p.a. with 248 (male) and 441 (female) ng eq ivalents aleo-emodin/ml. Maximum concentrations in plasma were about 3 times higher than those in ovaries and 10 times higher than those in testes. Because of the low activity concentrations in the reprod ctive organs TLC analysis was not possible. But if the metabolic profile of these organs is ass med to be the same as in plasma, concentrations of free aloe emodin can be calculated to be maximally abo t 2-4 ng/g in testes and 8-10 ng/g in ovaries after an oral dose of 4.5 mg/kg. Only liver, kidney and intestinal tract showed higher concentrations than plasma. Terminal half-life (for radioactivity) in blood was about 50 h (15).

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, aloe-emodin was detected as a metabolite in the plasma only sporadically and with maximum concentrations of less than 2 ng/ml. In the same study rhein was detected in the plasma in concentrations ranging from 6-28 ng/ml after single dose administration. In 7-day administration there was no evidence of accumulation of rhein.

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.

SupersededII.2 Pharmacodynamics

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. Aloe-emodin-9-anthrone is the main active metabolite, which acts specifically on the colon (13).

Ishii Y et al. 1990

(13) investigated the mechani m of action of aloe-emodin-9-anthrone in causing a significant increase in the wat cont nt of the at la ge intestine. Aloe-emodin-9-anthrone inhibited rat colonic sodium/potassium-ad nosine t iphosphatase (Na+/K+-ATPase) in vitro, and increased the paracellular perm ability across the at colonic mucosa in vivo. Therefore, it seemed that the increase in water content of the rat large int stine produced by aloe-emodin-9-anthrone was due to both inhibition of absor tion and stimulation of s cr tion without stimulation of peristalsis. Since, however,

pretreatment with lo ramide com l t ly pr v nted the increase of paracellular permeability induced

by aloe-emodin-9-anthron , but did not compl t ly reduce the concomitant increase in residual fluid volume, other multi le mechanisms of action might be involved in the increase of water content in the rat large intestine.

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 Clchannels. They showed that the inhibition of the Cl-channels’ activity was the strongest by aloe- emodin-anthrone and aloe-emodin. These anthraquinones reduce the Clpermeability of the cells, this infl ence being sometimes more pronounced than that of the Clchannel blocker 130B. In contrast to the investigations of Ishii Y et al. 1990 (13) both substances showed no pronounced inhibition activity of the Na+/K+-ATPase. Rhein, frangula-emodin and other anthraquinones with an additional phenolic hydroxyl group showed inhibition.

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 1,8-dioxyanthraquinone may depend, at least in part, on increased prostaglandin synthesis by the intestinal tissue.

Supersededand calcium ionophore A23187 on plat l t-activating factor (PAF) release by human gastrointestinal mucosal pieces in vitro. Ricinol ic acid and calcium ionophore stimulated release of PAF from human

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 (Na+,Cl) into the colonic epithelial cells (antiabsorptive effect) and increase of the leakiness of the tight junctions and stimulation of secretion of water and electrolytes into the lumen of the colon (secretagogue effect) resulting in enhanced concentrations of fluid and electrolytes in the lumen of the colon. The fluid absorption is r uc . This

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. L-arginine administ r d to rats pre-treated with the NO synthase inhibitor, drastically reduced the ff ct of this inhibitor. Giv n alone, L-arginine did not modify aloe-induced diar hoea. Ba al Ca2+-d p nd nt NO ynthase activity in the rat colon was dose-dependently inhibited by aloe (0.1 – 20 g/kg bw) and by aloin (0.1 – 1 g/kg bw), the active

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.

5-aminosalicylic acid (100 µg/ml) inhibit d PAF release induced by the drugs. The authors concluded that rhein exerted its laxative effects by a mechanism that did not involve PAF release, and that aloe- emodin may act artly via PAF release.

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 L-arginine, is an important enteric inhibitory neurotransmitter. In addition, NO-donating compounds stimulate anion secretion in rat and g inea-pig colon.

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 Na+/K+-ATPase and the release of NO are relevant to stimulate the secretion of electrolytes and the relaxation of smooth intestinal muscles. Furthermore, investigations outlined that NO plays a new physiopathological role regarding PAF, which causes the contraction of the smooth musculature.

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 aloe-emodin in the faeces. Test person E consumed an oral ferric product additionally. This product seemed to support the cleavage of aloin. This was confirmed when test person A received a ferric pro uct to. The author concluded that the laxative effect depends on the cleavage of aloin in aloe-emodin.

Kopp H 1979

(29) tested in an open study Chol-Kugeletten® for 10 days in a combin tr atm nt of a

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. Chol-Kug l tt n® contains amongst others 25 mg aloe extract, 7 mg celandine extract, 5 mg curcuma root xtract, 30 mg Fel Tauri depurat. sicc. (ox bile), 2.5 mg bisacodyl and 2.5 mg pepp rmint oil. Tw lve pati nts received Chol-Kugeletten® and 6 patients placebo. Three patients of the v rum group w re xclud d because of incomplete data. Before the therapy begun, and after 5 and 10 ays of oral a ministration of one tablet three times a day, the secretion capacity of the in ivi ual patients was measured by means of an intraduodenal tube by Bartelheimer’s method. At these ates the secretion capacity was measured before and hourly after intraduodenal application of 3.33 ml Chol-Kugeletten® suspension (corresponding to 1 Chol-Kugeletten® tablet) or plac bo for five tim s. The choleresis could be raised significantly for hours. No further increase of the quantity of the s cr tion was obtained after 5 or 10 days of administration. The author concluded that th re is a compl te d v lopment of the action of the preparation that sets in immediately. Both the y t mic and the local tol rability of Chol-Kugeletten® were good; the upper abdomen symptoms could be all viat d in both groups, but more with Chol- Kugeletten®. No details are given in the publication.

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 aloe-emodin produced reproducible antitumour effects. Aloe-emodin ca sed mainly cytostasis and accumulation of the cells in the S and G2-M phases of the cell cycle ring the first 48 h of treatment. Thereafter, massive cell death ensued.

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 aloe-emodin inhibited proliferation of the adherent MCC cells, with a slight advantage of aloe-emodin over emodin. Aloin had no effect on cell proliferation. The chemotherapeutic agents, cis-platinol (abiplastin), doxorubicin (adriablastin), and 5-fluorouracil, and the tyrosine kinase inhibitor STI 571, all independently inhibited the proliferation of adherent MCC cells. The addition of aloe-emodin potentiated their inhibitory effect, especially when low concentrations of the anticancer compounds were used.

Chen HC et al. 2004

(68) evaluated the chemopreventive role of aloe-emodin in human promyelocytic leukemia HL-60 cells in vitro by studying the regulation of proliferation, cell cycle and apoptosis. The authors concluded that aloe-emodin appears to exert its anticarcinogenesis properties by inhibiting proliferation and inducing cell cycle arrest, and apoptosis underwent activation of caspase-3 in human leukemia HL-60 cells.

Lee HZ et al. 2001

(69),

2003

(70), and

2005

(71) demonstrated that aloe-emodin induced a

significant change in the expression of lung cancer cell apoptosis-related proteins compared to those of Supercontrol cells.seded

¾ Anti-inflammatory effect

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 UV-B-induc d immune suppr ssion. Furthermore, aloesin inhibited tyrosine hydroxylase and dihydroxyph nylalanine (DOPA) oxi ase activities of tyrosinase from normal human melanocyte cell lysates. Th r fore the authors r gard this substance as a positive pigment-altering agent.

Staphylococcus aureus, Streptococcus pyogenes, Coryn bact rium x rose and Salmonella paratyphi. Aloe-emodin and chrysophanol were ineffective.

Another investigation by

Liu M et al. 1996

(24) how d pot nt antibact rial activity of aloe-emodin (source not mentioned) against methicillin- e i tant Staphylococcus aur us.

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 (41-50 mm), high (31-40 mm), medium (21-30 mm), and low (11-20 mm). High zones of inhibition were noted with the ethanol extracts of the three plants.

II.2.2 Interactions

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 QT-prolongation (87). Concomitant use with medicinal products inducing hypokalaemia (e.g. diuretics, adrenocorticosteroids and liquorice root) may aggravate electrolyte imbalance.

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 35-year old woman lost 5l of blood during surgery as a result of a possible interaction between Aloe vera and sevoflurane. The authors stated that compounds contained in Aloe vera can cause a reduction in prostaglandin synthesis, which may inhibit secondary aggregation of platelets. Sevoflurane inhibits thromboxane A2 formation by suppression of cyclooxygenase activity,

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 anthranoid-containing laxativ s like s nna preparations. Please refer to the assessment report on “Cassia senna L. and Cassia angustifolia Vahl, folium”.

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 anthranoid-containing laxatives in 1996 (2).

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 soft-formed motion.

It is normally suffici nt to take an anthranoid-containing laxative up to two to three times a week (100).

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 celandine-aloe vera-psyllium, or placebo, in a double-blind trial including a 14-day basal period and a 28-day treatment period. Twenty one of

these had simple constipation, and the others suffered from irritabl bowel syndrome with

constipation. Organic causes for constipation were excluded. Nineteen patients on celandine-aloe vera-

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 14-day basal period. Patients on celandine-aloe vera-psyllium took 10.1 +/- 4.1 capsules per week and patients on placebo 15.8 +/- 6.9 capsules (p=0.02). The mean number of bowel actions per week in patients on celandine-aloe vera-psyllium increased from 4.6 +/- 2.4 to 7.9 +/- 3.9 (p<0.002) and in the placebo group from 3.9 +/- 1.6 to 4.3 +/- 2.1 (p-value not mentioned). The stool consistency score decreased significantly in the verum group (p<0.002), while the placebo group

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 celandine-aloe vera-psyllium group had a higher basal pain score than those receiving placebo (p<0.005), and there was no statistically significant improvement in either this or the placebo group during the trial. Overall, 16 of 19 patients on celan ine-aloe vera- psyllium regarded themselves as improved as compared with only 4 of the 13 patients on placebo (p<0.05). No subjects developed any side-effects from the treatment.

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).

Conclusion

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 anthranoid-containing laxativ s (pl ase refer to the assessment report on “Cassia senna L. and Cassia angustifolia Vahl, folium”) support the efficacy of these anthranoid-containing herbal substances for short-t rm use in cas s of occasional constipation.

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. Aloe-emodin is quickly oxidised to rhein and an unknown metabolite, or conjugated.

Aloe extract

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.

Sup

Morimoto I. et al.

erseded

1982

(76) reported the results of the Ames test and the rec-assay for 104 crude extracts including aloe. The investigators found neither water nor methanol extracts of aloe to have

mutagenic activity in Salmonella typhimurium strains TA-98 or TA-100. A water extract of aloe was reported to produce a positive effect in the rec-assay using Bacillus subtilis (difference in iameter between the inhibition zones for H17 und M45 strains: 2-5 mm). Approximately 35% of the investigated extracts were found to have activity in this test.

Brown JP 1980

(77) reported that barbaloin, a C-glycoside of aloe-emodin anthron , was not active in the rec-assay.

Marquardt et al. 1987

(cited in the unpublished report of Brusick DJ 1994 (78)) conduct d a more thorough evaluation of aloe-extract in the Ames test. A wi e range of mutant strains (TA-97, TA-98, TA-100, TA-102, TA-1535, TA-1537, and TA-1538) was inclu e , and “f calas ” (gut flora enzymes) was employed in order to breakdown any potentially active glycosi es. The results of this investigation were negative with the maximum test concentration set at 3,000 µg/plate. Barbaloin was also reported negative in this study.

In 1992 Cytotest Cell Research GmbH & Co. conducted a s ri s of g n tic tests using a batch of commercial aloe-extract (also cited in the unpubli hed r port of Brusick DJ 1994 (78)). The Ames test (employing TA-1535, TA-1537, TA-1538, TA-98, and TA-100) only produc d a mutagenic effect in strain TA-1537 at 5,000 µg/plate without and with S9 mix but not at the n xt lower concentration of 1,000 µg/plate.

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.

Aloe-extract was shown to be clastog nic in CHO cells. In the absence of S9 mix, aloe-extract induce significant increas s in chromosome b akage at concentration of 3000 µg/ml (30-hour harvest) and 4000 µg/ml (24-hour harv st). No clastog nicity was observed with S9 mix at concentrations up to 4750 µg/ml. How v r, an in vivo t st for clastogenicity with aloe-extract (Bootman J et al. 1987a, cited in the un ublish d r ort of Brusick DJ 1994 (78)) produced no evidence of a response in the mouse micronucleus t st at a maximum applicable dose of 1.5 gm/kg (orally).

Aloe-emodin

Brown JP and Dietrich PS 1979 (79) reported that aloe-emodin was mutagenic in Salmonella typhim ri m strain TA-1537. The mutagenicity was observed in the absence of S9 mix (terms of revertants per nmol test agent: 0.22; terms of revertants per plate less background for a given quantity (µg) of test agent: 22 (50 µg) without S9 activation, 13 (50 µg) with S9 activation; 61 (100 µg)

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 aloe-emodin in a broad spectrum of in vitro assays. Positive results were obtained in the Ames test with Salmonella typhimurium strains TA1537, TA1538, TA98 and TA1978. In the HPRT test, no reproducible induction of mutations was obtained, while unscheduled DNA synthesis (UDS) an cell transformation was induced. These results led to the conclusion that aloe-emodin interacts with bacterial and mammalian DNA under certain in vitro conditions (see also assessment report on “Cassia senna L. and Cassia angustifolia Vahl, folium”).

Heidemann A et al. 1996 (34) undertook in vitro and in vivo experiments to clarify the genotoxic potential of the hydroxyanthraquinone aloe-emodin. The results confirmed that aloe-emodin is able to induce mutagenic effects in vitro. In in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow cells of Wistar rats; mouse spot test [DBA/2J x NMRI]) no indication of a mutagenic activity of aloe emodin was found. Information about a possible reaction of aloe-emodin with DNA was derived from an in vivo UDS assay. Hepatocytes of aloe-emodin treated male Wistar rats did not show DNA damage via repair synthesis. These data

suggest that aloe-emodin is able to interact with DNA under certain in vitro conditions. However, in Supersededvivo the results did not indicate a genotoxic potential. Therefore the authors assume that a genotoxic

risk for man might be unlikely.

Lee KH et al. 2000

(36) isolated di(2-ethylhexyl)phthalate (DEHP) from Aloe vera L. For his stu ies he used freeze-dried powder of leaves. The substance was isolated using solv nt xtraction and

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 di(2-ethylhexyl)phthalate (DEHP) and mono-(2- thylh xyl)phthalate (MEHP) were administered by stomach intubation (per os, PO) or by intrap riton al (IP) inj ction to pregnant ICR strain mice at varying doses on days 7, 8, and 9 of gestation. In groups given DEHP orally, resorptions and malformed foetuses increased significantly at 1,000 mg/kg. Fetal weights were also significantly suppressed. Anterior neural tube d f cts (an nc phaly and exencephaly) were the malformations most commonly produced. No teratog nic ff cts w re r v al by IPl oses of DEHP

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 S-9

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.

A 2-generation reproduction study of DEHP in rats (Schilling K et al.) has documented effects on reproductive performance and fertility in the F0 and F1 parental animals at 1,088 mg/kg bw/day. ubstance-induced signs of adverse developmental toxicity were noted in the progeny of the F0 and F1 parents from 340 mg/kg bw/day onwards. The No Observed Adverse Effect Level (NOAEL) for reproductive performance and fertility was 340 mg/kg bw/day and for developmental toxicity

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).

III.3.3 Conclusion

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). Aloe-emodin is quickly oxidised to rhein and an unknown metabolite or conjugat d.

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 breast-fee ing women are already excluded. Furthermore, the duration of use is limit d. Up to now no furth r r strictions are justified.

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 50-70 A.D. Aloe is a purgative for the stomach and abdomen and in jaundice. It represses haemoptysis. Aloe administered externally heals

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, non-active haemorrhoids, amenorrhea, ascarides; for the two last may be given by enema.

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.

Conclusion

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 aloe-emodin, might represent a genotoxic risk. However, results from in vivo investigations (34) did not indicate a genotoxic potential. In vitro assays overestimate the potential hazard from exposure and must be reevaluated by in vivo experiments.

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 (1,8-dihydroxy-9, 10-anthracenedione = danthrone) for 16 months at the concentration of 1%. Twelve out of 18 rats survived more than one year. Of these, 7 rats developed intestinal tumours of the colon or caecum, adenomas or adenocarcinomas. Besides these neoplasms, focal hyperplastic lesions of the glandular epithelium of the colon and caecum were frequently encountered in treated animals both with and without intestinal tumours. In the liver of

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). Carcinogen-induced hyperplastic lesions have been regard d as an important pr cursor change for malignancies in various experimental models.The authors th r fore stat that the l sions obtained here appear to indicate a certain carcinogenic potency of chrysazin in mic , and mouse intestine may be less sensitive than rat intestine to the carcinogenic action of the chemical. The incidence of hepatocellular carcinoma of mice given chrysazin (4/17) was significantly higher than that of the controls (0/19). However, benign hepatoc llular n oplasms w re also seen in the animals of the control group. The authors therefore conclud d that chrysazin nhanced the progression of spontaneously occuring hepatocarcinogenesis.

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, aloe-emodin, chrysophanol, and hein e ulted in a 2-3-fold increase of DNA synthesis; lucidin and purpurin were less active, and emodin, purpuroxanthin, and alizarin were essentially

methylcholanthrene. The r sults of th se in vit o studies suggest that hydroxyanthraquinones, possessing 2 hydroxy groups in 1,8-positions, e.g. danthron, rhein, and chrysophanol, may have tumour-promoting activiti s .

In a model of dim thylhydrazin (DMH)-induc d colorectal tumours in male mice neither aloin- nor sennoside-enriched di ts (0.03% corr sponding to 100 mg/kg/day) promoted incidence and growth of adenomas and carcinomas after 20 weeks as evidenced by different endpoint parameters, based on a macrosco ic evaluation and microscopic examination. In the DMH-induced tumour model a tumour incidence a eared which allowed an increasing or decreasing effect to be detected after additional treatment, i. . a 50% incidence of tumour-bearing animals. With regard to hepatotoxic and nephrotoxic effects, DMH itself enhanced plasma levels of GPT and SDH which were further significantly increased by coadministration of aloin. The anthranoids alone had no effect. No effects on ser m electrolyte concentrations were observed after any of the treatments (49).

The aim of the study of Schörkhuber M et al. 1998 (50) was to demonstrate the effect of the 1,8- dihydroxyanthraquinone (DHA)-laxatives, danthrone, rhein, aloe-emodin and sennidine, on colorectal tumour cells, because available information on their implication in colon carcinogenesis was still inconclusive. In SW480 carcinoma cultures, dose-dependent induction of urokinase secretion into the medium was the predominant effect. Simultaneously, cell numbers were decreased by DHA-aglyka, but not by sennoside nor the biphenylic laxative bisacodyl. DNA synthesis was not similarly reduced: 0.4-4 µM danthrone and sennidine even stimulated 5-bromo-2’-desoxyuridine (BrdU) uptake into DNA. When uptake was normalised to cell number, danthrone and sennidine doubled BrdU uptake/106 cells, 18 µM rhein and 0.7 µM aloe-emodin induced increases of 37 and 50%, respectively. This may at least partially be due to selective resistance of S-phase cells to DHA-caused cell loss. In VACO235 adenoma cells, sennidine and aloe-emodin did not affect urokinase secretion, but stimulated growth.

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).

Super¾ 14-week st dy in mice seded The size of the gro ps and the administered concentrations were the same as described above. This

¾ 16-day study in F344/N rats

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.

¾ 2-year (105 weeks) study in rats

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 12-month interim evaluations and at 2 years, emodin-related increases in the incidences of renal tubule hyaline droplets occurred in all exposed groups. The incidences of renal tubule pigmentation were significantly increased of all exposed groups of males at 2 years. There were negative trends in the incidences of mononuclear cell leukaemia in male and female rats, and the incidences in the 2,500 ppm groups were significantly decreased. In females exposed to 2,500 ppm,

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 12-month interim evaluation, the severity of n phropathy was slightly increased in males exposed to 625 ppm. Also at 12 months, the severity of nephropathy increased from minimal in the lower exposure groups to mild in females exposed to 1,250 ppm; the inci ence in this group was significantly increased compared to the control group. At 2 years, the severities of nephropathy were slightly increased in males expos d to 625 ppm and f mal s exposed to 1,250 ppm. The incidences of nephropathy were significantly incr as d in all xpos d groups of females. At the 12-month interim evaluation, the incidences of r nal tubule pigm ntation w re significantly increased

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 14-week study, negative results were seen in male mice, but a weakly positive response was observed in similarly ex osed females.

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 large-bowel cancer.

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 (anthranoid-containing) laxatives.

Sonnenberg A et al 1993

(55) erformed a meta-analysis, since individual case control studies failed to resolve the question whether constipation and use of cathartics (purgatives) represent significant risk factors of colorectal cancer. The analysis of 14 previously published (from 1954 to 1988) case control st dies revealed statistically significant risks for colorectal cancer associated with both constipation and se of cathartics, the pooled odds ratios (OR) and their 95 percent confidence intervals being 1.48 (1.32-1.66) and 1.46 (1.33-1.61), respectively. The increased risk applied similarly to both sexes, it was higher in cancer of the colon than rectum. Since constipation and cathartics are associated with much lower odds ratio than various dietary components, such as fat, meat, alcohol, and low-vegetable or low-residue diets, the authors concluded that their risk reflects the confounding influence of underlying dietary habits.

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 anthranoid-containing laxatives to determine if these preparations were potential colorectal carcinogenics. Results indicated no significant difference of the PMC rates between carcinoma (6.1%)

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 case-control study among men and women aged 30 – 62 years (424 incident cases and 414 random-digital-dial controls). Constipation was defined by “feeling constipated to the point of having to take something”. The adjusted relative risk (RR) was 2.0 [95% confidence interval (CI) = 1.2-3.6] for constipation 12-51 times per year, and 4.4 (95%CI = 2.1-8.9) for constipation 52 or more times a year. Cumulative lifetime use of commercial laxatives was also

Supersededlevels of homocysteine, folate and cobalamine in a population-based sample of aged people. Elevated plasma homocysteine secondary to reduced supply of folate and cobalamine, might indicate an

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 = 0.1-0.9 for less than 350 uses; RR = 0.9, 95% CI = 0.4-2.3 for 350 or more uses). The association with constipation remained. In this study, no subject reported use of anthranoid-containing laxatives.

Nusko G et al. 2000

(57) performed a prospective case control study at the University of Erlangen to investigate the risk of anthranoid-containing laxative use for the developm nt of color ctal a nomas or carcinomas. A total of 202 patients with newly diagnosed colorectal carcinomas, 114 pati nts with

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 0.4-1.7) and for carcinomas 0.93 (95% CI 0.5-1.7). Also, there were no diff r nc s b tw n the pati nt and control groups for duration of intake. Macroscopic and high grade microscopic m lanosis coli were not significant risk factors for the development of adenomas or carcinomas.

Willems M et al. 2003

(58) described a ca e of m lano is coli, which occurr d in a 39-year old liver transplant patient, who took an over-the-count r product containing alo , rh um and frangula. The typical brownish pigmentation of the colonic muco a d v lop d in a p riod of ten months. The anthranoid medication was stopped and follow-up colono copy one year later showed normal looking mucosa once more. Howeve , in cont a t to p evious examinations, a sessile polypoid lesion was

Roberts MC et al. 2003 (91) conduct d a population-based, case-control study with equal representation by white and black m n and wom n aged 40 – 80 years. Constipation, defined as fewer than three re orted bow l mov m nts p r w k, was associated with a greater than two-fold risk of colon cancer (OR 2.36; 95% CI = 1.41-3.93) adjusted for age, race, sex, and relevant confounders. The OR for consti ation was slightly higher for distal than for proximal colon cancers. There was no association with laxative use (OR 0.88; 95% CI = 0.69-1.11). The authors did not explicitly mention

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 long-t rm stimulant laxative use

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.

IV.1.3 Conclusion

Because of the possible genotoxic or tumourigenic ri k in xp rim ntal inv stigations and the results of Siegers 1993, pharmacovigilance actions for anthranoid-containing laxatives (2) were initiated in

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 long-term use of anthranoid-containing laxatives is till open. Some studies revealed a risk for colorectal cancer associat d with the use of anth aquinone-containing laxatives, some studies did not. However, a risk was also r v al d for constipation itself and underlying dietary habits. Further

laxatives. This finding disappears 6 – 12 months after stopping chronic laxative administration. Long-term stim lant laxative use may result in anatomic changes in the colon characterised by loss of ha stral folds.

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 long-term use (80).

IV.3 Contraindications

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 side-effects inclu e “aloe vera” besides others.

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 anthranoid-containing laxatives, aloe-containing m dicinal products should not be used in cases of intestinal obstructions and stenosis, atony, app ndicitis, inflammatory colon diseases (e.g. Crohn’s disease, ulcerative colitis), abdominal pain of unknown origin, s v re dehydration states with water and electrolyte depletion.

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 QT-prolongation, diuretics, adrenocortico teroids or liquorice root, have to consult a doctor before

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.

Müller-Lissner 2005 (92) concluded in his review that th arguments in favour of laxative-induced damage to the autonomous nervous system of the colon are based on poorly documented experiments and that, in contrast, the investigations that do not support such damage are well done. The studies in the cited references (Smith B 1968 (93); Riemann JF et al. 1980 (94) and 1982 (95); Berkelhammer C et al. 2002 (96); Meisel JL et al. 1977 (97); Pockros PJ et al. 1985 (98)) showed abnormalities observed in humans (damage to enteric nerves, smooth muscle atrophy; distension or ballooning of axons, reduction of nerve-specific cell structures and increase in lysosomes, and sometimes a total degeneration of whole nerve fibers; short-lived superficial damage to the mucosa). They were uncontrolled observations and the author therefore concluded that the cause of these damages can also be the constipation itself or pre-existing changes of unknown aetiology.

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 soft-formed motion (2).

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).

Yellow or red-brown (pH d p nd nt) discolouration of urine by metabolites, which is not clinically significant, may occur during the tr atm nt (s chapter II.1.2 Absorption, metabolism and excretion).

Luyckx VA et al. 2002 (72) r ort d a case of a 47-year old man from Soweto, South Africa, who develo acute oliguric renal failure and liver dysfunction after ingestion of an herbal remedy. The patient’s renal function recovered slowly, and dialysis was discontinued after several weeks, although ser m creatinine did not return to the normal range. Mass spectrometric and chromatographic analysis of the herbal remedy sed by the atient revealed the presence of “Cape aloes”.

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 45-year old patient, who regularly takes levothyroxine, developed glucosuria, albuminuria, haematuria, and leucocyturia after taking the aloe extract. This patient was suspected to have a toxic-interstitial nephritis and nutritive-toxic tubular injury. One week after dechallenge the urinary findings improved. The aloe extract was suspected to cause these adverse events. The extract was not specified. Therefore an assessment whether the extract is comparable with the preparations described in this assessment report or not is not possible. Nevertheless albuminuria and haematuria are known adverse reactions of chronic misuse of aloe preparations.

IV.7 Overdose

Like for all anthranoid-containing laxatives, the major symptoms of overdose/abuse are griping pain and severe diarrhoea with consequent losses of fluid and electrolyte, which should be replaced. Diarrhoea may cause potassium depletion, in particular. Potassium depletion may lead to cardiac disorders and muscular asthenia, particularly where cardiac glycosides, diuretics or

adrenocorticosteroids are being taken at the same time.

Superss bstances for short-term use in cases of occasionalededconstipation.

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 anthranoid-containing medicinal pro ucts may lead to toxic hepatitis (see below).

Hepatitis

Beuers U et al. 1991

(101) reported a case of toxic hepatitis related to abuse of s nna glycosi s in a

26-year old female, who had taken an extract of senna fruits corresponding to 100 mg of s nnoside B daily in addition to the usual dose of 10 g senna leaves twice a week in a laxative t a. Wh n the pati nt stopped taking senna, aminotransferases fell by 70% within a week and rang from 20 – 40 U/l subsequently. When the patient took senna alkaloids again, 2 months lat r, liv r function rapidly deteriorated and improved once more when the product was stopped.

Vanderperren B et al. 2005

(102) reported a case of a 52-year old woman, who had ingested, for more than 3 years, one litre of an herbal tea each day made from a bag containing 70 g of dry senna fruits. She developed renal impairment and acute hepatic failure with incr ase in prothrombin time

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 well-designed studies with mono-preparations of aloe are missing.

The conditions determined in the pharmacovigilance actions for anthranoid-containing laxatives have to be maintained for the moment because further investigations are needed to clarify the carcinogenic risk. The results of the most recent studies are inconsistent. However, a risk was also revealed for constipation itself and underlying dietary habits.

1 As referred to in the HMPC ‘Guideline on the assessment of clinical safety and efficacy in the preparation of Community herbal monographs for well-established and of Community herbal monographs/entries to the Community list for traditional herbal products/substances/preparations’ (EMEA/HMPC/104613/2005)

The use in children under 12 years of age is contraindicated and use during pregnancy and lactation is not recommended.

Traditional use

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.