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Comments on EFSA's opinion about the health claim "improvement of bowel function" for hydroxyanthracenic derivatives.

Dear Sir,

European Food Safety Agency (EFSA) Panel on Dietetic Products, Nutrition and Allergies recently recognized the health claim "improvement of bowel function" for hydroxyanthracenic derivatives containing plants and their preparations (EFSA, 2013,2014). (1) These plants are stimulant laxatives of well-established therapeutic use according to EMA (2006-2008). They are classified as "medication" and considered as a last line resource to treat constipation by World Gastroenterology Organization (WGO, 2010). (2) This medicinal use is also recognized by WHO (1999,2002). These organizations consider that medical supervision is needed in order to insure that a severe etiology will not be masked by the spontaneous consumption of active substances in constipation patients.

We would like to underline the sanitary problems that are likely to arise from uncontrolled delivery of products containing hydroxyanthracenic derivatives and from poor quality dietary supplements that could occur on the market. Noteworthy, these plants are all mentioned in the "EFSA Compendium of botanicals that have been reported to contain toxic substances" (EFSA, 2009), and American Food and Drug Administration (FDA) does not currently consider them nor their preparations as Generally Recognized as Safe (FDA, 2013).

Toxicity, misuse, drug interactions: The toxicity of these plants and their derived medicinal products is well documented and occurs in cases of prolonged use or overdose, as well as in specific populations. According to EMA, it "may lead to impaired function of the intestine and dependence on laxatives" (EMA, 2006c). Abuse of these products indeed leads to withdrawal syndrome with constipation. This symptom clearly is an incentive to repeated use (Lullman et al., 2005), as reported by many pharmacists. The most severe consequences are hypokalaemia, hypocalcaemia, metabolic acidosis, malabsorption, weight-loss, albuminuria, and haematuria, as mentioned by WHO (1999), EMA (2006-2008), French Drugs Agency (Agence Nationale de Securite des Medicaments) (ANSM, 1997) and ESCOP (2003). The observed hypokalaemia can lead to cardiac problems, and is a cause of drug interactions (ESCOP, 2003,2009; Williamson et al., 2009). EMA states that "hypokalaemia (resultingfrom long-term laxative abuse) potentiates the action of car diac glycosides and interacts with antiarrhythmic medicinal products, [... those] which induce reversion to sinus rhythm (e.g. quinidine), [... those] inducing QT-prolongation. Concomitant use with other medicinal products inducing hypokalaemia (e.g. diuretics, adrenocorticosteroids and liquorice root) may enhance electrolyte imbalance" (EMA, 2006-2008). It can be noticed that abuse leading to health risk is particularly likely to occur:

--In patients developing a laxative-dependency problem, especially in the elderly;

--In case of consumption for weight-loss purposes, especially associated to anorexia nervosa, as mentioned in assessment reports published by EMA (2006-2008).

In France, populations susceptible to misuse laxative products are in some extent protected by the drug status of these over-thecounter products, as they are deli vered by a pharmacist or under the supervision of a pharmacist only. Indeed, deliverance is supposed to be possible only in the conjunction of;

--Actual need of a laxative;

--When therapeutic effect cannot be achieved by a change of diet or the administration of bulk forming agents;

--When there are neither contra-indications nor any risks of drug interactions.

Some of these aspects were taken into account by EFSA panel: "In relation to the restrictions of use, (3) the Panel notes that stimulant laxatives should not be consumed continually for periods longer than one to two weeks" (EFSA, 2013). This statement slightly differs from the opinion of EMA, which considers that "normally it is sufficient to take [these] medicinal products up to two to three times a week", with a maximum duration of two weeks. In the above mentioned populations susceptible of being exposed to misuse, it is likely that some individuals will override EFSA advices, as reported by many pharmacists who frequently refuse delivery of over-the-counter laxatives. Indeed, misuse of laxative drugs appears to be highly prevalent in the global population (Austin et al., 2013; Croll et al., 2002; Motola et al., 2002; Neims et al., 1995; Roerig et al., 2010). Theophile et al. (2009) reported that 30% of laxative (including stimulant laxatives) users take self-prescribed laxatives daily for more than a year. Subsequent severe adverse effects were reported, as reviewed in assessment reports published by EMA (2006-2008).

Dose: EFSA considers that in order to claim an "improvement of bowel functions", no less than 10 mg of hydroxyanthracenic derivatives should be consumed daily. This is equivalent to the lower maximal dose proposed by EMA for adolescents (i.e. from the age 12), (4) and is indeed enough to obtain mild therapeutic effect in adults. According to community monographs published by EMA (2006-2007), "the correct individual dose is the smallest required to produce a comfortable soft-formed motion". This agency defines a maximal dose of 30 mg of hydroxyanthracenic derivatives per day in adults. In the list of plants that can be used in dietary supplements in Belgium, a maximal dose is defined as 18 mg per day for Cassia spp. and 25 mg per day for Rheum spp. (Moniteur Beige, 2012). The absence of a maximal dose in the opinion expressed by EFSA clearly constitutes a risk of overdose.

In the Belgian list, it is stated that, for Cassia and Rheum spp. derived dietary supplements, each batch of the product shall be controlled for hydroxyanthracenes content (Moniteur Beige, 2012). This statement is linked to a risk of overdose with poorly controlled products, and should have been considered by EFSA.

Age-limit: WHO, EMA and French Drugs Agency (ANSM) contraindicate the use of hydroxyanthracenic derivatives in children (age-limit: 12 years-old--sometimes 10 depending on the plant/agency). ESCOP does not recommend use in children below 10 (ESCOP, 2003, 2009). There are several risks linked with the use of laxatives in children, especially with this pharmacodynamic class (ESCOP, 2003; WGO, 2010). This was also not considered by EFSA, which only states that the target population of the claim is adults, without any specific restrictions mentioned in its conclusions.

Other health and vigilance issues: According to EMA, "the question of a possible carcinogenic risk of long-term use of anthranoid-containing laxatives is still open and the results of the more recent studies are inconsistent. Therefore the conditions determined in the pharmacovigilance actions for anthranoid-containing laxatives have to be maintained" (EMA, 2007b,c). The French "nutrivigilance" system is devoted to record side effects of dietary supplements, but such a system has not been implemented in every EU member country.

Other issues, such as breast-feeding and pregnancy, were considered by EMA and WHO. The latter contra-indicates hydroxyanthracenes during pregnancy. For EMA: "as a consequence of experimental data concerning a genotoxic risk of several anthranoids, e.g. emodin and aloe-emodin, use is not recommended during pregnancy" (EMA, 2006a,b). ESCOP (2003) considers that use is not recommended during the first trimester of pregnancy only.

Therefore we consider that the opinion expressed by EFSA panel may present a health risk due to:

--The absence of a maximal dose and of mentions regarding quality assessment:

--The absence of specific statements regarding drug interactions;

--The absence of specific statements regarding children and pregnancy;

--The status of these plants as dietary supplements and the subsequent absence of control in delivery which are likely to facilitate misuse.

These comments were submitted to the European Commission (SANCO.DDC2.E.4 "Nutrition, food composition and information/Nutrition and health claims" office) on 29th, November 2013, under a similar form, as permitted in authorization procedure for individual applications under Art. 13(5) of Regulation (EC) No 1924/2006. The HMPC also expressed its concern (EMA, 2014).

http://dx.doi.Org/10.1016/j.phymed.2014.02.015

References

ANSM, 1997. Les Cahiers de l'Agence no3, Medicaments a base de plantes. Agence du Medicament, La Plaine Saint Denis., pp. 35-39.

Austin, S.B., Penfold, R.B., Johnson, R.L., Haines, J., Forman, S., 2013. Clinician identification of youth abusing over-the-counter products for weight control in a large U.S. integrated health system. J. Eat. Disord. 1 (40), 1-7.

Croll, J., Neumark-Sztainer, D., Story, M., Ireland, M., 2002. Prevalence and risk and protective factors related to disordered eating behaviors among adolescents: relationship to gender and ethnicity. J. Adolesc. Health 31 (2), 166-175.

EFSA, 2009. EFSA Compendium of botanicals that have been reported to contain toxic substances. EFSAJ. 7 (9), 281.

EFSA, 2013. Scientific opinion on the substantiation of a health claim related to hydroxyanthracene derivatives and improvement of bowel function pursuant to Article 13(5) of Regulation (EC) No 1924/20061. EFSA J. 11 (10), 3412.

EFSA, 2014. Technical Report: Response to Comments on the Scientific Opinion on the Scientific Substantiation of Health Claims related to Hydroxyanthracene Derivatives and Bowel Function. EFSA supporting publication 2014: EN-550, 7 p.

EMA, 2006a. Community Herbal Monograph on Aloe barbadensis Miller and Aloe (various species, mainly Aloe ferox Miller and its hybrids), EMEA/HMPC/76310/2006 Corrigendum, 9 p.

EMA, 2006b. Community Herbal Monograph on Cassia senna L., fructus and Cassia angustiolia Vahl, fructus, EMEA/HMPC/51871/2006 Corr., 9 p.

EMA, 2006c. Community Herbal Monograph on Cassia senna L. and Cassia angustiolia Vahl, folium, EMEA/HMPC/51869/2006 Corrigendum, 10 p.

EMA, 2006d. Community Herbal Monograph on Rhamnus frangula L., cortex, EMEA/HMPC/76307/2006 Corrigendum, 8 p.

EMA, 2007a. Assessment Report on Aloe barbadensis Miller and Aloe (various species, mainly Aloeferox Miller and its hybrids), EMEA/HMPC/76313/2006, 24 p.

EMA, 2007b. Assessment Report on Cassia senna L., fructus and Cassia angustiolia Vahl, fructus, EMEA/HMPC/51870/2006, 6 p.

EMA, 2007c. Assessment Report on Cassia senna L. and Cassia angustiolia Vahl, folium, EMEA/HMPC/51868/2006 Corr., 32 p.

EMA, 2007d. Assessment Report on Rhamnus frangula L, cortex, EMEA/HMPC/76306/2006, 22 p.

EMA, 2007e. Community Herbal Monograph on Rhamnus purshianus D.C., cortex, EMEA/HMPC/513579/2006 Corr., 9 p.

EMA, 2007L Community Herbal Monograph on Rheum palmatum L. and Rheum officinale Baillon, radix, EMEA/HMPC/189624/2007 Corr., 9 p.

EMA, 2008a. Assessment Report on Rhamnus purshianus D.C., cortex, EMEA/HMPC/513580/2006, 27 p.

EMA, 2008b. Assessment Report on Rhubarb (Rhei radix), EMEA/HMPC/189626/ 2007, 31 p.

EMA, 2014. Committee on Herbal Medicinal Products (HMPC): Minutes of the 11-12 November 2013 meeting, EMA/HMPC/742564/2013, 28 January, pp. 5-6.

ESCOP, 2003. Aloe capensis: Frangulae Cortex: Rhamni purshiani Cortex: Rhei Radix: Senna Folium: Senna Fructus acutifoliae; Senna Fructus angustifoliae. European Scientific Cooperation on Phytotherapy Monographs, vol. 1., 2nd ed. Georg Thieme Verlag, Stuttgart, pp. 26-31, 169-173, 413-418, 419-424, 456-476.

ESCOP, 2009. Aloe barbadensis. European Scientific Cooperation on Phytotherapy Monographs, vol. 1., 2nd ed. Georg Thieme Verlag, Stuttgart, pp. 6-10.

FDA, 2013. Alphabetical List of SCOGS Substances. http://www.fda.gov/Food/ IngredientsPackagingLabeling/GRAS/SCOGS/ucm084104.htm

Lullman, H., Mohr, K., Hein, L, Bieger, D., 2005. Color Atlas of Pharmacology, 3rd ed. Georg Thieme Verlag, Stuttgart, pp. 177.

Moniteur Beige., 2012. Arrete royal modifiant l'arrete royal du 29 aout 1997 relatif a la fabrication et au commerce de denrees alimentaires composees ou contenant des plantes ou preparations de plantes (19 mars 2012), vol. 113. Moniteur Belge, pp. 20962-21058.

Motola, G., Mazzeo, F., Rinaldi, B., Capuano, A., Rossi, S., Russo, F., Vitelli, M.R., Rossi, F., Filippelli, A., 2002. Self-prescribed laxative use: a drug-utilization review. Adv. Ther. 19,203-208.

Neims, D.M., NcNeill, J., Giles, T.R., Todd, F., 1995. Incidence of laxative abuse in community and bulimic populations: a descriptive review. Int. J. Eat. Disord. 17 (3), 211-228.

Roerig, J.L., Steffen, K.J., Mitchell, J.E., Zunker, C, 2010. Laxative abuse: epidemiology, diagnosis and management. Drugs 70 (12), 1487-1503.

Theophile, H., Miremont-Salame, G., Abouelfath, A., Begaud, B., Haramburu, F., 2009. Patterns of laxative use in self-medication. Ann. Pharmacother. 43 (12), 2122-2123.

WGO, 2010. WGO Guidelines 2010. Constipation: A Global Perspective. http://www.worldgastroenterology.org/assets/export/userfiles/05_constipation. pdf

WHO, 1999. Aloe; Fructus Sennae: Folium Sennae; Rhizoma Rhei. WHO Monographs on Selected Medicinal Plants, vol. 1. World Health Organization, Geneva, pp. 33-42, 231-258.

WHO, 2002. Cortex Frangulae; Cortex Rhamni purshianae. WHO Monographs on Selected Medicinal Plants, vol. 2. World Health Organization, Geneva, pp. 114-123,259-268.

Williamson, E., Driver, S., Baxter, K., 2009. Stockley's Herbal Medicines Interactions. Pharmaceutical Press, London.

Sabrina Boutefnouchet

Laboratoire de Pharmacognosie, CNRS UMR 8638,

UFR Pharmacie, Univ. Paris Rene-Descartes, France

Pierre Champy *

Laboratoire de Chimie des Substances Naturelles, CNRS UMR 8076 BioCIS, UFR Pharmacie, Universite

Paris-Sud, France

Thierry Hennebelle

Groupe Substances Naturelles, EA 4481, UFR

Pharmacie, Universite Lille 2 Droit et Sante, France

Alexandre Maciuk

Laboratoire de Chimie des Substances Naturelles, CNRS UMR 8076 BioCIS, UFR Pharmacie, Universite

Paris-Sud, France

* Corresponding author at: Laboratoire de Chimie

des Substances Naturelles, CNRS UMR 8076 BioCIS, UFR Pharmacie, Univ. Paris-Sud, 5 rueJ.-B.

Clement, 92296 Chatenay-Malabry, France.

Tel.: +33 1 46 83 56 39; fax: +33 1 46 83 55 99.

E-mail address: pierre.champy@u-psud.fr

(P. Champy)

12 December 2013

(1) Root and rhizome of Rheum palmatum L and/or Rheum officinale Baillon and/or their hybrids, leaves or fruits of Cassia senna L. and/or Cassia angustifolia Vahl, bark of Rhamnus frangula L., bark of Rhamnus purshianus D.C., Aloe barbadensis Miller and/or various aloe species, mainly Aloeferox Miller (EFSA, 2013).

(2) These advices shall be considered in regard to possible interpretations of the health-claim "improvement of bowel function" by the public. EMA stated that "Senna traditionally used for purification of [...] bowel and other organs [...] is now obsolete" (EMA, 2007b).

(3) Other restrictions of use proposed by EFSA are: "The use of stimulant laxatives for more than two weeks requires medical supervision. Long-term use of stimulant laxatives should be avoided owing to the danger of electrolyte imbalance, impaired function of the intestine, and dependence on laxatives. Stimulant laxatives should only be used if an effect on bowel function cannot be achieved by a change of diet or the administration of bulk forming agents."

(4) Except for Rheum spp. (20-30 mg in adolescents once daily; 30 mg per day as the maximum dose in adults) and Senna (from 15 mg per day in adults and adolescents) (EMA, 2007b,c, 2008a,b). For the whole class, WHO proposes the adult daily doses 20-30 mg (WHO, 1999,2002). For ESCOP (2003,2009), doses vary from 10 to 30 mg per day depending on the species (up to 50 mg for Rhei Radix).
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Title Annotation:Correspondence; European Food Safety Agency
Author:Boutefnouchet, Sabrina; Champy, Pierre; Hennebelle, Thierry; Maciuk, Alexandre
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Jun 15, 2014
Words:2359
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