INTRODUCTION, NOMENCLATURE, AND GEOGRAPHICAL DISTRIBUTION
This article reviews the plant species commonly known as “senna” that have traditional and modern pharmaceutical uses as stimulant laxatives.
There were about 330 Cassia species, of which about 300 have been moved to the genus Senna for reasons of evolutionary relationships, with about 30 retained in the genus Cassia.1 As an example, 23 Sudanese Cassia species were reclassified into three allied genera: Senna Mill. (13 species), Chamaecrista Moench. (three species), and Cassia L. (seven species).2
In the United States, the standardized common name “senna” refers to Senna alexandrina Mill.3 This can be confusing because Cassia angustifolia, C. acutifolia, and C. senna remain accepted synonyms for Senna alexandrina. The European Pharmacopoeia continues to treat C. angustifolia and C. senna as distinct species, each with different geographic origins, morphology, quality and grade designations, and contents of active principles. As such, this article will describe these two species in terms of their Latin pharmacopeial and trade names.
This article does not address other types of senna used medicinally, such as American senna (C. marilandica), formerly official in the United States Pharmacopeia (USP)4; coffee senna (C. occidentalis), described in the Ghana Herbal Pharmacopoeia 20155; dog senna, also called Senegal senna or Tripoli senna (C. italica), listed in the Malian Pharmacopoeia6; purging senna (C. fistula), described in the Ayurvedic Pharmacopoeia of India Volume I7; ringworm senna (S. alata), described in the Malaysian Herbal Monograph 2015; sickle-pod senna (C. obtusifolia and/or C. tora), described in the Pharmacopoeia of the People’s Republic of China 20158 and in the Ayurvedic Pharmacopoeia of India Volume III; and tanner’s senna (C. auriculata), which is also used in Ayurvedic medicine.9
Cassia angustifolia (syn. S. alexandrina), the commercial supply of which is obtained from semi-arid to arid zones of India, and C. senna (syn. C. acutifolia and S. alexandrina), obtained from Sudan and Egypt, are perennial xerophytic (adapted to survive with little water) undershrubs,10 reaching 1 to 2 m (3.3-6.6 ft) in height, with small yellow flowers and compound leaves with four to eight pairs of leaflets that are bluish-green to pale green and emit a characteristic fetid odor when crushed.11 Leaflets of C. angustifolia range from 20 to 50 mm (0.79-1.97 in) in length and 7 to 20 mm (0.28-0.79 in) in width at the center, while C. senna leaflets range from 15 to 40 mm (0.59-1.58 in) in length and 5 to 15 mm (0.20-0.59 in) in width. Dried fruits (pods) of C. senna are usually 40 to 50 mm (1.58-1.97 in) long and at least 20 mm (0.79 in) wide, with six to seven seeds, and contain at least 3.4% of hydroxyanthracene glycosides (HAGs). The pods of C. angustifolia are usually 35 to 60 mm (1.38-2.36 in) long and 14 to 18 mm (0.55-0.71 in) wide, with five to eight seeds, and may contain only 2.2% or more of HAGs.12
Cassia senna, traded as “Alexandrian senna,” referring to the main Egyptian port from where it was exported historically,13 is indigenous to parts of northern Africa (Egypt and Sudan),14 eastern Africa,10 and across the Red Sea in Hejaz (a region in western Saudi Arabia).15 In Egypt, this species occurs in the southern part of the Eastern Desert (part of the Sahara Desert between the Nile River and the Red Sea) as well as in the Gebel Elba and Sinai regions.10 In Sudan, C. senna (referred to there as “Khartoum senna”) is widespread and occurs within the Nubian Desert and along the course of the Nile River from the central Sudanese state of Khartoum northwest to Dongola in the state of Northern in Sudan.16 The species is also widespread from northeastern Sudan along the Red Sea coast to the eastern African countries of Eritrea, Djibouti, Somalia, and Kenya.10
Cassia angustifolia, traded as “Tinnevelly senna” or “Indian senna,”11 is native to the Arabian Peninsula, Somaliland,17 and Yemen.18 It was introduced to India in the mid-18th century in the Tirunelveli District in Tamil Nadu, which was known as Tinnevelly during British colonial rule. Senna cultivation was introduced to the Indian state of Rajasthan only recently, near the end of the 20th century.19 Its occurrence in the wild in the Indian state of Gujarat indicates that it has become naturalized over the past approximately 250 years since its introduction.17 Three states in India (Tamil Nadu, Rajasthan, and Gujarat) now produce the majority of all senna in global trade.
HISTORY AND CULTURAL SIGNIFICANCE
“Cassia” is derived from the Greek kasia (meaning “aromatic shrub”), which was later used by Swedish botanist Carl Linnaeus (1707-1778) in reference to medicinal senna.20 The term “senna” is derived from the Arabic sanaa (meaning “thorny bush”), also sana in Persian and sena in Urdu.21 In his 1753 publication Species Plantarum, Linnaeus listed 26 Cassia species, including C. senna, and stated its habitat as Egypt.22 Danish-Norwegian botanist and herbalist Martin Henrichsen Vahl (1749-1804) later named C. angustifolia in his 1790 work Symbolae Botanicae, reporting its habitat as Arabia.23
Chemical analyses of wine residues absorbed into pottery jars dating to about 3150 BCE suggest that senna may have been a component of certain ancient Egyptian medicated wines, although the data are not yet conclusive.24 While some literature suggests that senna was used in ancient Egyptian medicine — as reportedly described in the Ebers Papyrus, a formulary of prescriptions dated to about 1550 BCE25 — other sources claim that no archaeobotanical evidence exists to support that senna was used in ancient Egypt.26 In 1834, Egyptian mummy expert Thomas Joseph Pettigrew (1791-1865) described one method of embalming that involved washing the inside of the body with a purgative liquor, which was supposedly composed of an infusion of senna and cassia (Cinnamomum spp., Lauraceae), followed by salting the body for 70 days.27 However, a paper published in 1960 in Economic Botany disputed Pettigrew’s account, arguing that it was extremely doubtful that senna or cassia were used in any embalming processes.14
While the use of senna as a cathartic was first documented sometime in the ninth century in Arabia,13 there is some archeological evidence of senna pod trade from the early Roman (first and second centuries) Egyptian Red Sea harbor of Berenike, which functioned as a trade hub between the Mediterranean and the Indian Ocean Basin.28 Arabian traders reportedly established trade between the Roman Empire and India of botanicals, including the pulp of purging senna (C. fistula) from India, Babylonia, and Arabia; senna from Cassia species native to Nubia, Arabia, and India; and a preparation of sickle-pod senna (C. tora).29 Some literature suggests that ninth-century physician Serapion the Elder, of Baalbek (in Lebanon), was the first to recommend medicinal uses of senna. Egyptian-Jewish physician Yitzhak ben Shlomo ha-Yisrael, also known as Isaac Judaeus (ca. 832-932), wrote that senna from Mecca was the best quality. In any case, Arabian physicians were responsible for the eventual introduction of senna to European medicine.18
Due to the known side effects of using senna as a monopreparation, such as mild abdominal discomfort or cramps, it has been used traditionally in formulations containing other herbs observed to counteract the side effects. In 1820, senna (C. senna leaves) was included in the primary Materia Medica of the first publication of the USP, as well as monographs for several traditional senna-containing medicinal preparations. These include:
- “Confection of Senna,” also called “Lenitive Electuary” (senna leaf with coriander [Coriandrum sativum, Apiaceae] fruit, licorice [Glycyrrhiza glabra, Fabaceae] root, fig [Ficus carica, Moraceae] fruit, prune [Prunus domestica, Rosaceae] fruit, tamarind [Tamarindus indica, Fabaceae] fruit pulp, and refined sugar [Saccharum officinarum, Poaceae])
- “Compound Infusion of Senna” (senna leaf with supertartrate of potass [cream of tartar], ginger [Zingiber officinale, Zingiberaceae] rhizome, and boiling water)
- “Infusion of Senna and Tamarind” (senna leaf with tamarind fruit, coriander fruit, sugar, and boiling water)
- “Aromatic Tincture of Senna,” also called “Warner’s Gout Cordial” (senna leaf with coriander fruit, fennel [Foeniculum vulgare, Apiaceae] fruit, red sanders [Pterocarpus santalinus, Fabaceae] wood, saffron [Crocus sativus, Iridaceae] stigma, licorice root, stoned (no stones, pits, or pips) raisins [Vitis vinifera, Vitaceae], and diluted alcohol)
- “Compound Tincture of Senna,” also called “Elixir Salutis” (senna leaf with bruised jalap [Ipomoea jalapa, Convolvulaceae] root, coriander fruit, caraway [Carum carvi, Apiaceae] fruit, bruised cardamom [Elettaria cardamomum, Zingiberaceae] seed, diluted alcohol, and sugar).4
In 1833, a monograph titled “Senna, U.S., (Sennae Folia)” was included in the first edition of the United States Dispensatory (USD), which permitted several different species to furnish the official drug, including C. acutifolia (syn. C. senna), C. elongata, and C. obovata (syn. S. italica). For use as a purgative, the USD monograph stated that although senna leaf is sometimes prepared in the form of a confection or tincture, the form of infusion (herbal tea) is almost universally preferred.13
Indian government ministries have established standards for the various grades and qualities of senna produced in India. In addition to the official senna monographs of the Indian Pharmacopoeia,30 the Ayurvedic Pharmacopoeia of India,7 and the Unani Pharmacopoeia of India (of the Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy, or AYUSH),21 India’s Ministry of Agriculture established “AGMARK” grade designations in 1964 that defined the quality of Tinnevelly senna (C. angustifolia) leaves and pods. Interestingly, grade designations were also established for permitted blends of Tinnevelly senna leaf with tanner’s senna leaf.31
In 1975, the US Food and Drug Administration (FDA) proposed the establishment of monographs for nonprescription, over-the-counter (OTC) laxative, antidiarrheal, emetic, and antiemetic drug products that listed various senna substances (e.g., senna leaf powder, senna fluidextract, senna fruit extract, senna pod concentrate, senna syrup, and sennosides A and B, crystalline) as safe and effective stimulant laxative active ingredients for short-term relief of constipation.32 Stimulant laxatives are agents that promote bowel movement by one or more direct actions on the intestines. Ten years later, in 1985, the FDA published a tentative final monograph for OTC laxative drug products listing the same senna ingredients with dosage and labeling statement requirements.33 However, in 1998, the FDA proposed to amend its tentative final monograph for OTC laxative drug products to reclassify aloe (Aloe barbadensis and A. ferox, Xanthorrhoeaceae) latex, bisacodyl, cascara sagrada (Frangula purshiana, Rhamnaceae) bark, and senna (including sennosides A and B) from Category I (Generally Recognized as Safe and Effective [GRASE]) to Category III (safety and/or efficacy unknown; further testing is required).34 In a 2002 final rule, only aloe and cascara were removed from the FDA monograph and placed into Category III. Senna and official preparations made from it remain classified as safe and effective OTC laxative active ingredients.35
The United States Pharmacopeia (USP) provides official monographs for “Senna Leaf USP,” “Senna Pods USP,” “Senna Fluidextract USP,” “Senna Oral Solution USP,” “Sennosides USP,” and “Sennosides Tablets.”36 Furthermore, in 2000, the FDA ruled that certain OTC drug monograph claims, including claims listed in its laxative drug monograph, would also be acceptable structure/function claim statements for dietary supplement products. In particular, this included the claim “for the relief of occasional constipation,” because occasional constipation is not a characteristic symptom of a disease.37 This led to the remarkable situation in which senna-based OTC drug products and dietary supplement products could now be labeled and marketed with the same label claim. However, supplement labels must bear the additional disclaimers: “This product is not intended to cure, treat, mitigate, or prevent a disease,” and “This claim has not been evaluated by the Food and Drug Administration.”
In 1993, the German Commission E approved the use of both “Senna leaf” and “Senna pod” as nonprescription medicines for treating constipation.38 Since then, national labeling standards monographs of European Union (EU) member states, such as those of the German Commission E, have been superseded by monographs of the European Medicines Agency (EMA). In 1999, comprehensive monographs (quality and therapeutics) for “Folium Sennae” and “Fructus Sennae” were included in volume one of the WHO Monographs on Selected Medicinal Plants.6 In 2006, the EMA published labeling standards monographs for senna leaf39 and senna pod40 (of PhEur-quality and supplied from either Alexandrian/Khartoum senna or Indian/Tinnevelly senna), applicable when used as active ingredients of licensed well-established use herbal medicinal products (WEU-HMPs) in the EU. Correspondingly, the European Directorate for the Quality of Medicines (EDQM) published quality standards monographs for “Alexandrian Senna Pods PhEur,” “Tinnevelly Senna Pods PhEur,” “Senna Leaf PhEur,” and “Senna Leaf Standardized Dry Extract PhEur.”12
CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND MEDICINES
Although the types of senna described in this article originate from northern and eastern Africa and neighboring Arabia, senna was incorporated into Asian and European systems of medicine hundreds of years ago. In countries where the Ayurvedic system of medicine is practiced, senna leaf (स्वर्णपत्री, svarnapatri in Sanskrit) is used in formulations for the treatment of constipation and diseases of the abdomen.7 In the Unani system of medicine, senna leaf (sana makki in Romanized Arabic) is used in formulations for treating arthralgia (joint pain), lumbago (backache), hip pain, sciatica, gout, cardiac asthma (a type of coughing or wheezing that occurs with left heart failure), scabies, acne, pimples, and colic.21 In Chinese medicine, senna leaf (番 瀉 葉 , fanxieye in Pinyin transliteration) is indicated for treating accumulation of heat marked by constipation and abdominal pain, as well as for edema.8
In the United States, the FDA classifies selected senna substances (Senna Leaf USP, Senna Pods USP, Senna Fluidextract USP, Senna Oral Solution USP, and Sennosides USP) as GRASE active ingredients of laxative drug products. The permitted indication for use statement is “for relief of occasional constipation,” which may be followed by the word “irregularity.”33 Senna is also permitted as a component of dietary supplement products, which require FDA notification within 30 days of marketing if a structure/function claim is made and product manufacturing that conforms with dietary supplement current Good Manufacturing Practices (cGMPs).41
HAGs are considered to be the primary active components of senna. The HAGs present in senna include both dianthrone glycosides (including sennosides A, A1, B, C, and D) and anthraquinone glycosides (including rhein-8-O-glucoside and rhein-8-sophoroside).42,43 The leaves and pods of senna contain slightly different amounts and ratios of these compounds; the leaves contain approximately 1.5-5% HAGs (75-80% of which are dianthrones), and the pods contain 2.2-3.5% HAGs (85-90% of which are dianthrones).42,44 The sennosides, particularly sennosides A and B, are thought to be primarily responsible for the purgative (laxative) effects of senna by increasing fluid secretion and influencing colonic motility and fecal transit time.6 Senna also contains naphthalene glycosides, which are not considered to be pharmacologically significant but can be used to distinguish C. angustifolia from C. senna (tinnevelin glycoside is found only in C. angustifolia and 6-hydroxymusizin glycoside is found only in C. senna).42 In addition to the various glycosides, senna leaves and pods contain small amounts of flavonoids (e.g., derivatives of kaempferol and isorhamnetin), mucilage (e.g., galactose, arabinose, and rhamnose), polyols (e.g., pinitols), minerals, and sugars.44
Human clinical trials largely have focused on senna’s laxative effects. Researchers have investigated senna’s ability to relieve different types of constipation (e.g., chronic, drug-induced, and postoperative) in various populations, including children, postpartum women, and the elderly. Similarly, senna has been investigated as a bowel-preparation method for use before diagnostic procedures such as colonoscopy or abdominal imaging.45,46 While most studies involve off-label uses for serious conditions (e.g., chronic constipation), the safety and efficacy of OTC senna preparations for non-serious conditions (e.g., occasional constipation) is well-established.33,39
The Natural Standard Research Collaboration (NSRC), an independent, science-based research organization, published a systematic review in 2011 that examined and graded evidence from randomized controlled trials (RCTs) of senna for the previously mentioned conditions. Although some of the reviewed studies reported significant favorable effects for chronic constipation, drug-induced constipation, and colonoscopy preparation, as discussed below, the NSRC ranked the overall scientific evidence as “unclear or conflicting.”45
Two of the seven reviewed studies on chronic constipation assessed the effects of a senna preparation in postpartum women. Both studies used Senokot (Avrio Health LP; Stamford, Connecticut), a standardized senna preparation that contains “the equivalent of 7 mg sennosides A and B” per dose.47 The first study was a single-blind comparative trial of 175 women published in 1973 that compared Senokot to Normacol (Norgine Limited; Amsterdam, Netherlands), a bulk-forming laxative that contains sterculia (Sterculia spp., Malvaceae) and frangula (Frangula spp., Rhamnaceae) bark powders and docusate sodium.48 The second study was an RCT of 267 women published in 1980 that compared Senokot to an identical placebo that contained powdered cornflakes and dried grass.47 Both studies found that Senokot was significantly better than the control at relieving constipation in this population of women.
Of the three studies on drug-induced constipation reviewed by the NSRC, only one small study found significant favorable effects for senna in relation to gastric emptying and small and large intestinal transit time.49 The 1993 study examined the effects of a senna preparation in 24 subjects who were given loperamide (an anti-diarrheal medication commonly sold under the brand name Imodium [Johnson & Johnson; New Brunswick, New Jersey]) to simulate opioid-induced constipation. Patients were given loperamide and gastrointestinal (GI) transit time was measured. GI transit time was remeasured after the patients were given one of three active preparations: (1) Sennatin, a product that contains 20 mg of purified sennosides; (2) Agiocur (MEDA Pharma GmbH & Co.; Bad Homburg, Germany), a fiber product that contains 20 g of psyllium (Plantago ovata, Plantaginaceae) seeds/husks; or (3) Agiolax (Flordis; Crows Nest, NSW, Australia), a combination product that contains 5.4 g of psyllium seeds/husks and 1.2 g of senna pods containing 30 mg of sennosides. Although the quality of the study was ranked as “poor,” the authors reported that the two preparations containing senna were able to significantly reduce GI transit time.
None of the four studies that examined the use of senna before abdominal diagnostic procedures reported significant effects, and only two of the 11 reviewed studies on the use of senna prior to colonoscopy found significant favorable effects. The first (Valverde et al., 1999) was a randomized, single-blind equivalence trial of 523 patients with colonic or rectal carcinoma that compared a senna preparation to polyethylene glycol (PEG), an osmotic laxative.50 The study, which was one of the few that the NSRC authors ranked as “good” quality, found that the senna preparation performed significantly better than PEG in preparing patients for abdominal imaging. The second study (Radaelli et al., 2005) was a randomized, single-blind equivalence trial comparing a senna preparation to PEG in 283 adults who were preparing for a colonoscopy.51 The authors concluded “that overall cleansing was better with senna compared to the standard PEG solution.”45
An earlier systematic review published in 2005 assessed the evidence supporting the use of traditional medical therapies for chronic constipation, including senna. The authors found no placebo-controlled trials of senna for the period reviewed and included only studies that compared senna preparations to other stimulant laxatives (e.g., products containing anthraquinone derivatives or bisacodyl, a conventional pharmaceutical drug for constipation) or lactulose (a conventional osmotic laxative used for constipation). “Three studies that compared a preparation containing psyllium and senna with lactulose suggested that the fiber/stimulant [psyllium/senna] combination was more efficacious and may even be more cost-effective,” the authors noted. However, the authors concluded that, overall, there was “a paucity of quality data” regarding the use of senna preparations for chronic constipation.46
FUTURE OUTLOOK AND SUSTAINABILITY
There are three main producers and exporters of senna leaves and pods: India (cultivated only), Sudan (mostly wild harvested and some cultivated), and Egypt (wild harvested and cultivated). India is now the world’s largest senna-producing region, with a cultivation area of about 22,000 hectares (54,363 acres). In the agricultural year (April to March) 2014-2015, India’s top three exported botanical drugs were psyllium husk and seed, sickle-pod senna (C. tora) seed, and senna (C. angustifolia) leaves and pods.19 In the 2015-2016 agricultural year, India exported 15,952,830 kg (35,169,970 lbs) of senna leaves and pods with a customs value of about $14,530,000. In the subsequent agricultural year 2016-2017, India exported 12,744,070 kg (28,095,865 lbs) of senna leaves and pods.52 More than 70% of India’s export volume of senna is imported by only 10 countries: Vietnam, China, Japan, Germany, Poland, the United States, Egypt, Spain, Thailand, and Mexico. Domestic consumption of senna leaves and pods by the Indian herbal drugs industry is estimated at about 1,284,350 kg (2,831,507 lbs) annually.19 Furthermore, India produces an estimated 180,000 kg (396,832 lbs) of sennosides (partially purified natural complex of anthraquinone glucosides obtained from senna leaflets and/or pods) annually, of which about 140,000 kg (308,647 lbs) are exported.53
In Sudan, senna pod — along with two other Sudanese botanicals, gum arabic (Acacia senegal and A. seyal, Fabaceae) and hibiscus flower (Hibiscus sabdariffa, Malvaceae) — ranks among the top 10 export commodities and is prioritized for increased export potential.54 In 2014, Sudan exported about 5,052,000 kg (11,137,754 lbs) of senna pods55 but only about 2,300,000 kg (5,070,632 lbs) in 2015.56 Separate data for Sudan’s exports of senna leaf are not provided. A relatively minor amount is produced in Egypt for export. One report estimated about 5,000 kg (11,023 lbs) was exported from the St. Katherine Protectorate, a national park in the South Sinai region, in one year.57 Senna, however, reportedly is the most common medicinal plant wild-collected by local Bedouin pastoralists living in downstream Wadi Allaqi, a major dry river in the southeastern part of the Eastern Desert of Egypt and a UNESCO Biosphere Reserve.58 The Bedouins use senna (local name senamekki) medicinally but also as a grazing resource and for fuel.59 The primary author of this article (JB) is aware, however, of increasing certified-organic cultivation of senna in Egypt.
Although Batanouny (1999) reported that wild senna has been overexploited in Egypt for trade, and should be cultivated in marginal land with limited water resources,10 the conservation status of C. senna has not yet been assessed according to the International Union for Conservation of Nature (IUCN) Red List Categories and Criteria. This would be relevant for the commercial supply of wild-collected senna from the Sudan and Egypt. The commercial supply of C. angustifolia is procured entirely from cultivation in India, where it is an introduced species, and, since the mid-2000s, cultivation of certified organic senna has increased steadily. Before 2000, there was almost no certified organic senna in the global market.
The main risks to a sustainable supply of senna leaves and pods for the global phytopharmaceutical market include increasingly unpredictable rainfall (for example, where the senna crop is monsoon-dependent) and the fact that senna is procured largely in conflict zones. Although the United States lifted sanctions against Sudan in 2017 that had been in place for two decades, there has been almost constant ethnic and rebel militia fighting since the mid-20th century.60 (The US Department of State continues to advise against travel to the Darfur region, Blue Nile state, and South Kordofan state due to risks of terrorism and civil unrest.61) In Egypt, both home-based and foreign-based terrorist organizations operate in parts of the country where senna is produced.60 In northwestern India, commercial senna cultivation takes place near the border with Pakistan, where terrorist organizations operate and where both countries’ militaries are perpetually on high alert. India conducts war games along the Rajasthan and Pakistan border in preparation for war in a potentially nuclear-contaminated battlefield.62
Supply interruptions and shortages tend to invite economic adulteration in trade. Substitutes or adulterants of the senna supply may include plant parts of the tree of heaven (Ailanthus glandulosa, Simaroubaceae); tanner’s senna; C. holosericea; dog senna (C. italica); Deccan senna (C. montana); bladder senna (Colutea arborescens, Fabaceae); Currier’s sumach (Coriaria myrtifolia, Coriariaceae); province senna or wild senna (Globularia alypum, Plantaginaceae); argel (Solenostemma argel, Apocynaceae) leaf, which is used as an herbal tea in Sudan; and hoary pea (Tephrosia apollinea, Fabaceae).10 Although the government of India’s “Senna Leaves and Pods Grading and Marking Rules” permit the admixing of leaves of C. auriculata with leaves of C. angustifolia for some lower-quality grades of senna blends,31 a recent study assessing the authenticity of market samples in India uncovered examples of products in two Tamil Nadu markets labeled as “C. angustifolia” that were actually C. auriculata.63
Given its almost global regulatory status as an essential, safe, and effective medicine for the relief of constipation, annual demand for senna leaves and pods and preparations made from them will likely continue to increase. If the supply of senna from Egypt and Sudan was interrupted for socio-political reasons, establishment of commercial production bases in other senna range states, such as Eritrea, Somalia, Djibouti, and/or Yemen, may pose similar challenges and risks.
—Josef Brinckmann and Tyler Smith
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