Thursday, 3 May 2018

Psyllium Plantago ovata (P. ispaghula), P. afra (P. psyllium), and P. indica (P. arenaria)

Issue: 117 Page: 8-17 Family: Plantaginaceae by Gayle Engels, Josef Brinckmann HerbalGram. 2018; American Botanical Council INTRODUCTION The genus Plantago comprises about 200 species,1 with 56 subspecies, 33 forms, one subform, 188 varieties, and nine subvarieties.2 The species commonly called psyllium are important because of their highly mucilaginous seeds. An herbaceous plant, psyllium has opposite leaves with a midrib as its primary venation, smooth or slightly toothed margins, and pubescent stems. Flowers are borne on a spike, are green or white, and produce a seed capsule with two seeds each.3 The center of diversity for Plantago species is believed to be central Asia, although some species are now widely dispersed,4 including 10 species in India,5 21 in Egypt,6 and 21 in Turkey.2 There are at least 12 Iranian endemic P. ovata ecotypes.7 Although occurring rarely, P. afra is found in the Mediterranean region of southern Europe, northern Africa (Egypt), and western Asia (Jordan, Syria, and Turkey). In Egypt, P. afra is distributed in the Sahara Desert east of the Nile River in the Red Sea region, Gebel Elba region, and Sinai region.6 Plantago ovata, native to the Mediterranean region and western Asia,8 occurs in the wild mainly in desert regions of the Northern Hemisphere between the 26th and 36th latitudes,9 from northern Africa to parts of the Arabian Peninsula,6 to the central Asian deserts of Kyzyl Kum (Turkmenistan) and parts of southern Asia (Afghanistan, Iran, and Pakistan).10 It was introduced to India via the settlement of Arab Muslims on India’s west coast during the Middle Ages.11 Currently, western India (Gujarat and Rajasthan) is the world’s largest psyllium-producing region, with a cultivation area of about 60,000 hectares (148,263 acres).10 Plantago ovata is also cultivated in Iran.12 Although much of the literature claims that P. ovata is the only commercially cultivated species of the genus,4 Flora of China states that P. indica (syn. P. arenaria), which is native to northern Africa, parts of Europe, southwestern Asia, and central Asia (Kazakhstan, Kyrgyzstan, and Tajikistan), is cultivated in several provinces of China for its medicinal seeds.13 Although the psyllium of global commerce is supplied almost entirely by P. ovata from India, the seeds and seed coats (husks) of three species are monographed in national pharmacopeias and therapeutic compendia under various common names, including psyllium, ispaghula, and/or plantago, depending on the country. For example, the European Pharmacopoeia (PhEur) defines “Psyllium seed” as the ripe, whole, dry seeds of P. afra (syn. P. psyllium) or P. indica (syn. P. arenaria), while describing the dried, ripe seeds of P. ovata (syn. P. ispaghula) as “Ispaghula seed.”14 On the other hand, the United States Pharmacopeia (USP) defines “Plantago seed” as the cleaned, dried, ripe seed of P. psyllium or P. indica (syn. P. arenaria), known in commerce as Spanish or French psyllium; or P. ovata, known in commerce as blond psyllium or Indian plantago seed. Furthermore, USP defines “Psyllium husk” as the cleaned, dried seed coat (epidermis) separated by winnowing and threshing from the seeds of P. ovata, known in commerce as blond psyllium, Indian psyllium, or ispaghula; or of P. arenaria (syn. P. psyllium), known in commerce as Spanish or French psyllium.15 The different official compendia give different preferences as to which Latin binomial is accepted and which is a synonym, which potentially makes the nomenclature confusing when comparing pharmacopeial standards. HISTORY AND CULTURAL SIGNIFICANCE The many similarly spelled common names used for P. ovata in India (isabgol, isabgul, isapghul, isobgul, ispaghula, and isubgol) are derived from the Persian words isap and ghol, meaning “horse ear,” which refers to the shape of the seed.16 The Latin term psyllium stems from the Greek psulla meaning “flea,” which refers to the flea-like size, shape, and color of the seed.8 French botanist Joseph Pitton de Tournefort (1656-1708) described several species of the genus Plantago in his book Institutiones rei herbariae, published in 1700, although none of the species mentioned in his text are the subject of this article.17 In his 1753 publication Species Plantarum, Swedish botanist Carl Linnaeus (1707-1778) listed 16 Plantago species, including P. psyllium, stating its habitat as southern Europe, and P. cynops, stating its habitat as India.18 Plantago cynops is now considered a synonym of P. afra. In his 1759 Systema Naturae, Linnaeus added P. indica,19 with an epithet and references that suggested a habitat much further east than Europe.20 Indian government ministries have established standards for the various grades and qualities of psyllium produced in India. In addition to the “Ispaghula husk” monograph of the Indian Pharmacopoeia (an institution of the Ministry of Health and Family Welfare),21 India’s Ministry of Agriculture established three distinct “AGMARK” grade designations in 1982 that defined the quality of psyllium seed husk (Isubgol Husk Grade I, Grade II, and Grade “Special”).22 In 2006, the National Multi-Commodity Exchange of India Ltd. (NMCE), governed by the Ministry of Finance, introduced isabgol seed futures (agreements to buy or sell isabgol at a specific date in the future at a set price through a government-regulated commodity exchange) into its commodity trading system, which also established quality specifications and compliance requirements as terms of the futures contracts.23 Psyllium ingredients are differentiated by grade designations according to purity (e.g., 95% purity), which correspond to specific uses and minimum effective doses (e.g., the percentage of pure husk and the swelling index correspond to efficacy as a laxative). Indian exporters generally specify at least seven different purity grades (70%, 80%, 85%, 90%, 95%, 98%, and 99%). The 70% purity grade, known as “Industrial Grade Kha-Kha Powder” or “Psyllium Industrial Dust,” is a byproduct used mainly as horse feed and in veterinary medicines, but also in landscaping to prevent soil erosion.24 Other post-processing byproduct grades include “Lali” and “Golaisab,” both used as cattle feed; “Chito,” used as pig feed; and “Khakho,” used to prevent slipping on ice.16 The 80%, 85%, and 90% grades are used mainly as food additives, pharmaceutical aids (excipients), and/or dietary supplement ingredients, respectively. Purity grades of 95%, 98%, and 99%, the therapeutic grades generally conforming to pharmacopeial quality standards, are used mainly as bulk-forming laxative active ingredients or as soluble fiber supplement ingredients.24 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 psyllium substances (e.g., plantago seed, psyllium seed, psyllium seed husk, psyllium hemicellulose, and psyllium hydrophilic mucilloid) as safe and effective bulk-forming laxative active ingredients for short-term relief of constipation.25 Bulk-forming laxatives are agents that increase bulk volume and water content of the stool, thereby promoting bowel movement. Ten years later, in 1985, the FDA published a tentative final monograph for OTC laxative drug products listing the same psyllium ingredients with dosage and labeling statement requirements.26 The following year, the FDA amended the tentative final monograph by modifying the directions for the use of bulk laxatives.27 In 1992, the FDA reopened the monograph to include new data on the combination of psyllium and bran laxative active ingredients.28 In 2007, the FDA again amended the laxative monograph in order to remove the granular dosage form of bulk-forming psyllium ingredients for safety reasons (risk of choking). This rule did not apply to psyllium laxatives in nongranular dosage forms such as powders, tablets, or wafers.29 Because it is a requirement that OTC drug active ingredients adhere to USP quality standards, there are official monographs for “Plantago Seed USP” (dried, ripe seed of P. psyllium, P. indica, or P. ovata), “Psyllium Hemicellulose USP” (alkali-soluble fraction of the husk from P. ovata), “Psyllium Husk USP” (seed coat from the seeds of P. ovata, P. arenaria, or P. psyllium), and “Psyllium Hydrophilic Mucilloid for Oral Suspension USP” (dry mixture of Psyllium Husk USP with suitable additives). In 1998, the FDA decided to authorize certain health claims on the association between soluble fiber from psyllium seed husk and reduced risk of coronary heart disease (CHD).30 Furthermore, in 2000, the FDA ruled that certain OTC drug monograph claims, including claims listed in its laxative drug monograph, would now 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.31 This led to the remarkable situation in which psyllium-based OTC drug products and dietary supplement products could now be labeled and marketed with the same claim statement. And, due to the newly FDA-authorized health claim, some psyllium product labels began to carry both a “Drug Facts” box and a “Supplement Facts” box because different dosage, instructions, and other labeling statements applied depending on whether the product was intended to be used as an OTC laxative drug or as a dietary supplement for heart health. In 1985, the German Commission E approved the use of “Black Psyllium Seed” (P. afra and/or P. indica) as a nonprescription medicine for treating chronic constipation and irritable bowel. Subsequently, in 1990, the Commission E approved the use of both “Blond Psyllium Seed” (P. ovata) and “Blond Psyllium Seed Husk” for treating “chronic constipation; disorders whereby easy bowel movements with a loose stool are desirable, e.g., in patients with anal fissures, hemorrhoids, following anal/rectal surgery; during pregnancy; as a secondary medication in the treatment of various kinds of diarrhea and in the treatment of irritable bowel.”32 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 2006, the EMA published labeling standards monographs for “Psyllii semen” (seed of P. afra or P. indica),33 “Plantaginis ovatae seminis tegumentum” (seed coat of P. ovata),34 and “Plantaginis ovatae semen” (seed of P. ovata)35 (which were superseded by revised monographs in 2013), 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 in the PhEur for “Ispaghula Husk PhEur” (episperm and collapsed adjacent layers removed from the seeds of P. ovata), “Ispaghula Seed PhEur” (dried ripe seeds of P. ovata), and “Psyllium Seed PhEur” (ripe, whole, dry seeds of P. afra or P. indica).14 In 1999, a comprehensive monograph (quality and therapeutics) for “Semen Plantaginis” (dried, ripe seed of P. afra, P. indica, P. ovata, or P. asiatica) was included in volume one of the WHO Monographs on Selected Medicinal Plants.36 A subsequent monograph for “Testa Plantaginis” (epidermis and collapsed adjacent layers removed from the seeds of P. ovata) entered volume three of the WHO Monographs on Selected Medicinal Plants in 2007.37 CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND MEDICINES In India, “Ispaghula” is listed in the National List of Essential Medicines and monographed in the National Formulary of India as a laxative drug indicated for treatment of constipation and irritable colon syndrome.38 In the United States, the FDA classifies selected defined psyllium substances (Plantago Seed USP, Psyllium Hemicellulose USP, Psyllium Husk USP, and Psyllium Hydrophilic Mucilloid for Oral Suspension USP) as Generally Recognized as Safe and Effective (GRASE) bulk-forming 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.” Psyllium Husk USP may also be used in combination with another bulk-forming laxative active ingredient, Malt Soup Extract, which is obtained from partially germinated grain of one or more varieties of barley (Hordeum vulgare, Poaceae) that contain amylolytic enzymes. FDA also permits Psyllium Hemicellulose USP to be used in combination with the stimulant laxative active ingredient Sennosides USP (a partially purified natural complex of anthraquinone glucosides isolated from senna [Senna alexandrina, Fabaceae] leaflets and/or pods).26 Psyllium is also permitted as a component of dietary supplement products, requiring 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).39 Additionally, food supplement products that provide 7 g or more per day of soluble fiber from psyllium seed husk, of a purity of no less than 95% as required in the Psyllium Husk USP monograph, may be labeled with an FDA-authorized health claim to the effect of: “Soluble fiber from foods such as psyllium husk, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease.”30 MODERN RESEARCH Plantago species have complex chemical profiles, but the mucilaginous polysaccharide responsible for psyllium’s main mechanism of action is primarily made of xylose and arabinose (arabinoxylan), with small amounts of galactose, glucose, rhamnose, and galacturonic acid.40 This mucilage is thought to provide most of the antidiarrheal, laxative, demulcent, and emollient effects of psyllium. Numerous clinical studies, systematic reviews, and meta-analyses have been conducted on psyllium for its cholesterol-lowering, blood pressure-lowering, laxative, and related effects. Prior to the year 2000, at least eight clinical studies showed the efficacy of psyllium for treating hyperlipidemia alone. Two meta-analyses and one systematic review support the beneficial effects of psyllium supplementation on blood lipids. In a 1997 meta-analysis of 12 studies on 404 adults with mild-to-moderate hypercholesterolemia, it was shown that subjects who ate a psyllium-enriched cereal (≤ 3 g soluble fiber/day; species not stated) experienced lowered total cholesterol (TC; a 5% reduction) and low-density lipoprotein cholesterol (LDL-C; a 9% reduction) but not high-density lipoprotein cholesterol (HDL-C).41 A 2014 systematic review of 232 more recent studies also demonstrated the cholesterol-lowering effects of eating psyllium-enriched cereal, adding that improved glucose or insulin responses were seen in diabetic patients who ate high-fiber, psyllium-based cereals compared with regular cereals.42 A meta-analysis published in 2000 excluded studies on psyllium-enriched cereals and focused on studies in which subjects supplemented a low-fat diet with 10.2 g psyllium per day for eight or more weeks. Pooled data on 656 subjects in eight studies showed that psyllium significantly lowered TC by 4% and LDL-C by 7%.43 One randomized, double-blind, placebo-controlled, parallel clinical trial in 2014 evaluated the effects of psyllium on 51 children and adolescents (6-19 years old) with mild-to-moderate hypercholesterolemia. All subjects followed the National Cholesterol Education Program (NCEP) Step 2 diet (55% of calories as carbohydrates, 15% as protein, less than 30% as fat [less than 7% as saturated fatty acids], and less than 200 mg cholesterol daily) for six weeks. After two weeks, they were randomly assigned to take either 7 g of psyllium from P. ovata (Laxofibra [3.5 g hydrophilic mucilloid/5 g powder]; Almeida Prado Pharmaceutical Laboratory; São Paulo, Brazil) twice daily or placebo. At eight weeks, mean TC and LDL-C concentrations in the psyllium group were 6.7% and 11% lower than baseline values, respectively. Lipid profiles of the psyllium group were also significantly lower than those of the placebo group at eight weeks, but no significant changes were observed in the psyllium group in triglyceride or HDL-C concentrations, or in the LDL-C:HDL-C ratio. Additionally, normal cholesterol values were achieved in six (23%) of the 26 subjects in the psyllium group.44 Strangely, while the relief of constipation is one of the primary uses of psyllium, few high-quality clinical studies have investigated this use, and none thus far in the 21st century, as revealed in two meta-analyses conducted in 2012 and 2014.45,46 One of the few randomized, double-blind studies that evaluated psyllium for its benefits in chronic constipation compared it with docusate sodium and was published in 1998. After a two-week baseline placebo phase, subjects (N = 170, 20-70 years old) with chronic idiopathic constipation were randomly assigned to take 5.1 g psyllium (Smooth Texture Sugar-Free Orange-Flavored Metamucil; Procter & Gamble; Cincinnati, Ohio) plus docusate sodium placebo twice a day for two weeks or 100 g docusate sodium plus psyllium placebo. At the end of weeks one and two, the psyllium group showed a significant increase in stool water content (2.33% at the end of the treatment phase), corresponding to softer stools, compared to the docusate sodium group (0.01% at the end of the treatment phase). This effect started three days after initiation of treatment and increased over the treatment period. Additionally, in week two, psyllium increased stool output better than docusate sodium (359.9 g/week versus 271.9 g/week, respectively), and bowel movement (BM) frequency (3.5 BMs/week versus 2.9 BMs/week, respectively).47 A 2017 randomized, double-blind study investigated the effects of psyllium on abdominal pain and stool patterns in children with irritable bowel syndrome (IBS). After two weeks eating their normal diet followed by an eight-day diet that excluded carbohydrates (which are thought to cause IBS symptoms), children (7-18 years old) who did not experience ≥ 75% improvement in abdominal pain continued to the treatment phase. Subjects were randomly assigned to take psyllium (6 g for children 7-11 years old, 12 g for children 12-18 years old; Konsyl Pharmaceuticals; Easton, Maryland; no other information provided) or placebo for six weeks. Outcomes were measured by pain/stool diaries, breath hydrogen/methane, gut permeability, and microbiome composition. After treatment, the psyllium group experienced a significant reduction in pain compared to placebo (mean reductions of 8.2 ± 1.2 versus 4.1 ± 1.3, respectively, per the Numerical Rating Scale [NRS-11]). There were no significant changes in the other measurements between groups.48 In 2018, a systematic review and meta-analysis reviewed randomized controlled trials that evaluated the effect of viscous soluble fiber (VSF) on blood pressure. Studies were included if they addressed the effects of VSF supplements (psyllium, -glucan, guar gum, konjac [Amorphophallus konjac, Araceae], or pectin) or diets enriched with VSF on systolic blood pressure (SBP) or diastolic blood pressure (DBP), had a follow-up period of at least four weeks, and used fiber from a single source so that differences between fiber types could be evaluated. A total of 22 studies were reviewed, and the authors concluded that supplementation with VSF, particularly psyllium, can have a modest but statistically significant effect on lowering SBP and DBP, and that their review was the first to show that psyllium can significantly lower SBP.49 Since controlling hunger between meals is a challenge for some individuals trying to change their eating habits, Brum et al. (2016) investigated the effects of psyllium on satiety in two sequential randomized, double-blind, placebo-controlled, crossover design studies. In the first study, healthy subjects (N = 30, 18-55 years old) took 3.4 g or 6.8 g Metamucil in 295.7 mL water or placebo before breakfast and lunch for three days, or 10.2 g before breakfast only for three days. Meals were provided based on estimated individual energy requirements. Significant mean reductions in hunger and desire to eat and increased fullness between meals were experienced with all three doses compared to placebo, with the 6.8 g dose resulting in the most consistent satiety. In the second study, subjects (N = 44) took 6.8 g Metamucil in 295.7 mL water or placebo before breakfast (energy-restricted) and lunch on days one and two, and before breakfast (energy-restricted) only on day three. While the psyllium group experienced statistically significant reductions in mean hunger and desire to eat and increased fullness over three days compared to placebo, the satiety was less than in the first study.50 FUTURE OUTLOOK In the 2015-2016 agricultural year (April to March), India exported 38,055,580 kg (83,898,193 lbs) of psyllium husk and 1,552,530 kg (3,422,743 lbs) of psyllium seed. In the subsequent crop year 2016-2017, India exported 35,422,980 kg (78,094,303 lbs) of husk and 1,005,170 kg (2,216,021 lbs) of seed. On average, the United States imports about 45% of India’s total annual psyllium husk export quantity, and most of the remainder is imported by Germany, Italy, Mexico, Pakistan, the United Kingdom, Belgium, Malaysia, Australia, France, and China.51 More than 99% of psyllium husk imported by the United States originates from India.52 The main importers of Indian psyllium seed, however, are Germany, Iran, Sweden, Pakistan, and the United Arab Emirates.51 Based on data from the past five years, the United States imports an average of about 16,270,080 kg (35,869,386 lbs) of psyllium husk annually, placing psyllium among the top medicinal plants imported and used in the United States. (For comparison, in 2016, the United States imported about 542,000 kg [1,194,905 lbs] of ginseng [Panax spp., Araliaceae] root from China, Canada, and South Korea).52 The significant use of psyllium is not quantified in the various annual market surveys that rank herbal dietary supplement consumption in the United States,53 likely because most psyllium products are labeled and marketed as OTC botanical drug products, although many are labeled as both OTC drugs and fiber supplement products. India dominates the world market in the production and export of psyllium ingredients. Some of the main buyers include the Procter & Gamble Company (Metamucil), Morepen Laboratories Ltd. (Dr. Morepen Fibre-X Sat Isabgol),8 Konsyl Pharmaceuticals (Konsyl Original Formula), and Madaus GmbH (Agiolax), among others.54 Of India’s total psyllium production, about 75% of the crop from Gujarat state and about 90% of the crop from Rajasthan state is exported. About 93% of the crop exported from Gujarat and Rajasthan is psyllium husk. There are about 70 Indian companies that export psyllium husk and seed, with the leading processors and exporters based in Sindhpur in the Mehsana district and in Palanpur in the Banaskantha district of Gujarat state.8 According to Batanouny (1999), P. afra is endangered in Egypt due to habitat loss. Although there is some cultivation, the species is in need of ex situ conservation.6 The International Union for Conservation of Nature (IUCN) European Red List of Medicinal Plants assigns P. afra, P. indica (syn. P. arenaria), and P. ovata to the conservation category of least concern (LC), meaning that these Plantago species are not threatened in Europe.55 Lal et al. (2009) reported an urgent need to collect more variability from both wild and cultivated populations of P. ovata (i.e., diverse genotypes must be collected, evaluated, and used for direct introduction in cultivation or as parents for conservation and crop improvement purposes). It is predicted that the rapid replacement of P. ovata landraces (domesticated, locally adapted, traditional varieties) by highly uniform varieties will continue, leading to an eventual disappearance of genetic resources that have adapted over hundreds of years.11 There are at least six high-yielding varieties of P. ovata cultivated in India, including P. ovata var. “Jawahar Isabgol 4” available from the Medicinal and Aromatic Plant (MAP) unit at the College of Horticulture, Mandsaur in Madhya Pradesh and P. ovata var. “Niharika” released by the Central Institute of Medicinal and Aromatic Plants (CIMAP) in Lucknow, Uttar Pradesh.8 The genetic diversity of psyllium crops is a major concern to some plant breeders and germplasm curators. In a study to determine the genetic diversity and relationships among 38 genotypes of seven Plantago species in India, a diversity analysis using phenotypic and molecular markers showed that the seven species were significantly different from each other but variability within P. ovata was very limited. The authors suggest that induced mutation could be used to widen the range of variation in breeding strategies to improve crop yield and disease resistance.56 Since P. ovata is an introduced crop in India, productivity has been constrained by biotic stress (caused in plants due to damage instigated by other living organisms) and abiotic stress (caused in plants by drought, flooding, extreme temperatures), leading to heavy losses in quality and yield. Crop improvement has been difficult due to limited genetic resources. Some agronomists suggest that among the approximately 200 wild crop relatives of P. ovata there exists a reservoir of important genes that they believe, if introgressed to cultivated P. ovata through marker-assisted breeding, could lead to genetic improvement of the crop.57 Introgression is the incorporation (usually via hybridization and backcrossing) of alleles (a variant form of a gene) from one species into the gene pool of a second, divergent species.58 Research to characterize the genetic variability of wild P. ovata genotypes that occur in southern Iran is also being carried out for the purpose of breeding new varieties.59 Given its almost global regulatory status as an essential, safe, and effective medicine for relief of constipation and as a good source of soluble fiber for heart health, annual demand for psyllium will probably continue to increase. Indian psyllium is already a large-scale export-oriented crop. The questions are whether genetic variability can be preserved and used for maintaining and improving crop quality and yields and whether India will maintain its long-term dominance on psyllium cultivation for the international market. —Gayle Engels and Josef Brinckmann References Singh N, Lal RK, Shasany AK. Phenotypic and RAPD diversity among 80 germplasm accessions of the medicinal plant isabgol (Plantago ovata, Plantaginaceae). Genet Mol Res. 2009;8(4):1273-1284. Tutel B, Kandemir I, Kuş S, Kence A. Classification of Turkish Plantago L. species using numerical taxonomy. Turk J Bot. 2005;29(1):51-61. Applequist W. The Identification of Medicinal Plants: A Handbook of the Morphology of Botanicals in Commerce. Austin, TX: American Botanical Council; St. Louis, MO: Missouri Botanical Garden Press; 2006. Dhar MK, Friebe B, Kaul S, Gill BS. Characterization and physical mapping of ribosomal RNA gene families in Plantago. Ann Bot. 2006;97(4):541-548. 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