Abstract: Hemorrhoidal disease is a common problem which is usually not managed properly with pharmacologic interventions and will eventually require surgery. However, there are many medicinal plants that were successfully used for the treatment of hemorrhoids in the traditional and folk medicine of different countries. In this study, these medicinal plants have been reviewed and their mechanism of action and their major chemical constituents responsible for their activities have been assessed individually. Among various herbal medicines, Aesculus hippocastanum, Boswellia species, Cissus quadrangularis, Euphorbia prostrata, Juniperus species, Melastoma malabathricum, Myrtus communis and Verbascum species have got higher support from scientific evidence. These medicinal plants may exert their beneficial effects in hemorrhoids by their anti-inflammatory, analgesic and venotonic activities. Several chemical constituents were identified in these plants which may be responsible for their pharmacological activities, of which, flavonoids, terpenoids, triterpenes and tannins are the majors.
INTRODUCTION
“Hemorrhoids” are vascular cushions with a thick submucosa involving the smooth muscle, connective tissues and blood vessels around the anus. Any enlargement, bleeding and protrusion of these cushions is responsible for pathologic hemorrhoids (Thomson, 1975).
Many elements are involved in development of pathologic changes within the hemorrhoidal cushions such as genetics, dysregulation in evacuation of the feces like constipation or diarrhea, sustained strain due to several diseases or conditions and aging. These issues lead to increased pressure within the submucosal arteriovenous plexus and ultimately contribute to swelling of the cushions, laxity of the supporting connective tissue and protrusion into and through the anal canal (Sneider and Maykel, 2010; Lohsiriwat, 2012). Hemorrhoidal disease is a prevalent difficult, for instance, about one million new cases are detected each year in the United States. The estimate is that 5% of the general population is affected by symptoms from hemorrhoids, with 50% of people over the age of 50 having experienced symptoms related to hemorrhoids at some point in time (Sneider and Maykel, 2010). Current conventional treatment of hemorrhoids includes lifestyle modification, pharmacologic therapies and surgery. Pharmacologic therapies include drugs like calcium dobesilate as a venotonic agent, topical agents containing anesthetics and corticosteroids and physical therapies such as ice and sitz baths (Lohsiriwat, 2012). In the current years, medicinal plants have been considered as potentially effective and more tolerable agents for the treatment of different pathological conditions in the gastrointestinal system from mouth to rectum (Rahimi and Abdollahi, 2012a; Rahimi et al., 2009, 2010). The medicinal plants with anti-bleeding, venotonic, anti-inflammatory and antinociceptive activities may be useful for treatment of hemorrhoids. In this study, the medicinal plants with any capacity used for the management of hemorrhoids have been criticized and their possible mechanisms of action and their major chemical constituents responsible for their activities have been appraised.
PLANTS FOR THE TREATMENT OF HEMORRHOIDS
Medicinal plants with antihemorrhagic activity and their possible mechanisms of action and their components responsible for their activity have been discussed below. Table 1-3 show in vitro, in vivo and clinical studies related to their antihemorrhagic activity, respectively.
Aesculus hippocastanum L.: The seed of Aesculus hippocastanum has been used in Europe to treat hemorrhoidal disease (Kucukkurt et al., 2010; Anonymous, 2009).
| Table 1: | In vitro studies on plants used in TIM for treatment of hemorrhoids |
| Cox: Cyclooxygenase, ACh: Acetylcholine | |
| Table 2: | In vivo studies on plants used in TIM for treatment of hemorrhoids |
| EPP: Ethyl phenylpropiolate, TPA: 12-O-tetradecanoylphorbol-13-acetate | |
A clinical trial on A. hippocastanum confirmed that clinical and endoscopic symptoms after average six days of administration to patients with acute symptomatic hemorrhoids was improved (Pirard et al., 1976). The key active component found in A. hippocastanum seed extract is aescin. The aescin is a combination of triterpene saponins existing in two forms of α and β. Of these two forms, β-aescin is the active one. Aesin has anti-inflammatory, venotonic and anti-edematous activities (Sirtori, 2001).
Boswellia species: Gum resins of Boswellia species, particularly B. serrata Roxb. ex Colebr. and B. carterii Birdw. have been used in traditional Iranian medicine for the management of hemorrhoids (Arzani, 2005). There are many reports about the anti-inflammatory action of gum resin and its major constituents, boswellic acids (Siddiqui, 2011; Ammon, 2006). Boswellic acids are pentacyclic triterpenes with anti-inflammatory and anti-cancer activities (Poeckel and Werz, 2006).
Cestrum species: Cestrum auriculatum L'Hér. and C. hediundinum have been used in Peruvian traditional medicine for treatment of hemorrhoids. These two species have shown in vivo analgesic effects and in vitro anti-inflammatory activity (Kawano et al., 2009).
Cissus quadrangularis Linn.: The C. quadrangularis, a medicinal plant indigenous to Asia and Africa, is used for treatment of hemorrhoids. C. quadrangularis demonstrated analgesic, anti-inflammatory and venotonic activities. The analgesic property of C. quadrangularis is because of inhibition of some local mediators and nociceptors in charge for pain in central nervous system and likewise anti-inflammatory effects in the peripheral tissue by reduction of the release and synthesis of related mediators, principally prostaglandins (Panthong et al., 2007). Administration of C. quadrangularis to patients with hemorrhoids condensed the magnitude of hemorrhoids and relieved inflammation and pain (Segsunviriya and Choomprabutra, 1989).
| Table 3: | Clinical studies on plants used in TIM for treatment of hemorrhoids |
Commiphora species: Gum resins from Commiphora mukul (Hook. ex Stocks) Eng. and C. myrrha (Nees) Engler. have been used as efficacious plant materials for the treatment of hemorrhoids in traditional Iranian medicine. C. myrrha showed anti-inflammatory and antinociceptive activities (Su et al., 2011, 2012). Anti-inflammatory activity C. mukul was demonstrated in vitro (Francis et al., 2004). Terpenoids and guggulusteroids from C. mukul showed potent anti-inflammatory activity (Francis et al., 2004; Kimura et al., 2001).
Euphorbia prostrata aiton: A preliminary study showed that Euphorbia prostrata can be used for the treatment of grade I and II of hemorrhoids with satisfactory efficacy and safety (Gupta, 2011). The mechanisms of action of this plant in hemorrhoids include an increase in lymphatic drainage, reduction in capillary permeability, improvement of venous tone, protection of capillary bed microcirculation and inhibition of inflammatory reactions. As reported, flavonoids in Euphorbia are robust inhibitors of thromboxane A2, prostaglandin E2 and leukocyte stimulation, relocation and adhesion (MacKay, 2001). Studies with the standardized extract of E. prostrata, when administered orally showed an inhibition of both carrageenan-induced paw edema and histamine-induced edema (Singla and Pathak, 1990). Ellagic acid is another major constituent of E. prostrata extract and has been reported to suppress the histamine release (Choi and Yan, 2009).
Ginkgo biloba L.: Ginkor-fort®, a commercial product from Ginkgo biloba leave extract in combination with troxerutin (a flavonoid) and heptaminol (a vasodilator) showed beneficial effects in patients with hemorrhoids (Sumboonnanonda and Lertsithichai, 2004; Hep et al., 2000; Soullard and Contou, 1978). Ginkgo biloba may exert their beneficial effects in hemorrhoids by its anti-inflammatory and venoprotective activity (Chan et al., 2007).
Juniperus species: Several juniperus species are used as a remedy for hemorrhoids in Turkish folk medicine. Between 5 different species of Juniperus, only methanol extracts of fruit and leaves from J. oxycedrus subsp. oxycedrus and J. communis var. saxatilis showed significant antinociceptive and anti-inflammatory activities (Akkol et al., 2009). Among different compounds present in Juniperus species, diterpenoids such as hinokiol isolated from J. polycarpos was shown to exert anti-inflammatory activity (El-Sayed, 1998). Nevertheless, the active antinociceptive and anti-inflammatory constituents in other Juniperus species have not been deliberated yet.
Melastoma malabathricum L.: The powdered leaves and roots have been used to relieve the discomfort of hemorrhoids in Malay folk medicine. The flower has been also used for hemorrhoidal bleeding. The antinociceptive, anti-inflammatory and wound remedial activities of this plant were demonstrated by various in vivo studies (Zakaria et al., 2006; Susanti et al., 2008; Sulaiman et al., 2004; Sunilson et al., 2008). The reported activities may be attributed to different chemical constituents identified in this plant such as flavonoids and tannins (Joffry et al., 2012).
Myrtus communis L.: Myrtus communis is a medicinal plant used in traditional Iranian medicine for treatment of hemorrhoids (Aghili, 2009). Anti-inflammatory and antinociceptive activities of M. communis have been evaluated in several studies (Al-Hindawi et al., 1989; Hosseinzadeh et al., 2011; Amira et al., 2012). Flavonoids are one of the major components of this plant and may play the chief role in these pharmacological properties of M. communis (Montoro et al., 2006).
Onosma species: Onosma species are used for the treatment of hemorrhoids in Turkish folk medicine. Screening of different Onosma species for their anti-inflammatory and antinociceptive effects demonstrated significant activity of O. isauricum, O. sericeum and O. aucheranum (Tosun et al., 2008). Onosmins as flavonoid type compounds in Onosma species were found to inhibit lipoxygenase enzyme activity (Ahmad et al., 2005). Moreover, in the root barks of several Onosma species accumulation of naphthaquinones of alkannin and shikonin derivatives have been reported. These compounds possess significant anti-inflammatory activity (Kundakovic et al., 2006; Tanaka et al., 1986).
Phlomis species: Phlomis species has been used in Spanish folk medicine for treatment of hemorrhoids (Limem-Ben Amor et al., 2009). There are some reports on antinociceptive and vascular protective effects of Phlomis species (Sarkhail et al., 2003; Mohajer et al., 2005; Ismailoglu et al., 2002). Two phenyl propanoid compounds including forsythoside B and alyssonoside may play the major role in vascular protective activity of this plant (Ismailoglu et al., 2002). These species also contain a considerable amount of flavonoids, which show beneficial effects in treatment of hemorrhoids (Limem-Ben Amor et al., 2009).
Plantago ovata Forssk: Results of clinical trials showed the beneficial effects of seed husk from Plantago ovata on patients with hemorrhoids (Webster et al., 1978; Moesgaard et al., 1982; Perez-Miranda et al., 1996). The seed husk of Plantago can reduce bleeding, improve the symptoms and reduce hemorrhoidal cushions. Plantago was also used for posthemorrhoidectomy complications. As reported, treatment of patients with P. ovata after open hemorrhoidectomy diminished tenesmus rate, pain and markedly shortened postoperative hospital halt (Kecmanovic et al., 2006). P. ovata is a bulking laxative and causes softening of stool. It also exerts its beneficial effects by producing fairly large amounts of short-chain fatty acids. Anaerobic fermentation of the soluble non-starch polysaccharides from Plantago seed results in the production of the propionate, butyrate and acetate in the intestines. These fatty acids may play a critical role in balancing of normal flora of colon and reducing inflammation of the anorectal region (Anonymous, 2002).
Verbascum species: Different species of Verbascum have been used to treat hemorrhoids in traditional Turkish medicine. Aqueous extract of the V. mucronatum flower has shown anti-inflammatory, antinociceptive and wound healing activities. Fractionation of this extract demonstrated that iridoid glycosides, especially verbascoside are responsible for these activities (Akdemir et al., 2011). Besides V. mucronatum, other species of Verbascum including V. latisepalum and V. salviifolium, V. lasianthum, V. pterocalycinum var. mutense and V. salviifolium displayed significant antinociceptive and anti-inflammatory activities (Tatli et al., 2008a, b; Kupeli et al., 2007a). Methanol extract of V. lasianthum showed significant anti-inflammatory and antinociceptive activity. Fractionation of these extract leads to isolation of different iridoid glycosides of which, aucubin and ilwensisaponin A were found responsible for the mentioned pharmacological activities (Kupeli et al., 2007b).
DISCUSSION
Traditional and folk medicines of different countries are an invaluable source to discovery of effective drugs with lower incidence of side effects in modern medicine (Rahimi et al., 2010, 2012; Rahimi and Ardekani, 2013). Many of medicinal plants discussed in this study for the management of hemorrhoids have historical backgrounds in traditional medicine for this application. The medicinal plants can improve the symptoms of hemorrhoids such as pain, bleeding, itching, heaviness and tenesmus, rectal prolapse, number of hemorrhoidal cushions and recurrence and increase the rate of wound healing. Their mechanisms of action include anti-inflammatory, anti-nociceptive, venotonic and venoprotective activities or even stool softening by absorption of water absorption as observed for Plantago ovata. As shown in Table 4, different classes of compounds, especially flavonoids, triterpenes, tannins and terpenoids may be responsible for anti-hemorrhoidal activity. The chemical structures of some of the natural compounds which may have a role in treatment of hemorrhoids have been shown in Fig. 1. There are some products from flavonoids in the market; the most popular of them is Daflon, hesperidin in combination with diosmin. A meta-analysis of 14 clinical trials on the use of flavonoids for the treatment of hemorrhoids indicated that flavonoids improve symptoms such as bleeding, persistent pain and itching (Alonso-Coello et al., 2006). The exact mechanisms of action of flavonoids remain unclear but the possible ones are refining venous tone, boosting lymphatic drainage, dropping capillary hyperpermeability along with anti-inflammatory activities (Meyer, 1994).
There are several plants in traditional Chinese medicine used for stopping bleeding from hemorrhoids and their efficacy has been supported by some clinical trials; but because their scientific names had not been determined in these papers and only it has been implied in their Chinese names; we could not consider them (Gan et al., 2010).
Medicinal plants used for treatment of hemorrhoids can also be used for post-hemorrhoidectomy complications such as pain and bleeding thus reducing the use of chemical analgesics and increasing wound healing rate (Rahimi and Abdollahi, 2012b).
The problem of current medicinal plants in treatment of hemorrhoids is that most of them although have traditional use history but lack enough evidence needed for approval as a new drug in the current time. This means that most of the studies have been in vitro or in vivo but in a systematic manner and thus there are many gaps in their efficacy and safety profile. So the first recommendation is to complete efficacy and safety profile of these plants and then go through clinical trials to prove their efficacy. In the meantime, mixture of these medicinal plants may be more useful by possible synergism that needs to be elucidated.
| Fig. 1(a-p): | Chemical structures of some natural compounds found beneficial in the treatment of hemorrhoids, (a) Aesin, (b) Beta-boswellic acid, (c) Alpha-Boswellic acid, (d) Ellagic acid, (e) Hinokiol, (f) Shikonin, (g) Forsythoside B, (h) Lamiide, (i)Alyssonoside, (j) Aucubin, (k) Hesperidin, (l) Diosmin, (m) Troxerutin (n) Kaempferol-3-glucoside, (o) Alpha-Amyrin and (p) Onosmin B |
| Table 4: | Chemical constituents of medicinal plants responsible for their anti-hemorrhoidal activity |
Final notice is that medicinal plants are the valuable source of preparing new drugs for hemorrhoidal disease, but they need to be considered by scientists to go through scientific efficacy and safety tests.
ACKNOWLEDGMENT
Authors acknowledge assistance of Iran National Science Foundation.