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An Evidence-Based Study on Medicinal Plants for Hemorrhoids in Medieval Persia

Hemorrhoids is one of the most common gastrointestinal diseases. There are several therapeutic options associated with some complications. Therefore, researchers look for traditional medicines as a potential resource for introduction of new natural drugs. The current study reports an evidence-based review of herbal remedies for hemorrhoids in traditional Persian medicine. A comprehensive survey about hemorrhoids on the most important manuscripts of traditional Persian medicine was done. Then, scientific data banks were searched for possible related properties of each herb in the conventional medicine. We reported some historical aspects of traditional Persian medicine view on classification, examination, and predisposing factors of hemorrhoids. In addition, we have reported 105 medicinal plants belonging to 51 families. More than half of the reported herbs exhibited anti-inflammatory and analgesic effects. Although lack of human studies regarding the mentioned herbs is noted, positive results from experimental findings can be considered for new drug discovery supported by traditional and medieval experiences.

Hemorrhoids or hemorrhoidal disease is often considered as one of the most common gastrointestinal diseases with a high prevalence. 1 In the United States, about 10 million people reported hemorrhoids. 2 The cause and etiology of this condition is not thoroughly clear. 3 Factors such as irregular bowel habits and low-fiber diets as well as genetics may lead the patient to this condition. 4 Bleeding from the lower gastrointestinal segments is most likely to be the main prevalent etiological reason of the incidence of hemorrhoids. 5 Anal pain and discomfort, itching, bleeding, swelling, and perceived mass in the perianal zone are considered as the main symptoms of hemorrhoids. 6,7 Treatment lines for hemorrhoids are discussed as conservative approaches such as dietary fiber and oral fluids, rest, and nonsteroidal anti-inflammatory drugs as well as surgical techniques associated with degrees of complication. 4,8 The first known description about hemorrhoids dates back to nearly 1700 BC, when Egyptians wrote on papyrus about the treatment of this disease. In the history of medicine, other traditional medical systems have discussed about hemorrhoids and related treatment. There are some historical investigations about the disorder. 9 Based on humoral theory, traditional Persian medicine is an ancient and popular medical paradigm with numerous therapeutic options for various diseases and complications. [10][11][12] Early Persian scholars and physicians have dedicated their experiences and knowledge to make this medical paradigm fluorish. 13,14 Reported therapeutic options in Persian medical manuscripts are mainly herbal remedies and could be defined as potential medicaments. Reviewing the herbal remedies for each specific disease, by searching through main traditional Persian medicine references, could help the researchers to assess and introduce new and effective natural medicines. 15,16 It is notable that oral and topical botanical preparations may effectively treat early stages of hemorrhoids. These medicaments can also be applied as adjuvant therapies in advanced stages. 17 Therefore, the current study aimed to compile herbal remedies for hemorrhoids in traditional Persian medicine and discuss their relevant pharmacologic properties in contemporary medicine.

Materials and Methods
Chapters related to hemorrhoids (Bavāsir in Persian) and medicinal plants were selected and studied from printed editions of Kitāb al-hāwī f ī al-tibb (The Comprehensive Book on Medicine) by Rhazes (9th and 10th centuries AD), Canon of Medicine by Avicenna ( Figure 1) (10th and 11th centuries), Ikhtiyārāt-I Badī'ī (Selections for Badī'ī) by Hājjī Zayn al-'Attār (14th century), Tuhfat al-mu'minīn (Present for the Faithful) by Daylamī Tunakābunī (17th century) and Makhzan al-adviyah (The Storehouse of Medicaments) by Alavī Shīrāzī (18th century). [18][19][20][21][22] These pharmacopeias are known as the most important and comprehensive resources in traditional Persian medicine, which are also repetitively used by natural healers in Iran. 23 For concise nomenclature of herbal medicines, other textbooks such as Dictionary of Medicinal Plants, 24 Matching the Old Medicinal Plant Names with Scientific Terminology, 25 and Dictionary of Iranian Plant Names 26 as well as Indian Medicinal Plants 27 were used. Medicaments with unidentified scientific name were finally omitted from the results.
Scientific data banks such as Medline and Scopus were searched to seek for possible related properties of each herb in the current medicine. According to the treatment lines and pathophysiology of hemorrhoid condition, the investigated pharmacologic effects were anti-inflammatory, analgesic, antinociceptive, and vasodilatory.

Results and Discussion
Hemorrhoids (Bavāsir) has been defined as a vascular mass in the anal canal that could be presented either internally or externally and may be associated with bleeding. Aspects of the examination of hemorrhoids have been categorized into factors such as bleeding, presentation, location, humoral etiology, and prognosis. With reference to traditional Persian medicine, the most important predisposing factors included intrinsic factors such as constipation, depression, inadequate sleep, intraabdominal hypertension, and age >40 years as well as extrinsic factors like autumn season, dry climates, and bad food regimen. The main reason of the incidence has been remarked as blood aggregation near the anus and anal canal. 28 Treatment approaches in traditional Persian medicine have been reported as lifestyle modification, management of the underlying diseases and topical or systemic drug administration as well surgery. Accordingly, natural remedies for hemorrhoids included laxatives, analgesics, and anti-inflammatory agents as well as medicines that affect the veins in the location. In these cases, remedies were administered according to their astringent or healing properties. 19 By searching through pharmaceutical manuscripts of Persian medicine, 105 medicinal plants belonging to 51 families were derived and identified ( Table 1). The most cited family was Fabaceae followed by Apiaceae and Lamiaceae. Similar to the current medicine, generally reported routes of administration in traditional Persian medicine for the management of hemorrhoids were oral and topical. In addition, dosage forms and preparations were decoction and maceration of the herbal parts for oral route and oil, ash, and enema for topical route. Moreover, some herbs were also used in an unusual topical dosage form as smoke.
Apart from the oral administration of medicinal plants for hemorrhoids, many medicinal herbs were used topically in an oil dosage form. In this regard, essential oil of the aromatic plants was being extracted under hydrodistillation procedure. On the other hand, oil-bearing seeds such as almond and castor oil plant were subjected to direct compression to extract the fixed oil. It is remarkable that in traditional Persian medicine the oil dosage forms containing nonoily parts have also been prepared. To do this, soft parts of a plant were soaked in heated sesame or olive oil for a certain time. The resulting oil sample was defined as the finished product. On the other hand, the plants' hard tissues such as roots or barks were boiled in water. Subsequently, the resulting extract was boiled in combination with sesame or olive oil until its water part was lost. 29 According to the current knowledge, management of hemorrhoids includes modification of the dietary and lifestyle, medications, and radical surgery. Remedies to treat hemorrhoids underlie analgesic, anti-inflammatory, and local anesthetic and venotonic properties. 30   Many of the contemporary medical strategies for treatment of hemorrhoids are similar to those mentioned by the medieval Persian practitioners. On the other side, many of the reported herbs (Table 1) may manage the disorder with the aforementioned mechanisms of action.
Ethanol extract of Adiantum capillus-veneris aerial parts (200 mg) was evaluated for anti-inflammatory activities by evaluating the spleen index and tumor necrosis factor-related protein expression in lipopolysaccharide-induced mice. The extract could normalize the lipopolysaccharide-induced elevation of the spleen index as well as tumor necrosis factor and thus could be introduced as a natural anti-inflammatory resource. 31 Ethanol extract and ethyl acetate fraction of Adiantum capillus-veneris have also shown antinociceptive effects (300 mg/kg orally) by tail-flick method and writhing test. 32 Anti-inflammatory activities of freeze-dried Allium cepa sprout have been evaluated by the lipoxygenase inhibitor screening assay. Results confirmed the respective activity with a dose-related response. 33 In another investigation, hydroalcoholic extract of Allium cepa peels was evaluated for antihypertensive and vasorelaxant properties. Outcomes revealed a reduction in the aorta contractions, which could be related to the quercetin content in the extract. 34 This finding can be considered for application of this plant in the management of hemorrhoids. In addition, antispasmodic activities of saponins from the polar extract of Allium cepa bulb in guinea pig isolated ileum have been confirmed. 35 Concerning the anti-inflammatory properties of Allium ampeloprasum, steroidal saponins have been isolated and its effectiveness has been confirmed. 36 Mangifera indica is another treatment modality for hemorrhoids. To assess the anti-inflammatory effects of Mangifera indica aqueous extract, an investigation has been carried out on dextran sulfate sodium-induced colitis in rats. In that study, the extract was administered either rectally for 7 days or orally over 2 weeks at a dose of 150 mg/kg. Anti-inflammatory effect of Mangifera indica was subsequently checked by myeloperoxidase activity. The extract showed anti-inflammatory effects by reduction of ulceration and myeloperoxidase activity. 37 In an investigation, vascular effects of Mangifera indica extract and mangiferin (a Cglucosylxanthone derivative) were evaluated in the vascular smooth muscle cells and mesenteric resistance arteries of Wistar Kyoto rats. 38 Another study proved the analgesic effect of Mangifera indica aqueous extract using acetic acid-induced abdominal constriction as well as formalin-induced licking. 39 The anti-inflammatory activity of Semecarpus anacardium has been shown in a study by reduction in the carrageenaninduced paw edema and cotton pellet granuloma. 40 Also, a 3-oxotriterpene, namely oleanonic acid, has been isolated from Pistacia terebinthus and assessed for possible antiinflammatory effects (50% inhibitory concentration [IC 50 ] ¼ 17 mM) in another study. 41 The vasorelaxant activity of Rhus coriaria leaves extract has been examined in an isolated rabbit's aorta ring with or without endothelium. Results confirmed the vasorelaxant effect, which was endothelium dependent. 42 The analgesic and anti-inflammatory activities of Pimpinella anisum have been proved in animal models. An investigation showed that oral application of Pimpinella anisum essential oil (100 mg/kg) was as effective as aspirin with regard to the analgesic property. 43 Regarding the inhibitory activities on muscarinic receptors, Pimpinella anisum aqueous and ethanol extracts as well as essential oil showed muscle relaxant effects on isolated tracheal chains in guinea pig. 44 This could be considered as possible relaxant effects on veins.
Sesquiterpene dienones from Ferula assa-foetida showed nuclear factor-kB inhibitory activity which could be considered as agents for inflammatory disturbances. 45 The antiinflammatory effect of the Ferula assa-foetida ethanol extract has been clinically assessed and confirmed in the irritable colon. 46 In an animal study, Ferula assa-foetida gum extract showed antispasmodic (3 mg/mL) and hypotensive effects (0.3-2.2 mg/100 g body weight) due to the presence of relaxant compounds. 47 Using hot plate and acetic acid induced writhing tests, analgesic activity of Ferula assa-foetida (25, 50, and 100 mg/kg) in comparison with sodium diclofenac (30 mg/kg) or morphine sulfate (8 mg/kg) was confirmed in animal model. 48 Using acetic acid-induced writhing and hot-plate tests, Apium graveolens ethanol extract has shown analgesic effects in animal model. 49 Polar fraction of the plant also revealed to have antiinflammatory activity in carrageenan-induced edema in rats. 50 Apium graveolens has also possessed hypotensive effect in animal model 51 and thus may be useful in the management of hemorrhoids.
Cuminum cyminum showed both antinociceptive and antihypertensive activities which can be useful for the current complications. Aqueous extract of Cuminum cyminum seeds was administered orally (200 mg/kg body weight for 9 weeks) in rats and it improved plasma nitric oxide, declined blood pressure and ameliorated inflammatory and oxidative stress. 52 Cuminum cyminum also possessed antinociceptive effects in animal models. Cuminum cyminum essential oil (0.0125 and 0.20 mL/kg) could exhibit a significant and dose-dependent analgesic effect in chronic and inflammatory pain model. 53 Ferula gummosa has been evaluated for possible antispasmodic activity on the ileum contractions. Because of the presence of a-pinene and b-pinene, Ferula gummosa essential oil possessed relaxant effects. 54 During 8 weeks of the intervention, Anethum graveolens showed anti-inflammatory effects in patients with diabetes type II (3.3 g/d dry powder) as compared to placebo. 55 Moreover, antinociceptive activity of the herb also showed antispasmodic effects on the rat ileum. 56 In that study, Anethum graveolens fruit hydroalcoholic extract could relax the ileum with cumulative concentrations (0.5-4 mg/mL).
Anti-inflammatory activities of Phoenix dactylifera have been proved in the rats with chronic inflammation model. Foot swelling was significantly reduced by the methanol and aqueous extracts by 67.8% and 61.3%, respectively. 57 Antinociceptive and anti-inflammatory activities of Cocos nucifera have been evaluated in an animal study. The analgesic activity was assessed in comparison with morphine and antiinflammatory effect was confirmed on the rat paw edema induced by histamine. 58 Cocos nucifera also showed hypotensive and relaxant activities, which could be considered for hemorrhoids. In an investigation on salt-induced hypertensive rats, Cocos nucifera ethanol extract reduced the mean systolic blood pressure. 59 As a popular medicinal plant, Matricaria chamomilla has been repeatedly evaluated for anti-inflammatory and antinociceptive effects. The a-bisabolol from Matricaria chamomilla essential oil was fed to animals and proved by inflammatory model of paw edema and model of nociception. 60 The anti-inflammatory activity of Achillea millefolium crude extract has also been confirmed experimentally via in vitro protease inhibition assays. Flavonoid-enriched fraction inhibited the human neutrophil elastase (IC 50 ¼ 72 mg/mL), which could represent it as a potent anti-inflammatory medicament. 61 Additionally, antinociceptive and hypotensive activities of Achillea millefolium were evaluated and proved in animal models. 62,63 Tanacetum parthenium showed anti-inflammatory effects and made reduction in erythema in a methyl nicotinateinduced vasodilation model. 64 Sesquiterpene lactones and other components of Tanacetum parthenium inhibited the generation of thromboxane B 2 and leukotriene B 4 . 65 Antinociceptive and anti-inflammatory effects of Tanacetum parthenium have been evaluated against acetic acid-induced writhing and carrageenaninduced paw edema in mice and rats, respectively. 66 Anti-inflammatory properties of Berberis vulgaris have been assessed and proved in another study. Root ethanol extract was effective in a chronic inflammatory model of adjuvant arthritis. 67 Antinociceptive activity of isoquinoline alkaloids from Berberis vulgaris root significantly exhibited dosedependent inhibitory activity against acetic acid-induced increase in vascular permeability via oral administration. 68 Fruits of BV possessed hypotensive effects on deoxycorticosterone acetate-induced hypertension in rats. 69 Lepidium sativum showed anti-inflammatory and analgesic effects by inhibition of carrageenan-induced paw edema in rats and prolongation of the mice reaction time on hot plate. 70 Moreover, the antihypertensive activity of the Lepidium sativum aqueous extract was orally checked and proved in spontaneously hypertensive rats (20 mg/kg), revealing a significant reduction in blood pressure (P < .01) in 3 weeks. 71 Via 5-lipoxygenase, boswellic acids from Boswellia sacra inhibited the leukotriene synthesis. Therefore, Boswellia sacra can be presented as a herbal medicament with antiinflammatory activity. 72 The anti-inflammatory effects of Commiphora mukul have been proved in 2 investigations via inhibitory activities on lipid peroxidation and cyclooxygenase in an experimental assessment, 73 and anti-arthritis activity in male and female patients. 74 Some fractions of the fruits' aqueous extract of Capparis spinosa potently inhibited the carrageenan-induced paw edema in mice, which can prove Capparis spinosa anti-inflammatory activity. 75 Capparis spinosa aqueous extract also exhibited rapid vasorelaxant activity (10 mg/mL) during the plateau phase of contraction. 76 Regarding the anti-inflammatory effects on knee osteoarthritis, significant improvement has been observed in the colchicines (from Colchicum autumnale L.) plus nimesulide group in comparison to placebo plus nimesulide. Visual analog scale for index knee pain showed 52.6% improvement in the colchicine group versus 17.6% for the placebo group. 77 Anti-arthritic effects of Terminalia chebula hydroalcoholic extract was assessed and proved by modulatory effect of the extract on pro-inflammatory cytokine expression in experimental models. 78 Ethanol extracts of Terminalia bellirica and Terminalia chebula showed antinociceptive effects at 200, 400, and 800 mg/kg on chronic pain due to the presence of saponins, triterpenoids, carbohydrates, tannins, and proteins. 79 A lead compound isolated from the roots of Bryonia alba (<80 mM) effectively suppressed nitric oxide generation, which is responsible for inflammation. 80 Cucurbitacin R (1 mg/kg, oral) from Cucurbita pepo has shown considerable anti-inflammatory effects on adjuvantinduced arthritis in rats by reduction in joint damage and footpad soft-tissue swelling. 81 Using formalin-induced inflamed method, methanol extract of Cucurbita pepo fruits showed analgesic activities as compared with indomethacin. 82 Compared with amlodipine (0.9 mg/kg), Cucurbita pepo seed oil (40 or 100 mg/kg) has exhibited antihypertensive effects on rats with hypertension induced by nitric oxide synthesis inhibitor in 6 weeks. 83 Ecballium elaterium (EE) fruit juice showed analgesic activity in animal models. 84 Analgesic and anti-inflammatory effects of Citrullus colocynthis root and stem aqueous extracts have been evaluated by carrageenan-induced paw edema test in rats and acetic acid writhing assay in mice. 85 Extracts revealed to possess inhibitory activities. The organic extracts of roots, seeds, and fruits of Citrullus colocynthis also underwent the previous tests and exhibited respective effects. 86 Using writhing test in mice, the analgesic effect of Cyperus longus (10 and 20 mg/kg) has been proved in comparison with indomethacin (5 mg/kg). 87 Methanol extract of Ricinus communis root has shown anti-inflammatory effects (250 and 500 mg/kg) in the carrageenan-induced hind paw edema model. 88 Furthermore, Ricinus communis leaves possessed antinociceptive activity via writhing test, paw licking, and tail immersion method in mice (100, 125, and 150 mg/kg). 89 By reduction in abdominal constrictions in acetic acidinduced pain model, Vigna unguiculata revealed antinociceptive activities in an investigation. 90 Antinociceptive and anti-inflammatory activities of Alhagi maurorum alcoholic extract have been evaluated and proved by hot plate and carrageenan-induced paw edema tests, respectively. Results were attributed to high flavonoid contents. 91 Relaxant effect of Alhagi maurorum aqueous-acetic acid extract on guinea pig ureter has also been evaluated and confirmed in a study. 92 Trigonella foenum-graecum mucilage has exhibited maximum edema inhibition percentage and shown antiinflammatory activity against arthritis-induced joints in rats (75 mg/kg for 21 days). 93 Also, alkaloid-and flavonoid-rich fractions of the methanol extract of Trigonella foenum-graecum possessed antinociceptive activities (100 mg/kg) as effective as morphine (5 mg/kg). 94 Compared with indomethacin (10 mg/kg), methanol and ethanol extracts of Cicer arietinum (500 mg/kg) were checked for possible anti-inflammatory effect and showed maximum effects from the second and fifth hours of administration. 95 A flavonoid, isoliquiritigenin, from Glycyrrhiza glabra showed analgesic activity in acetic acid-induced writhing response and hot plate test at the high dose. 96 The anti-inflammatory effect of hydroalcoholic extract of Tamarindus indica leaves was assessed by the carrageenaninduced hind paw edema. The antinociceptive activities of the extract were evaluated using tail-flick, acetic acid-induced writhing, and the hot plate models. The extract was effective at doses of 500, 750, and 1000 mg/kg body weight, with regard to both properties. 97 Hypericum perforatum revealed to have anti-inflammatory effects against carrageenan-induced paw edema in mice regarding modulation of cyclooxygenase II expression. 98 Hypericum perforatum lipophilic extract showed topical antiinflammatory and antiphlogistic effects in the mices ear edema induced with croton oil. 99 Using spectrophotometric assay on activated human neutrophils, anti-inflammatory effects of isoflavonoids from Iris germanica rhizomes were assessed and confirmed. 100 Methanol extract of Juglans regia has been evaluated for anti-inflammatory activity. The extract significantly decreased the tumor necrosis factor-a-induced endothelial expression in both vascular cell adhesion and intracellular adhesion molecule in human aortic endothelial cells. 101 In a cell-based contemporary assay, some secondary metabolites from Vitex agnus-castus showed anti-inflammatory activity and lipoxygenase inhibition. 102 Methanol extract of Vitex agnus-castus revealed antispasmodic effects on the isolated rabbit's jejunum (3.0 mg/mL). 103 Antinociceptive activities of Mentha piperita have been evaluated using acetic acid-induced writhing and hot plate tests in mice which were dose dependent. On the other hand, the herb possessed anti-inflammatory effects using xylene-induced ear edema. 49 Ocimum basilicum aqueous extract (500 mg/kg body weight for 10 weeks) has exerted significant vasorelaxant effects on the rat's thoracic aorta. 104 By confirmed inhibition of pro-inflammatory cytokines and mediators, Ocimum basilicum methanol extract can be introduced as an antiinflammatory agent. 105 Among various types of Ficus carica extracts, ethanol extract (600 mg/kg) exerted maximum anti-inflammatory activity by using cotton pellet granuloma and carrageenaninduced rat paw edema methods. 106 Antinociceptive and anti-inflammatory effects of Myrtus communis were confirmed by hot plate and writhing as well as xylene-induced ear edema and cotton pellet tests. Aqueous and ethanol extracts exhibited significant antinociceptive and anti-inflammatory effects. 107 Alkaloid extract of Peganum harmala seeds possessed antinociceptive effect (12.5 and 25 mg/kg) against acetic acid intraperitoneal injection. 108 Bioassay-guided purification of Peganum harmala seeds resulted in isolation of vasorelaxant components active against phenylephrine-induced contraction of the rat's isolated aorta. 109 Chelidonium majus has exerted anti-inflammatory effect in animal model. Chelidonium majus methanol extract was fed to collagen-induced arthritis mice (400 and 40 mg/kg/d for 4 weeks) and significantly suppressed the collagen-induced arthritis progression. 110 Sesamum indicum seeds oil has been evaluated for possible antinociceptive and anti-inflammatory effects. Using paw licking (100,200, or 400 mg/kg) and hot plate (200 or 400 mg/kg) as well as application of carrageenan, the oil revealed to be effective. 111 Compared with that of the control group (P < .05), Phyllanthus emblica exhibited anti-inflammatory effect against acute inflammation models as acetic acid-induced mice peritonitis and carrageenan-induced rat paw edema. 112 By using acetic acid-induced writhing and tail-flick tests, oral administration of methanol extract of Plantago major seeds showed antinociceptive effects in mice (400 mg/kg). Also, large doses of Plantago major leaves exerted some effect as compared with the controls. 113 In addition, Plantago major exhibited anti-inflammatory activity at 20 and 25 mg/kg as compared to indomethacin and placebo. 114 In another study, the aqueous extract of leaves (1 g/kg) could reduce acetic acid-induced writhing and carrageenan-induced paw edema and pleurisy. 115 Portulaca oleracea was shown to have anti-inflammatory and antinociceptive effects in animal models. The antinociceptive effect of Portulaca oleracea petroleum ether extract was assessed and confirmed by acetic acid-induced writhing, formalin test, and tail immersion method in mice. The antiinflammatory activity was proved by carrageenan-induced hind paw edema in rats. 116 Nigella sativa oil (50-400 mg/kg) could dose dependently exert antinociceptive effects by hot-plate, acetic acid-induced writhing, and tail-pinch tests on oral administration. 117 The mentioned tests as well as carrageenan-induced paw and croton oil-induced ear edema tests were performed on Nigella sativa seed polyphenols. Intraperitoneally, Nigella sativa seed polyphenols exhibited dose-dependent inhibition in paw edema. 118 A topical ointment from water extract of the roots of Potentilla reptans was applied on the mouse ear inflammation (2.5 mg/ear) induced by croton oil (10 mg/ear). Potentilla reptans ointment could significantly reduce the inflammation as compared with the controls' ear. 119 The anti-inflammatory and analgesic effects of Citrus medica peel extract was observed by using carrageenan-induced inflammatory pain as well as plantar, hot plate, pin prick, and mechanical allodynia tests in rats (400 mg/kg). 120 Ruta graveolens methanol extract showed potent edema inhibition (20 mg/kg for 21 days) in arthritis rat model, 121 and thus could be introduced as an anti-inflammatory agent.
The anti-inflammatory activity of Salvadora persica was assessed and confirmed in an animal study. According to the findings, ethyl acetate and hydroalcoholic extracts of Salvadora persica (100 mg/mL) significantly reduced the edema thickness and decreased secretion of inflammatory mediators. 122 Ethyl acetate fraction of Smilax china revealed in vitro (IC 50 ¼ 38 mM) and in vivo (10 and 50 mg/kg) antiinflammatory effects by lipoxygenase-and carrageenaninduced hind paw edema models, respectively. 123 Bioassay tests on isolated steroidal saponins from the Smilax china butanol extract showed the inhibitory effects of those isolates on cyclooxygenase II at 10 À5 M. 124 Smilax china aqueous extract was evaluated for anti-inflammatory (egg albumin-induced edema) and antinociceptive (hot-plate test) activities (1000 mg/kg) and possessed significant effects. 125 Solanum melongena showed dose-dependent analgesic activity (100, 250, and 500 mg/kg) by using the acetic acidinduced writhing test. 126 Methanol extract of Hyoscyamus niger seeds has been assessed for in vivo analgesic and anti-inflammatory activities. Hyoscyamus niger showed dose-dependent analgesic effect by reduction in writhing response and was effective on inflammation (using carrageenan-induced paw edema). 127 Withania somnifera aqueous fraction has been evaluated for possible efficacy to produce pro-inflammatory molecules from lipopolysaccharide-stimulated macrophage cell lines. Dose-dependently, Withania somnifera extract could inhibit the lipopolysaccharide-induced production of interleukin-1 and thus may be introduced as a treatment for inflammatory diseases. 128 Compared with that of the indomethacin, Withania somnifera root powder could suppress the increase in paw diameter and lysosomal enzyme activity to the normal level (1 g/kg). 129 Using hot-plate or formalin tests, analgesic effect of ethanol extract of Datura stramonium seeds was experimented via oral and intraperitoneal administration in male NMRI rats. Intraperitoneally, Datura stramonium extract could potentially alleviate the pain in formalin and hot-plate tests (more than 100 mg/kg). The effective dose for oral administration was marked at >400 mg/kg. 130 The chloroform fraction from the methanol extract of Physalis alkekengi demonstrated significant inhibitory effects on the production of nitric oxide, cyclooxygenase, and tumor necrosis factor. Therefore, it may be introduced as an antiinflammatory medicament. 131 Aloe vera has long been known as an anti-inflammatory agent. A study has evaluated the effects of Aloe vera aqueous, chloroform, and ethanol extracts on carrageenan-induced paw edema in rat. The chloroform and aqueous extracts could suppress the edema. 132 Anti-inflammatory properties of the aloe vera gel on inflammatory bowel disease has also been experimentally confirmed. 133 Using different pain models, curcumenol and also a dichloromethane fraction from Curcuma zedoaria hydroalcoholic extract has shown potent but dose-dependent analgesic activity (ID 50 from 12 to 29 mmol/kg). 134 Sesquiterpene compounds, furanodiene, and furanodienone from Curcuma zedoaria methanol extract exerted anti-inflammatory activity (0.1 mmol) by suppressing 12-O-tetradecanoylphorbol-13-acetate-induced inflammation of mouse ears. 135 Zingiber officinale has demonstrated anti-inflammatory and analgesic activities in experimental studies. Using acetic acid and hot-plate tests as well as fresh egg albumin-induced pedal edema, Zingiber officinale ethanol extract (50-800 mg/kg intraperitoneally) exhibited significant but dose-dependent analgesic and anti-inflammatory effects, as compared with morphine (10 mg/kg) and diclofenac (100 mg/kg). 136 A main ingredient, 6-gingerol (25-50 mg/kg) could exert analgesic and antiinflammatory activities by acetic acid-induced writhing and formalin-induced tests. 137 Previously, a study has been carried out on medicinal herbs for hemorrhoids reported from different countries' folk and traditional medicine. 138 Those medicinal plants have been used to improve such symptoms as pain, bleeding, heaviness, and rectal prolapse. Mechanisms underlying those improvements were anti-inflammatory, venoprotective, analgesic, venotonic, and laxative. The current study reviewed anti-inflammatory, analgesic, venotonic, and vasorelaxant effects with regard to the medieval medicinal plants. The analgesic or antiinflammatory effects of 64 out of 105 reported medicinal plants have been experimented and proved by previous investigations. Besides 2 reports on human studies, most investigations were performed as an animal study. Active secondary metabolites such as flavonoids, tannins, and terpenoids are responsible for the aforementioned properties. Among those classes of active compounds, flavonoids have been evidently used to treat hemorrhoids. These compounds, seemingly, suppress the progressive symptoms and reduce the pain and inflammation as well as bleedings. 139

Conclusion
The current study aimed to evidently investigate the possible mechanism underlying the treatment effect of plants traditionally reported for hemorrhoids in traditional Persian medicine. More than half of the reported herbs exhibited antiinflammatory and analgesic effects. Although lack of human studies regarding the mentioned herbs and pharmacological effects is observed, positive results from experimental findings can be considered for new drug discovery supported by traditional and medieval experiences.