Scientific Evaluation of the Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications

Hemorrhoidectomy is an impressive surgery that relieves discomfort in patients who suffer from grade 3 or 4 hemorrhoids. This review is designed to investigate useful herbs for managing post-surgery complications by presenting an overview of Avicenna ’s view compared to new scientific evidences. The herbs with anti-inflammatory, analgesic, anti-bleeding, antispasmodic, and wound-healing properties may be important for managing patient discomfort. Avicenna’s most frequently prescribed herbs were selected using Bavasir as a keyword (traditional term for hemorrhoids) from volumes 2 and 5 of the Canon of Medicine textbook, and they were investigated in scientific databases including Scopus, PubMed, Web of Science, Science Direct, and Cochrane Library to obtain researches that confirmed their efficacy. Among the different herbs, Hypericum perforatum and Portulaca oleraceae were the most supported in scientific databases. Other herbs including Anethum graveolens , Cocos nucifera , Ferula assa-foetida , Myrtus communis , Ocimum basilicum , and Plantago major were next in order, while Arte-misia absinthium , Solanum melongena , and Trigonella foenum-graecum exhibited few related pharmacological effects. The results established Avicenna ’s claims regarding the importance of these herbs in post hemorrhoidectomy complications. Although there were many in vitro and/ or in vivo researches on the selected herbal medicines, there were no obtained clinical studies on patients after their hemorrhoidectomy surgeries. So, the aforementioned herbs, especially H. perforatum and P. oleraceae , are recommended for future clinical studies. Among the different classes of compounds, flavonoids were the most responsible phytocomponents for displaying pharmacological effects. [GMJ.2017;6(3):166-84] DOI:10.22086/gmj.v0i0.774


Introduction
H emorrhoids is the most prevalent rectal disease and is described as the enlarge-ment and distal dislocation of rectal cushions [1,2].Intensified pressure on the vascular plexus of hemorrhoids, mainly due to straining or pregnancy, seems to play a major role in the development of hemorrhoids [3].A hemorrhoidectomy is an impressive surgery that relieves discomfort in patients suffering from grade 3 or 4 hemorrhoids [4].This surgery is also used in situations like non-operative therapy failures, patient preference, and concomitant anorectal diseases including anal fistulas or fissures [2].The main complications after a hemorrhoidectomy can include inflammation, acute and chronic pain, unhealed wounds, fecal urgency, and rectal bleeding [5,4].The main cause of post hemorrhoidectomy pain is ascribed to the spasmodic condition of the internal anal sphincters [6].Avicenna is a famous ancient physician who wrote the well-known book "Canon of Medicine" [7,8].He thoroughly described "Bavasir" (the traditional term for hemorrhoids) in his book.He also recommended surgery for severe conditions of hemorrhoids and proposed different herbal medicines to manage post-surgery complications [9].The herbs with anti-inflammatory, analgesic, anti-bleeding, antispasmodic, and wound-healing properties may be important in managing post hemorrhoidectomy complications.

Materials and Methods
In this review study, volumes 2 and 5 from the Canon of Medicine were investigated using the key terms from the Bavasir (hemorrhoids) chapter.The search terms in this chapter were Zede varam (anti-inflammatory), Zede vaja/ dard (pain reliever), and Zede khoon rizi/sayalan (means anti-bleeding).Then, most of the prescribed herbs were collected in individual or polyherbal formulations.Afterward, the scientific name of each herb was found in textbooks that matched traditional plant names to their scientific names [10][11][12].Next, scientific databases including Scopus, PubMed, Web of Science, Science Direct, and Cochrane Library were searched to obtain reports of any related pharmacological effects including anti-inflammatory, analgesic/ antinociceptive, anti-bleeding, antispasmodic, and wound healing, as well as any active constituents and possible mechanisms of each herb.Data were collected from 1987 to August 2016.

Results
The proposed herbs' scientific and traditional names, parts used, and routes of administration are presented in Table-1.Table-2 summarizes the reported scientific studies' results regarding the herbal medicines, their used parts, extracts, and pharmacological models.These results are also discussed below.

Anethum graveolens L.
The aqueous extract of A. graveolens fruits exhibited more potent antinociceptive effects than its volatile oil in vivo [13]. A. graveolens revealed significant analgesic effects in the late phase of formalin tests.Further, its aerial parts demonstrated potent analgesic activity during hot plate tests in vivo [14].Sabinene, the most active constituent in the essential oil, may be responsible for the plant's notable anti-inflammatory effects due to its inhibitory effects on inducible nitric oxide synthase [15].Moreover, Naseri et al. attributed this species' anti-inflammatory effects to its monoterpenoid constituents including carvone and limonene [16].In addition, the herb exerted its antispasmodic properties via its inhibitory effect on calcium channels [17].

Artemisia absinthium L.
A. absinthium revealed its anti-inflammatory and analgesic effects in different in vivo models [18,19].The fresh leaves' essential oil in 4 and 8 mg/kg doses considerably reduced edema in rats.The presence of phytochemicals like neradiol, santolina triene, α-piene and trans-β-farnesene may have an important role in the plant's pharmacological effects [19].

Cocos nucifera L.
C. nucifera exhibited anti-inflammatory and analgesic effects in various in vivo models [20][21][22][23].During a hot plate test on rats, a 200 mg/kg dose of an aqueous extract of husk fiber significantly prolonged the reaction time to heat stimulants.This effect was reversed by naloxone (an opioid antagonist).So, it can be concluded that opioid receptors mediate this analgesic effect [20].The presence of phytoconstituents like polyphenols, saponins, and flavonoids can be important for a plant's antinociceptive and anti-inflammatory properties [21].C.nucifera's water extract displayed a significant inhibition during the second phase of a formalin-induced licking test in mice through a dose-dependent manner [23].In the burn wounds model, after 16 days of a C.nucifera oil topical application, improvements in the wound contractions were seen.However, this effect was more powerful when C. nucifera was com-bined with silver sulfadiazine cream [24].
Ferula assa-foetida L. F. assa-foetida showed significant analgesic properties in vivo [25,26].This effect was most potent in 10 mg/kg doses.In a dose of 2.5 mg/kg, the plant significantly reduced edema in vivo.These pharmacological effects were not reversed by antagonists like naloxone, glibenclamide, theophylline, etc. Phytochemicals including monoterpens, flavonoids, and phenolic constituents had notable lipoxygenase inhibitory effects [26].Furthermore, F. assa-foetida's essential oil and oleo gum resin exhibited antispasmodic activity through a remarkable reduction in acetylcholine-induced contraction method [27].

Hypericum perforatum L.
Although its antinociceptive effects were confirmed by different in vivo models [28][29][30], there were no significant properties observed in the acetic acid-induced writhing test [29].Further, H. perforatum hydroethanolic extract revealed dose-dependent antinociceptive effects that were reversed by naloxone [30].Phytochemicals including pseudohypericin, hypericin, and flavonoids may be responsible for its anti-inflammatory effects due to its iNOS, COX-2, and PGE-2 inhibitory effects [31][32][33].Among the different extracts and pure compounds of H. perforatum that were investigated on mice with croton oil-induced ear edema, liophilic extract and amentoflavone demonstrated the most considerable anti-inflammatory properties [34].This plant exerted wound-healing effects in vivo and in vitro [35][36][37][38].Enhancements in polygonal fibroblasts and collagen granules were seen in the cultured NIH3T3 fibroblast model [36].
H. perforatum exerted its wound-healing effects via an increase in the wound closure percentage and wound contraction and tissue regeneration in vivo [35].Wound-healing effects of the species' aerial parts can be attributed to its quinoids, flavonoids, tannins, xanthones, and naphtaquinones [35][36][37][38].The species also exerted its smooth muscle relaxant properties by releasing phytochemicals such as hyperforin and kaempferol.However, this effect was potently reduced by naloxone [39].In addition, the herb showed calcium antagonistic and phosphodiesterase inhibitory properties in vitro [40,41].

Myrtus communis L.
M. communis displayed its analgesic and anti-inflammatory effects in in vitro and in vivo models [42][43][44][45].Tannins, alkaloids, and flavonoids play an important role in these pharmacological effects [42].Acylphloroglucinol phytoconstituents including myrtucommulone (MC) and semimyrtucommulone, which were isolated from plant leaves, displayed cyclooxygenase-1 and 5-lipoxygenase inhibitory effects in vitro [45].In addition, MC showed anti-inflammatory properties in carrageenan-induced paw edema and pleurisy models [44].Moreover, the plant acts as an antispasmodic agent by blocking the calcium channels in vitro [46].

Ocimum basilicum L.
The leaves of O. basilicum revealed antinociceptive effects in vivo [44,45].The presence of linalool in the essential oils and flavonoids of the species' ethanolic extract is ascribed to its antinociceptive properties [47,48].It seems that the possible mechanisms of its antinociceptive properties are its inhibitory effects on prostaglandins and prostacyclins synthesis, as well as its interaction with opioid receptors [47].Its robust anti-inflammatory effects were confirmed using in vitro and in vivo models [49][50][51].Aqueous extracts showed more potent anti-inflammatory properties than ethanol extracts in vitro [49].The species demonstrated anti-inflammatory effects via its reductive action in producing inflammatory mediators such as tumor necrosis factor-α (TNF-α), Interleukin-1β, IL-2, and NO [50].Phytoconstituents such as eugenol, rosmarinic acid, and estragole may play a significant role in its anti-inflammatory effects [49,51].Moreover, the species manifested antispasmodic properties in vitro [52,53].
Plantago major L. P. major ethanol extracts with a polyphenol composition at a 1 mg/mL concentration demonstrated powerful wound-healing effects ex vivo [54].There were no significant antinociceptive properties observed during the tail flick test [55].While its notable anti-inflammatory effects were proven using different in vitro and in vivo methods [55][56][57], there were no observed significant anti-inflammatory effects using a dextran-induced edema [55].Among the herb's various extracts, P. major's methanol and ethanol extracts were the most potent reductions in the inflammatory cytokines levels in vitro [57].
Portulaca oleraceae L. P. oleraceae exhibited analgesic effects in vivo [58].The aqueous extract of its aerial parts exerted anti-inflammatory effects by inhibiting the effects on TNF-α action in vitro [59].Alkaloid phytocompounds, especially oleracimine, exerted intense anti-inflammatory properties by inhibiting the effects on nitric oxide generation and suppressing the effects on IL-6, TNF-α, and PGE-2 secretions in vitro [60].Additionally, crude extracts of aerial parts displayed potent wound-healing effects in doses of 50 mg/kg by reducing the in-wound surface and enhancing tensile strength in vivo [61].The plant also manifested smooth muscle relaxant effects in vitro.
Because phentolamine significantly reduced the herb's relaxant effects, it can be proposed that adrenergic receptors are involved in the herb's antispasmodic effects [62].
Solanum melongena L. S. melongena demonstrated powerful analgesic properties using acetic acid-induced writhing tests in 500 mg/kg doses.Phytochemicals like flavonoids, alkaloids, and tannins were reported to be the most important agents for its analgesic property [63].Lignanamides, which are presented in the ethanol extract of the roots, exhibited inhibitory effects on nitric oxide generation in vitro [64].Additionally, 200 and 400 mg/kg doses of S. melongena displayed less inhibitory effects on paw edema (42.62%) compared to aspirin, which was used as a reference drug (64.5%)[65].
The herb's leaves revealed significant antinociceptive effects at doses of 2000 mg/kg in vivo [66].Mandegary et al. reported that alkaline chloroform and aqueous fractions of the seeds' methanolic extracts, which contained alkaloids and flavonoids, showed powerful antinociceptive and anti-inflammatory properties [67].Moreover, the analgesic and anti-inflammatory effects of the seeds' methanolic extracts can be attributed to their glycoside and steroid constituents [69].The presence of tannins and flavonoids in the leaves' metha-nol extract may antagonize the prostaglandin and bradykinin actions [68].T. foenum-graecum may exert its robust anti-inflammatory effects by reducing COX-2 and 5-LOX activities and has a stabilizing effect on red blood cells against lyses due to its steroidal saponins, flavonoids, and polyphenols [72,74,77].
The pharmacological effects of the aforementioned herbs are summarized in Table-3.
Reported phytoconstituents of each herb along with their observed pharmacological effects are illustrated in Table-4.

Discussion
Herbal medicines with vigorous historical backgrounds are great sources to discover novel drugs [78,79].The Canon of Medicine prescribed eleven important herbs for the management of post hemorrhoidectomy complications (  [67,68,77].However, lignans had less importance, and there was only one report about their anti-inflammatory effects [64].
Although there was no clinical study that observed the selected herbs' effects on patients after hemorrhoidectomy surgery, there are some clinical studies on hemorrhoid patients.For example, Mosavat et al. confirm Allium ampeloperasum L. cream's po-tent anti-bleeding effects on symptomatic patients [80,81].Moreover, Yousefi et al. revealed that Commiphora mukul can improve some patients' discomforts such as constipation and bleeding severity [82].
Our review study revealed that most of Avicenna's prescribed herbs demonstrate potent related pharmacological effects in modern medicine.So, these herbs are good candidates for future clinical purposes.However, these plants need to be evaluated by scientists and go through clinical trial tests to confirm their efficacy and safety.The second suggestion is to examine the plant mixtures to observe their possible synergistic effects.

Conclusion
H. perforatum L. and P. oleraceae L. have revealed most support through scientific databases.They showed anti-inflammatory, analgesic, antinociceptive, antispasmodic, and wound-healing effects.All of the mentioned herbs displayed analgesic and anti-inflammatory effects.While 36% of medicinal plants displayed wound-healing properties, 54% of them exhibited antispasmodic activities.These results don't establish wound-healing or antispasmodic activities for all of the discussed plants; however, these species may not have been tested for their pharmacological effects, and future research on them are recommended.Among the various phytocomponents, only flavonoids exhibited all of the mentioned pharmacological effects.

2 . 2 .
Scientific Studies On the Main Prescribed Herbs by Avicenna for the Management of Scientific Studies On the Main Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications

Table 1 .
Main Herbs Prescribed by Avicenna for the Management of Post Hemorrhoidectomy Complications

Table 2 .
Scientific Studies On the Main Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications

Table 2 .
Scientific Studies On the Main Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications Cocos nucifera L.

Table 2 .
Scientific Studies On the Main Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications

Table 2 .
Scientific Studies On the Main Prescribed Herbs by Avicenna for the Management of continue in page 175 continue of

Table 2 .
Scientific Studies On the Main Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications

Table 3 .
Pharmacological Effects of the Main Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications

Table 4 .
Reported Phytoconstituents of the Main Prescribed Herbs by Avicenna for the Management of Post Hemorrhoidectomy Complications

Table -
Table-3).As demonstrated in Table-4, different classes of phytoconstituents especially flavonoids, polyphenols, terpenoids, alkaloids, and tannins are responsible for the discussed pharmacological effects.Flavonoids displayed all of the mentioned pharmacological effects