European Journal of Integrative Medicine 30 (2019) 100935 Contents lists available at ScienceDirect European Journal of Integrative Medicine journal homepage: www.elsevier.com/locate/eujim Clinical trial Effects of Terminalia chebula Retz. in treatment of hemorrhoids: A double – T blind randomized placebo – controlled clinical trial ⁎ Pouran Andarkhora, Amir Sadeghib, Mahmood Khodadoosta, , Mohammad Kamalinejadc, Latif Gachkard, Saeed Abdib, Arman Zargarane a Department of Traditional Medicine, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran b Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences, Tehran, Iran c School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran d Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran e Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran ARTICLE INFO ABSTRACT Keywords: Introduction: Hemorrhoids are one of the most common complaints affecting the gastrointestinal tract. The Hemorrhoids treatment of hemorrhoids in modern medicine causes many side effects. In Persian Medicine (PM), Terminalia. Terminalia chebula Retz chebula Retz. is one of the best choices for the treatment of hemorrhoids. The aim of this study was to evaluate Herbal therapy the efficacy and safety of T. chebula on hemorrhoids. Rectal diseases Materials and methods: Microbial tests and standardization of T. chebula were conducted prior to the preparation Persian medicine of the capsules. Patients (n = 104) meeting the inclusion criteria were randomly assigned to either the herbal Randomized controlled trial intervention (T. chebula) or placebo capsules, four times daily on an empty stomach for four weeks. Outcomes included pain, constipation, hemorrhoids mass size, and bleeding. Results: There was a significant difference between the two groups in terms of pain in the first and fourthweeks (p = 0.003, p = 0.025 respectively). Also, constipation and reduction of hemorrhoids mass size were sig- nificantly different between the intervention and placebo groups(p = 0.001, p < 0.001, respectively). However, there were no differences between the two groups in bleeding days(p = 0.123) during the four weeks. All variables (pain, constipation, haemorrhoids mass size, and hemorrhoids hemorrhage) had significant differences (p < 0.001, p = 0.002, p < 0.001, p = 0.003) between the two groups two months after the end of the treat- ment, respectively. Conclusion: This study suggests that T. chebula may be effective on hemorrhoids and potentially supplement for the treatment -of hemorrhoids. 1. Introduction Austria, respectively [4,5]. In UK, the incidence is reported as 40% according to a screening colonoscopy [6]. Because of the high pre- Hemorrhoids are abnormal dilated vascular channels which are valence and incidence of this disease, it is considered as one of the dislocated by changes in the supporting tissue of anal cushions [1]. socioeconomic and medical problems worldwide [1]. Internal hemorrhoids are categorized into four grades: grade I hemor- The most common symptoms and signs that patients with hemor- rhoids are prominent blood vessels without prolapse; grade II hemor- rhoids present include bleeding, prolapsing masses, and itching [7]. The rhoids are prominent blood vessels with prolapse, but spontaneous re- treatment method will be decided depending on grading of hemor- duction; grade III hemorrhoids refer to prominent blood vessels with rhoids. The preferred treatment in the first and second-degree hemor- prolapse requiring manual reduction; and grade IV hemorrhoids are rhoids is medical therapy which involves local hygiene, addition of prominent blood vessels with prolapse and inability to be manually dietary fiber, increased water intake, stool softeners, avoidance of reduced [2]. The true prevalence and incidence of hemorrhoids is un- straining, and cortisone suppository [7–9]. Most patients with con- known [3]; however, some epidemiological studies have indicated that servative treatment will need a definitive treatment later [5]. In pa- prevalence ranges from around 4.4% to 38% in the general population tients with grade I, II, III hemorrhoids who have not been treated by in the United States and according to a colorectal cancer screening in medical treatment, some office-based procedures should be applied ⁎ Corresponding author at: School of Traditional Medicine, No. 8, Shams Alley, Vali-e-Asr Street, Tehran, Iran. E-mail address: [email protected] (M. Khodadoost). https://doi.org/10.1016/j.eujim.2019.100935 Received 19 December 2018; Received in revised form 2 July 2019; Accepted 3 July 2019 1876-3820/ © 2019 Published by Elsevier GmbH. P. Andarkhor, et al. European Journal of Integrative Medicine 30 (2019) 100935 such as rubber banding, sclerotherapy, and infrared photocoagulation Beheshti University of Medical Sciences (Tehran, Iran) and registered [7,9]. Surgical hemorrhoidectomy should be reserved for patients with by voucher NO. SBMU-8070. grade IV hemorrhoids and some patients with grade III hemorrhoids who have not responded to office procedures or cannot tolerate them 2.3.2. Microbial tests [7,9]. There are many complications following office-based procedures The Total Viable Aerobic Count (TVAC) of the organisms was de- and operations such as stenosis, infection, fibrosis, fecal incontinence, termined by most probable number (MPN) method. Briefly, the T. urinary retention, and ectropion [8,9]. chebula powder was prepared in 10-fold dilution series by sterile normal Given the importance of the disease and its treatment complica- saline, after which 1 ml sample of each dilution was inoculated in tri- tions, new approaches should be found for prevention and treatment of plicate into three broth culture tubes containing 9 ml of Soy Casein hemorrhoids. Application of medicinal plants and complementary Digest Broth (SCDB) for incubation at 35 °C for 5 days. TVAC was de- therapies is usually considered as a novel source in finding new re- termined based on comparing the number of tubes with growth against medies [10]. Persian Medicine (PM) is one of the main traditional the USP tables [29]. systems of medicine which was the main medical paradigm in the The sample were tested for 5 microorganisms including Europe and western Asia until the 17th century AD [11]. Persian Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, practitioners have used natural remedies for preventing and treating Salmonella spp, and Candida albicans according to WHO method [30]. different diseases [12]. Terminalia. chebula Retz. is one of the main medicinal plants which was used for hemorrhoids in PM for centuries [12,13]. T. chebula has 2.3.3. Determination of gallic acid as a marker by HPTLC method been mentioned as a purgative agent of Black bile (suada) and Phlegm Recent findings suggest that gallic acid is the main constituent of T. (balgham) (two important causes of hemorrhoids in humoral theory of chebula. It was determined for standardization of the product produced PM) in Al Qanun fi al-Tibb (Canon of Medicine) written by Avicenna and in this study. For preparation and standardization of the sample, 0.5 g Al Hawi (Liber Continens) written by Rhazes in 10th and 11th century AD, of dried fruit powder with 10 ml ethanol in a flask was placed in an respectively [14,15]. Since it is astringent, the sugar derived from su- ultrasonic chamber at 50ᵒC for 30 min. The amount of gallic acid was garcane is added to it for preventing its harmful effects (as a mosleh) determined on HPTLC plates (10 × 10) pre-coated with silica gel 60F- [16]. In addition to PM, this herb was mentioned to shrink the he- 254 as the stationary phase by CAMAG automatic TLC sampler 4. The morrhoid mass size and stop the bleeding in other traditional systems of linear ascending development was carried out in a CAMAG automatic medicines like Ayurveda [17]. developing chamber (ADC2) with mobile phase consisting of toluene: There are many poly herbal formulations containing T. chebula ethyl acetate: formic acid 5:4:1 (v/v/v). After development, the plate whose efficacy against bleeding and hemorrhoid mass size hasbeen was air dried for 5 min and scanned immediately at 272 nm using TLC shown in both animal [18] and human studies [19–23]. scanner III (CAMAG scanner-III). A TLC visualizer was employed for the Meanwhile, current findings suggest that T. chebula contains various photo documentation of the plates [31]. compounds including tannins, polyphenols, terpenes, glycosides [10,24], flavonoids [24,25], alkaloids, anthocyanins [10] which possess 2.3.4. Preparing the drug and placebo anti-inflammatory, antimicrobial [10,26], mild laxative, analgesic, as- In order to provide T. chebula capsules, each capsule was filled with tringent, antifungal [10], wound healing [10,27], and anti-ulcerogenic 250 mg of T. chebula powder (without seeds) and 250 mg of sugar [28] effects. which were ground and passed through a sieve with mesh size 40. Although there is some experimental research evidence as well as Further, the capsules were filled with 250 mg starch for preparing evidence from traditional use on the efficacy of T. chebula for hemor- placebo capsules. Both T. chebula and placebo capsules were prepared rhoids, there have been no clinical evaluations on its use. Therefore, in in the Sanabol Daru Co. (a pharmaceutical