Management of Dushtavrana WSR to Chronic Non-Healing Ulcers by using Guduchi Triphaladi Guggulu, Gandharva Haritaki Churna orally along with Lekhan Karma, Jaluaka Avacharan, Nimb Patra Kashay Dhavana and Nimbadi ointment Local Application: A Single Arm Exploratory Study

INTRODUCTIONA chronic non-healing ulcer is defined as an ulcer that is not healed by 40-50% after four weeks of appropriate treatment.1 Treatment of Chronic Non-Healing ulcers has always been a challenging task for surgeons. New treatment modalities are being developed to treat such ulcers effectively. Ayurveda has great potential in treating such conditions due to its multidimensional approach. Sushrut Samhita, a surgical treatise of Ayurveda, emphasizes on diagnosis and management of various types of ulcers. In Sushrut Samhita, Shashti Upakramas i.e., 60 different treatment modalities are explained for the treatment of ulcers. These modalities are to be used in specific phases of the process of ulcer healing.2 Many factors are responsible for the non-healing of any type of ulcer. Some of them are Lack of oxygenation, infections, systemic diseases like diabetes mellitus, hypertension, lack of nutrition, Stress, etc.3 Ayurveda also has explained various reasons for delayed or non-healing of ulcers like ulcers with pus discharge, foreign bodies, presence of poisonous substances at the ulcer site, involvement of deeper structures, etc.4 The primary target in the treatment of chronic non-healing ulcers is the reinitiation of the healing process. It can be achieved by eliminating confounding factors along with the promotion of the healing process. The treatment modalities like Vranashodhana, Vranadhavana, Vranaropana along with Koshthashodhana can be used to eliminate the confounders and re-initiate the healing process. Sahasrayoga is a famous book of formulations traditionally used in Kerala. It has many simple yet effective formulations indicated for several diseases. One such formulation named as Guduchi-Triphaladi Kashayam is indicated in skin diseases, ulcers, and inflammations.5 It contains Guduchi (Tinospora cordifolia (Thunb.) Miers), Triphala (combination of Terminalia chebula Retz., Terminalia bellirica (Gaertn.)Roxb., Emblica officinalis Gaertn.), and Daruharidra (Berberis aristata DC). The combination is to be used in decoction form along with Guggulu. According to the principles of Ayurveda, Virechana is indicated in the treatment of Chronic Ulcers6 . Gandharva Haritaki Churna, a simple combination of Erand Taila and Haritaki Churna PO can do virechana on a daily basis. Additionally, Haritaki also has Vranaropana property.7 To facilitate the healing of ulcer, absence of any necrotic tissue, hypergranulation, fibrosed edges is important. To achieve that Surgical Debridement of the ulcer is necessary. Sushruta also mentions this under the title Lekhan Karma. A proper ulcer care regimen is an essential part of the treatment of ulcer healing. One of the components of the ulcer care regimen is cleaning or washing the ulcer. Antiseptic solutions are commonly used for this purpose. Sometimes de-sloughing agents are also required. Nimba (Azadirachta indica) is a commonly available plant traditionally used for ulcer care. It has antimicrobial as well as cleansing properties making it a suitable agent for ulcer wash.8 Another component of the ulcer care regimen is the dressing material. Various ointments, creams, medicated gauze, etc. are being used for dressing for decades. An ideal dressing material should be antiseptic, should keep the ulcer area moist, and should promote healing. Ayurveda texts have various formulations for the dressing of ulcers. One such formulation, specifically mentioned for non-healing ulcers in Sushrut Samhita Chikitsa- Sthan Chapter 1, is the paste of Nimba Patra Churna (Neem Leaf powder), Tila Churna (Sesamum powder), Madhu (Honey) and Ghrita (Ghee). The combination is said to have Vranashodhana (Cleansing) and Vranaropana (Healing) actions.9 Ayurvedic texts describe the qualities of Aushadha (Treatment) as Bahukalpa (Multiple Modalities), Bahuguna (Multiple Actions), Sampanna (Of Superior Quality and Yogya (Rightly Chosen). Also, Bheshaja is of three types- Antah-parimarjan (Internal), Bahiparimarjan (External)and Shastra-pranidhan (Surgical). Combination of these can give better results in Chronic Non-Healing Ulcer. Keeping this in mind this study using a set of internal and external medication along with a surgical (Lekhan Karma) and a para-surgical (Jalauka Avacharan) procedure is proposed for the treatment of Chronic Non-Healing Ulcer. NEED OF STUDY- Non-healing ulcers are a major health problem worldwide and needs a multidimensional approach. Sometimes, intractable non-healing ulcers are inevitable and detrimental to the lower limb and are a major cause of non-traumatic lower limb amputations. It is estimated that 6% of the global population are afflicted by chronic ulcers. It needs more holistic and integrated medical management for further progression and to salvage the from social deprivation and financial burden. The patients with Chronic non-healing ulcers (CNHU) needs timely intervention with tissue debridement, topical antimicrobial, compression, Oxygenated blood supply. Acharya sushruta has mentioned that Jaluaka/ leech is suitable device to remove dushita Rakta and to supply oxygenated blood to affected part until normal circulation can be restored. Pain relief from leech therapy is rapid, effective, and longlasting. Acharya Sushruta has also mentioned the importance of Lekhan Karma to promote the healing of ulcers by removing the confounding factors like hypergranulation, fibrosed edges, etc. In addition to that Various Kalpas are given to maintain the ulcer sterile and promote healing. Guduchi Triphaladi Kashay (Guduchi, Triphala, Daruharidra) mentioned in Sahasrayoga is a very simple yet completely unexplored formulation indicated in Tvak Roga, Vrana and Shotha. It is to be taken along with Guggulu for period of 1 month. Nimbadi Kalka (Nimba, Tila, Madhu, Ghrita) is mentioned in Sushrut Samhita. It is indicated in Non-Healing Ulcers. Daily administration of Kashaya and Kalka can be a tedious job. To increase the ease of administration and palatability, dosage form of the formulations will be changed from Kashay to Kashay Bhavita Guggulu and Kalka to Ointment. Many studies have been done to assess the antimicrobial as well as ulcer healing activity of Nimba (Azadirachta indica), Tila (Sesamum indicum), Honey, and Ghee independently. One Study about the efficacy of Nimbadi Kalka (Nimba Tila Madhu Ghrita) in Diabetic Foot Ulcers has been published10 . The aim of this study is to evaluate the efficacy and duration of healing by utilizing Lekhan Karm, Jalauka Avacharan (sterile medicinal leeches) nearer or over the ulcer site, Guduchi Triphaladi Guggulu and Gandharv Haritaki Churn orally along with Nimb Patra Kashay and Nimbadi ointment locally.

OBJECTIVE: Primary Objective:

1. To evaluate the healing effect of Guduchi Triphaladi Guggulu, Gandharva Haritaki Churna orally along with Lekhan Karma, Jaluaka Avacharan, Nimb Patra Kashay Dhavana and Nimbadi ointment Local Application in the management of Dushta Vrana WSR to Chronic Non-Healing Ulcer Secondary Objective:
2. Study the antimicrobial activity of selected formulation.
3. To study the Histopathological analysis of ulcer tissue, VEGF-AA, Hydroxyproline Assay.

STUDY DESIGNStudy Type- Single Arm Exploratory Study Masking- Open Label Study Centre- All India Institute of Ayurveda, New Delhi. Sample Size- Minimum 50 patients. DRUG DELIVERY REGIMEN AND POSOLOGY Drug Route of administration Dose Duration Lekhan Karma prior to application of ointment

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Guduchi Triphaladi Guggulu Oral 1 gm TDS 28 Days Gandharv Haritaki Churna Oral 10 gm HS 28Days Nimba Patra Kwatha Vrana Dhawan As per wound size 28Days Nimbadi Ointment Local Application As per wound size 28 Days Jalauka Avacharan Local Application 3 Leeches of Medium Size 2 times/ week- till healthy granulation is achieved. (Max. up to 4 weeks.)

CLINICAL STUDYEnrolment of Patients All the patients will be enrolled from Shalya Samanya OPD of All India Institute of Ayurveda, New Delhi. Inclusion Criterion

1. Age group between 19 to 70
2. Chronic non-healing ulcers (Diabetic Ulcer, Venous Ulcer, Traumatic Ulcer, Burns) Exclusion Criterion
3. Patients with WBC count above 12000/mm3
4. Immunocompromised patients like HIV, HbsAg, HCV positive patients
5. Pressure sores
6. Known case of TB, Leprosy ulcer, Malignant Ulcers
7. Pregnant females
8. Uncontrolled Diabetes, Hypertension.
9. Hepatic and Liver Failure Investigations Prior To StudyCBC, RBS/FBS, PPBS, HbA1C, LFT, KFT, HIV, HBsAg, HCV, X-ray of relevant part. ASSESSMENT CRITERIASubjective Criteria1) Bates-Jensen ulcer assessment tool (On Day 0, Day 7, Day 14, Day 21, Day 28.) Objective Criteria1) Ulcer Swab C/SDay 0, Day 7, Day 14,
10. Digital Ulcer assessment using Digital imaging and processing with Software Image J (developed by NIH) 13 | Page Day 0, Day 14, Day 28.
11. Histopathological Analysis of by Edge BiopsyDay 0, Day 14, Day 28.
12. Growth Factor – VEGF-AA using ELISA MethodDay 0, Day 14, Day 28.
13. Hydroxyproline Assay using ELISA MethodDay 0, Day 14, Day 28.

Withdrawal CriteriaThe patient will be withdrawn from the trial if1) The patient is willing to discontinue treatment. 2) The patient is showing the following symptoms-

• Core temperature > 38.30C or < 360C
• HR > 90 bpm
• Reduced Capillary Refill
• TLC > 12000/mm3
• Platelet Count < 1.0 Lakh/mm3
• INR > 1.5 Rescue TreatmentThe patient will be shifted to conventional treatment (protocol) after assessment. PRIMARY END POINTReduction in wound size more than 50% of its original size or complete healing. SECONDARY END POINTS1) Documentation of Antimicrobial activity of selected formulations.

2. Evaluation of Healing activity by Histopathological analysis of ulcer tissue, VEGF-AA, Hydroxyproline Assay.