PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Osteoarthritis and its treatment: A comprehensive review

Akash Garg & Meenakshi Bajpai*

Akash Garg: Institute of Pharmaceutical Research (IPR), GLA University, NH-2, - Road, Chaumuhan, Mathura, (), Pin – 281406 Meenakshi Bajpai: Institute of Pharmaceutical Research (IPR), GLA University, NH-2, Mathura-Delhi Road, Chaumuhan, Mathura, Uttar Pradesh (India), Pin – 281406

*Corresponding Author Prof. Meenakshi Bajpai Institute of Pharmaceutical Research (IPR), GLA University, Mathura NH-2, Mathura Delhi Road, Chaumuhan Mathura, Uttar Pradesh (India) Pin - 281406 Mob: +91 9811330854 Email: [email protected]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 159 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Abstract Osteoarthritis is the most occurring disease today mainly in elderly patient which lead to inflammation and pain in joints. In this loss of elasticity occur due to change in the cartilage. According to different systems of medicine, there are different concepts of osteoarthritis. Ayurveda is one of the oldest systems of medicine used for treatment of chronic disorders like osteoarthritis. The other system includes unani and siddha concept. In unani system, the main cause of osteoarthritis is unbalanced state of mind and siddha system includes degeneration of articular cartilage in synovial joints. The allopathy concept of medicine is the most widely used nowadays which involve inflammation of joints due to activation of some enzymes like cyclooxygenase, lipoxygenase, interleukin etc. This review mainly focuses on the concept and treatment of osteoarthritis in different systems of medicine. Keywords: Osteoarthritis, Unani, Siddha, Ayurveda, Allopathy, cyclooxygenase. Introduction Arthritis is the common disease of joints which take place with the increase in age. In this, a person feels pain in joints and it most commonly take place in knee, hip, feet, spine etc. but it also occurs at finger, shoulder, wrist etc. People feel more pain in the cold and damp weather. It includes osteoarthritis, Rheumatoid arthritis, gout, ankylosing spondylitis, juvenile idiopathic arthritis, psoriatic arthritis, reactive, septic and thumb arthritis.

Fig: Thumb arthritis[93] Osteoarthritis is the disease which may take place when the tissue which is covering the joints break down and these tissues provide support to the ends of the joints when joints move like walking, running etc. In this, people feel too much pain and it get worsen with the age and it affect millions of people worldwide. [1]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 160 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Fig: Osteoarthritis[94] Rheumatoid arthritis is the auto-immune disorder in which the body attacks its own body joints and tissues. It is the most dangerous inflammatory disorder which can also affects our skin, heart, blood vessel etc. it mainly affects the joint’s lining which may result in the joint deformity and bone erosion. In severe condition, it can also cause disability of patient. [2]

Fig: Rheumatoid arthritis[95] Gout is the disorder which can affect anyone at any age because it takes place when uric acid crystals deposits at the joints and cause intense pain and inflammation. The attack takes place suddenly even in the midnight also. The affected joint is swollen and hot. [3]

Fig. Gout[96] Ankylosing spondylitis is a type of inflammatory disease in which some of the vertebrae of the spine of a person get fuse which make them less flexible and stiff and cause inflammation, pain and forward posture and if ribs get fuse or affected, then, a patient feels difficulty in deep breathing. [4]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 161 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Fig. Ankylosing arthritis[97] Juvenile idiopathic arthritis is the disorder of children, as the name suggest juvenile (child with age below 18). So, this is a type of rheumatoid arthritis which most commonly take place in juvenile child. [5]

Fig. Juvenile Idiopathic arthritis[98] Psoriatic arthritis is a type of arthritis which commonly takes place in people which has psoriasis (a disease in which person has red patches with silvery scales). The person having psoriasis when diagnosed they are also having psoriatic arthritis. [6] Reactive arthritis is a type of arthritis which take place due to triggering by the infection of other part of body like genitals, urinary tract intestine etc. It is also called as Reiter’s syndrome. [7]

Fig. Reactive arthritis[99]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 162 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Septic arthritis is the painful infection in joints which take place due to bacteria or viruses travelling in our body via blood stream or it can take place when any bacteria or virus enter directly into the joints by any injury. [8]

Fig: Septic arthritis[100] Osteoarthritis Osteoarthritis is the joint pain disorder which affects 10% male and 18% female over the age of 60 years. The main risk factor for osteoarthritis is age. Change in the morphology of femoral and tibial bone can result in the development of knee osteoarthritis. If, there is the difference in the length of the legs, then, the chances of osteoarthritis are more in the shorter leg than the longer one. [9,10,11,12] Pathogenesis: Earlier, osteoarthritis is only known to be the disease of cartilage degradation but now it is known to be the disease which affect complete joint in which activation of matrix protease has main role. Synovium, cartilage and subchondral bone has the main role in pathogenesis of osteoarthritis. In osteoarthritis, synovitis is the most common feature. In this, synoviocytes’s proliferation and tissue hypertrophy with increasing vascularity takes place. [13] Cartilage contain a type II collagen which form a meshwork and it receive stabilisation from other collagen and non-collagen type protein and give tensile strength to cartilage. On activation, chondrocytes produce cytokines (IL6 and TNF) and matrix degrading enzyme (metalloproteinases) and these are having pathogenic effect. [1, 14] Subchondral bone forms a bridge between the cartilage and trabecular bone. A study showed that osteoblasts become active with the expression of inflammation responding agents. [15, 16] Development of osteoarthritis Level 1 – The matrix of cartilage breaks by proteolytic means. Level 2 – The surface of cartilage erodes and fibrillates and releases collagen & proteoglycan in synovial fluid. Level 3 – In synovium broken cartilage product causes chronic inflammation which further causes increase in cartilage breakdown. [83]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 163 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Development of osteoarthritis

Level 1 Level 3 Level 2 Fig: Development of osteoarthritis[83] Diagnosis Osteoarthritis can only be diagnosed if a patient has symptoms by imaging and biochemical markers. Traditionally, it is diagnosed by plain film radiography which includes the change in width of joint space, formation of osteophytes and subchondral cyst development. Now, MRI and ultrasonography are also used for imaging purpose. There are several biomarkers which are released during inflammation like cytokines and enzymes which degrade matrix. The concentration of these biomarkers can be measured synovial fluid, blood and urine also. There are other biomarkers also like CTX II and oligomeric matrix protein whose concentration can be measured in urine and serum respectively. [1]

By using biochemical By using imaging Diagnosis markers

Radiography Cytokines MRI

Computed tomography Several enzymes

Ultrasonography

Bone scanning

Fig: Diagnosis of osteoarthritis[1]

Pain mechanisms in osteoarthritis Pain is the most common symptom which involves elevation of periosteal osteophytes, vascular blockage of subchondral bone, fatigueness in muscles, inflammation of synovial membrane which causes nociceptors activation, contracture and effusion of joints, swelling of synovial sac, tearing of

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 164 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

tissue and psychological factors. In arthritis of lumbar spine, the region from L3 to L5 gets affected & its symptoms include radicular pain, spondylolisthesis. [83] Treatment: Osteoarthritis can be treated by change in the lifestyle like weight loss and exercise, surgery like joint distraction and periarticular osteotomy and NSAIDs like aceclofenac.[1] TABLE1: TREATMENT OF OSTEOARTHRITIS [1] Lifestyle modification Weight loss, exercise Symptom improvement and reduced risk of symptomatic osteoarthritis Surgery Debridement of FAI lesion Symptom improvement sustained beyond 5 years Joint distraction (6−12 weeks) Sustained symptomatic improvement with evidence of cartilage regeneration Regenerative surgical techniques Microfracture of subchondral Slight improvement in pain and bone defect filling Cell-based therapies1 Slight improvement in pain and defect filling Drug targeting Cartilage degradation Doxycycline108 Structural modification but no symptomatic benefit FGF-18 (intra-articular) Structural modification but no symptomatic benefit Drug targeting cartilage degradation Strontium ranelate Improvement in symptoms and structure

Diagnosis in allopathy: [60,63,64] It can be diagnosed either by using biochemical markers or by using imaging techniques. 1) Normal radiography – It is the cost-effective method and give fast results. It shows the loss of space between joints, cyst and subchondral bony sclerosis. [61,62] 2) Computed tomography – It is rarely used in diagnosis of primary osteoarthritis. It is used in case of improper alignment of foot & ankle joints or patellofemoral joints. 3) Magnetic resonance imaging – It is used to visualize articular cartilage and other joint tissues directly but it is not used unless surgical repair is required. [66,85] 4) Ultrasonography – It is used to monitor degeneration of cartilage and provide guidance for injections of joints. [65]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 165 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

5) Bone scanning – It is used for diagnosis of osteoarthritis in hands and can be used to differentiate it from other bone diseases like bone metastases. Different biomarkers are released during inflammation which can be measured using synovial fluid, urine or blood and help in diagnosis of osteoarthritis.

Management and treatment in allopathy

The treatment involves both pharmacological and non-pharmacological therapy. a) Non pharmacological therapy include providing education to patients related to disease, loss of weight, doing regular exercise, occupational and physical therapy. b) Pharmacological therapy – The American college of rheumatology recommends following – [76,77,78] 1) For hand arthritis – topical capsaicin, topical NSAID trolamine salicylate, oral NSAID tramadol. 2) For knee arthritis – oral and topical NSAIDs, acetaminophen, tramadol, intra articular corticosteroid injections. 3) For hip arthritis – Acetaminophen, oral NSAIDs, tramadol, intra- articular corticosteroid injections, surgery (arthroscopy, osteotomy)  For patients with high resistant pain tramadol can be used but, in a study, conducted it was found that the mortality rate increased in case of patients aged 50yrs taking tramadol compared to the patients taking other NSAIDs. It affects the safety profile of drug. [68,69]  In case of patients with gastrointestinal toxicity from NSAIDs, proton pump inhibitor like misoprostol is also prescribed and selective COX-2 inhibitor like celecoxib can be used instead of non-selective NSAIDs.

Arachidonic acid NSAID s

COX-2

Prostaglandins

Mediate pain and inflammation

Fig: Mechanism of action of NSAIDs[101]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 166 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

 In June 2018, the USFDA approved use of calcium channel blocker amlodipine with celecoxib as amlodipine decrease the blood pressure which further decrease the risk of heart disease which is higher in case of patients taking celecoxib.  Hydroxychloroquine, used for rheumatoid arthritis can be used in case of hand arthritis to provide relief from synovitis but in a randomized study on 210 patients, it does not show any benefit in case of hand arthritis.[70]  Duloxetine, selective serotonin nor-epinephrine reuptake inhibitor can be used for treatment of osteoarthritis. A randomized double blinded trial was done on knee osteoarthritis patients for moderate pain relief using duloxetine instead of NSAIDs and reduction in pain and improvement in function was found. Some side effects found were dry mouth, nausea, fatigueness, constipation, reduced appetite. [74,75]  The intra-articular therapy includes injection of sodium hyaluronate and corticosteroids which provides reduction in pain and swelling. [71,72,73]  For knee osteoarthritis, steroid injection can be given to get relief from pain but in a study carried out by Mcalindon et al on 140 patients treated with steroid injection consisting of 40mg triamcinolone and found that no reduction in pain and increase loss of cartilage.  The FDA approved in October 2017 triamcinolone acetonide injectable suspension for treatment of knee osteoarthritis. [80]  The injection of sodium hyaluronate for knee osteoarthritis was approved by FDA.  The trials on drug milnacipran are going on for treatment of osteoarthritis. This drug also has higher efficacy as compared to drug Duloxetine.  Strontium ranelate can also be used for treatment of osteoarthritis it was proven that narrowed joint space increased in patients treated with drug as compared to patients treated with placebo. It also inhibits resorption of subchondral bone and restore the balance between catabolic and anabolic effect of chondrocytes.  MMP -13 & ADAMTS-5 are the main enzymes responsible for osteoarthritis. Chen et al studied the effect of ADAMTS-5 inhibitor on knee joint of rats for treatment of osteoarthritis. He used combination therapy of hyaluronic acid hydrogel and ADAMTS-5 inhibitor i.e. 114810 which improved degeneration of cartilage and increased cartilage regeneration after eight weeks. The antibody of syndecan-4 can also be used for treatment of osteoarthritis as syndecan-4 is responsible for activation of ADAMTS-5.  The combination therapy of apocynin & Paeonol can be used as they possess chondroprotective and anti-inflammatory properties. They have been tested in animal model and has provided improvement in pain as compared to NSAIDs.[102]  Photoactivated platelet rich plasma therapy can be better treatment option for treatment of patients with chronic knee osteoarthritis. The study was done on 232 patients having age between 40-70yrs were treated with this therapy for 12yrs. The results of study demonstrated improvement in pain, reduced damage of cartilage and bone and improved joint tissue. [110]  Sprifermin, which is a recombinant human fibroblast factor-18, improved knee osteoarthritis but up to lesser extent and phase 3 trial are still to be done.  Intra-articular capsaicin also improved knee osteoarthritis but phase-3 are still to be done.  Cathepsin A improved structural development in knee osteoarthritis compared to placebo but doesn’t improve symptoms.[103]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 167 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Osteoarthritis in Unani system of medicine In unani system of medicine, osteoarthritis is termed as tehjurul mafasil in which the word tehjurul means inflammation and mafasil means joints. According to this system, osteoarthritis occurs due to variation in state of mind when diversion of unhealthy matter occurs towards joints. The main factor responsible for osteoarthritis accumulation includes Ghair tabbayi akhlaat (unbalanced mind state) such as safravi (choleric), predominance of damvi (sanguine), saudavi (melancholic), balgami (phelgamatic) and khilt (mind state or mixture of any two Ghair tabbayi akhlaat). The other factor responsible is Sue-mijaz (abnormal character) which can be either due to Sue-mijaz madda (with any unhealthy matter) or Sue-mijaz saada (without any unhealthy matter). [79,82] Pathophysiology In this mainly all the tissues of joints are affected which includes muscles, cartilage, capsule, bone, synovium etc. In cartilage, the degradation of agreecan and collagen occur mainly by agreecanase, stromelysin and collagenase. It also causes fibrillation of cartilage surface, decrease in thickness of cartilage, formation of osteophytes and formation of vertical clefts. Thinning of cartilage and remodeling of bone also occur and causes hyperplasia. [84] Causes The main causes are obesity, age, large consumption of cold food, heredity, increased exposure to cold weather, imbalance of biochemicals, cell disorders and increased use of joints. [84] Symptoms 1) Pain during movement 2) Swelling of joints 3) Difficulty in movement 4) Stiffness Diagnosis It can be diagnosed on the basis of clinical history and X-rays. The X-rays show following characteristics- a) Excessive bone formation around joints b) Osteophytes c) Formation of Subchondral cyst d) Narrowing of joint space. Treatment The treatment of osteoarthritis can be done by using either herbal drugs or home remedies.  Herbal drugs used include Curcuma longa, Boswellia serrata, Withania somnifera, Commiphora wighitti, Zingiber officinalis, Asparagus racemose, Triphala etc.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 168 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

a) Curcuma longa act by inhibiting the enzymes cyclooxygenases, phospholipase A2 and lipooxygenases leading to reduced inflammation. b) Boswellia serrata act by inhibiting lipooxygenases which is responsible for formation of inflammatory marker leukotrienes and thus reduces both pain and inflammation. c) Withania somnifera act by reducing the production of tissue necrosis factor alpha (TNF- α) and interleukines subtypes. d) Commiphora wighitti inhibit the enzyme nuclear factor kB responsible for many autoimmune and inflammatory diseases. It deacreases both pain and inflammation in joints. e) Zingiber officinalis act by inhibiting the enzyme cyclooxygenases responsible for inflammation. f) Asparagus racemosus provide soothing effect by inhibiting inflammatory agents such as TNF- α and interleukein 1B (IL-1B). g) Triphala includes Terminalia chebula, Terminalia belerica and Emblica myroblan having anti-inflammatory properties.[84]

Phospholipids Zingiber officinalis Boswellic acid inhibit here inhibit here Arachidonic acid

5-Lipoxygenase cyclooxygenase pathway pathway

Prostaglandins, Leukotrienes thromboxane

Fig: Mechanism of action of boswellia and zingiber [88]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 169 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Curcuma longa Commiphora wighitti Asparagus racemosus

Inhibit secretion of TNF-α, nuclear factor kB, interleukin 1B, phospholipase A2

Anti-inflammatory activity

Fig: Mechanism of action[90]

h) Aujaja (capsule form), Habb-i-Mafasil (pills form) and Majun suranjana (Majun form) of Merendra persica (Suranjan shirin), variety of Colchicum is used for treatment of arthritis. [104] i) For the treatment of knee osteoarthritis, efficacy of Qai, Munzij wa Mus’hil-e-balgham & dalk with Roghan-e-chobchini was determined by carrying out open labelled, pre and post clinical study on 30 patients. The formulation was found to be safe and effective for treatment of knee osteoarthritis. [105]

Home remedies includes Sesame oil, ginger tea, fenugreek and Dashmula. a) 10-12 pieces of Ginger are boiled in 8 cups of water and consumed within a day. b) Doing massage of sesame oil helps to remove pain and stiffness by improving blood circulation. c) Soak 1gm of fenugreek in boiled water and keep overnight and consume in the morning after proper mixing. d) Dashmula is a mixture of ten roots including Tribulus terrestris (gokshura), Desmodium gangeticum (shalaparni), Solanum xanthocarpum, Uraria picta (prishnaparni), Gmelina arborea (beach wood), Aegle marmelosa (Indian bael), Oroxylum indicum, Premma serratifolia (arani), Stereospermum suaveolens and Solanum indicum. In this the powder is dissolved in water and boiled till it remains half and it is consumed 3-4 times a day after filtration before meal to get relieve from pain and inflammation.  Other remedies include loss of weight, consuming omega-3 fatty acid, vit. C and Vit. D rich diet and control of blood sugar level. Preventive measures Mental status of a person is mainly responsible for imbalance of humors which can be balanced by following six essentials-

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 170 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

1) Makool wa mashroob (food & drink) 2) Hawa (air) 3) Naum wa yagza (sleep & wakefulness) 4) Harkat wa sukoon-e-nafsaani (mental work & rest) 5) Harkat wa sukoon-e-badani (body movement & rest) 6) Istifraagh wa ehtabaas (retention & evacuation)

Treatment of osteoarthritis in ayurvedic system of medicine In spite of different treatment provided by health professionals, Ayurveda is one of the earliest methods for treatment of osteoarthritis. In this, vata affects the various joints and cartilages. It provides herbal drugs with anti-inflammatory properties for treatment of arthritis without the side effects which occur due to conventional system of medicine. The American college of rheumatology presented that herbal medicines were as effective in treating knee arthritis as glucosamine and Celebrex and with minimum side effects. It states that other herbal drugs including ginger, turmeric, boswellia, shatavri, guggul, Withania and triphala all show anti- inflammatory properties. [81,86,87] Anti-arthritic activity of Enicostemma littorale was determined by measuring paw volume in rats. Freund’s adjuvant induced arthritic model was used in which paw volume decreased up to 15.81% at a dose of 150mg/kg body weight. [107] A randomized, double-blind, placebo controlled parallel group study was done to determine effectiveness of E-OA-07 (Lanconone) for knee osteoarthritis. The result revealed improvement in pain, movement and stiffness. It contains mixture of seven herbal ingredients and was developed by Enovate Biolife. [109] In Ayurveda, the main cause of Osteoarthritis is the vata imbalance. The disorder generated due to the increase in vata is called as vata vyadhi (group of disorder) and in vata vyadhi, a disorder of joint come which is called as sandhi gata vata (osteoarthritis). Vata is responsible for the movement of body but when it reaches above its point, then it causes degeneration of the body as vata is having absorption property. Consumption of dry food, wake up late night, chronic indigestion, trauma etc. are the main factor for impairing vata. When, impaired vata enters into streams, sandhi gata vata take place. Symptoms: The sign and symptoms of increased vata are pain in joints, poor strength, dryness, wrinkles etc. Management: This can be achieved by fasting, by oiling or liquefying the joint by using several herbal oils, by managing the lifestyle, food etc.[94] The marma therapy is found to be effective for treatment of knee osteoarthritis. Marma therapy include massage on four point of legs (Gshipra, gulpha, indravasti, janu). The therapy was found to be beneficial for both short term and long-term pain relief. It led to improvement in Shotha (swelling), Atopa (crepitus), shola (pain) and stabdhata (stiffness). [108]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 171 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Meditation In Ayurveda, spiritual and emotional health play important role in alleviating health problems because it involves balancing of mind and spirit as well along with body. It causes decrement in inflammation along with various changes within the body. A study was conducted by Dr. Jon kabat zinn to see the effect of meditation on reduction of pain on a group of patients who were suffering from persistent pain. Randoplh in 1999 conducted a study in which patients were given yoga and meditation classes and found that in patients who were taking these classes, the pain reduced by 79% as compared to those not taking classes along with conventional medicines i.e. it enhances the effect of conventional treatment. Yoga Yoga is a science which is required for living a self-esteemed and a balanced life. Yoga provides increased balance, strength and flexibility which are important in case of osteoarthritis patients. There are different asanas for different parts- a) For spine: - Pachimottanasana, Bhujangasana, utthita parsvakonasana, matsyendrasana. b) For knees and hips: - Trikonasana, Garudasana. c) For legs: - virabhadrasana  Pachimottanasana- It is used to increase flexibility of spine and lengthen the toes but is contraindicated in diarrhea and andominal surgery.  Bhujangasana- It is used to increase muscle strength of abdomen, back, and whole upper body and lengthen the spine but contraindicated in hernia.  Utthita parsvakonasana- It is used to increase flexibility of shoulders, spine and chest and strength of knees, ankles and legs but it is contraindicated in neck injuries.  Matsyendrasana- It is used to stretch chest & shoulder and lengthen the spine & is contraindicated in spinal disc herniation.  Trikonasana- It promotes stretching of thighs and increase the strength of legs but it is contraindicated in knee and neck injury.  Garudasana- It is used to increase strength and stretching capacity of ankles, thighs, hips and shoulders and is contraindicated in shoulder, knee and ankle injury  Virabhadrasana- It is used to stretch the shoulder & chest muscles and strengthen the muscles of legs and knees but is contraindicated in knee and ankle injury. [91] Treatment of osteoarthritis in siddha system of medicine Azhal keelyayu is a joint disease involving synovial joints in which degeneration of articular cartilage occurs. It can be either primary or secondary. Primary osteoarthritis occurs at older age and it is more prevailing in women after 40yrs of age because of degeneration of bone which occurs due to deficiency of female hormone like estrogen.[67] Secondary osteoarthritis can occur at any age due to any injury like fracture, inflammation which causes rupturing of articular cartilage. It mainly affects spine, knee and hips. It mainly involves disarray of pitham or azhal

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 172 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

which causes drying of lubricating fluid present in the joint. This results in difficulty in movement and inflammation. The main causes are- weight gain, lack of exercise, hypothyroidism, stress. Treatment This system of medicine provides measures to eliminate the main cause of disease rather than providing medicines to eliminate pain or symptoms. Azhal is mainly responsible so firstly it has to be decreased. For this,  decoction of Drakshaj, Meghanatha thylam, Ponnavarai choornam and Vellai ennai are used.  Decoction of petals of rose, Nilavagai and Drakshaj can also be used. Sangu parpam (calcite) obtained from Turbinella pyrum shell by biomass derivation is found to be useful for treatment of arthritis. [106] Internal medicines For preventing cartilage degeneration, restoring dried synovial fluid and increase the strength of muscles, following medicinal drugs can be used: -  Nilavembu kudineer, Amukkura choornam, Neermulli kudineer,  Thrikadugu choornam, Muthu parpam, Mrumugha chendooram,  Payazha parpam, Kalameghanarayana chendooram, Vanga chunnam,  Poornachandrodayam, Vathamadakki tablet, Serankottaj etc. preparations. External therapies It includes applying bandage on knee using Mahamasha thylam or Ulunthu thylam. Kukkil vennai, Chitramoola thylam, Kukkil thylam and Siyappu can also be used. Other treatment includes: -  Exercise for strengthening muscles should be done.  Avoid lifting heavy weight.  Body weight should be maintained by avoiding heavy diet and water and fluid intake should be more.  Yogasanas like vaiarsanam, trikonasanam, padmasanam etc. should be done.  Doing meditation can also provide relief.[92]

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 173 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Table2: Formulations for the treatment of osteoarthritis

S.No. Formula- Drug Polymer/Excipi Inference System of Reference tion ent medicine 1. Nanogel Curcumin Chitin This nanogel have good skin Ayurveda 17 penetration capacity due to which it shows good drug loading, release and selective toxicity towards melanoma cells. 2. Nano Curcumin Chitosan, poly- These formed nanogels Ayurveda 18 hydrogel (N- protect the drug and modify isopropylacryla its release by incorporation of mide) stimuli responsive confirmation and biodegradable bonds into the polymeric network and overcome the problem of aqueous solubility, instability and absorption of curcumin. 3. Nanogel Curcumin Dextrin It shows controlled release Ayurveda 19 and remove the problem of low water solubility and bioavailability. 4. Nanogel Curcumin Carboxymethyl The folic acid conjugated Ayurveda 20 chitosan, casein, curcumin revealed low IC50 folic acid value and high cytotoxicity as compared to free curcumin and polymer loaded curcumin. 5. Nanogel Curcumin Poloxamer 188 It showed that it can be used Ayurveda 21 & 407 for increasing the bioavailability of curcumin within aqueous humor by increasing the permeation and retention in cornea. 6. Gel Curcumin Poloxamer 407, It led to increased Ayurveda 22 phosphatidylcho penetration of curcumin in line skin and also protected it from degradation. 7. Nanogel Curcumin Alginate It exhibited that 70% of the Ayurveda 23 aldehyde gelatin drug is released at acidic pH in tumor cells due to metabolic drug products accumulation and increased

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 174 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

bioavailability and therapeutic efficacy. 8. Gel Curcumin, Pluronic F127, Carbopol 934 have better gel Ayurveda 24 Boswellia, oil carbopol 934, properties as compared to of HPMC, sodium other polymers and provide wintergreen alginate, pectin highest drug release, better pH, clarity and homogeneity and Spreadibility. 9. Gel Cardiosperm Carbopol 934, Results depicted reduction in Ayurveda 26 um carbopol940 paw volume, spleen and halicacabum, thymus weight and TNFα vitex level which confirms the anti- negundo arthritic activity of gel. 10. Anti- Boswellic Carbopol 940 It resulted in higher anti- Ayurveda 31 inflammat acid inflammatory activity of ory nanogel of AKBA as Nanogel compared to its conventional gel due to very small size of polymeric nanoparticles and its mucoadhesive property. 11. SLN gel Piperine compritol 888 Reduction in level of TNF α Ayurveda 33 ATO, precirol and accumulation of piperine ATO5 in skin was found. 12. Nanogel Tridax Carbopol The results revealed that Ayurveda 35 procumbens Carbopol 934 showed excellent properties with highest drug release and no skin irritation. 13. Gel Urtica diocia Carbopol 934 It was concluded that Ayurveda 36 polysaccharides in its extract have prolong anti- inflammatory activity in rat paw edema test. 14. Nanoemul Quercetin Carbitol, The nanoemulgel increased Ayurveda 38 gel poloxamer 407 the bioavailability as compared to its gel due to presence of carbitol and poloxamer 407. 15. Aqueous Withania The chondroprotective action Ayurveda 39 extract of its aqueous extract by direct inhibition of gelatinase activity of collagenase type2 was observed. 16. Gel Curcumin, Sesame oil as The activity of poly herbal Ayurveda 40 arni, rasna, base formulation was found to be chinese better as compared to

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 175 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

chaste tree, marketed one and also the oil Solanum having more content of Vitex xanthocarpu negundo was having more m anti-inflammatory activity as compared to others. 17. Root Withania The results indicated that on Ayurveda 42 powder treatment with root powder of Withania Somnifera, the paw volume reduced to normal level and the inhibition of release of lysosomal enzyme by stabilizing action of Withania somnifera. 18. extract Boswellia On treatment with extract, the Ayurveda 43 serrata patient reported decrease in knee pain with good tolerance due to its anti-inflammatory activity. 19. Acetone Boswellia The study revealed that it has Ayurveda 44 extract for carterii anti-arthritic and anti- arthritis inflammatory activity. The level of TNF-α and interleukin-1beta also decreased with no side effects. 20. Arthritis Curcumin, Poly £- Both quercetin and curcumin Ayurveda 45 quercetin caprolactone inhibit activation of neutrophil, angiogenesis and proliferation of synoviocyte. At molar concentration, curcumin inhibited collagenase and stromelysin expression while quercetin has no effect. 21. Arthritis Turmeric The results depicted that Ayurveda 46 three curcuminoids in its extract are responsible for anti-arthritic activity while the other ingredients in turmeric crude extract inhibit the protective effect. 22. NLC Boswellic Poloxamer 188 Boswellic acid inhibit the Ayurveda 47 based gel acid activation of nucleic acid transcription factors TNF- kappa-β and synthesis of TNF-α.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 176 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

23. Gel for Boswellia Aerosil 200 Boswellic acid act as anti- Ayurveda 48 gout serrata inflammatory agent which acid inhibit the activation of nucleic acid transcription factors TNF-kappa-β and synthesis of TNF-α. 24. Hydrogel Triptolide Carbomer 940 No local and systemic Ayurveda 49 toxicity of triptolide loaded hydrogel thickened microemulsion was observed in different animals and mild skin irritation was observed. 25. Gel Tripterygium The Tripterygium wilfordii Ayurveda 50 (double wilfordii hook F was found to be safe blinded and effective in patients with randomiz rheumatoid arthritis. ed controlled design) 26. Polyherba Turmeric, Carbopol 940 Both the formulation Ayurveda 51 l gel in garlic, neem, exhibited good zone of conc. Of tulsi, inhibition but the activity of 0.5% and cinnamon, 0.5% was better as compared 0.1% tomato to that of 0.1%. 27. Gel Curcumin Phosphatidylcho It caused decrease in joint Ayurveda 53 line pain and improvement in function of joints. Curcumin act by reducing the level of cyclooxygenase, lipoxygenase, nuclear factor kappa B and genomic expression. 28. Extract Boswellia Tween 20 All provided anti- Ayurveda 54 (1:1, 1:2, serrata, inflammatory activity but the 2:1) Curcuma ratio of 1:2 exhibited better longa activity and potency in comparison to other two. 29. Transder Nuxvomica Carboxymethyl Brucine inhibited the Ayurveda 56 mal gel cellulose symptoms of arthritis and synoviocyte’s proliferation. It acts as anti-inflammatory by inhibiting the synthesis of prostaglandin. 30. Herbomin Turmeric, Hard gelatin The study predicted that this Ayurveda 57 eral Withania, formulation significantly capsule Boswellia, reduces the severity of pain

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 177 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

articulin-F due to the anti-inflammatory action of ingredients 31. Sesame Sesame oil Sesame oil eliminated Ayurveda 55 oil orally cisplatin induced hepatic & renal injuries & decreased lipid peroxidation & production of hydroxy radical & nitrite in blood and tissue without affecting the anti- tumor efficacy. 32. Gel Diclofenac HPMC K100M, HPMC K100M have high Allopathy 25 sodium carbopol 934P swelling property which modify the release of drug and glycerine as permeation enhancer increase the penetration of drug in skin. 33. Transder Diclofenac Carbopol 934P, The formulation containing Allopathy 27 mal gel sodium HPMCK4M, drug and Carbopol 934P in Sodium CMC the ratio of 1:2 showed sustained release of drug with desired therapeutic concentration of drug. 34. Gel Diclofenac Gellan gum Increase in the release and Allopathy 28 sodium transport of drug was observed. 35. Glutathione Both glutathione and Allopathy 29 liposomal glutathione reduced the rheumatoid factor and malondialdehyde levels but liposomal glutathione showed better effect. 36. Nanogel Aceclofenac Carbopol 940 The nanogel increased the Allopathy 30 permeability, stability and provided sustained release of drug due to increase in the contact between drug and skin due to availability of more surface area and hydration and overcome the problems of oral administration like gastric disturbances, low bioavailability. 37. Anti- Tenoxicam Noveon It increased permeability of Allopathy 32 inflammat polycarbophil drug to skin due to ory AA-1 availability of more surface

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 178 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

Nanogel area and hydration and the anti-inflammatory activity was found to be better. 38. SLN Meloxicam Carbopol 940 The nanogel provided Allopathy 34 based gel controlled release due to depot of drug in skin and better anti-inflammatory activity and skin tolerability properties as compared to its nano emulsion. 39. Nanogel Etoricoxib Stearic acid and The use of stearic acid Allopathy 37 tween 80 increased the entrapment of drug and tween 80 resulted in reduction in particle size which resulted in fast and controlled release of drug. 40. Anti- Ketoprofen, Poly (lactic-co- It acted as suitable drug Allopathy 52 inflammat spantide II glycolic acid), delivery system for ory chitosan percutaneous delivery of both Nanogel drugs into deep layers of skin for treatment of various anti- inflammatory disorders. 41. Nanoparti Glucosamine Gelatin The nanoparticles prepared Allopathy 41 cles sulphate were small in size having high entrapment efficiency which led to increased bioavailability. 42. Nanogel Methotrexate Sodium The nanogel increased the Allopathy 58 carbonate skin penetration and sodium carbonate increased the solubility and release of drug and caused reduction in prostaglandin synthesis. 43. Mixture Asarun, The mixture was effective in Unani 59 Tukhme reducing the severity of karafs, Filfil disease in patients with daraz, Gule osteoarthritis of knees. baboona, Gule tesu

Conclusion: Osteoarthritis is a chronic inflammatory disorder which involves all types of tissues like bones, muscles but the major changes occur in cartilage. It mainly occurs due to unhealthy lifestyle of individual which affects the quality of their life. The different concepts of treatment discussed above involves both herbal and non-herbal treatment strategy but the chances of side effects are

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 179 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

more in case of allopathic as compared to other systems of medicine. The best way to treat osteoarthritis involves lifestyle modification like doing regular exercise, eating healthy diet, doing asanas regularly and meditation. References: - 1) Jones SG, Palmer AJ, Agricola R, price AJ, Vincent TL, Weinans H, Carr AJ. Osteoarthritis. Lancet. 2015; 386: 376-387. 2) Firestein SG. Evolving concepts of rheumatoid arthritis. Nature. 2003; 423: 356-361. 3) Chol HK, Mount DB, Reglnato AM. Pathogenesis of gout. American college of physicians’ internal medicine. 2005; 143: 499-516. 4) McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, Hill RA, Jones A, Mota RM, Walley T. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation. Health technology assessment. 2007; 11(28). 5) Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007; 369: 767-78. 6) Moll JMH, Wright V. Psoriatic arthritis. Seminars in arthritis and rheumatism. 3(1): 55- 78. 7) Pope JE, krizova A, Garg AX, Philbrook HT, Ouimet JM. Campylobacter reactive arthritis: A systematic review. 2007; 48-54. 8) Goldenberg DL. Septic arthritis. Lancet. 1998; 351: 197-202. 9) Woolf AD, Pfl eger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003; 81: 646–56. 10) Neogi T, Bowes MA, Niu J, et al. Magnetic resonance imaging-based three-dimensional bone shape of the knee predicts onset of knee osteoarthritis: data from the osteoarthritis initiative. Arthritis Rheum 2013; 65: 2048–58. 11) Harvey WF, Yang M, Cooke TD, et al. Association of leg-length inequality with knee osteoarthritis: a cohort study. Ann Intern Med 2010; 152: 287–95. 12) Lawrence RC, Felson DT, Helmick CG, et al, and the National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.Arthritis Rheum 2008; 58: 26–35. 13) Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone 2012; 51: 249–57. 14) Vincent TL. Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix.Curr Opin Pharmacol 2013; 13: 449–54. 15) Weinans H, Siebelt M, Agricola R, Botter SM, Piscaer TM, Waarsing JH. Pathophysiology of peri-articular bone changes in osteoarthritis. Bone 2012; 51: 190–96. 16) Sanchez C, Pesesse L, Gabay O, et al. Regulation of subchondral bone osteoblast metabolism by cyclic compression. Arthritis Rheum 2012; 64: 1193–203. 17) Mangalathillam S, Rejinold NS, Nair A, Lakshmanan VK, Nair SV, Jayakumar R. Curcumin loaded chitin nanogels for skin treatment via the transdermal route. Nanoscale. 2012; 4: 239-50. 18) Luckanagul JA, Pitakchatwong C, Bhuket PRN, Muangnoi C, Rojsitthisak P, Chirachanchai S, Wang Q, Rojsitthisak P. Chitosan based polymer hybrids for thermo- responsive nanogel delivery of curcumin. Carbohydrate polymers. 2017; 1-27.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 180 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

19) Goncalves C, Pereira P, Schellenberg P, Coutinho PJ, Gama FM. Self-assembled dextrin nanogel as curcumin delivery system. Journal of biomaterials and nanobiotechnology. 2012; 3: 178-184. 20) Priya P, Raj RM, Vasanthakumar v, Raj V. Curcumin loaded layer by layer folic acid and casein coated carboxymethyl cellulose/ casein nanogels for treatment of skin cancer. Arabian Journal of Chemistry. 2017: 1-52. 21) Liu R, Sun L, Fang S, Wang S, Chen J, Xiao X, Liu C. Thermosensitive in situ nanogel as ophthalmic delivery system of curcumin: development, characterization, in vitro permeation and in vivo pharmacokinetic studies. Pharmaceutical development and technology. 2015: 1-7. 22) El-Refaie W, Elnaggar YSR, EL-Massik MA, Abdallah OY. Novel curcumin loaded gel core hyaluosomes with promising burn-wound healing potential: Development, in-vitro appraisal and in-vivo studies. International journal of pharmaceutics. 2015; 88-98. 23) Sarika PR, James NR, Anil Kumar PR, Raj Deepa K. Preparation, characterization and biological evaluation of cucumin loaded alginate aldehyde-gelatin nanogels. Materials Science and Engineering. 2016; 251-57. 24) Agrawal P, Bajpayee M, Singh SP. Formulation and evaluation of herbal gel containing Boswellia serrata, Curcuma longa extract and oil of wintergreen for rheumatoid arthritis. International bulletin of drug research. 2(3): 31-40. 25) Baviskar DT, Biranwar YA, Bare KR, Parik VB, Sapate MK, Jain DK. In vitro and In vivo evaluation of diclofenac sodium gel prepared with cellulose ether and Carbopol 934P. Tropical journal of pharmaceutical research. 2013; 12(4): 489-94. 26) Aiyalu R, Govindarjan A, Ramasamy A. Formulation and evaluation of topical herbal gel for the treatment of arthritis in animal model. Brazilian journal of pharmaceutical sciences. 2016; 52(3): 493-507. 27) Bhanja S, Kumar PK, Sudhakar M, Das AK. Formulation and evaluation of diclofenac transdermal gel. Journal of advanced pharmacy education and research. 2013; 3(3): 248- 59. 28) Carmona-moran CA, Zavgorodnya O, Penman AD, Kharlampieva E, Bridges SL, Hergenrother RW, Singh JA, Wick TM. Development of gellan gum containing formulations for transdermal drug delivery: Component evaluation and controlled drug release using temperature responsive nanogels. International journal of pharmaceutics. 2016: 1-40. 29) Kadry MO. Liposomal glutathione as a promising candidate for immunological rheumatoid arthritis therapy. Heliyon. 2019: 1-4. 30) Phatak AA, Chaudhari PD. Development and evaluation of nanogel as a carrier for transdermal delivery of aceclofenac. Asian pharma press. 2012; 2(4): 125-132. 31) Goel A, Ahmad FJ, Singh RM, Singh GN. Anti-inflammatory activity of nanogel formulation of 3-actyl-11-keto-β-Boswellic acid. Pharmacologyonline. 2009; 3: 311-318. 32) Chopade S, Khabade S, Patil A, Powar S. Formulation development and evaluation of anti-inflammatory potential of topical tenoxicam nanogel on animal model. International journal of recent scientific research. 2018; 9(12): 29951-29957.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 181 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

33) Bhalekar MR, Madgulkar AR, Desale PS, Marium G. Formulation of piperine solid lipid nanoparticles for treatment of rheumatoid arthritis. Drug development and industrial pharmacy. 2017: 1-26. 34) Khurana S, Bedi PMS, Jain NK. Preparation and evaluation of solid lipid nanoparticles based nanogel for dermal delivery of meloxicam. Chemistry and physics of lipids. 2013: 65-72. 35) Patil OA. Tridax Procumbens Linn nanogel as alternative treatment for rheumatoid arthritis. Indian Journal of novel drug delivery. 2018; 10(2): 76-83. 36) Liao JC, Wei ZX, Ma ZP, Zhao C, Cai DZ. Evaluation of root extract gel from Urtica dioica as analgesic and anti-inflammatory therapy in rheumatoid arthritis in mice. Tropical journal of pharmaceutical research. 2016; 15(4): 781-785. 37) Kesharwani R, Sachan A, Singh S, Patel D. Formulation and evaluation of solid lipid nanoparticle based topical gel of etoricoxib. Journal of applied pharmaceutical science. 2016; 6(10): 124-131. 38) Aithal GC, Nayak UY, Mehta C, Narayan R, Gopalkrishna P, Pandiyan S, Garg S. Localized in situ nanoemulgel drug delivery system of quercetin for periodontitis: developmental and computational simulations. Molecular Diversity Preservation International and Multidisciplinary Digital Publishing Institute. 2018; 23: 1-15. 39) Sumantran VN, Kulkarni A, Boddul S, Chinchwade T, Koppikar S, Harsulkar A, Patwardhan B, Chopra A, Wagh UV. Chondroprotective potential of root extracts of Withania Somnifera in osteoarthritis. Journal of Bioscience. 2007; 32(2): 299-307. 40) Chokshi KS, Ladola DB, Suthar JS, Solanki AJ, Ptael S, Ahir KB. To prepare a polyherbal formulation containing Pluchea lanceolata and Vitex negundo and evaluate its anti-inflammatory activity by topical application. American journal of pharmtech research. 2012; 2(4): 756-760. 41) Ei-Hossiny AS, Ward AA, Mostafa DM, Abd-EI-Messieh SL, Abdel-Nour AL, Darwish MM, Khalil WA. A newly developed transdermal treatment of osteoarthritis using gelatin nanoparticles. International journal of biological and pharmaceutical research. 2015; 6(4): 264-272. 42) Rasool M, Varalakshmi P. Suppressive effect of Withania somnifera root powder on experimental gouty arthritis: An in vivo and in vitro study. Chemico-biological interactions. 2006; 164: 174-180. 43) Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of boswellia serrata extract in treatment of osteoarthritis of knee- A randomized double-blind placebo- controlled trial. Phytomedicine. 2003; 10: 3-7. 44) Fan AY, Lao L, Zhang RX, Zhou AN, Wang LB, Moudgil KD, Lee DYW, Ma ZZ, Zhang WY, Berman BM. Effects of an acetone extract of boswellia carterii gum resin on adjuvant induced arthritis in lewis rats. Journal of ethnopharmacology. 2005; 101: 104- 109. 45) Jackson JK, Higo T, Hunter WL, Burt HM. The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis. Inflammation research. 2006; 55: 168-175.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 182 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

46) Funk JL, Oyarzo JN, Frye JB, Chen G, Lantz RC, Jolad SC, Solyom AM, Timmermann MN. Turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritis. Journal of natural products. 2006; 69(3): 351-355. 47) Shinde S, Ghorpade K, Gattani SG. design and development of boswellic acid loaded nanostructured lipid carrier based anti -psoriatic nano gel for dermal delivery. World journal of Pharmaceutical research. 2019; 8(7): 1045-1061. 48) Pal P, Shams S, Alam S. Formulation and evaluation of herbal gel of boswellia serrata for the management of gout. International journal for pharmaceutical research scholars. 2014; 3(3): 242-250. 49) Xu L, Pan J, Chen Q, Yu Q, Chen H, Xu H, Qju Y, Yang X. In vivo evaluation of the safety of triptolide-loaded hydrogel-thickened microemulsion. Food and chemical toxicology. 2008; 46: 3792-3799. 50) Jiang Q, Tang XP, Chen XC, Xiao H, Liu P, Jiao J. Will Chinese external therapy with compound Tripterygium wilfordii hook F gel safely control disease activity in patients with rheumatoid arthritis: design of a double-blinded randomized controlled trial. BMC complementary and alternative medicine. 2017; 17: 1-6. 51) Bhinge SD, Bhutkar MA, Randive DS, Wadkar GH, Todkar SS, Kakade PM, Kadam PM. Formulation development and evaluation of antimicrobial polyherbal gel. Annales Pharmaceutiques Françaises. 2017; 75: 349-358. 52) Shah PP, Desai PR, Patel AR, Singh MS. Skin permeating nanogel for the cutaneous co- delivery of two anti-inflammatory drugs. Biomaterials. 2011; 33: 1607-1617. 53) Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, Togni S, Appendino G. Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients. Altern Med Rev. 2010;15(4):337-44. 54) Mishra NK, Allan JJ. Evaluation of anti-inflammatory activity and potency of herbal formulation consists of different proportions of Curcuma longa and Boswellia serrata by using Cotton pellet granuloma and xylene induced mice ear edema model. International Journal of PharmTech Research. 2010;2(3):1855-60. 55) Hsu DZ, Chen KT, Lin TH, Li YH, Liu MY. Sesame oil attenuates cisplatin-induced hepatic and renal injuries by inhibiting nitric oxide-associated lipid peroxidation in mice. Shock. 2006 ;27(2):199-204. 56) Wu P, Liang Q, Feng P, Li C, Yang C, Liang H, Tang H, Shuai C. A novel brucine gel transdermal delivery system designed for anti-inflammatory and analgesic activities. International journal of molecular sciences. 2017 Apr;18(4):757. 57) Kulkarni RR, Patki PS, Jog VP, Gandage SG, Patwardhan B. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. Journal of ethnopharmacology. 1991 May 1;33(1-2):91-5. 58) Singka GS, Samah NA, Zulfakar MH, Yurdasiper A, Heard CM. Enhanced topical delivery and anti-inflammatory activity of methotrexate from an activated nanogel. European Journal of Pharmaceutics and Biopharmaceutics. 2010;76(2):275-81.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 183 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

59) Tarannum A, Sultana A, Rahman KU. Clinical efficacy of certain Unani herbs in knee osteoarthritis: A pretest and post-test evaluation study. Ancient science of life. 2016 Apr;35(4):227. 60) Buckland-Wright JC, Verbruggen G, Haraoui PB. Session 3: Imaging. Radiological assessment of hand OA. Osteoarthritis and cartilage. 2000 Nov 1;8:S55-6. 61) Jewell FM, Watt I, Doherty M. Plain radiographic features of osteoarthritis. Osteoarthritis. Oxford University Press. Oxford. 1998:217-37. 62) Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M. OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis and cartilage. 2007 Sep 1;15(9):981-1000. 63) Recht MP, Kramer J, Marcelis S, Pathria MN, Trudell D, Haghighi P, Sartoris DJ, Resnick D. Abnormalities of articular cartilage in the knee: analysis of available MR techniques. Radiology. 1993 May;187(2):473-8. 64) Hunter DJ. Advanced imaging in osteoarthritis. Bulletin of the NYU hospital for joint diseases. 2008 Jan;66(3):251. 65) Keen HI, Wakefield RJ, Conaghan PG. A systematic review of ultrasonography in osteoarthritis. Annals of the rheumatic diseases. 2009 May 1;68(5):611-9. 66) Recht MP, Goodwin DW, Winalski CS, White LM. MRI of articular cartilage: revisiting current status and future directions. American Journal of Roentgenology. 2005 Oct;185(4):899-914. 67) Loughlin J. The genetic epidemiology of human primary osteoarthritis: current status. Expert reviews in molecular medicine. 2005 May;7(9):1-2. 68) Zeng C, Dubreuil M, LaRochelle MR, Lu N, Wei J, Choi HK, Lei G, Zhang Y. Association of tramadol with all-cause mortality among patients with osteoarthritis. Jama. 2019 Mar 12;321(10):969-82. 69) Kelly JC. Tramadol Linked to Higher Mortality in Osteoarthritis. Medscape Medical News. March 12, 2019. Available at https://www.medscape.com/viewarticle/910232 70) Kingsbury SR, Tharmanathan P, Keding A, Ronaldson SJ, Grainger A, Wakefield RJ, Arundel C, Birrell F, Doherty M, Vincent T, Watt FE. Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis: a randomized trial. Annals of internal medicine. 2018 Mar 20;168(6):385-95. 71) Neustadt DH. Intra-articular injections for osteoarthritis of the knee. Cleveland Clinic journal of medicine. 2006 Oct 1;73(10):897. 72) Hochberg MC, Altman RD, Brandt KD, Clark BM, Dieppe PA, Griffin MR, Moskowitz RW, Schnitzer TJ. Guidelines for the medical management of osteoarthritis. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1995 Nov;38(11):1535-40. 73) Lineker SC, Bell MJ, Boyle J, Badley EM, Flakstad L, Fleming J, Lyddiatt A, MacDonald J, McCarthy J, Zummer M. Implementing arthritis clinical practice guidelines in primary care. Medical teacher. 2009 Jan 1;31(3):230-7. 74) Citrome L, Weiss–Citrome A. A systematic review of duloxetine for osteoarthritic pain: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed?. Postgraduate medicine. 2012 Jan 1;124(1):83-93.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 184 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

75) Frakes EP, Risser RC, Ball TD, Hochberg MC, Wohlreich MM. Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial. Current medical research and opinion. 2011 Dec 1;27(12):2361-72. 76) Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch V, Wells G, Tugwell P. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis care & research. 2012 Apr;64(4):465- 74. 77) Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SM, Kraus VB, Lohmander LS, Abbott JH, Bhandari M, Blanco FJ. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and cartilage. 2019 Nov 1;27(11):1578-89. 78) Jevsevar DS, Brown GA, Jones DL, Matzkin EG, Manner PA, Mooar P, Schousboe JT, Stovitz S, Sanders JO, Bozic KJ, Goldberg MJ. The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee. JBJS. 2013 Oct 16;95(20):1885-6. 79) Arshid IQ, Siddiqui MA, Sarfaraz MD, Nasimul H. An Overview of Waja uz Zahr (Low Back Pain) and its Management in Unani System of Medicine. Pathogenesis. 2013 Oct 16;9:10. 80) McAlindon TE, LaValley MP, Harvey WF, Price LL, Driban JB, Zhang M, Ward RJ. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. Jama. 2017 May 16;317(19):1967-75. 81) Kessler CS, Pinders L, Michalsen A, Cramer H. Ayurvedic interventions for osteoarthritis: a systematic review and meta-analysis. Rheumatol Int. 2015;35(2):211–32. 82) Tarannum A, Sultana A, Ur Rahman K. Clinical efficacy of certain Unani herbs in knee osteoarthritis: A pretest and post-test evaluation study. Anc Sci Life. 2016;35(4):227. 83) Editor C. Osteoarthritis. 2020;(cmc):1–47. 84) nisa A, Hameed A, et al. Osteoarthritis and Unani Treatment-a Review. Int J Adv Res. 2018;6(4):991–5. 85) Braun HJ, Gold GE. Diagnosis of osteoarthritis: Imaging. Bone [Internet]. 2012;51(2):278–88. Available from: http://dx.doi.org/10.1016/j.bone.2011.11.019 86) Chopra A, Saluja M, Tillu G, Sarmukkaddam S, Venugopalan A, Narsimulu G, et al. Ayurvedic medicine offers a good alternative to glucosamine and celecoxib in the treatment of symptomatic knee osteoarthritis: A randomized, double-blind, controlled equivalence drug trial. Rheumatol (United Kingdom). 2013;52(8):1408–17. 87) Misra R, Kundagol M, Chacko J. AYURVEDIC APPROACH TO OSTEOARTHRITIS- A CASE REPORT. 2016;4(3):53–6. 88) KL G, Salunkhe KS. REVIEW ON: ANTI-INFLAMMATORY HERBAL GEL OF BOSWELLIA SERRATA & VITEX NEGUNDO. 89) Gupta M, Kaur G. Withania somnifera as a potential anxiolytic and anti-inflammatory candidate against systemic lipopolysaccharide-induced Neuroinflammation. Neuromolecular medicine. 2018 Sep 1;20(3):343-62. 90) http://www.phcog.com/viewimage.asp?img=PhcogMag_2017_13_49_90_197709_f6.jpg

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 185 PROTEUS JOURNAL ISSN/eISSN: 0889-6348

91) https://www.integrativepractitioner.com/practice-management/news/an-ayurvedic-approach-to- osteoarthritis. 92) https://siddham.in/osteoarthritis-siddha-medicine-treatment. 93) https://search.creativecommons.org/photos/dcab95b5-dca3-4c36-ac00-7c9ce8a1d02c 94) http://ayurtattvam.blogspot.com/2010/09/osteoarthritis-ayurveda-management.html. 95) https://www.freepik.com/free-vector/diagram-showing-rheumatoid-arthritis-hand. 96) https://www.freepik.com/free-vector/human-anatomy gout. 97) https://www.freepik.com/premium-photo/spondylosis-scoliosis-film-x-ray-lumbar- sacrum-spine-show-crooked-spine. 98) https://www.gentryvisualization.com/juvenile-idiopathic-rheumatoid-arthritis-affected- knee-joint/. 99) https://ayucliniko.com/articles/natural-treatment-reactive-arthritis/. 100) https://www.freepik.com/premium-photo/medical-x-ray-knee-joint-image-with- arthritis-gout-rheumatoid-arthritis-septic-arthr_3582696.html 101) Piazuelo E, Lanas A. Clinical effects of NSAIDs and COXIBs in colon cancer prevention. In NSAIDs and Aspirin. Springer, Cham. 2016;203-218. 102) Wu Y, Goh EL, Wang D, Ma S. Novel treatments for osteoarthritis: an update. Open access rheumatology: research and reviews. 2018; 10:135. 103) Ghouri A, Conaghan PG. Prospects for Therapies in Osteoarthritis. Calcified Tissue International. 2020 Feb 13:1-2. 104) Afsahul KM, Anjum F. Suranjan (Colchicum autumnale L. and merendra persica): Great resolvent herbs of Unani system of medicine-a review. 105) Mohammad SA, Ansari AN. Efficacy of Qai, Munzij wa Mus’ hil-e-Balgham and Dalk with Roghan-e-Chobchini in Waja-ur-Rukba. 106) Shailaja R, Tamilarasan G, Parthasarathy K, Parameswaran S. Biomass-derived thermal preparation of calcite, from phyto-capped marine gastropod shell, Turbinella pyrum L. Advanced Powder Technology. 2020 Jun 30. 107) Sanmugarajah V. A REVIEW ON THERAPEUTIC AND PHARMACOGNOSTIC PROPERTIES OF VELLARUGU (ENICOSTEMMA LITTORALE BLUME). International Journal of Ayurveda and Pharma Research. 2020 May 6:47-67. 108) Mishra A, Shrivastava V. Evaluation of Efficacy of Marma Therapy with Janu Basti in the Management of Janu Sandhigata Vata (Osteoarthritis of Knee). Dev Sanskriti Interdisciplinary International Journal. 2020 Feb 20; 15:29-45. 109) Srivastava S, Chaudhary JA, Girandola RN. Effect Of E-OA-07 On Improving Joint Health and Mobility In Individuals With Knee Osteoarthritis: A Randomized, Double- Blind, Placebo-Controlled, Parallel Group Study. Journal of Pain Research. 2019; 12:3365. 110) Mohiuddin AKM, Lewis P, Choudhury KN, Sadiq BU. Clinical outcome of photoactivated platelet-rich plasma in the treatment of knee osteoarthritis. Rheumatology and Orthopedic medicine. 2018; 4: 1-4.

VOLUME11 ISSUE 8 2020 http://www.proteusresearch.org/ Page No: 186