Clinical Efficacy of Pankajakasthuri Orthoherb Tablets in Managing Various Signs and Symptoms Associated with Patients Diagnosed with Osteoarthritis: Open Clinical Trial

) Clinical Efficacy of Pankajakasthuri Orthoherb Tablets in Managing Various Signs and Symptoms Associated with Patients Diagnosed with Osteoarthritis: Open Clinical Trial.


Introduction
Osteoarthritis (OA) is a slowly evolving degenerative and inflammatory disease, highly prevalent, limits health and well-being (especially in the elderly population) and is one of the most common causes of physical incapacity in the world.OA commonly falls under the umbrella term of "degenerative diseases" that are associated with aging.OA is the most common form of arthritis, affecting around 250 million people globally and is one of the leading causes of disability that affects the joints [1].The prevalence of knee osteoarthritis is about 22-39% in India, and an estimated 32.5 million Americans are affected by it each year [2,3].
The main symptoms and signs are joint pain, stiffness, limitation on motion, joint deformity, and different degrees of joint inflammation [4].Various modalities to manage knee joint pain range from conservative management, such as exercise, oral medication, including nonsteroidal anti-inflammatory agents, and joint injections, to surgical treatment.All medications for osteoarthritis have the potential for side effects [5][6][7] depending on the type of drug or individual involved.
Therefore, to overcome all these issues and find a more harmless and equally efficacious therapeutic option, researchers are considering plants as a source of medicine.Initially, these plant-based medicinal systems formed the foundation of folk or ethno medicines, practiced in India.Concerns regarding the safety and costs of conventional arthritis therapies have sparked interest in natural remedies.In addition, difficulty with chronic pain management in arthritis has led to the investigation of herbal therapies.Herbs may offer a complementary or alternative method for effective and safe treatment.
Pankajakasthuri Herbals India Pvt. Ltd. formulated Orthoherb Tablets, a polyherbal Ayurvedic formulation, that was proven to have a significant role in managing the pain and inflammation in joints due to various etiologies and pathophysiologies like osteoarthritis, polyarthritis, rheumatoid arthritis and other chronic degenerative disorders.This polyherbal formulation contains active herbal ingredients like Ricinus communis, Adathoda vasica, Aegle marmelos, Azadirecta indica, Sida retusa, Tragia involucrata, Abrus precatorius, Cyclea peltata, Scoparia dulcis etc.
The present study was designed to investigate the efficacy of Pankajakasthuri Orthoherb Tablets, which has been claimed to be effective in managing the various signs and symptoms associated with osteoarthritis.

Study Design
This study was conducted as an open label clinical study at Pankajakasthuri Ayurveda Medical College Hospital, Killy, Kattakada, Trivandrum, Kerala, India.

Ethics Approval and Consent to Participate
The study was approved by the institutional ethical committee.The study was performed in accordance with the protocol, and all subjects provided written, informed consent.The study protocol was approved by the institutional ethical committee and registered with the Clinical Trials Registry, India (CTRI registration number: CTRI/2018/02/012189).

Selection and Inclusion Criteria
The following are the inclusion criteria: Subjects of either gender, aged 18 to 70 years, with OA symptoms for a minimum of 6 months and a maximum of 5 years; Classical Signs and Symptoms of Osteoarthritis -Pain during movement and weight bearing, Swelling, Stiffness.Also fulfilling the classical criteria of Sandhigatavata mentioned in Ayurvedic texts-Shoola i.e., Akunchana prasarana vedana, Shotha and Sthambha; Diagnosed case of OA Knee based on the Kellegren-Lawerence grading scale (Grade-1 & 2); and subjects willing to sign the informed consent form.

Exclusion Criteria
The major exclusion criteria include: Secondary Arthritic conditions, Fractures, Ligament tear, Dislocation, Osteomyelitis, SLE; Tumors Bone density disorders; Anatomical joint deformities, NSAID/Analgesic/steroid treatment for Osteoarthritis; Patients who have undergone major surgery in the affected joint.
Participants who met the inclusion criteria were recruited to the trial.

Interventions and Dosage
The intervention used in this clinical trial was Pankajakasthuri orthoherb.The dosage fixed for Pankajakasthuri orthoherb tablets in the study was 2×500 mg three times daily for a period of six months.

Study Procedures
On the screening visit, the patient's voluntary, written, informed consent was taken and general and systemic examinations were performed.The diagnosis of OA of the knee joint was confirmed by clinical evaluation and radiographs of the knee joint (ACR Diagnostic Criteria for the Diagnosis of OA of the Knee).
On the baseline visit, 500 patients were enrolled who met the inclusion and exclusion criteria.All enrolled subjects were assigned to a single group and were given 'Pankajakasthuri orthoherb tablets' a polyherbal formulation, in a dose of 2 tablets trice daily, orally after meals, for 180 days.Recruited patients were advised to continue their daily activities and exercises that they had been doing before the enrollment and to continue the same until the end of the study period.

Follow-up Assessment
Follow-up visits were scheduled for patients at the second, fourth, and sixth months.On each follow-up visit, the patient's general and systemic physical examinations were performed.Assessment of the symptoms of OA was done on the VAS-OA Index.A global assessment of the overall efficacy of the study treatment was also done by the investigator and the patient on every follow-up visit.

Statistical Analysis
A paired t-test was used to assess changes from baseline measurements for both the primary and secondary outcomes between each treatment group.Student's t-test was used to compare differences between the treatment groups in the change from baseline for continuous outcome measures.P ≤ 0.05 was used as the level of significance for all analyses.All analyses were performed using PASW Statistics 18 (SPSS Inc., Chicago, IL, USA)

Effect of Treatment with Pankajakasthuri Orthoherb Tablets on Signs and Symptoms
The effect of treatment with Pankajakasthuri orthoherb tablets on signs and symptoms associated with osteoarthritis is given below (Tables 2-6).The results of this study clearly demonstrated that Pankajakasthuri orthoherb tablets significantly improved various signs and symptoms associated with OA.

Effect of Pankajakasthuri Orthoherb Tablets on Pain in Osteoarthritis Patients
The mean score of the symptoms was 3.410 before treatment, and it was reduced to 2.436 with a mean difference of 0.974±0.574on the second month after treatment, and it was further reduced to 0.102 (a mean difference of 3.308±0.605)during the 6 th month follow-up period (Table 2).This data showed that 6-month treatment with Pankajakasthuri orthoherb tablets on patients resulted in significant progression of osteoarthritic pain.

Effect of Pankajakasthuri Orthoherb Tablets on Oedema in Osteoarthritis Patients
The mean score of the oedema symptoms before treatment was 2.460, which was reduced to 1.562 with a mean difference of 0.898±0.303on the second month after treatment, and further reduced to 0.000 (a mean difference of 2.460±0.711)during the sixth month follow-up (Table 3).Thus, it was clear that 6-month treatment with Pankajakasthuri orthoherb tablets on patients resulted in significant progression of osteoarthritic oedema.

Effect of Pankajakasthuri Orthoherb Tablets on Stiffness in Osteoarthritis Patients
The mean score of the stiffness symptoms before treatment was 3.208, which was reduced to 2.208 with a mean difference of 1.000±0.506on the second month after treatment, and further reduced to 0.102 (a mean difference of 3.106±0.746)during the sixth month follow-up (Table 4).Thus, it was clear that 6-month treatment with Pankajakasthuri orthoherb tablets on patients resulted in significant progression of osteoarthritic oedema.

Effect of Pankajakasthuri Orthoherb Tablets on Tenderness in Osteoarthritis Patients
The mean score of the tenderness symptoms, which was 2.616 before treatment, reduced to 1.490 with a mean difference of 1.126±0.565on the 2 nd month after the treatment, which further reduced to 0.000 (mean difference of 2.616±0.487)during the 6 th month follow-up (Table 5).As a result, it was clear that 6-month treatment with Pankajakasthuri orthoherb tablets on patients resulted in significant progression of OA tenderness.

Effect of Pankajakasthuri Orthoherb Tablets on Pain on Movement in Osteoarthritis Patients
The mean score of the symptoms, which was 3.336 before treatment, was reduced to 2.360 with a mean difference of 0.976±0.482on the second month after treatment, and then to 0.102 (a mean difference of 3.234±0.767)on the sixth month follow-up (Table 6).Hence it can be concluded that the treatment with Pankajakasthuri orthoherb tablets significantly cured the signs and symptoms associated with OA (Fig. 1)

Discussion
Arthritis is the most common inflammatory disease in elderly individuals.The symptoms are characterized by inflammation, pain, and stiffness mainly in the musculoskeletal system [8].Pain is the most important symptom of this disease.Many medications for osteoarthritis have the potential for side effects [4][5][6][7].Because of the side effects of oral painkillers, public interest in the use of complementary medicine, especially traditional herbal medicines, has increased [9].Many herbal remedies are recommended for joint pain in traditional medical treatises [9,10].Therefore, demands for the development of safer medications have increased during the last few decades.As a result, we developed Pankajakasthuri orthoherb tablets, which contain 22 herbs that have previously been shown to be effective in the treatment of rheumatoid arthritis.This study found that Pankajakasthuri orthoherb tablets significantly reduced OA-related knee pain and increased joint mobility.
The improvement in knee mobility could be due to the supplement's effects on reducing inflammation and initiating tissue repair.The increase in joint space width seen is an interesting finding.This suggests that, over and beyond pain reduction, some physiological changes could be contributing to the improvement experienced by the patient.The physiological changes could include-repair or regeneration of connective tissue (collagen/ cartilage) and/or an increase in the secretion of lubricating synovial fluid or changes in the synovial fluid characteristics.
Guggulu (Commiphora wightii), one of the major ingredients used for the manufacture of Pankajakasthuri orthoherb tablets, possesses anti-inflammatory and analgesic actions.It helps in the prevention of degenerative changes that may occur in bones and joints due to arthritis.Guggulu reduces inflammation and joint stiffness as well as pain associated with arthritis, and increases joint mobility [11].Earlier pharmacological studies on Guggulu have established its anti-inflammatory and anti-arthritic activities in formaldehyde-induced arthritis, in albino rats [12].Significant anti-inflammatory and anti-arthritic activities of oleo-gum resin have been reported against carrageenan-induced rat paw edema, granuloma pouch, as well as adjuvant arthritis [13].There are several studies that report decreased inflammation and joint swelling after administration of the extracts of Guggulu resin.
Nirgundi (Vitex nigundo) possesses analgesic and antiinflammatory actions [14].It has been used to treat disorders characterized by shopha (swelling) and shula (pain) in the majority of the nighantus [15].Its preventive effect on the development of formaldehyde induced experimental arthritis has been observed [16].The present study supports these earlier observations and recommendations by the Nighantus.
Aegle marmelos (L.) Correa (AM) commonly known as Beal or Bilva belongs to the family Rutaceae has been widely used in Ayurveda for the treatment of Sandhigata vata.The anti-arthritic activity of various Aegle marmelos extracts was tested in vitro against protein denaturation against bovine serum albumin and egg albumin.The fruit extract of Aegle marmelos showed significantly higher anti-arthritic activity with increasing concentration.The flavonoids and triterpenoids present in Aegle marmelos may be the reason for this anti-arthritic activity.Hence, Aegle marmelos can be used as an anti-arthritic agent [17].
Eranda (Ricinus communis) leaf extract shows a significant antiarthritic effect at the 200mg/kg and 400mg/kg dose levels.It is possible that this is due to the presence of phytochemicals such as flavonoids and saponins.10 The results of an 80% methanolic extract (500 mg/kg) and total flavonoid fractions (50 mg/kg) were on par with diclofenac sodium (20 mg/kg).Ricinus communis leaves have anti-inflammatory potentials, and flavonoids dominate this activity in the extract [18].Pashanabheda (Curculiginis orchioides) curculigoside exhibited significant anti-arthritic activity in vivo and in vitro.This may be mediated by inhibition of pro-inflammatory cytokine release and downregulation of JAK/STAT pathway proteins, as well as an increase in NF-κB and IκB expression.According to the findings of this study, curculigoside could be considered a potential candidate drug for arthritis treatment [19].
The extract of Punarnava (Boerhaavia diffusa) possesses potentially useful anti-arthritic activity in Complete Freunds Adjuvant model.Study has shown that 1000 mg petroleum ether extract of roots of B. diffusa shown 81.58 % response as comparable to standard drug (Indomethcin) and 500 mg petroleum ether extract of roots of B. diffusa shown 41.92 % as comparable to standard [20].

Conclusion
This study demonstrated that Pankajakasthuri orthoherb tablets improve OA symptoms and can be an effective treatment option for patients with OA.Since this formulation consists of herbs, it can be taken long-term, without the side effects associated with other pain medications.

Figure 1 :
Figure 1: Effect of Prolonged Treatment of Pankajakasthuri Orthoherb Tablets on OA Patients

Table 1
showed that, according to age, out of 500 patients, 0% were in the age group of 0-16 years.2.8% were in the age group of 16-30 years.19.4% were in the age group of 31-45 years.43.2% were in the age group of 46-60 years.34.6% were in the age group of 61 or older