ARTHRELLA TABLETS

a) Clinical Pharmacology: Pharmacodynamics; Pharmacokinetics; bioavailability

Pharmacological group.
Disease-Modifying Anti-Rheumatic Drug (DMARD)

Pharmacological properties.
Pharmacodynamics. Arthrella® a fixed combination disease-modifying arthritis
rheumatoid drug (DMARD). The clinical efficacy of Arthrella tablets is
comparable to that of diclofenac sodium. It is known to help in rheumatoid
arthritis, juvenile rheumatoid arthritis, seronegative arthritis, psoriatic arthritis
and non-articular rheumatoid conditions such as fibromyalgia and soft tissue
rheumatism.

Clinical Pharmacology

Sedative: Henbane (also used to control symptoms associated

with disorders of the GI tract) Specific
Symptomatology—It is specific in excitable mental
conditions, and in the violent and noisy delirium of
fevers and acute inflammations, to subdue the
excitement and to induce sleep.

Immunomodulatory & DMARD: Suvarna Paan (Gold) Gold compounds primarily

depress the immune response. A study conducted
by the University of Pittsburg revealed that gold
salts restrain the release of HMGB1 from cells. This
is carried out by blocking the two molecular helper’s
namely nitric oxide and interferon beta which
facilitate the release of HMGB1 from the cells.

Experts explained that when the HMGB1 is released,

it provokes the immune system to increase
inflammations. This results in an uneven
distribution of the HMGB1 throughout the body.
Now the most important observation that they made
was that the synovial fluids and tissues contain high
proportions of HMGB1 that can cause much agony
and discomfort at joints.
Gold inhibits the release of HMGB1 which provokes
inflammation, the key process underlying the
development of rheumatoid arthritis by interfering
with the activity of two helper molecules that ease
HMGB1's release from the cell, interferon beta and
nitric oxide. When HMGB1 is released from the cell -
- either through normal processes or cell death -- it
becomes a stimulus to the immune system and
enhances inflammation.

Gold also suppresses the function of another

important component of the immune system, MHC
class II proteins, which are associated with
autoimmune diseases such as rheumatoid arthritis.
Brian DeDecker, Stephen De Wall, and colleagues
from the Harvard Medical School found that gold
therapy works by freeing autoimmune-provoking
peptides from MHC class II proteins.

DeDecker and co-author Stephen De Wall

undertook a large-scale search for new drugs that
would suppress the function of an important
component of the immune system, MHC class II
proteins, which are associated with autoimmune
diseases. MHC class II proteins normally hold pieces
of invading bacteria and viruses on the surface of
specialized antigen presentation cells. Presentation
of these pieces alerts other specialized recognition
cells of the immune system, called lymphocytes,
which starts the normal immune response. Usually
this response is limited to harmful bacteria and
viruses, but sometimes this process goes awry and
the immune system turns toward the body itself,
causing autoimmune diseases such as juvenile
diabetes, lupus, and rheumatoid arthritis.They
found that platinum was just one member of a class
of metals, including a special form of gold, that all
render MHC class II proteins inactive.

A 2-year double-blind study was made of gold salt

treatment in 27 patients who had active rheumatoid
arthritis for less than 5 years. The gold salt (gold
sodium thiomalate) was well tolerated in 13 of 15
 patients. Improvement, measured by physical
examination, ring sizes, and grip strength, was
significant in the treated group. Radiologic
examination showed that the bone and cartilage
destruction was arrested in several patients, and the
mean progression rate of destruction was
significantly slowed for the treated group.

From the Rheumatology and Neurology Divisions,

Henry Ford Hospital, Detroit, Michigan, and the
Department of Internal Medicine, Baylor College of
Medicine, Texas Medical Center, Houston, Texas.

Nervine Stimulant: Nux vomica increases reflex excitability. Endogenic

and exogenic stimuli reach the targeted organ without
hindrance and, as a result, possess a strengthened
effect that can be attributed to the alkaloid strychnine.
The toxic principle strychnine deadens the inhibitory
synapse of the CNS and results in overextended
musculature reactions. The strychnine and brucine
components act as competitive antagonists of the
neurotransmitter glycine. The drug is psychoaaateptic
due to an increase in reflex action, i.e., endogenic and-
~e)tGgenic stimuli reach-the targeted organ without
hindrance and as a result have a strengthened effect.
In addition, strychnine is cholinolytic in animal
experiments. The Ayurvedic Pharmacopoeia of India
recommends detoxified seeds in paralysis, facial
paralysis, sciatica and impotency. Homeopathic
remedies use a very dilute solution of nux vomica to
treat atonic muscles, constipation, paralysis and pain.

Laxative: Ricinus communs (Castor oil)

Antidiarrhoeal activity: Nux vomica counteracts the laxative effects of the

castor oil

Anagelsic & Antiinflammatory: Zingiber officinale (Cox 2 inhibitor: Ginger has

powerful Cox 2 inhibitors and demonstrates 56%
 inhibition of inflammatory prostaglandins (creation of
prostaglandins appears to be mainly a function of Cox
2 activity). Ginger contains melatonin, a hormone
secreted by the pineal gland and metabolically related
to serotonin. Melatonin is structurally related to an
internationally recognized NSAID known as
indomethacin, and Japanese research confirmed that
ginger has at least 4 prostaglandin inhibitors more
powerful than indomethacin.), Boswellia (The resin
of Boswellia serrata is used traditionally for a variety
of inflammatory diseases, such as rheumatoid
arthritis, osteoarthritis, and cervical spondylitis
(inflammation of the vertebrae). The main
constituents of the resin are boswellic acids, which
have been found to inhibit the synthesis of
leukotrienes (inflammatory compounds produced
when oxygen interacts with polyunsaturated fatty
acids). A number of chronic inflammatory conditions
are associated with leukotriene formation. Unlike
pharmaceutical corticosteroids which inhibit
leukotriene synthesis, boswellic acids exhibit no
significant side effects or toxicity. Boswellic acids
have been found specifically to inhibit 5-
lipoxygenase, the key enzyme of leukotriene
biosynthesis. Boswellic acids were found to be
effective in reducing the symptoms of rheumatoid
arthritis in clinical trials), Oroxylum indicum (In
Thailand one teaspoon of stem bark juice is given
with a cup of milk twice daily to treat rheumatic pain;
aqueous and alcoholic extracts were tested using
three different in vitro systems for effects relevant to
anti-inflammatory activity. The aqueous extracts of O.
indicum significantly reduced myeloperoxide
release), Vitex negundo (Telang et al first noticed non
steroidal anti-inflammatory drugs (NSAID) like
activity of VN).

Pharmacokinetics. Whereas Arthrella® is a multicomponent preparation, its

kinetics caused by an additive effect of its components and conducting trials is
impossible. Actions: Arthrella® reduces inflammation, relieves joint pain,
erythema and oedema. It arrests the production of aam (an endotoxin) by
 improving digestion and metabolism; it also provides strength to bones, muscles
and ligaments and repairs damages.

b) Efficacy: controlled studies; uncontrolled studies;

Efficacy, Disease-Modifying Effect and Safety of Arthrella Tablets v/s Diclofenac in

the Management of Rheumatoid Arthritis: A Randomized, Comparative, Double
Blind Study

Patients diagnosed with RA having acute pain, swelling and joint inflammation,
controlled with synthetic NSAIDs, and who required maintenance treatment to prevent
a recurrence and to minimize joint stiffness and swelling were included in the study.
RA test was performed at baseline for all patients enrolled in the study. However, RA
negative patients with clinical features of RA were also enrolled.

Patients with acute flare, overt joint deformity, joint pain following trauma, patients
who required surgical intervention and patients with history of gastritis, peptic ulcer
and bleeding ulcers were excluded from the study.

Eighty patients diagnosed as suffering from RA who needed drug therapy were
enrolled in the study. A written informed consent was obtained from all patients before
enrolling them in the study. They were divided into two groups: Group A patients were
administered tablet Arthrella in a dose of one tablet twice daily, while Group B patients
were administered tablet diclofenac 50 mg twice daily for a minimum period of 12
weeks. Evaluation of patients was performed every
15 days. Patients who were on other medications underwent a washout period of 15
days, following which they were started on one of the two drugs. The two preparations
were made to appear identical and were blinded.

From this trial, it can be concluded that the clinical efficacy of Arthrella tablets is
comparable to that of diclofenac sodium. Arthrella tablets can be used for reducing the
pain and inflammation of RA. The efficacy of the drug in the management of RA can be
attributed in part to its anti-inflammatory action as also to its disease-modifying
activity. No side-effects of Arthrella were reported by the patients in this trial.

c) Safety: adverse drug reactions in volunteers and where a new chemical moiety
has been marketed for less than five (5) years, adverse drug reactions in patients.

No side-effects of Arthrella were reported by the patients in the trials in India.

Some elderly patients have reported a slight increase in appetite.