RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA

4th ‘T’ Block, Jayanagar, BANGALORE-560041

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 / Name of the Candidate and
Address / NILESH TRIVEDI
s/o Mr. ARUN TRIVEDI
23,Sainath colony ‘B’ block barwani M.P.
Barwani-451551
2 / Name of the Institution / AL-AMEEN COLLEGE OF PHARMACY
Hosur Road,
Lal Bagh main Gate
Bangalore – 560027
Karnataka
3 / Course of Study and
Subject / M.Pharm
(Pharmaceutical Marketing And Management)
4 / Date of Admission /
11 Jan-2010
5 / Title of the Topic:
“ TO STUDY THE CURRENT & FUTURE TRENDS OF NSAID’S & BIOLOGICAL RESPONSE MODIFIERS IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS.”
6 / Brief resume of the intended work:
6.1 - Need for the study :-
Rheumatoid arthritis is a systemic auto-immune disorder. Auto-immune disorders such as RA offer a growth opportunity for pharmaceutical companies, having a patient potential requiring a chronic treatment approach often with high cost and novel biologics. The pharma industry today is turning its development focus towards auto-immune treatments.
In 2008, the Indian Rheumatology Association (IRA) updated its recommendations for the use of traditional disease-modifying antirheumatic drugs (DMARDs) and also added recommendations for using biological agents to treat RA. Prior to this change, the RA market in India had been dominated by palliative agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. High-priced biologics are expected to contribute significantly to market growth, even though only a minority of patients will be able to afford them.1
In India, the prevalence of RA is found to be around 0.75% in the adult population.The overall prevalence is approximately three times greater in women than in men.It presents a high incidence in women of child bearing age.2
The present project is being undertaken “To study the current & future trends of NSAID’s & biological response modifiers in the management of rheumatoid arthritis.”
6.2 Review of literature:-
Rheumatoid arthritis is a common chronic systemic inflammatory disease that results in progressive disability and increased mortality. Early disease is characterised primarily by inflammation of the synovium(the inner membrane of the capsule of synovial joints),As the disease progresses the patient suffers destruction of cartilage and bone.Extra-articular features commonly include general malaise, fatigue, weight loss, fever, and anaemia.More severe disease may be associated with vasculitis, pericarditis, pleurisy, pleural effusion, pulmonary interstitial fibrosis, scleritis and sjogren’s syndrome.
Since there is no cure, management is aimed at relieving pain and inflammation, and improving or maintaining joint function, using physiotherapy as well as drugs.3
Medical management of rheumatoid arthritis involves five general approaches. The first is the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAID’s) and simple analgesics to control the symptoms and signs of the inflammatory process. These agents are rapidly effective at mitigating signs and symptoms, but they appear to exert minimal effects on the progression of the disease. Recently, specific inhibitors of the isoform of cyclooxygenase (COX) that is up regulated at inflammatory sites (COX-II) have been developed. COX-II sepcific inhibitors (CSIs) have been shown to be as effective as classic NSAIDs, which inhibit both isoforms of Cox, but to cause significantly less gastro duodenal ulceration.4The second line of therapy involves use of low-dose oral glucocorticoids. Although low-dose glucocorticoids have been widely used to suppress signs and symptoms of inflammation, recent evidence suggests that they may also retard the development and progression of bone erosions. Intra-articular glucocorticoids can often provide transient symptomatic relief when systemic medical therapy has failed to resolve inflammation. The third line of agents includes a variety of agents that have been classified as the disease-modifying or slow –acting antirheumatic drugs. These agents appear to have the capacity to decrease elevated levels of acute-phase reactions in treated patients and, therefore, are thought to modify the inflammatory components of RA and thus its destructive capacity. Recently, combinations of disease-modifying antirheumatic drugs(DMARDs) have shown promise in controlling the signs and symptoms of RA.5 A fourth group of agents are the TNF-neutralizing agents, which have been shown to have a major impact on the signs and symptoms of RA. A fifth group of agents are the immunosuppressive and cytotoxic drugs that have been shown to ameliorate the disease process in some patients.6
NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ANTIPYRETICS-ANALGESICS FOR RHEUMATOID ARTHRITIS:-
ASPIRIN:-
Aspirin is acetylsalicylic acid. It is one of the oldest analgesic – antiinflammatory drugs. Aspirin is a weak analgesic but it effectively relieves inflammatory pain.
Adverse effects:-It may produce rashes, fixed drug eruption, urticaria, rhinorrhoea, asthma, and anaphylactic reactions. Aspirin therapy in children with rheumatoid arthritis has been found to raise serum transaminases, indicating liver damage.
Contraindications:-Aspirin is contraindicated in peptic ulcer, bleeding tendencies, in children suffering from chicken pox or influenza.
In chronic liver disease: cases of hepatic necrosis have been reported
It should be avoided in diabetics, in those with low cardiac reserve or frank CHF and in juvenile rheumatoid arthritis.
Dose and dosage forms:-75 to 350 mg tablets and Lysine acetylsalicylate 900 mg + glycine 100 mg/vial for dissolving in 5 ml water and i.v.injection.7
IBUPROFEN:-
It is a propionic acid derivative. Small clinical studies suggest that the propionic acid derivatives are comparable in efficacy to aspirin for control of the signs and symptoms of rheumatoid arthritis and osteoarthritis, perhaps with improved tolerability.
Adverse effects: - Ibuprofen and all its congeners are better tolerated than aspirin. Side effects are milder and their incidence is lower. Gastric discomfort, nausea and vomiting are the most common side effects.
CNS side effects includes headache, dizziness, blurring of vision, tinnitus and depression.
Contraindications: - Because they inhibit platelet function, use with anticoagulants should, nevertheless, be avoided.
Similar to other NSAID’s, they are likely to decrease diuretic and antihypertensive action of thiazides, furosemide and β blockers.
Dose and dosage forms:-400-600 mg tablets and available as 100mg/5 ml suspension.8
NAPROXEN:-
It is particularly potent in inhibiting leucocytes migration –may be more valuable in acute gout.
Adverse effects: - As Ibuprofen Naproxen is better tolerated than aspirin. Side effects are milder and their incidence is lower. Gastric discomfort, nausea and vomiting are the most common side effects.
CNS side effects includes headache, dizziness, blurring of vision, tinnitus and depression.
Contraindications: - because they inhibit platelet function, use with anticoagulants should, nevertheless, be avoided.
Similar to other NSAID’s, they are likely to decrease diuretic and antihypertensive action of thiazides, furosemide and β blockers.
Dose and dosage forms:-250 - 500mg tablets.7
ARYL-ACETIC ACID DERIVATIVES:-
DICLOFENAC SODIUM:-
An analgesic –antipyretic- antiinflammatory drug, similar in efficacy to naproxen. It inhibits PG synthesis and is somewhat COX-2 selective.
Adverse effects: - These are generally mild: epigastric pain, nausea, headache, dizziness, and rashes. Reversible elevation of serum amino-transferases has been reported more commonly.
Dose and dosage forms:-50 mg TDS, then BD oral, 75 mg deep i.m.
100 mg SR tablets, 50 mg enteric coated tablets, 25mg/ml in 3 ml amp. for i.m. inj.9
OXICAM DERIVATIVES :-
PIROXICAM:-
It is a long-acting potent NSAID with antiinflammatory potency similar to indomethacin and good analgesic antipyretic action. It is a reversible inhibitor of COX; lowers PG concentration in synovial fluid and inhibits platelet aggregation – prolonging bleeding time.
Adverse effects:-The g.i. side effects are more than ibuprofen, but it is better tolerated and less ulcerogenic than indomethacin or phenylbutazone; causes less faecal blood loss than aspirin. Edema and reversible azotaemia have been observed.
Dose and dosage forms: - 20 mg BD for two days followed by 20 mg OD.
10, 20 mg capsule, 20 mg dispersible tablets,20 mg/ml inj in 1 and 2 ml amps.7
SELECTIVE COX- 2 INHIBITORE (coxibs)
CELECOXIB :-
The COX-2 selectivity of celecoxib is modest (6-20 folds). It exerts antiinflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as effective as naproxen or diclofenac without affecting COX-1 activity in gastroduodenal mucosa.
Pharmacokinetic properties: - Celecoxib is slowly absorbed, 97% plasma protein bound and metabolized primarily by CYP2C9 with a t1/2 of ~ 10 hours.
Adverse effects: - Common unwanted effects may include headache, dizziness, skin rashes, and peripheral edema caused by fluid retention. As with all COX-2 inhibitors, consideration should be given to the possibility of serious adverse cardiovascular events. Because of the potential role of COX-2 in the healing of ulcers, the drugs should be avoided, if possible, by patients with pre-existing disease.
Dose and Dosage forms: - It is avilable in the form of 100 and 200 mg capsules.7
ETORICOXIB :-
This newer COX-2 inhibitor has the highest COX-2 selectivity. It is suitable for once-a-day treatment of osteo/rheumatoid/acute gouty arthritis, and similar conditions, without affecting platelet function or damaging gastric mucosa.
The t1/2 is ~ 24 hours.
Side effects: - These are dry mouth, aphthous ulcers, taste disturbance and paresthesias.
Dose and dosage forms:-60 mg OD ,60, 90 120 mg tablets.7
PARECOXIB:-
It is a prodrug of valdecoxib suitable for injection, and to be used in postoperative or similar short-term pain, with efficacy similar to ketorolac.
Dose and dosage forms:-40 mg oral/i.m./i.v./repeated after 6-12 hours .40 mg/vial inj, 40 mg tablets.
VALDECOXIB:-
Uses and administration:- Valdecoxib is an NSAID reported to be a selective inhibitor of cyclo-oxygenase- 2 (COX-2). It is given by mouth in the treatment of osteoarthritis and rheumatoid arthritis.
Adverse effects:-As for NASIDs in general. Serious skin reactions such as exfoliative dermatitis, stevens-johnsen syndrome, and toxic epidermal necrolysis have been reported with valdecoxib. Other hypersensitivity reactions including anaphylaxis and angioedema have also occurred.
Indications & dosage:- Osteoarthritis: Rheumatoid arthritis:- adult;10 mg once daily.10
BIOLOGIC RESPONSE MODIFIERS:-
ADALIMUMAB:-
It is a recombinant human monoclonal tumour necrosis factor (TNF) antibody that binds specifically to TNF-α and blocks its interaction with endogenous cell-surface TNF receptors. It also modulates biological responses that are induced or regulated by TNF.
Adverse effects and precautions: -It may cause acute infusion reactions during or within 1 to 2 hours of infusion, particularly with the first or second dose. Symptoms include fever, chills, pruritus, urticaria, dyspnoea, chest pain, and hypertension or hypotension.
Effects on the heart: -The FDA has reported on 47 patients who developed heart failure while receiving long –term therapy with tumour necrosis factor antibodies for arthritis condition or Crohn’s disease.
Injection site reactions including erythema, itching, pain, and swelling are the most common adverse reactions with adalimumab; however most reactions are mild and do not result in drug withdrawal.
Interactions: - Methotrexate is reported to reduce the clearance of adalimumab by up to 44% .9
ANAKINRA:-
Anakinara is a recombinant receptor antagonist of interleukin-1, an inflammatory mediator found in the plasma and synovial fluid of patients with rheumatoid arthritis.
Mechanism: - Anakinra is a recombinant human IL-1ra that differs from native IL-1ra by the addition of an N-terminal methionine. Anakinra blocks the biologic activity of IL-1 by binding to IL-1R type I with the same affinity as IL-1 beta.
Dosage: - The recommended dose of anakinra is 100 mg/day administered daily by subcutaneous injection. The dose should be administered at approximately the same time each day. An auto injection system is available for the medication.
Usual Time to Effect: - 2 to 4 weeks.
Side Effects: - The most commonly observed side effect in all of the clinical trials with anakinra is injection site reactions, occurring in approximately two-thirds of patients. These reactions are present as erythema, itching, and discomfort and typically resolve over one to two months. In some patients these reactions can be severe leading to drug discontinuation.
A modest increase in the risk of serious infection was observed in RA patients in clinical trials treated with anakinra in combination with DMARDS other than TNF inhibitors, compared to placebo with DMARDs (2 % vs 1%). The risk of serious infections of anakinra in combination with a TNF inhibitor is approximately 7% and this combination of biologics isnotrecommended. Opportunistic infections including tuberculosis are less common with anakinra than with TNF antagonists.9
RITUXIMAB :-
B cells are an important inflammatory cell with multiple functions in the immune response. They serve as antigen presenting cells, can secrete cytokines, and differentiate into antibody-forming plasma cells. The depletion of B cells has been shown to be effective in reducing signs and symptoms of RA and in slowing radiographic progression. One B cell depleting agent, Rituximab, is currently available for the treatment of rheumatoid arthritis. Rituximab was originally developed to treat non-Hodgkin’s lymphoma and has been used to treat this malignant condition of lymphocytes and lymph nodes for several years. Early studies in patients with rheumatoid arthritis showed rituximab caused a rapid and sustained depletion of circulating B cells in the circulation with clinical improvements in many patients as well. Further clinical studies have now demonstrated that rituximab is effective in decreasing signs and symptoms and in slowing radiographic progression in RA patients who have failed other DMARD therapies.
Mechanism:- Rituximab is a chimeric monoclonal antibody that binds to the CD20 molecule on the B cell surface leading to the removal of B cells from the circulation. A single course of ritximab (2 infusions of 1000 mg each given 2 weeks apart) leads to a rapid and sustained depletion of B lymphocytes in the peripheral blood. This effect is sustained for 6 months to 1 year or even longer. The levels of the autoantibody rheumatoid factor decrease, but the levels of other antibodies typically remain within the normal range after the first infusion. The clinical effects are hypothesized to occur from decrease in B cell cytokines, interactions between B cells and T cells, or due to reductions in autoantibody levels.
Time to onset:- Effects from rituximab are not seen for up to 3 months after an infusion. Effects however may last 6 months and up to 2 years following a single infusion course.
Dosing: - The currently approved dose is 1000 mg administered intravenously over 3-4 hours with two doses given 2 weeks apart. Patients typically receive intravenous corticosteroids with each infusion and premedication with diphenhydramine and acetaminophen. The optimal time for readministarion is not yet clear. Some have advocated a fixed dosing regimen of every 6 months, while others have advocated waiting until a patient begins to flare before retreating. Studies are ongoing to evaluate redosing schedules. The extent and duration of B cell depletion has not been clearly correlated with efficacy. Nor has the reconstitution of normal levels of B cells been well correlated with loss of efficacy.