TO STUDY THE CLINICAL EFFECTIVENESS OF

DIACEREIN AS ADD ON THERAPY TO DICLOFENAC

SODIUM IN PATIENTS OF OSTEOARTHRITIS KNEE

PLAN OF THESIS
FOR APPROVAL OF SUBJECT OF THESIS
TO BE SUBMITTED
IN PARTIAL FULFILMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
M.D. (PHARMACOLOGY)
OF THE
BABA FARID UNIVERSITY OF HEALTH SCIENCES,
FARIDKOT.

2006 DR KULJINDER SINGH

DEPARTMENT OF PHARMACOLOGY,
GOVERNMENT MEDICAL COLLEGE, AMRITSAR
 BABA FARID UNIVERSITY OH HEALTH SCIENCES
FARIDKOT
APPLICATION FORM FOR APPROVAL OF THE SUBJECT
OF THESIS FOR MD (PHARMACOLOGY)
1. Name of the Candidate Dr. Kuljinder Singh
2. Father’s Name S. Balwinder Singh
3. Mother’s Name Smt. Bachan Kaur
4. Address of the candidate for House no. 566/11,Onkar nagar Gurdaspur

correspondence
5. Month and year of passing December, 2005

MBBS Examination
6. Name of the University from Baba Farid University of Health Sciences,

which Graduated Faridkot

7. Present Occupation Postgraduate Student, Department of

Pharmacology, Government Medical College,

Amritsar.
9. Date of Joining M.D. Course 15th June, 2006
10. Likely date of appearing June, 2009
11. Proposed Subject of Thesis TO STUDY THE CLINICAL
EFFECTIVENESS OF DIACEREIN AS
ADD ON THERAPY TO DICLOFENAC
SODIUM IN PATIENTS OF
OSTEOARTHRITIS KNEE
12. Facilities for work on the Facilities are available in the Department of

subject of thesis Pharmacology and Orthopedics.

13. Detailed scheme according to Plan attached

which the candidate proposes to

work
14. Name and address of the Dr.Jaswant Rai.
M.D.
Supervisor(s)
Professor and Head,
Department of Pharmacology,
Government Medical College,
Amritsar.
( SUPERVISOR )

Dr. Rakesh Sharma

M.S.
Assistant Professor,
Department of Orthopedics,
Government Medical College,
Amritsar.
( CO-SUPERVISOR )

CERTIFICATE OF SUPERVISORS

This is to certify that facilities for work on the subject of thesis titled “ TO
STUDY THE CLINICAL EFFECTIVENESS OF DIACEREIN AS
ADD ON THERAPY TO NSAIDS IN PATIENTS OF
OSTEOARTHRITIS KNEE” exist in the department of Pharmacology and
Orthopaedics, Government medical College, Amritsar and will be provided
to the candidate. We will see that data being included in the thesis are
genuine and collected by the candidate himself under supervision and
guidance.
Dr.Jaswant Rai
M.D.
Professor and Head,
Department of Pharmacology,
Government Medical College,
Amritsar
(SUPERVISOR )

Dr. Rakesh Sharma

M.S.
Associate Professor,
Department of Orthopedics,
Government Medical College,
Amritsar.
( CO-SUPERVISOR )

ABSTRACT OF PLAN OF THESIS

Title TO STUDY THE CLINICAL
EFFECTIVENESS OF DIACEREIN AS ADD
ON THERAPY TO DICOFENAC SODIUM
IN PATIENTS OF OSTEOARTHRITIS KNEE
For the degree of M.D. Pharmacology
Name of the Candidate Dr. Kuljnder Singh
Supervisor Dr. Jaswant Rai, MD, FAIMS, FIMSA, Professor
& Head, Dept. of Pharmacology
Co-Supervisor Dr. Rakesh Sharma, MS, Assistant Professor, Dept.
of Orthopaedics.
Institution Department of Pharmacology and Orthopaedics,
Govt. Medical College, Amritsar

BACKGROUND
Osteoarthritis is a chronic progressive degenerative disease involving the
articular system. Medical therapy of osteoarthritis consists of NSAIDS and
Disease modifying drugs for Osteoarthritis (DMOAD’s). NSAIDS provide
symptomatic relief and have their adverse effects.
In the present study clinical effectiveness of Diacerein as add on therapy
to NSAIDS and prevention of their side effects will be evaluated. This study
will be prospective, single blinded, parallel, placebo controlled, intention to
treat study lasting three months, involving 60 patients of osteoarthritis
attending the department of Orthopaedics, Guru Teg Bahadur Hospital,
Amritsar, randomized into 2 groups, A and B of 30 patients each. Group A
will receive Tab. Diclofenac sodium 100 mg sustained release mg once daily
for three months and matched placebo as capsule once daily for first month
and twice daily for second and third month. Group B patients will receive
Tab. Diclofenac 100 mg sustained release once daily for three months and
capsule Diacerein 50 mg once daily for first month and twice daily for
second and third month. Patients will be examined on day zero, three & six
weeks and then at third and fourth month according to the Visual Analogue
Scale(VAS), Patient’s and Physician’s Global Assessment & X-ray. Results
will be analysed using appropriate statistical methods.

GOVERNMENT MEDICAL COLLEGE, AMRITSAR

Name of the candidate Dr Kuljinder Singh

Department Department of Pharmacology
Topic
TO STUDY THE CLINICAL EFFECTIVENESS OF DIACEREIN AS
ADD ON THERAPY TO DICLOFENAC SODIUM IN PATIENTS OF
OSTEOARTHRITIS KNEE
Examination M.D. Pharmacology
Date of enrolment 15th June, 2006
Professor of speciality Dr. Jaswant Rai, M.D.
Supervisor(s) of the Thesis Dr. Jaswant Rai.
M.D.
Professor and Head,
Department of Pharmacology,
Government Medical College,
Amritsar.
(Supervisor )

Dr. Rakesh Sharma

M.S.
Assisstant professor,
Department of Orthopedics,
Government Medical College,
Amritsar.
( Co-Supervisor )

MEMBERS OF THE THESIS/ SIGNATURE WITH STAMP

RESEARCH COMMITTEE
1. Head of institute/ college
2. Chairman of Thesis Committee
. Member of Thesis Committee
. Member of Thesis Committee
. Member of Thesis Committee
3. Chairman Ethical Committee
. Member Ethical Committee
. Member Ethical Committee

TO STUDY THE CLINICAL EFFECTIVENESS OF DIACEREIN AS

ADD ON THERAPY TO DICLOFENAC SODIUM IN PATIENTS OF
OSTEOARTHRITIS KNEE

Osteoarthritis is a chronic progressive degenerative disease involving the

articular system. It is an insidious and progressive condition that mainly
affects the weight bearing joints and is seen most commonly late in life.1
Although men and women are equally affected, onset of osteoarthritis is
earlier in women.2 The prevalence of the condition in the 75 to 90 year old
population is about 85%.3 Osteoarthritis is characterised by the degradation
of cartilage, subchondral sclerosis, cyst formation and osteophyte
formation.1,4 Risk factors associated with the development of osteoarthritis
include increasing age, obesity, postmenopausal women, occupation and
sporting activities.4
More than 80% of all people over the age of 55 years have
radiographic evidence of osteoarthritis. The primary impact of arthritis in the
elderly is a decrease in physical functioning. This can be a cause of other
health related problems such as weight gain, cardiovascular disease,
gastrointestinal distress, decreased social functioning, increased work
disability and increased health care utilization. Currently, the objective of
therapy for osteoarthritis is the reduction of pain and improvement in the
functional status of the patient. So when treating for osteoarthritis goals have
been suggested three fold. The first is the management of pain and other
symptoms, the second is the need to maintain or improve joint function and
the third, so far not completely achievable goal is to modify the long term
biochemical process of osteoarthritis.5 The main symptom is pain especially
with the use of the joints. Other clinical signs and symptoms of osteoarthritis
are tenderness, limitation of movement, crepitus, occasional effusion,
varying degrees of local inflammation without systemic effects and mild to
severe discomfort during the activities of daily living.6
Management of osteoarthritis of the knee is based on
both non-pharmacological as well as pharmacological measures in addition
to surgical ones. Non-pharmacological measures are in the form of patient
education to reduce over weight, physical therapy and occupational therapy.
Medical therapy of osteoarthritis mainly includes non-steroidal anti-
inflammatory drugs (NSAIDS) which have been found useful in relieving
pain, stiffness and joint swelling in Osteoarthritis.7 Common side effects of
NSAIDS are upper gastrointestinal events like dyspepsia, nausea, abdominal
pain, mucosal lesions, serious complications such as bleeding and
perforations have been associated with their use which is due to non-
selective inhibition of COX enzyme.8 Selective COX-2 inhibitors have
adverse effects on the cardiovascular system and may contribute to the onset
of acute myocardial infarction and thromboembolic events.9 This has been
the major limitation to their use and has kept the pharmacological options
open to develop newer drugs which could provide relief in pain, reduce the
side effects of NSAIDS and modify the pathology of Osteoarthritis.10 Drugs
which modify the pathology of Osteoarthritis include Glucosamine-
Chondroitin sulphate and Diacerein. There is weak evidence to
support the use of glucosamine hydrochloride in combination
with chondroitin sulphate to manage symptoms of OA in
patients with moderate to severe disease and also these do
not prevent the cartilage destruction by NSAIDS.11-12
There is evidence that cytokines such as interleukin-1β (IL-1β)
and tumour necrosis factor α cause degradation of the cartilage.13 Diacerein,
a purified compound with anthraquinone structure, has been shown to
inhibit, in vitro14and in vivo15, the production and activity of interleukin- 1
and the secretion of metalloproteases16, without affecting the synthesis of
prostaglandins.17 This drug is administered orally as 50 mg twice daily.
Diacerein is entirely converted into rhein before reaching the systemic
circulation. Rhein itself is either eliminated by the renal route (20%) or
conjugated in the liver to rhein glucuronide (60%) and rhein sulfate (20%);
these metabolites are mainly eliminated by the kidney. The pharmacokinetic
characteristics of diacerein are about the same in young healthy volunteers
and elderly people with normal renal function, both after a single dose (50
mg) or repeated doses (25 to 75 mg twice daily). Rhein kinetics after single
oral doses of diacerein are linear in the range 50 to 200 mg. However, rhein
kinetics are time-dependent, since the non-renal clearance decreases with
repeated doses. This results in a moderate increase in maximum plasma
concentration, area under the plasma concentration-time curve and
elimination half-life. Nevertheless, the steady-state is reached by the third
administration and the mean elimination half-life is then around 7 to 8 hours.
Taking Diacerein with a standard meal delays systemic absorption, but is
associated with a 25% increase in the amount absorbed. Mild-to-severe
(Child Pugh's grade B to C) liver cirrhosis does not change the kinetics of
diacerein, whereas mild-to-severe renal insufficiency (creatinine clearance <
2.4 L/h) is followed by accumulation of rhein which justifies a 50%
reduction of the standard daily dosage. Rhein is highly bound to plasma
proteins (about 99%), but this binding is not saturable so that no drug
interactions are likely to occur, in contrast to those widely reported with
nonsteroidal anti-inflammatory drugs. Except for moderate and transient
digestive disturbances (soft stools, diarrhoea), diacerein is well tolerated and
seems neither responsible for gastrointestinal bleeding nor for renal, liver or
hematological toxicity.18
In several animal models, diacerein has shown
beneficial effects on cartilage by preventing the macroscopic or microscopic
lesions of the joint tissue.19 Further-more in several clinical trials of 2-6
months duration diacerein significantly reduced as compared with placebo
the pain and functional impairment in patients with hip or knee
osteoarthritis.20
Diclofenac sodium is an established therapy in treatment of
osteoarthritis of knee. It is an aryl–acetic acid derivative NSAID. It is a non-
selective inhibitor of prostaglandin synthesis. It is available in various
dosage forms for different routes of drug administration. Bioavailability of
diclofenac is 30-70% due to first pass metabolism. It accumulates in
synovial fliud with good tissue penetration. Gastrointestinal adverse effects
are more common in form of epigastric pain, nausea, gastric ulceration and
GIT bleeding.21 Diclofenac is eliminated following biotransformation to
glucoroconjugated and sulphate metabolites which are excreted in urine,
very little drug is eliminated unchanged.22 In present study, clinical
effectiveness of Diacerein as add on therapy to Diclofenac sodium will be
studied.

AIMS & OBJECTIVES

To study the clinical effectiveness of Diacerein, as add on therapy to

diclofenac sodium in management of osteoarthritis of knee

MATERIALS AND METHODS

Drugs to be investigated:-
 1. Capsule Diacerein 50 mg once daily for first month and twice
daily for second and third month.
2. Tablet Diclofenac sodium 100 mg sustained release once
daily.

Patients:-
A total of 60 patients of symptomatic osteoarthritis knee visiting
the OPD/Wards of the Department of Orthopaedics, Guru Teg
Bahadur Hospital attached to the Government Medical College,
Amritsar will be selected for the present study once the inclusion
Criterion is fulfilled.

INCLUSION CRITERIA
1. Patients with symptomatic osteoarthritis of age 35 to 60 years who
fulfill American College of Rheumatology criterion for the diagnosis
of osteoarthritis will be enrolled.
2. Patients having symptomatic osteoarthritis either as a new case or as
an old case following discontinuation of treatment with NSAIDS or
other analgesic medications with a washout period of one week.
3. All these patients will be examined as per the baseline criterion and
included in the study if they fit this criterion.

EXCLUSION CRITERIA
1. Age less than 35 years or more than 60 years.
 2. The patients who present with active concomitant gastroduodenal
disorders, hepatic and renal impairment within last 30 days prior to
receiving the study drug.
3. Patient with cardiovascular disorders.
4. Pregnant females or those who are planning their pregnancy during
the study.
5. Patients who have received oral, intramuscular, intraarticular or soft
tissue injections of corticosteroids within last four weeks before
receiving the first dose of the medication understudy.
6. Patients diagnosed to have any inflammatory arthritis, gout or acute
trauma of the knee, hip or spine.
7. Patients with a known hypersensitivity to NSAIDS.
8. Patients with any known contraindication of the said drugs.
9. Female patients on oral contraceptive pills.
• The approval of the ethics committee of the institution will be
obtained.

• Informed consent will be sought from all the patients included in

the present study.

EXPERIMENTAL METHODS
This study will be a prospective, single blind, placebo controlled, intention
to treat 60 patients of osteoarthritis visiting the OPD/Wards of the
Department of Orthopaedics, Guru Teg Bahadur Hospital attached to the
Government Medical College, Amritsar. This study will be conducted in
accordance with the principles of good clinical practice and the Decleration
of Helsinki.
Patients will be divided into 2 groups, A & B consisting of 30 patients
each. Patients will be randomly recruited into two groups A and B. The
duration of the study will be twelve weeks. Patients will be examined on day
zero, three & six weeks and at three month according to the Visual Analogue
Scale(VAS), Patient’s and physician’s Global Assessment & X-ray. Patients
will be followed up for further three weeks. Patients will be advised leg
raising exercises and to avoid squatting. Compliance will be ensured by
asking the patients to bring the empty blister packs of the medications at
every visit.

EXPERIMENTAL GROUPS
Group A
Patients in this group will receive Tab. Diclofenac 100 mg
sustained release mg once daily for three months and placebo as capsule
once daily for first month and twice daily for second and third month.

Group B
Patients in this group will receive Tab. Diclofenac 100 mg
sustained release once daily for three months and capsule Diacerein 50 mg
once daily for first month and twice daily for second and third month.

PARAMETERS
Screening or baseline clinical assessment of osteoarthritis will include
patient’s assessment of arthritic pain on a Visual Analogue Scale ( VAS ),
on a scale of 0-24 based upon the Western Ontario and Macmaster
Universities ( WOMAC ) osteoarthritis index, patients and physician’s
global assessment of osteoarthritis.

VISUAL ANALOGUE SCALE ( VAS ) :

A visual analogue scale which is a 100mm long line with the
extremes marked as ‘no pain’ (0)on one end while the extremely unbearable
pain [(100) at the start of treatment] on the other end will be used for this
study. In all these patients pain at the start of therapy will be taken as
marked on extreme end (100). During the treatment course patient will be
asked to put a mark on the line to correlate the amount of pain felt at that
time. Then with a scale the point marked will be quantified and accordingly
the improvement will be assessed.
__________________________________________________________
0 100
No pain Unbearable pain

WOMAC Osteoarthritis Index23

The WOMAC Osteoarthritis index score and the osteoarthritis
severity index score will be calculated on a scale based upon the Western
Ontario and Macmaster Universities ( WOMAC ) osteoarthritis index. The
WOMAC measures three separate dimensions, five regarding pain, two
regarding joint stiffness and seventeen concerning physical function.
The 24 items included in the WOMAC questionaire are:

Pain ( 5 Items )
How much pain do you have while

• Walking on a flat surface

• Going up or downstairs

• At night while in bed

• Sitting or lying

• Standing upright

Stiffness ( 2 Items )

How severe is your stiffness after

• First awakening in the morning

• Lying resting later in the day

Function ( 17 Items )

What degree of difficulty do you have while

• Descending stairs

• Ascending stairs
• Rising from sitting

• Standing

• Bending to floor

• Walking on a flat surface

• Getting in/out of a car or other vehicle

• Going shopping

• Putting on socks/stockings

• Rising from bed

• Taking off socks/stockings

• Lying in bed

• Getting in/out of bath

• Sitting

• Sitting on/off toilet

 • Heavy domestic duties

• Light domestic duties

Each item will be rated on a 5- point scale

0 = None,

1 = Mild,

2 = Moderate,

3 = Severe,

4 = Extreme,
Yielding maximum possible subscale scores of 20, 8 and 68 for pain,
stiffness and physical functioning respectively. WOMAC composite scores (
possible range 0-96 ) will be calculated by addition to individual item
scores.

Patient’s Global Assessment:

Patient’s global assessment will be utilized to know the patients overall
perception of his condition. Accordingly the patients will be put in various
categories in relation to their condition. This will be labelled as very good,
good, fair, poor and very poor. This will be first done to assess the patient’s
condition at the time of screening and then as a prognostic criteria post
treatment for ascertaining any improvement or deterioration in the patient’s
condition.

Physician’s global assessment:

Physician’s global assessment will be used to know the physician’s
assessment of the patient’s condition. Accordingly the physician will
categorize the patient’s condition as very good, good, fair, poor and very
poor. This will be done by the physician at the time of screening and then as
a prognostic criterion post treatment for assessing any improvement or
deterioration in patient’s condition.

Baseline Laboratory Investigations:

The investigation that will be carried out will be:
X-ray of both the knees AP view in standing position will be taken to
corroborate the diagnosis of osteoarthritis at day 0 and will be repeated at
three months to see the improvement if any. Routine investigations will be
done in the respective departments of Government Medical College,
Amritsar.
All the data generated from the study will be tabulated and expressed
as a mean ± S.D. of each variable. Comparison will be done by student’t’
test and expressed as 'p' value for each parameter.

CASE HISTORY RECORD

Sr. No. Date

NAME
OPD No.
AGE/SEX
Father's/Husband's Name

Education

Occupation

ADDRESS Phone

PRESENT COMPLAINTS:
HISTORY OF PRESENT ILLNESS:
PAST HISTORY:
H/O Diabetes
H/O Hypertension
H/O Angina / MI
H/O CAD
H/O Renal disease
H/O Liver disease
H/O Tuberculosis
H/O Stroke

FAMILY HISTORY:
H/O Diabetes
H/O Hypertension
H/O CAD
H/O Tuberculosis
H/O Stroke

PERSONAL HISTORY:
Obesity
Addictions Tobacco/alcohol/others
Life style
Food habits
Socioeconomic status

TREATMENT HISTORY
 H/O Any drug allergy
H/O Medication for diabetes
Whether taking any concomitant medication

EXAMINATION
Height Weight
Pulse Blood Pressure Respiratory Rate
Anemia Edema Clubbing
Cyanosis Jaundice Cervical LN
CNS

CVS

ABDOMEN

RESPIRATORY SYSTEM

Arthritic Disorder:-

1.
2.

Duration of illness: Years________ Months__________

Treatment Group:

CLINICAL ASSESSMENT DETAILS

DAY O 3WEEKS 6WEEKS 3rd MONTH 4th MONTH
PAIN ASSESSMENT ON V.A.S.
WOMAC SCALE ASSESSMENT
(A) PAIN
1. Walking on a flat surface
2. Going up or down stairs
3. At night while in bed
4. Sitting or lying
5. Standing upright
(B) STIFFNESS
 1. Severity of stiffness after first waking in the
morning
2. Severity of stiffness after sitting/lying or
resting later in
the day.
(C) FUNCTION: DEGREE OF DIFFICULTY
WHILE
1. Descending stairs
2. Ascending stairs
3. Rising from sitting
4. Standing
5. Bending to floor
6. Walking on a flat surface
7. Getting in/out of car or any other vehicle
8. Going shopping
9. Putting on socks/stockings/shoes
10. Rising from bed
11. Taking off socks/stockings/shoes
12. Lying in bed
13. Letting in/out of bath
14. Sitting
15. Getting on/off toilet
16. Heavy domestic duties
17. Light domestic duties
PATIENT’S GLOBAL ASSESSMENT
(1) Very Good
(2) Good
(3) Fair
(4) Poor
(5) Very Poor
PHYSICIAN’S GLOBAL ASSESSMENT
(1) Very Good
(2) Good
(3) Fair
(4) Poor
(5) Very Poor

SAFETY ASSESSMENT
DAY 0 3WEEKS 6WEEKS 3 MONTHS
G.I.T
Pain Abdomen
Diarrhoea
Dyspepsia
Flatuence
Nausea
BODY AS A WHOLE
Back Pain
Peripheral Edema
Accidental Injury
CENTRAL AND PERIPHERAL
NERVOUS SYSTEM
Dizziness
Headache
PSYCHIATRIC
Insomnia
RESPIRATORY
Pharyngitis
Rhinitis
Sinusitis
U.R.I
Wheezing/Breathlessness
SKIN
Rash
OTHERS

SEVERITY OF ADVERSE EFFECTS:

-- Absent
+ Mild
++ Moderate
+++ Severe
Withdrawl from the study:_______________
Date of withdrawl from the study:_________
Reasons:___________________________________________________________
____________________________________________________________________

Investigators’s comments on the relationship between the adverse effects and the
drug________________________________________________________________

Informed Consent

I, _______________________________ exercising my free power of

choice , hereby give my consent to be included in the study entitled “TO STUDY
THE CLINICAL EFFECTIVENESS OF DIACEREIN AS ADD ON
THERAPY TO DICLOFENAC SODIUM IN PATIENTS OF
OSTEOARTHRITIS KNEE.” I have been informed to my satisfaction by the
attending doctor, in a manner and language that I understand the purpose and
nature of the study, nature of drug treatment, safety of the procedures and the side
effects associated with the drugs. I am also aware of my right to opt out of the trial
at any time during the course of the study without having to give the reasons for
doing so. I have been told about the procedures of the study and agree to take part
in the investigations required.

Patient’s Name____________________________
Signature ________________________________
Dated___________

Doctor’s Name Dr Kuljinder singh

Signature ________________________________

Witness________________________________
Signature ________________________________
Dated_____________

BIBLIOGRAPHY

1. Torri G, Vignati C, Agrifoglio E. Aceclofenac versus piroxicam

in the management of osteoarthritis of the knee: a double-blind

controlled study. Curr. Ther Res. 1994; 55 (5): 576-83.

2. Berkow R, Fletcher AJ, editors. The Merck Manual. 16th ed.

Rahway, NJ: Merck Research Laboratories, 1992.

3. Diaz C, Rodriguez de la Serna, Geli C. Efficacy and tolerability

of aceclofenac versus diclofenac in the treatment of knee

osteoarthritis: a multicentric study. Eur J Rheumatol Inflamm.

 1996; 16 (1): 17-22.

4. Creamer P, Hochberg MC. Osteoarthritis. Lancet. 1997 Aug 16;

350: 503-9.

5. Jones AC, Doherty M. The treatment of osteoarthritis Br. J Cl

Pharmacol. 1992; 33: 357-63.

6. Hochberg MC, Altman RD, Brandt KD. Guidelines for the

medical management of Osteoarthritis. Part II. Osteoarthritis of the

knee. Arthritis Rheum. 1995; 38: 1541-46.

7. Mankin HJ. Clinical features of osteoarthritis. In: Kelly WN,

Harris ED, Ruddy S, Sledge CB, editors. Textbook of

Rheumatology. 2nd ed. Philadelphia: WB Saunders; 1993.

p. 1347-84.

8. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of

non-steroidal anti-inflammatory drugs. N Engl J Med. 1999;

340(24): 1888-99.

9. Silverstein FE, Faich G, Goldstein JL,et al. Gastrointestinal toxicity

with celecoxib vs nonsteroidal anti-inflammatory drugs for

osteoarthritis and rheumatoid arthritis: the CLASS study. A

randomized controlled trial. Celecoxib Long-term Arthritis Safety

Study. JAMA 2000;284:1247-55

10. Needleman P, Isakson PC. The discovery and function of COX-2. J

Rhematol. 1997; Suppl 49: 6-8.

11. Leeb, B.F., Glucosamine and chondroitin sulfate for the

treatment

osteoarthritis.Arthritis & Rheumatism, 2001. 45(6): p.

537-8.

12. Pelletier, J.P., M. Yaron, B. Haraoui, P. Cohen, M.A.

Nahir, D.

Choquette, I. Wigler, I.A.Rosner, and A.D. Beaulieu,

Efficacy and

safety of diacerein in osteoarthritis of the knee:a

double-blind,

placebo-controlled trial. The Diacerein Study Group.

Arthritis

&Rheumatism, 2000. 43(10): p. 2339-48.

13. Van de loo FA,Joosten LA,Van Lent PL,Amtz OJ,Van Den Berg

WB,Role of interleukin-I,tumour necrosis factor alpha and interleukin

6 in cartilage proteoglycan metabolism and destruction:effect of in

situ blocking in murine antigen and zymosan induced

arthritis.Arthritis rheum 1995;38:164-72

14. Martel-Pelletier J, Mineau F, Jolicoeur FC, Cloutier JM,

Pelletier

JP. In vitro effects of diacerhein and rhein on

interleukin-1 and
 tumor necrosis factor-alpha systems in human
osteoarthritis synovium

and chondrocytes. J Rheumatol 1998;25:753–62.

15. Moore AR, Greenslade KJ, Alam CAS, Willoughby DA.

Effects of

diacerhein on granuloma induced cartilage breakdown

in the

mouse. Osteoarthritis Cartilage 1998;6:19–23.

16. Boittin M, Redini F, Loyau G, Pujol JP. Matrix

deposition and

collagenase release in cultures of rabbit articular

chondrocytes

exposed to diacethylrhein. Osteoarthritis Cartilage

1993;1:39–40

17. Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-

Pelletier J.

Diacerhein and rhein reduce the interleukin 1b

stimulated inducible

nitric oxide synthesis level and activity while

stimulating

cyclooxygenase-2 synthesis in human osteoarthritic

chondrocytes.

J Rheumatol 1998;25:2417–24.

18. Nicolas P,Tod M,Padion C,Petitjean O Clinical Pharmacokinetics

 Diacerein. 1998 Nov;35(5):347-59

19. Mazieres B. Diacerhein in a post-contusive model of

osteoarthritis:

structural results with “prophylactic” and “curative”

regimens

Osteoarthritis Cartilage 1997;5(Suppl A):73.

20. Nguyen M, Dougados M, Berdah L, Amor B. Diacerhein

in the

treatment of osteoarthritis of the hip. Arthritis Rheum

1994;37:

529–36.

21. Schrefer J Mosby’s Gen Rx: A comprehensive

reference for generic and brand drugs. Mosby’s Inc. 10th Ed.

2000a;(3) 475-79

22. Davies NM,Anderson clinical pharmacokinetics of diclofenac.

Therapeutic insights and pitfalls.Clin Pharmacokinet. 1997

Sep:33(3): 184-213

23. Roos EM, Klassbo M, Lohmander LS. WOMAC osteoarthritis

index reliability, validity and responsiveness in patients with

arthroscopically assessed osteoarthritis. Scand J Rheumatol. 1999;

28: 210-15.

24. Zhao Z, Mcmillen JI, Markenson JA. Evaluation of the functional

status of health-related quality of life of pateints with

osteoarthritis. Pharmacotherapy 1999; 19: 1269-78.