Transcript COX-2 selective (NSAID)

IN THE NAME OF GOD
• In patients with noninflammatory OA, we recommend initiating
drug treatment with acetaminophen (paracetamol, APAP), rather
than a nonsteroidal antiinflammatory drug (NSAID), especially in
patients with only mild to moderate pain (Grade 1A). Patients
should be cautioned not to exceed the recommended dose.
• Acetaminophen was modestly inferior to NSAIDs for pain and function in
four systematic reviews
Acetaminophen
 First choice
 Inhibits central PGs
 Dose: 325-650 mg q 4-6 hr (max: 4 g/day)
Acetaminophen
 Adverse effects:
 Hepatotoxicity
 Renal failure (combined with NSAIDs)
 Hypertension (regular long-term use)?
 Drug interactions:
 Isoniazid
 Warfarin
‫فرآورده های دارویی‬
• Acetaminophen (Tylenol®, Tylophen®)
–
–
–
–
–
–
–
Tab 80 mg, 325 mg, 500 mg
Tab Acetaminophen Codein (300 mg + 10 mg)
A.C.A
Elixir, Susp., Syrup 120 mg/5 ml
Drop 100 mg/ml
Supp. 125 mg, 325 mg
Amp 1 g (Apotel®)
NSAIDs
 analgesic properties at lower doses
 antiinflammatory effects at higher doses
 similarly beneficial in OA
NSAIDs
•
•
•
•
•
•
•
•
•
•
Acetylsalicylic acid (ASA, Aspirin)
Ibuprofen
Diclofenac
Tolmetin
Piroxicam
Mefenamic acid
Indomethacin
Naproxen
Meloxicam (partially selective)
celecoxib
• Nonselective NSAID vs. another nonselective NSAID
• Many trials found no clear differences between various
nonaspirin, nonselective NSAIDs or partially selective NSAIDs
(meloxicam, nabumetone, etodolac) in efficacy for pain relief or
improvement in function.
• In one short-term trial, salsalate and aspirin did not differ
significantly in efficacy for pain relief or symptom
improvement.
• COX-2 selective (NSAID) vs. nonselective NSAID
• COX-2 selective NSAIDs and nonselective NSAIDs did not
clearly differ in efficacy for pain relief, based on many goodquality, published trials.
• COX-2 selective NSAID vs. different COX-2 selective
NSAID Celecoxib and rofecoxib did not differ
significantly in efficacy for pain relief at commonly
used and comparable doses, based on consistent
evidence from six good-quality trials.
• No studies compared efficacy of COX-2s other than
celecoxib and rofecoxib.
Phramacokinetic
 High bioavailability
 High protein-binding
 Half-life: ranging
from 1 hr for
Tolmetin to 50 hr for Piroxicam
Hepatic elimination
Efficacy
 Similar efficacy
 Adequate trial: 2-3 weeks
 Combination: no additional benefit
New COX-2 inhibitors
Etoricoxib
Lumiracoxib
• Etoricoxib was associated with fewer GI adverse events
(perforations, symptomatic ulcers, and bleeds) than nonselective
NSAIDs in a fair-quality meta-analysis of 10 trials.
• In primarily short-term trials, systematic reviews of RCTs suggest
that etoricoxib has a similar CV safety profile compared to other
NSAIDs, with the possible exception of naproxen. Definitive
conclusions are not possible because of small numbers of CV
events.
• Results from one large trial (TARGET) found fewer adverse GI
events with lumiracoxib than with naproxen and ibuprofen.
• There was no statistically significant difference in rates of
serious CV events between lumiracoxib relative to naproxen or
ibuprofen in TARGET.
• Too few events have been reported in RCTs to accurately assess
CV risk associated with lumiracoxib.
Adverse effects:
gastrointestinal
nausea, dyspepsia, anorexia, abdominal
pain, flatulence, and diarrhea:
Affect 10% to 60% of patients
To minimize: should be taken with food or milk,
except for enteric-coated products
Adverse effects:
gastrointestinal
 GI Bleeding
 GI Ulcer and its complications:
 Perforations
 gastric outlet obstruction
 bleeding
 about 16,500 deaths are associated annually
with NSAID use in RA or OA patients.
Risk factors for GI toxicity
 history of complicated ulcer
 History of dyspepsia
 use of multiple NSAIDs, including aspirin
 use of high-dose NSAID
 use of anticoagulant or antiplatelet agents
 age older than 65 years
 concomitant use of corticosteroids
 cardiovascular disease
‫‪ ‬رابطه ضعیف بین زخم گوارشی و عالیم وجود دارد؛ بنابراین‪:‬‬
‫‪ ‬کنترل سالیانه ‪CBC‬‬
‫‪ ‬تست خون مخفی در مدفوع )‪ (OB‬قابل اعتماد نیست‪.‬‬
Prevention of ulcers in high-risk
patients
 COX-2 selective NSAIDs
 PPIs
 Misoprostol
Adverse effects:
cardiovascular
 Rofecoxib
 Celecoxib: at high doses (> 400 mg/day)?!
 Traditional NSAIDs: no significant risk
 Diclofenac: some concern?
Choice
For those with increased GI risk but not on
aspirin:
 a COX-2 selective inhibitor, or
 a traditional NSAID with a PPI
For those taking regular low-dose aspirin for
cardiovascular risk (with or without increased GI
risk):
 a traditional NSAID with a PPI, or
 a COX-2 selective inhibitor with a PPI
• In fair-quality meta-analyses of arthritis trials, most of which evaluated short term
use, celecoxib caused fewer ulcer complications than nonselective NSAIDs and did
not increase the risk of myocardial infarction.
• Celecoxib 400 mg twice daily was associated with an increased risk of serious
CV events (CV death or myocardial infarction) relative to placebo in a long-term trial
of polyp prevention.
• Celecoxib was associated with an increased risk of myocardial infarction relative to
placebo in the most comprehensive systematic review of RCTs. Most of the 5 CV
events with celecoxib were reported in two large polyp-prevention trials evaluating
200 mg or 400 mg twice daily, or 800 mg once daily.
• About 3.5 additional myocardial infarctions occurred for every 1,000 patients treated
for 1 year with celecoxib compared to placebo.
• No clear difference in GI safety was found among nonselective NSAIDs
at commonly used doses.
• The CV safety of naproxen was moderately superior to that of any
COX-2 selective NSAID in a large systematic review of RCTs.
• There were 3.3 additional myocardial infarctions for every 1,000 patients
treated with any COX-2 inhibitor instead of naproxen for 1 year.
• The CV safety of nonselective NSAIDs other than naproxen (data
primarily on ibuprofen and diclofenac) was similar to that of COX-2
selective NSAIDs in a large systematic review.
• In indirect analyses, naproxen was the only nonselective NSAID
associated with neutral CV risk relative to placebo.
Adverse effects:
renal disease
 acute renal insufficiency
 Tubulointerstitial nephropathy
 Hyperkalemia
 renal papillary necrosis
 Clinical features:
 increased serum Cr and BUN
 hyperkalemia
 elevated blood pressure
 peripheral edema
 weight gain
High-risk patients






chronic renal insufficiency
congestive heart failure
severe hepatic disease
nephrotic syndrome
advanced age
taking diuretics, ACEIs, cyclosporine, or
aminoglycosides
 monitoring of Cr at baseline and within 3 to 7
days of drug initiation
Other side effects
 Hepatotoxicity:
 Diclofenac & sulindac
 hypersensitivity reactions
 central nervous system complaints:
drowsiness, dizziness, headaches, depression, confusion, and
tinnitus
 Among currently marketed NSAIDs, only diclofenac was
associated with asignificantly higher rate of liver-related
discontinuations compared with placebo (1 additional case
for every 53 patients treated with diclofenac).
Use in aspirin-sensitive asthma
 NSAIDs are contraindicated
 Celecoxib is tolerated.
NSAIDs:
Drug interactions
 Warfarin
 Lithium
 ASA (should be taken 8 hrs after or 30 min before NSAID)
 Celecoxib (CYP2D6 inhibitor)
‫فرآورده های دارویی‬
• ASA (Aspirin)
– Tab (chewable) 100 mg
– Tab EC 80 mg, 81 mg
– Tab 325 mg
– Tab MC 500 mg
– Tab A.C.A
• Ibuprofen (Motrin®, Advil®)
– Tab 200 mg, 400 mg
– Cap (softgel) 200 mg, 400 mg (Gelofen®)
– Susp. 100 mg/5 ml
– Topical Gel 5%
• Diclofenac sodium (Voltaren®)
–
–
–
–
–
–
–
–
Tab EC 25 mg, 50 mg, 75 mg (Voltaren ®)
Tab SR 75 mg (Voltaren® SR)
Tab SR 100 mg (Alfen XL®, Voltaren® Retard)
Cap SR 100 mg (Modafenac® Pain Off®)
Supp. 50 mg, 100 mg
Topical gel 1%
Amp 75 mg/3 ml (IM)
Ophtalmic drop 0.1%
• Diclofenac potassium (Cataflam®)
– Tab 50 mg (sugar coated)
• Tolmetin
– Tab 200 mg
• Mefenamic acid (Ponstan®)
– Cap 250 mg
• Piroxicam (Feldene®)
– Cap 10 mg
– Topical gel 0.5%
– Amp 20 mg (IM)
– Supp. 20 mg
• Indomethacin (Indocid®)
– Cap 25 mg
– Tab SR 75 mg
– Supp. 50 mg, 100 mg
• Naproxen
– Tab 250 mg
– Tab EC 500 mg
– Supp. 500 mg
• Celecoxib (Celebrex®, Cobix®, Celexib®)
– Cap 100 mg, 200 mg
• Meloxicam (Mobic®)
– Tab 7.5 mg, 15 mg
• Ketorolac
– Tab 10 mg
– Amp 30 mg (IV, IM)
– Eye drop 0.5% (Acular)
Topical Therapies
 Capsaicin
 NSAIDs
 Rubefacients (methylsalicylate)
Glucosamine-Chondroitin
 Stimulation of proteoglycan production
 Exact role is unclear
 Safe
 A trial is reasonable
 At least 1500 mg/1200 mg daily
• In one large, good-quality trial the combination of pharmaceutical-grade glucosamine
hydrochloride plus chondroitin (not currently available in the United States) was not
superior to placebo among all patients studied. Neither glucosamine nor
chondroitin alone was superior to placebo. In an analysis of a small subgroup of
patients with at least moderate baseline pain, there was a modest benefit for pain
relief from the combination, but this did not appear to be a preplanned analysis.
• Systematic reviews of older trials found glucosamine modestly superior to oral
NSAIDs and placebo in most trials, but there was some inconsistency between trials,
most trials had some flaws, and results may not be directly applicable to the United
• States because the positive trials primarily evaluated pharmaceutical-grade
glucosamine available in Europe.
• 􀂃 Only 2 of 20 placebo-controlled trials assessed effects of
glucosamine on radiologic
• disease progression. One fair- and one good-quality trial found
pharmaceutical-grade
• glucosamine superior to placebo for progression of knee joint space
narrowing over 3
• years.
• 􀂃 Glucosamine and chondroitin were generally well tolerated and
no serious adverse
• events were reported in clinical trials.
• In the United States, glucosamine is not approved
by the Food and Drug Administration for medical
use in humans.
• Since glucosamine is classified as a dietary
supplement in the US, safety and formulation are
solely the responsibility of the manufacturer;
evidence of safety and efficacy is not required as long
as it is not advertised as a treatment for a medical
condition.
• The U.S. National Institutes of Health is currently
conducting a study of supplemental glucosamine in
obese patients, since this population may be
particularly sensitive to any effects of glucosamine
on insulin resistance
• In most of Europe, glucosamine is approved as a
medical drug and is sold in the form of
glucosamine sulfate.
• In this case, evidence of safety and efficacy is
required for the medical use of glucosamine and
several guidelines have recommended its use as
an effective and safe therapy for osteoarthritis
• The Task Force of the European League Against
Rheumatism (EULAR) committee has granted
glucosamine sulfate a level of toxicity of 5 in a 0100 scale, and recent OARSI (OsteoArthritis
Research Society International) guidelines for
hip and knee osteoarthritis indicate an
acceptable safety profile
Glucosamine-Chondroitin
Adverse effects: nausea, bloating, cramps, allergic
reactions
Do not cause hyperglycemia
Different brands have different efficacy and
safety
‫فرآورده های دارویی‬
• Cartigen® (Glu.)
– Cap 500 mg, 1500 mg
• PreFlex® (Glu. + Cond.)
– Cap 500 mg, 750 mg
• Nutri Flex® (Glu. + Cond.)
– Caplet 500/400 mg
• Glucogin (Glu. + Cond. + Ginger + Nutrients)
–
•
•
•
Caplet 600/100 mg
Glucosamine & Condroitin
Ginger concentrate
Se, Zn, Mn, Chromium, Folic acid, Vit D3 (400 IU), Vit E
• ArthroStop® RAPID (Glu. + Cond. + Bowellin®)
–
•
•
•
•
Caplet 530/200 mg
Glucosamine
Condroitin
Bowellia serrata extract
Mn, Vitamin C
• Triple Flex® (Glu. + Cond. + MSM)
– Caplet 500/400 mg
• Move Free® Advanced (Glu. + Cond. + Hyal. + Extr.)
–
•
•
•
•
Caplet 750/100 mg
Glucosamine
Condroitin
Hyaluronic acid
Uniflex proprietary extract
• The effect of chondroitin sulfate in patients with
osteoarthritis is likely the result of a number of
reactions including
• its anti-inflammatory activity, the stimulation of
the synthesis of proteoglycans and hyaluronic
acid, and the decrease in catabolic activity of
chondrocytes inhibiting the synthesis of
proteolytic enzymes, nitric oxide, and other
substances that contribute to damage cartilage
matrix and cause death of articular
chondrocytes.

Chondroitin is in dietary supplements used as an
alternative medicine to treat osteoarthritis and also
approved and regulated as a symptomatic slow-acting
drug for this disease (SYSADOA) in Europe and some
other countries.

It is commonly sold together with glucosamine.
Chondroitin and glucosamine are also used in veterinary
medicine
Methylsulfonylmethane
(MSM)
is
an
organosulfur compound with the formula
(CH3)2SO2. It is also known by several other
names including DMSO2, methyl sulfone, and
dimethyl sulfone.
 MSM is sold as a dietary supplement and
marketed with a variety of claims, often in
combination with glucosamine and/or chondroitin
for helping to treat or prevent osteoarthritis.
 According to one review, "The benefits claimed
[for MSM] far exceed the number of scientific
studies. It is hard to build a strong case for its use
other than for treating arthritis problems

Intraarticular glucocorticoid
can provide excellent pain relief
particularly when a joint effusion is present
After injection, the patient should minimize
activity and stress on the joint for several
days.
Intraarticular glucocorticoid
Initial pain relief: within 24 to 72 hours (peak:
1 week after injection)
Relief lasts up to 4 to 8 weeks.
three or four injections per year
Intraarticular glucocorticoid
 Adverse events:
 Systemic:
hyperglycemia, edema, elevated
blood pressure, dyspepsia, and,
rarely, adrenal suppression
 Local:
infection, osteonecrosis, tendon
rupture, and skin atrophy
• 10
mg
for
small
joints
(interphalangeal,
metacarpophalangeal, and metatarsophalangeal
joints)
●20 mg for medium-sized joints (wrists, elbows,
ankles, and acromioclavicular joints)
●40 mg for larger joints (shoulders, knees, hips).
Hyaluronic acid
reconstitutes synovial fluid
reduces symptoms
For unresponsive patients
Weekly injections (3 to 5)
‫فرآورده های دارویی‬
• Sodium hyaluronate
o
o
o
o
o
o
Hyalgan®
FermathronTM
Orthovisc®
Synvisc®
Suplasyn®
High Hyalplus
 Pre-filled syringe 20 mg
Other drugs
 Opioids
 Tramadol
 Piascledine
 Teltonal FK 480
 Duloxetine
Tramadol
• Tramal®, Biomadol®
– Tab 50 mg, 100 mg
– Cap 50 mg, 100 mg
– Tab SR 50 mg, 100 mg, 200 mg
– Amp 50 mg, 100 mg (IM, IV)
‫‪Avocado/Soybean oil‬‬
‫‪• 1:2 ratio‬‬
‫‪• Cap 300 mg‬‬
‫•‬
‫•‬
‫•‬
‫•‬
‫مهار کالژناز تحریک شده توسط ‪IL1‬‬
‫مهار ترشح ‪MMP-3‬‬
‫تحریک ترشح ‪TIMP-1‬‬
‫تحریک سنتز کالژن توسط کندروسیت ها‬
‫‪Avocado/Soybean oil‬‬
‫• عوارض گزارش شده به ‪:FDA‬‬
‫–‬
‫–‬
‫–‬
‫–‬
‫–‬
‫–‬
‫–‬
‫ایست قلبی تنفسی‬
‫افزایش کراتینین سرمی‬
‫بی اختیاری مدفوع‬
‫احساس ناخوشی )‪(malaise‬‬
‫افت فشار خون وضعیتی‬
‫زردی‬
‫پورفیری‬
‫‪ o‬عدم قطعیت ارتباط این عوارض با دارو‬
Systematic review of soy isoflavone
supplements on osteoporosis in women.
• The present meta-analysis reveals that soy isoflavone supplements
significantly increase bone mineral density and decrease the bone
resorption marker urinary DPD. It shows no significant effect on bone
formation markers serum bone alkaline phosphatase. The significant
effect of soy isoflavones on BMD and urinary DPD is relative to
menopausal status, supplement type, isoflavone dose and intervention
duration.
• isoflavone dose above 75 mg/d.
Teltonal 480 FT®
• Arthroherb®
• Tab 480 mg
• Devil’s claw root extract (Harpagophytum procumbens)
– Harpagoside
• anti-inflammatory
‫®‪Teltonal 480 FT‬‬
‫• منع مصرف‪:‬‬
‫– زخم گوارشی‬
‫– کودکان زیر ‪ 12‬سال‬
‫– بارداری و شیردهی‬
‫• موارد احتیاط مصرف‪:‬‬
‫– سنگ صفراوی‬
‫– عدم تحمل الکتوز‬
‫– دیابت‬
‫• روش مصرف؟‬
‫®‪Teltonal 480 FT‬‬
‫• عوارض‪:‬‬
‫– اسهال‬
‫– تهوع و استفراغ‬
‫– گیجی‬
‫– سردرد‬
‫– واکنش های حساسیتی‬
Rheumatidin® (Celadrin®)
• Softgel cap 350 mg
• Celadrin® is made from a patented complex
blend of special esterified fatty acids, derived
from bovine tallow oil.
• Celadrin® works similar to, but much more
dramatically than the essential fatty acids EPA
and DHA from fish oils.
• Celadrin®
decreases
inflammation
and
lubricates cell membranes throughout the body,
restoring fluids that cushion bones and joints to
promote flexibility and mobility. Over time,
because of the reduction of inflammation
delivered by using Celadrin®, the joints and
surrounding tissue have an opportunity to
promote healthy joints.
• For oral application, Celadrin® was studied using a
double-blind, multi-center, placebo-controlled trial
(the most scientifically validated type). Sixty-four
participants between the ages of 37 to 77 were given
Celadrin® capsules and were evaluated at the
beginning of the trial, at 30 days and at the end of the
68 day study.
• Compared to those given a placebo, those who were
given Celadrin® had more flexibility, fewer
aches, less pain and were able to walk further
distances than the placebo group.
• The study therefore concluded that Celadrin®, when
taken orally improved joint and mobility problems.
• Celadrin ® empowers glucosamine to perform
faster and more efficiently in building joint
cartilage as well as accelerating and promoting
joint health.
• The dual action of Celadrin® and glucosamine
provide rapid joint cushioning, quickly alleviate
inflammation, build cartilage and restore the
entire joint area.
• Bromelain extract is a mixture of proteindigesting (proteolytic) enzymes or proteases,
and several other substances in smaller
quantities. The proteolytic enzymes are
sulfhydryl proteases, since a free sulfhydryl
group of a cysteine side chain is required for
function
• As a potential anti-inflammatory agent, it may
be useful for treating arthritis, but has neither
been confirmed in human studies for this use,
nor is it approved with a health claim for such an
effect by the Food and Drug Administration or
European Food Safety Authority
• While there have been studies which positively
correlated the use of bromelain with reduction of
symptom severity in osteoarthritis,“
• the majority of the studies have methodological
issues that make it difficult to draw definite
conclusions", as none definitively established
efficacy, recommended dosage, long term safety, or
adverse interaction with other medications.
• Walker AF, Bundy R, Hicks SM, Middleton RW
(2002). "Bromelain reduces mild acute knee
pain and improves well-being in a dosedependent fashion in an open study of otherwise
healthy adults". Phytomedicine 9 (8): 681–6.
• Hale LP, Greer PK, Trinh CT, James CL
(2005). "Proteinase activity and stability of
natural
bromelain
preparations".
Int
Immunopharmacol 5 (4): 783–93.
Mixodin
‫• یکسودین از عصاره های طبیعی زردچوبه‪ ،‬زنجبیل و فلفل سیاه که مواد موثره‬
‫کورکومین‪ ،‬جینجرول و پایپرین موجود در این ادویه ها در آن خالص و تغلیظ‬
‫شده‪ ،‬تهیه گردیده است‪ .‬ترکیبات میکسودین شامل عصاره زردچوبه "‬
‫کورکومین" ‪ 300‬میلی گرم‪ ،‬عصاره زنجبیل " جینجرول " ‪ 7.5‬میلی گرم و‬
‫عصاره فلفل سیاه " پایپرین " ‪ 3.75‬میلی گرم می باشد‪.‬‬
‫‪Mixodin‬‬
‫• دوز‪ :‬روزی ‪ 3-2‬کپسول‬
‫• منع مصرف‪ :‬بارداری‪-‬شیردهی‪ ،‬سنگ کلیه و کیسه صفرا‬
‫• هشدار‬