Common and Rare Side Effects for Mobic oral

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

Conditions:

• systemic mastocytosis
• anemia
• increased risk of bleeding due to clotting disorder
• an increased risk of bleeding
• alcoholism
• high blood pressure
• a heart attack
• chronic heart failure
• abnormal bleeding in the brain resulting in damage to brain tissue, called a hemorrhagic stroke
• a blood clot
• stomach or intestinal ulcer
• bleeding of the stomach or intestines
• kidney transplant
• visible water retention
• abnormal liver function tests
• pregnancy
• a rupture in the wall of the stomach or intestine
• tobacco smoking
• increased cardiovascular event risk
• time immediately after coronary bypass surgery
• chronic kidney disease stage 4 (severe)
• chronic kidney disease stage 5 (failure)
• kidney disease with likely reduction in kidney function
• aspirin exacerbated respiratory disease
• history of gastric bypass surgery
• history of kidney donation

Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use.

CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

Global analysis of gastrointestinal safety of a new nsaid, meloxicam

With NSAIDs, pick the one that works best, and stick with it – News – Sarasota Herald-Tribune

Dear Dr. Roach: I’m a 79-year-old man in generally good health. What is not under control is the lower back pain I have been suffering due to disk deterioration. I have been able to control it with physical therapy, stretching exercises, chiropractic and occasional NSAID medication. As I’m getting older, the pain is getting worse, and I have to rely on pain medication, consisting of ibuprofen 800 mg, meloxicam 7.5 mg, salsalate 750 mg and naproxen.

I am well aware of the side effects, and I would like your professional opinion about the safest one of these to take now that it seems I need them more often. — L.T.

Dear L.T.: My first point of advice is that you should absolutely not mix these medications. You should pick one and stick with it. Using multiple types of nonsteroidal anti-inflammatory drugs leads to higher toxicity without additional benefit.

My second point is that there is no “safest” NSAID. It depends on the dose and the type of adverse event you are worried about. For example, there is weak-to-moderate evidence that naproxen is safer than others specifically in the risk for heart disease. Salsalate has less effect on platelets (blood clotting cells) and therefore a lower risk of gastrointestinal bleeding. Ibuprofen has a very low rate of overall gastrointestinal effects at most doses: 800 mg is the maximum dose and carries a higher risk than 400 or 600 mg, but of course the total daily dose is important too.

These drugs all have different therapeutic effects on different people. One person might have such good pain relief with meloxicam 7.5 mg daily — better than what they have with ibuprofen 800 mg three times daily — that this drug might be safest for him or her, even if in studies it has a slightly higher rate of gastrointestinal bleeding than ibuprofen when used at a higher dose.

Dear Dr. Roach: My 53-year-old son carries the cystic fibrosis gene. Will his sons and nephews carry the gene? — C.S.

Dear C.S.: There are over 2,000 mutations in the gene that causes cystic fibrosis, the CFTR gene. In order to have clinical disease, a person must have two abnormal genes. Ninety percent of people with CF have at least one copy of the f508del mutation, making it the most common.

It is likely your son has one abnormal gene and one normal gene. If that is the case, each of his children has a 50% chance of getting the abnormal gene, and a 50% chance of inheriting the normal gene. If the child’s mother has two normal genes, a child who got the abnormal gene would be a CF carrier, like your son. However, if the mother is also a carrier, then each child would have a 25% chance of having CF; a 50% chance of being a carrier, and a 25% chance of having no copy of the abnormal mutation at all.

Since he might have a second abnormal (but less dangerous) mutation, the situation with CF is complicated. A genetic counselor with access to all the specifics of your situation can provide personalized information.

Dr. Roach writes:  A recent column on chigger bites generated many letters. Many of these were folk remedies, such as putting nail polish or oil on the bite. This is based on the misconception that chiggers burrow into the skin and can be suffocated, but this isn’t how chiggers work. They do attach to the skin, and the digestive enzymes in their saliva dissolve a hole in your skin. That’s why washing with soap and water after exposure is important.

Others wrote about preventing a chigger bite in the first place. Most readers recommended DEET, but others recommended sulfur powder. Both are effective.

Readers may email questions to [email protected].

Cyclooxygenase-2 Enzyme Inhibitors: Place in Therapy

2. Non-steroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions. Br Med J.
[Clin Res] 1986;292:614.

3. Singh G.
Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med.
1998;105:31S–8S.

4. Wolfe MM,
Lichtenstein DR,
Singh G.
Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med.
1999;340:1888–99[Published erratum appears in N Engl J Med 1999;341:548]

5. Kendall BJ,
Peura DA.
NSAID-associated gastrointestinal damage and the elderly. GI disease in the elderly series: article five in the series. Pract Gastroenterol.
1993;17(11):13–2029.

6. Lanza FL.
A guideline for the treatment and prevention of NSAID-induced ulcers. Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol.
1998;92:2037–46.

7. Lichtenstein DR,
Syngal S,
Wolfe MM.
Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract. The double-edged sword. Arthritis Rheum.
1995;38:5–18.

8. Fries JF.
NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatol Suppl.
1991;28:6–10.

9. Silverstein FE,
Graham DY,
Senior JR,
Davies HW,
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Bittman RM,

et al.
Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med.
1995;123:241–9.

10. Simon LS,
Hatoum HT,
Bittman RM,
Archambault WT,
Polisson RP.
Risk factors for serious non-steroidal-induced gastrointestinal complications: regression analysis of the MUCOSA trial. Fam Med.
1996;28:204–10.

11. Griffin MR.
Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury. Am J Med.
1998;104:23S–9S.

12. Singh G,
Rosen Ramey D.
NSAID induced gastrointestinal complications: the ARAMIS perspective—1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol Suppl.
1998;51:8–16.

13. Gabriel SE,
Jaakkimainen L,
Bombardier C.
Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med.
1991;115:787–96.

14. Fu JY,
Masferrer JL,
Seibert K,
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Needleman P.
The induction and suppression of prostaglandin h3 synthase (cyclooxygenase) in human monocytes. J Biol Chem.
1990;265(28):16737–40.

15. Crofford LJ.
COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol.
1997;24(suppl 49):15–9.

16. Vane JR,
Bakhle YS,
Botting RM.
Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol.
1998;38:97–120.

17. Gierse JK,
Koboldt CM,
Walker MC,
Seibert K,
Isak-son PC.
Kinetic basis for selective inhibition of cyclooxygenases. Biochem J.
1999;339(part 3):607–14.

18. Lipsky PE,
Isakson PC.
Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheumatol.
1997;24(suppl 49):9–14.

19. Needleman P,
Isakson P.
The discovery and function of COX-2. J Rheumatol.
1997;24(suppl 49):6–8.

20. McEboy GK, ed. AHFS Drug information 2000. Bethesda, Md.: American Society of Health-System Pharmacists, 2000.

21. Celecoxib for arthritis. Med Lett Drugs Ther.
1999;41:11–2.

22. Ehrich EW,
Dallob A,
De Lepeleire I,
Van Hecken A,
Riendeau D,
Yuan W,

et al.
Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther.
1999;65:336–47.

23. Rofecoxib for osteoarthritis and pain. Med Lett Drugs Ther.
1999;41:59–61.

24. Simon LS,
Weaver AL,
Graham DY,
Kivitz AJ,
Lipsky PE,
Hubbard RC,

et al.
Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA.
1999;282:1921–8.

25. Langman MJ,
Jensen DM,
Watson DJ,
Harper SE,
Zhao PL,
Quan H,

et al.
Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA.
1999;282:1929–33.

26. Peterson WL,
Cryer BC.
COX-1 sparing NSAIDs—is the enthusiasm justified?[Editorial] JAMA.
1999;282:1961–3.

27. McAdam BF,
Catella-Lawson F,
Mardini IA,
Kapoor S,
Lawson JA,
FitzGerald GA.
Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A.
1999;96:272–7[Published erratum appears in Proc Natl Acad Sci U S A 1999;96:5890]

28. Schafer AI.
Effects of nonsteroidal anti-inflammatory therapy on platelets. Am J Med.
1999;106:25S–36S.

29. Cryer B,
Feldman M.
Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology.
1999;117:17–25.

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From the Food and Drug Administration. JAMA.
1999;281:786.

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1999;106:13S–24S.

32. Lipsky PE.
The clinical potential of cyclooxygenase-2-specific inhibitors. Am J Med.
1999;106:51S–7S.

33. Hawkey CJ.
COX-2 inhibitors. Lancet.
1999;353:307–14.

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The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA.
1999;282:1254–7.

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Agrawal N,
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1999;94:2752.

Canadian Pharmacy: Buy Mobic Online

Mobic Product Description

Drug Uses

Mobik is an oral drug indicated to control and reduce symptoms of all grades of severity:

• Rheumatoid or autoimmune arthritis
• Knee arthrosis, degenerative arthritis and other types of painful osteoarthritis

Daily intake of Mobic helps to get rid of stiffness in joints, cracking sound, mild swelling, pain and other symptoms of joint damage. The daily dosage of Mobic may vary, but in each case it should be adjusted till the desired anti-inflammatory and analgesic effects.

The recommended dosage of Mobic may vary from 7.5 to 15mg per day. Mobic should be taken at the same time for better control over symptoms of disorders of the musculoskeletal system.

Missed dose

If you take Mobic spaced by a 24-hour interval, take the missed dose on the same day as soon as possible. Do not increase your dose and do not take additional anti-inflammatory agents to make up the missed Mobic dose.

More Information

Anti-inflammatory drug Mobic can be indicated to children above 24 months, diagnosed with juvenile rheumatoid arthritis. Dosage of Mobic for children to eliminate pain and inflammation in the joints makes 0.125mg /kg, every 24 hours.

Storage

Anti-inflammatory drug Mobic should be stored in a tightly closed, original container at room temperature (30°C). Drug should be protected from direct sunlight and kept out of sight and reach of children.

Mobic Safety Information

Warnings

Before to start the Mobic-therapy, the patients should learn that failure to follow an appropriate dosage regimen increases risks of blood clots, myocardial necrosis, ulceration, and bleeding in the bowel. Such risks are particularly high in the patients, who have had before and /or treated these or similar diseases. The lowest effective dose of Mobic and comliance with the recommended treatment duration minimize any risks.

Disclaimer

Information about management of pain and inflammations, contained in the review of Mobic, is intended for informational and educational purposes only. This information is not suited to be a replacement for professional medical advice of therapist, rheumatologist or other health care specialist. The online pharmacy is not responsible for any damage, arising from the use of this information about the anti-inflammatory drug Mobic.

Mobic Side Effects

Usually adverse effects of Mobic are not serious. Most common adverse effects of Mobic are reported as: diarrhea, flatulence, nausea, dizziness, headache, upper respiratory tract infections (including sore throat), indigestion, oedema or skin rash. In rare cases Mobic is reported to cause: somnolence, tinnitus, colitis, dry mouth, allergic reaction, flushes, hives, leukocytopenia, palpitations, hepatitis and worsening liver function.

Medications to Avoid Before Surgery

The medications listed below (and potentially many others) may have an effect on your blood’s ability to coagulate. Please review all your medications-both over the counter and prescription drugs-with your surgeon. In many cases, your medication will have no effect on your surgery, and you be counseled to continue with your medication as usual, but your surgeon must be aware of what you are taking and all prescriptions should be documented in your medical record. In no case should you medicate yourself with any drugs (even if they are not listed here) without the knowledge of your primary care physician and your surgeon.

Common Medications

• Aspirin (Anacin, Ascriptin, Bayer, Bufferin, Ecotrin, Excedrin)
• Choline and magnesium salicylates (CMT, Tricosal, Trilisate)
• Choline saliclate (Arthropan)
• Celecoxib (Celebrex)
• Diclofenac potassium (Cataflam)
• Diclofenac sodium (Voltaren, Voltaren XR)
• Diclofenac sodium with misoprostol (Arthrotec)
• Diflunisal (Dolobid)
• Etodolac (Lodine, Lodine XL)
• Fenoprofen calcium (Nalfon)
• Flurbiprofen (Ansaid)
• Ibuprofen (Advil, Motrin, Motrin IB, Nuprin)
• Indomethacin (Indocin, Indocin SR)
• Ketoprofen (Actron, Orudis, Orudis KT, Oruvail)
• Magnesium salicylate (Arthritab, Bayer Select, Doan’s Pills, Magan, Mobidin, Mobogesic)
• Meclofenamate sodium (Meclomen)
• Mefenamic acid (Ponstel)
• Meloxicam (Mobic)
• Nabumetone (Relafen)
• Naproxen (Naprosyn, Naprelan)
• Naproxen sodium (Aleve, Anaprox)
• Oxaprozin (Daypro)
• Piroxicam (Feldene)
• Rofecoxib (Vioxx)
• Salsalate (Amigesic, Anaflex 750, Disalcid, Marthritic, Mono-Gesic, Salflex, Salsitab)
• Sodium salicylate (various generics)
• Sulindac (Clinoril)
• Tolmetin sodium (Tolectin)
• Valdecoxib (Bextra)

Herbal Supplements

• Echinacea
• Ephedra
• Feverfew
• Fish Oil
• Garlic
• Ginko Biloba
• Ginger
• Green Tea
• Kava Kava
• St. John’s Wort
• Valerian
• Vitamin E
• Vitamin C (large doses)

Birth Control

• Birth control pills
• Estrogen replacement
• Estrogen creams or patches

Blood Thinners

• Coumadin
• Warfarin sodium
• Ximlagatran
• Clopidogrel
• Plavix

Comparative Effects of Dexamethasone and Meloxicam on Magnitude of the

Mohadeseh Manzari Tavakoli, Bahman Abdi-Hachesoo, Saeed Nazifi, Najmeh Mosleh, Seyedeh Alemeh Hosseinian, Peyman Nakhaee

Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

Purpose: Dexamethasone has been widely used to treat acute inflammatory diseases and endotoxic shocks in animal models. Meloxicam is one of the most commonly used anti-inflammatory agents in avian species. However, little is known about the effects of dexamethasone and meloxicam on lipopolysaccharide (LPS)-induced acute inflammatory response in birds. In the present study, LPS-challenged broiler chickens were used to investigate the comparative protective effects of meloxicam and dexamethasone on LPS-induced acute inflammatory responses.
Methods: Lipopolysaccharide (LPS)-induced acute lung injury (ALI) histopathological scores, selected serum acute phase reactants, inflammatory mediators, and gangliosides were evaluated in broiler chickens inoculated with E. coli LPS and simultaneously treated with two doses of meloxicam (0.5 and 2 mg/kg BW) and dexamethasone (2 and 4 mg/kg BW).
Results: LPS-induced ALI scores were not significantly different between the meloxicam-treated, dexamethasone-treated, and untreated positive control groups at 4 hours after LPS inoculation. Interleukin-6 concentrations were also statistically the same among the positive control, dexamethasone-treated, and meloxicam-treated groups at 3 and 12 hours after LPS inoculation. However, these anti-inflammatory drugs reduced adenosine deaminase, ceruloplasmin, lipid-bound sialic acid, protein-bound sialic acid, and total sialic acid in LPS-inoculated broiler chickens at 12, 24, and 48 hours after LPS inoculation in a drug- and dose-dependent manner. Ovotransferrin concentrations were not significantly different between positive control and treatment groups at 12 hours after LPS inoculation. However, twenty-four hours after LPS inoculation, all the treated groups, except the one treated with 0.5 mg/kg meloxicam, showed significantly lower concentrations of ovotransferrin as compared with the positive control group.
Conclusion: Our results showed that dexamethasone was more effective than meloxicam in inhibiting the LPS-induced response in broiler chickens by diminishing the serum levels of adenosine deaminase, ceruloplasmin, and gangliosides.

Keywords: lipopolysaccharide, meloxicam, dexamethasone, interleukin-6, acute phase proteins, chickens

Introduction

Lipopolysaccharide (LPS), or bacterial endotoxin, is a major pathogenic part of the outer membrane of Gram-negative bacteria and is considered to have an important role in the onset of Gram-negative sepsis, inflammation, shock, failure of multiple organs, and finally occurrence of high mortality. ¹ The inoculation of chickens with LPS has led to significant changes in the plasma proteome within 12-hour post infection.² Inflammation is a complex homoeostatic process which is associated with many infectious diseases and consequently leads to a prominent systemic critical reaction known as acute phase response (APR).^3,4 The APR, following the inflammatory process triggered by LPS from Gram-negative bacteria involves variations in the serum levels of different acute phase proteins (APPs), cytokines, enzymes, and metabolites with the aim of restoring the physiologic homeostasis of the host organism.^5,6 Therefore, acute endotoxemia could be considered as an appropriate inflammation model for gaining insight into the inflammatory processes.⁷ Alterations in the circulating levels of APPs are associated with the onset and durability of LPS inflammation; accordingly, APPs have been widely used as appropriate markers for investigating the health status of humans and other mammals. ^8,9

Upon exposure to various inflammatory conditions, such as acute bacterial endotoxemia resulting from LPS inflammation, circulating leukocytes release pro-inflammatory cytokines, which are necessary for the recruitment of neutrophils to the site of inflammation and the regulation of different metabolic responses.^10–12 These cytokines are involved in the regulation of the synthesis of APPs in the liver and have a mediating role in inducing the febrile response during inflammation and the development of the inflammation process by raising APPs.¹³

The need for gaining knowledge on different aspects of immune reactions of chickens during infections and different environmental or nutritional situations has led to the increased interest for investigations on APPs in chickens.¹⁴ Adenosine deaminase (ADA) is an enzyme that accelerates the conversion of adenosine to inosine and regulates extracellular adenosine and inosine concentrations in mammals. ¹⁵ ADA, as an endogenous regulator of the innate immune system, is essential in the proliferation and differentiation of T lymphocytes. In addition, ADA is involved in controlling the magnitude of purinergic response under physiological conditions and, to a larger extent, pathological events, such as inflammation.^16,17 Ovotransferrin, as a positive APP in chickens, increases during the APR triggered by a variety of experimentally induced inflammatory reactions and performs its bacteriostatic role by diffusing through the outer membrane of Gram-negative bacteria.^18,19 Serum ovotransferrin is used as a biomarker of inflammatory diseases in chickens.²⁰ Ceruloplasmin is a multifunctional antioxidant protein which accumulates and transports the copper within the body. The role of ceruloplasmin as an APP became evident by observing that its level increases in different infectious diseases.²¹

As a family of neuraminic acid derivatives, sialic acids are involved in many biological and pathological phenomena located at the end chain of many APPs. The majority of sialic acids found are either protein-bound or lipid-bound, and only a few of them are in free form.²² Sialic acids have a principal role in cell-to-cell identification and interaction, which mediate various cell-cell adhesion processes in the inflammation and immune response.²³ Sialic acids concentration increases immediately following various bacterial and viral inflammatory responses associated with various diseases in humans and animals. Hence, the evaluation of sialic acids concentration may be helpful in the diagnosis and prognosis of inflammatory diseases.^24–26

Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively used as analgesics to alleviate pain and treat inflammatory musculoskeletal diseases and other inflammatory ailments, such as LPS endotoxemia. The NSAIDs mechanism of action is to inhibit prostaglandins and thromboxanes production as the major mediators in the inflammation process. This feature of NSAIDs makes them a more appropriate candidate, compared to their steroidal counterparts, to be applied in a targeted approach for treating inflammation. ²⁷

Meloxicam is a COX-2-selective NSAID in its therapeutic dose. However, the COX-2 specificity of meloxicam decreases at high doses and the drug could bind to COX-1 with some controversial effects.²⁸ Pharmacokinetics and toxicological effects of meloxicam have been evaluated in chickens and other avian species.²⁹ Empirical dose ranges of meloxicam (0.5–2.0 mg/kg BW) has been used for the various inflammatory conditions and postoperative pain managements in different bird species with no adverse effects on either the renal and intestinal organs or the immune and hematopoietic system of birds.²⁹ These qualifications explain why meloxicam has become the most commonly used anti-inflammatory medication in avian species.³⁰

Dexamethasone, as a synthetic derivative of cortisol, targets the phospholipid-arachidonate cascade to control inflammatory reactions.³¹ It has been shown that dexamethasone can modulate the production of cytokines and acute phase proteins in the acute phase of inflammation. ^32,33 Despite the limitations specified in the pharmacopeia regarding the use of dexamethasone as a steroidal drug, its use has been approved in few cases such as septic shock and Gram-negative endotoxemia with a dose range of 2–4 mg/kg in different avian species.^30,34,35

To our knowledge, no report is available about the comparative effects of dexamethasone and meloxicam on magnitude of the acute inflammatory response induced by bacterial LPS in avian species. In the present study, based on the previously described LPS-induced inflammation model in broiler chicken,^36–38 LPS-challenged broiler chickens were used to investigate the comparative protective effects of these anti-inflammatory compounds on LPS-induced acute inflammatory responses.

Materials and Methods

Animals

Fifty-four one-day-old Ross 308 male chicks were provided by a local commercial poultry farm (Fars province, Iran) and raised in an environmentally controlled poultry house in the Animal Research Unit of Shiraz University Veterinary School for five weeks under the standard environmental conditions and in compliance with the production parameters recommended by the broiler producer company. ³⁹ All the birds used in this experiment were handled in accordance with the technical regulations and the guidelines set out by the committee of animal ethics of Shiraz University, Iran. The protocols of the study were approved by the Ethics Committee of Shiraz University (IACUC no: 4687/63).

Experimental Group

The chickens, aged five weeks, were divided into six groups of 9 birds each. The mean body weight of all chickens was 1.65 ± 0.2 kg. The positive LPS group was intravenously (IV) injected with LPS of E. coli O55 B5 (Sigma-Aldrich, USA) at a dose of 0.5 mg/kg. The birds in the negative control group were injected with the same volume of pyrogen-free water.

The other four groups were treated with meloxicam 5% (Razak, Iran) and dexamethasone 0.2% (Razak, Iran), as anti-inflammatory drugs, in combination with LPS. Immediately after the IV inoculation of LPS, meloxicam and dexamethasone were intramuscularly (IM) injected in the pectoral muscles at two different doses, ie 0. 5 mg/kg, 2 mg/kg and 2 mg/kg, 4 mg/kg, respectively.⁴⁰

Histological Examination

Four hours after LPS administration, three chickens were randomly selected from each group and euthanized. Their upper right lung lobes were removed and stored in 10% buffered formalin for one week. The samples were dehydrated, embedded in paraffin, cut into 5-µm sections, and stained with hematoxylin and eosin (H&E) according to standard procedures. Four microscopic fields (100×), which contained at least a tertiary bronchus per field, per tissue sample for each bird were randomly chosen and observed by a light microscope. Five high-power fields (HPF), containing an interatrial septum, were randomly assigned to each field. All sections were scored according to the previously described criteria for LPS-induced acute lung injury,⁴¹ with some modifications for chicken lungs. In brief, the thickness of the interatrial septum, infiltration of inflammatory cells, and hemorrhage were scored in each HPF using a blinded approach. Acute lung injury scores (ALI scores) for each item was categorized according to the following scale: 0: minimum damage; 1: mild damage; 2: moderate damage; 3: severe damage; 4: maximum damage. Accordingly, the final ALI score for each field varied within a range from 0 to 12.

Serum Sampling

Blood was collected from the jugular vein at 3 h and 12 h after LPS injection to determine IL-6 concentration and at 12, 24, and 48 h after LPS injection to measure the adenosine deaminase, ceruloplasmin, ovotransferrin and, gangliosides (TSA, LBSA, PBSA). The sera were separated by centrifugation at 750g for 15 min and stored at −20 C until further use.

IL-6 and Ovotransferrin Assays

The serum levels of IL-6 and ovotransferrin were measured using a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) and commercial chicken-specific kits (Shanghai Crystal Day Biotech, Shanghai, China). The sensitivity of IL-6 and ovotransferrin kits was 0.53 ng/L and 0.024 mg/mL, respectively. The intra-assay and inter-assay precision of these kits were CV < 8% and CV < 10%, respectively.

Gangliosides (TSA, LBSA, PBSA) Assay

Serum total sialic acid (TSA) concentration was determined by the thiobarbituric acid method. Lipid-bound sialic acid (LBSA) concentration was determined using the method described by Katopodis et al.⁴² Protein-bound sialic acid (PBSA) concentration was measured by subtracting LBSA from the serum TSA.

Adenosine Deaminase (ADA) Assay

ADA concentration was assessed by an enzymatic-calorimetric assay kit (Diazyme Laboratories, Gregg Court, California, USA).

Ceruloplasmin Determination

The measurement of the serum ceruloplasmin level was performed with the method suggested by Bestujeva and Kolb.⁴³

Statistical Analysis

Results are expressed as mean ± SD. For the analysis of serum data, one-way analysis of variance (ANOVA), followed by Tukey’s post hoc test, was used. In cases of a failed normality test, Kruskal–Wallis ANOVA was performed followed by Dunn’s post hoc test. For histopathological scoring, non-parametric Mann–Whitney U-test was performed. Statistical analyses were conducted with SPSS software (version 16.0, SAS Institute Inc., Cary, NC, USA). P < 0.05 was considered significant.

Results

Histopathology

The histopathological examination of H&E-stained lungs showed that LPS treatment, compared to the control condition (negative control: Figure 1A), clearly stimulated a diffuse inflammatory response, severe hemorrhage, and thicker interatrial septum as observed in the positive control (Figure 1B), meloxicam-treated, and dexamethasone-treated groups (Figure 1C–F).

Lipopolysaccharide-induced ALI scores were not significantly different between the meloxicam-treated, dexamethasone-treated, and untreated positive control groups (P> 0.05) (Figure 2).

Interleukin-6 and Acute Phase Proteins

The concentration of ADA in the positive control at 12, 24, and 48 hours after LPS inoculation was significantly higher than that of the negative control (P≤0.05). Meloxicam treatment (0.5 and 2 mg/kg) had no significant effects on ADA concentration in comparison with the positive control group (P> 0.05). In contrast, dexamethasone treatment (2 and 4 mg/kg) significantly lowered the ADA concentration in comparison with the positive control and meloxicam-treated groups at 12, 24, and 48 hours after LPS inoculation (P≤0.05) (Figure 3A). Ceruloplasmin concentrations were not significantly different between the positive control group and 0.5 mg/kg meloxicam-treated group at 12, 24, and 48 hours after LPS inoculation (P> 0.05). However, 2 mg/kg meloxicam significantly decreased ceruloplasmin concentrations in comparison with the positive control group at the same time points mentioned above (P≤0.05). On the other hand, ceruloplasmin concentrations were significantly reduced in 2 and 4 mg/kg dexamethasone-treated groups compared with those of the positive control group (P≤0.05) (Figure 3B). Ovotransferrin concentrations were not significantly different between the positive control and treatment groups at 12 hours after LPS inoculation (P> 0.05). Twenty-four hours after LPS inoculation, all the treated groups, except the one treated with 0.5 mg/kg of meloxicam, had significantly lower concentrations of ovotransferrin compared with the positive control group (P≤0.05). Unfortunately, it was not possible to measure ovotransferrin level at 48 hours after inoculation because of inadequate serum storage (Figure 3C).

The injection of 0.5 and 2 mg/kg meloxicam did not significantly alter the lipid-bound sialic acid concentration compared with that of the positive control group (P> 0.05). On the other hand, the injection of 2 and 4 mg/kg dexamethasone significantly changed the lipid-bound sialic acid concentration in comparison with that of the positive control group at 12, 24, and 48 hours after LPS inoculation (P≤0.05) (Figure 3D). Different doses of meloxicam and dexamethasone significantly decreased the concentration of protein-bound sialic acid in comparison with that of the positive control group (P≤0.05). Dexamethasone was significantly more effective than meloxicam in decreasing the concentration of protein-bound sialic acid at 12, 24, and 48 hours after LPS inoculation (P≤0.05) (Figure 3E). The total sialic acid level was not significantly different between the positive control and meloxicam-treated groups at 12 hours after LPS inoculation (P> 0.05). However, dexamethasone significantly decreased the total sialic acid level in comparison with that of the positive control and meloxicam-treated groups at 12 hours after LPS inoculation (P≤0.05). Twenty-four hours after LPS inoculation, dexamethasone and meloxicam significantly reduced the total sialic acid level in a dose-dependent manner compared with that of the positive control group. Forty-eight hours after LPS inoculation, the effect of 0.5 mg/kg meloxicam treatment on the total sialic acid level was not significantly different from that of the positive control (P> 0.05). On the other hand, 2 mg/kg meloxicam and dexamethasone treatments significantly decreased the total sialic acid level in comparison with that in the positive control and 0.5 mg/kg meloxicam-treated groups (P≤0.05) (Figure 3F).

Interleukin-6 concentrations were not significantly different between the positive control and treatment groups at 3 and 12 hours after LPS inoculation (P> 0.05) (Figure 3G).

Discussion

The present study was designed to explore the extent that dexamethasone or meloxicam could modulate LPS-induced lung inflammation, serum APPs concentration, and IL-6 level in broiler chickens. Some special features of avian lungs, such as a single basal lamina and a thin squamous epithelium layer at the blood-gas interface, predispose their respiratory systems to bacterial pathogens and possibly LPS-induced acute lung injury.⁴⁴ In some previous studies, E. coli-derived LPS were used to induce the model of acute lung injury in chickens.^37,44,45 In the current experiment, LPS treatment in the positive control group clearly stimulated a diffuse inflammatory response, severe hemorrhage, and thicker interatrial septum, which resulted in higher ALI scores in the positive control group as compared with those in the negative control group. Ansari et al⁴⁴ found indistinguishable margins between different parts of the pulmonary lobules, along with a narrowed lumen of the pulmonary atria and obvious congestion and heavy leukocytes infiltration of the pulmonary parenchyma 12 hour after LPS inoculation to broiler chickens. Intravenous LPS administration to the broiler chickens also caused a decrease in circulating white blood cells and appreciable sequestration of the leukocytes to the lungs.³⁷ In our study, LPS-induced ALI scores were not significantly different among the dexamethasone-treated, meloxicam-treated, and untreated positive control groups. The effects of dexamethasone and meloxicam administrations on the LPS-induced acute lung injuries has not been studied previously in avian species. However, some previous evidence show that pre- and simultaneous treatment with dexamethasone can attenuate LPS-induced acute lung injury in mouse models.^46,47 In addition, Dexamethasone inhibited LPS-induced hydrogen sulphide biosynthesis in a mouse model which can contribute to the anti-inflammatory effect of dexamethasone in endotoxic shock.⁴⁸ Moreover, it has been shown that meloxicam could decrease endotoxin-induced acute lung injury in rabbits.⁴⁹

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a major role in regulating immune responses, acute phase reactions, and hematopoiesis. In accordance to our study, De Boever et al³⁷ showed maximum levels of secreted IL-6 at 3 h after intravenous LPS administration in the broiler chickens. In the current study, dexamethasone and meloxicam administrations did not significantly affect the concentration of LPS-induced IL-6 in the serum of chickens at 3 and 12 hours after LPS injection. The effects of dexamethasone and meloxicam administrations on the LPS-induced IL-6 secretion had not been studied previously. However, De Boever et al³⁸ showed that the administration of other anti-inflammatory drugs, including tepoxalin, sodium-salicylate, and ketoprofen did not influence the concentration of IL-6 in plasma 3 hours after LPS administration.

In a previous study, Adanin et al⁵⁰ showed that the prevention of adenosine degradation could attenuate proinflammatory cytokine responses after LPS inoculation in rats. They suggested that the inhibition of ADA could be a novel therapeutic approach to control the systemic inflammatory response. In this study, serum ADA activity was significantly higher in the E. coli LPS-treated group than in the negative control group. Meloxicam administration was not associated with a significant effect on ADA concentration. However, the ADA concentration in the dexamethasone-treated groups was lower than that of the positive control and meloxicam-treated groups. Yazar et al⁵¹ indicated that dexamethasone could significantly decrease ADA levels in E. coli LPS endotoxemia in rats.

It is well documented that the concentration of sialic acid immediately rises following different inflammatory stimuli.^52–54 In the present study, the concentrations of total sialic acid, lipid-bound sialic acid, and protein-bound sialic acid were significantly higher in the LPS-challenged groups than in the negative control group. The administration of meloxicam did not significantly affect LBSA level but reduced PBSA in comparison with the positive control group. Dexamethasone was more effective than meloxicam in reducing LBSA, PBSA, and TSA.

In this study, the ceruloplasmin concentration was significantly higher in LPS-inoculated chickens in comparison with that of non-inoculated birds. The increase in the ceruloplasmin concentration in the serum of chickens after LPS injection was consistent with the findings of Butler et al,²¹ Curtis and Butler,⁵⁵ and Baert et al.³⁶ Moreover, dexamethasone, as a corticosteroid, showed greater effects on ceruloplasmin concentrations than did meloxicam. Baert et al³⁶ showed that different doses of sodium salicylate, as an NSAID, did not have significant effects on E. coli LPS endotoxemia in broiler chickens. Our findings are in accordance with that of a previous study, which showed that anti-inflammatory drugs, including tepoxalin, sodium salicylate, and ketoprofen, did not have significant effects on LPS-induced ceruloplasmin concentrations.³⁸

Rath et al²⁰ reported that the concentration of ovotransferrin in chickens increases during inflammatory processes and microbial infections. Furthermore, they suggested that ovotransferrin concentration could be considered a diagnostic marker of infection and inflammation. In our study, 24 h after LPS injection, ovotransferrin concentration in E. coli LPS-inoculated positive control group was significantly higher than that of the negative control group. Horvatić et al² recorded the maximum concentration of ovotransferrin at 24 h after E. coli LPS inoculation in chickens. In our study, all the treated groups, except the one treated with 0.5 mg/kg meloxicam, showed significantly lower ovotransferrin concentrations compared with those of untreated positive control group.

Conclusion

Different doses of dexamethasone and meloxicam did not have significant effects on LPS-induced ALI scores and serum IL-6 levels. However, these anti-inflammatory drugs reduced adenosine deaminase, ceruloplasmin, ovotransferrin, lipid-bound sialic acid, protein-bound sialic acid, and total sialic acid in LPS-inoculated broiler chickens. Dexamethasone was more effective than meloxicam in the reducing of these LPS-induced markers.

Shiraz University
10.13039/50110000507197GCU4M271378
This work was supported by a grant from Shiraz University (grant number 97GCU4M271378).

Disclosure

The authors declare no conflicts of interest.

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Meloxicam, a non-steroidal anti-inflammatory drug with selective suppression of the cyclooxygenase-2 isoenzyme: clinical efficacy

In another randomized, double-blind study involving 258 patients with knee OA, the efficacy of meloxicam at a dosage of 15 mg per day was comparable to that of controlled release diclofenac at a dosage of 100 mg per day after 6 weeks of treatment [30]. Both approaches to pharmacotherapy showed clinical improvement in pain on movement, overall efficacy, and concomitant use of paracetamol (acetaminophen).Somewhat better positive dynamics was noted with the use of meloxicam, however, no significant difference was found between the two approaches to treatment. With the use of diclofenac, a greater number of cases of lateral GI reactions were noted than with the use of meloxicam (26% versus 16%).

Degner et al studied the efficacy of meloxicam treatment in the context of its planned use in a prospective long-term (6 months) observational cohort study [32].Patients (n = 4526) were diagnosed with an exacerbation of chronic rheumatic disease requiring treatment with NSAIDs. The most common diagnoses were OA (n = 2593) and rheumatoid arthritis (n = 1402). Patient groups were randomized to receive therapy with meloxicam (n = 2530) or other NSAIDs (diclofenac, ibuprofen, piroxicam, or indomethacin; n = 1996). The majority of patients (78%) in the meloxicam group received a low dose (≤ 7 mg per day). There were no significant differences in efficacy scores (general health, pain, disease activity, and functional impairment) as measured by a 4-point verbal rating scale (VRS) between the two treatment groups.General health indicators decreased from 2.27 ± 0.84 at the beginning to 1.58 ± 0.77 after taking meloxicam (difference -0.69) and from 2.25 ± 0.81 to 1.66 ± 0.75 – after taking a comparable NSAID
(-0.59). Changes in values ​​were similar when studying the intake of meloxicam in comparison with alternative NSAIDs, they were: -1.71 versus -1.61 for pain on movement; -1.62 against
-1.61 – for the indicator pain at rest;
-1.48 versus -1.38 – for the indicator of disease activity; -1.57 versus -1.53 ​​- for the indicator of functional disorders.However, recipients of meloxicam had significantly fewer alimentary canal adverse reactions (1.80% versus 3.20%; relative risk 0.56 [95% CI 0.39–0.82]). Significant differences in favor of meloxicam were also observed in such indicators as the occurrence of abdominal pain, the development of gastritis, dyspepsia and gastrointestinal bleeding. At the same time, although both treatment groups were well comparable in age, sex and diagnosis, there were cases of selective prescription of meloxicam in patients who did not respond to NSAIDs, there were side effects due to taking NSAIDs in previous courses of treatment or in people with more severe forms of the disease.Overall, the findings of this study confirmed the efficacy / tolerance profile of meloxicam from controlled clinical trials.
Rheumatoid arthritis
Rheumatoid arthritis (RA) is a progressive degenerative disease in which various joints (predominantly small) are affected, and is characterized by their inflammation and systemic manifestations. The main goal of RA treatment is to control disease activity, slow down the development of joint damage, reduce pain and inflammation, and provide patients with the possibility of normal life activity [33].Since joint damage and disability develop rapidly in patients with RA, early diagnosis and prompt administration of effective therapy are key factors in the treatment of this disease [34]. Although the primary treatment is the early prescription of disease-modifying antirheumatic drugs (DMARDs), NSAIDs (often used in combination with DMARDs) play a significant role in relieving RA symptoms [35]. It should be noted that NSAIDs provide a quick response, but have no effect on long-term structural changes and, therefore, cannot be prescribed as first-line therapy in place of DMARDs.Criteria used for the clinical evaluation of drugs for RA include pain, physical disability, patient and investigator overall assessment, number of swollen / tender joints, rheumatic tests, and radiographic progression on long-term studies (≥ 1 year) [36]. Most studies investigating the effectiveness of NSAIDs look at symptomatic parameters (pain relief, morning stiffness, and fatigue).
The efficacy of meloxicam in relieving RA symptoms and its tolerability have been studied in numerous open and controlled studies.In a multicenter double-blind study to determine the effective dose of the drug, 423 patients with RA were divided into groups for treatment with meloxicam at a dose of 7.5 or 15 mg per day for 3 weeks [37]. Both dosages were effective, with significant improvements over baseline Ritchie articular index (a parameter for assessing joint tenderness) and morning pain scores (pIn a randomized, double-blind, placebo-controlled study of 468 RA patients after 3 weeks of meloxicam dose 15 mg / day showed significantly better results compared to placebo in three of the four primary efficacy parameters (patient and investigator-assessed disease activity and reduction in painful joints; p An open-label study of 357 RA patients investigated the long-term efficacy and tolerability of meloxicam at a dosage of 15 mg per day for more than 18 months [39].In this study, there was significant improvement from baseline on several parameters, including disease dynamics, general condition, Richie score, morning stiffness, hand grip strength, and morning or night pain. After about 6 months of treatment, these values ​​improved to the maximum. At the same time, the average indicator of overall effectiveness (assessed by patients on a VAS from 0 [excellent] to 10 [useless]) was 3.32 cm (3.1 cm is the standard deviation). It is noteworthy that the effectiveness persisted throughout the study, and the rates of discontinuation of treatment due to lack of effectiveness and the occurrence of adverse reactions were 11.4% and 13.7%, respectively.The most common adverse reactions were gastrointestinal (28%), musculoskeletal (21%), cutaneous (18%) and respiratory (15%) disorders. As noted by the researchers, the data obtained in this trial on the efficacy and tolerability of meloxicam testified in favor of this drug compared with data on other non-selective NSAIDs. This is confirmed by the results of direct comparison of data on meloxicam and the most commonly used NSAIDs.
In a double-blind, 6-month study of 379 patients with RA, meloxicam 7.5 mg / day was equally effective across all primary efficacy endpoints (patient and investigator overall efficacy, number of swollen and painful joints) and most secondary efficacy endpoints, such as the use of naproxen at a dose of 750 mg per day [40].And only in terms of the degree of joint swelling and the number of cases of drug discontinuation due to lack of effect, naproxen treatment had an advantage over meloxicam therapy. However, meloxicam had better tolerance compared to naproxen: there were fewer gastrointestinal side reactions (30.3% versus 44.7%), there were fewer cases of treatment cancellation due to side effects from the gastrointestinal tract, an improved hematologic / biochemical profile was observed (in terms of hemoglobin, serum creatinine and urea).

Intramuscular (IM) administration of NSAID solutions may be appropriate for the short-term treatment of rheumatic diseases associated with acute pain, such as exacerbations of RA, OA or sciatic nerve neuralgia, since it allows you to quickly reach the maximum concentration of the drug in the blood plasma (C _max ) and, therefore, lead to a rapid onset of the clinical effect. With i / m administration of melaxicam C _{, max} is reached within 1.5 hours (compared to 5-6 hours for oral administration), thus, this route of administration can be considered as the preferred method for treatment in cases requiring rapid analgesia [22].The efficacy of oral versus IM meloxicam 15 mg daily over a 7-day period was compared in a double-blind, placebo-controlled study in 346 patients with RA [41]. Although there were no significant differences between the two modes of administration of the drug in terms of general pain or disease activity (for which a significant improvement was achieved in comparison with placebo; p <0.001), nevertheless, with i / m administration, the value of the parameters, the rate of effect ( within the first 6 hours) and the duration of morning stiffness (p = 0.012 and p = 0.026, respectively, compared with oral administration) were higher.The number of patients who had a decrease in pain within 6 hours after starting treatment with oral or IM administration of meloxicam was 47% and 61%, respectively (p-0.005). Local tolerance for meloxicam injections was the same as for placebo injections.

Other diseases of the musculoskeletal system
Meloxicam has also been used successfully to treat pain associated with ankylosing spondylitis (ankylosing spondylitis) or other musculoskeletal disorders that could cause acute periarticular inflammation or lower back pain.Ankylosing spondylitis is an inflammatory disease in which the spine is primarily affected (although peripheral joints may also be affected). Extra-articular rheumatic diseases are characterized by inflammation of the periarticular tissues (eg, tendons, ligaments, or joint capsule) in the absence of infection or systemic disease; in this case, as a rule, the development of acute tendinitis of the biceps tendons or muscles of the shoulder girdle is observed. Since pain together with functional disorders are the main symptoms in ankylosing spondylitis and other extra-articular rheumatic diseases, pharmacological therapy is often based on the use of NSAIDs [42, 43].A randomized, double-blind, placebo-controlled study compared the short- and long-term efficacy and tolerability of meloxicam at a dosage of 15 and 22.5 mg per day and piroxicam at a dosage of 20 mg per day in patients with ankylosing spondylitis (n = 473) [44]. After 6 weeks of treatment, the percentage of respondents (-50% improvement in the VAS of the general assessment of the condition and the indicator of interruption of treatment due to lack of efficacy) in the 4 study groups was: 21% (placebo), 43% (piroxicam), 50% (meloxicam in dose of 15 mg per day) and 47% (meloxicam at a dose of 22.5 mg per day).However, the rates in all three active treatment groups were significantly different from those of the placebo group (pIn an international double-blind study conducted by Vidal et al. [45], the efficacy of meloxicam was evaluated for the reduction of acute periarticular shoulder pain. In this 2-week study, where The primary efficacy endpoint was pain relief as assessed by the patient after 7 days of treatment, 599 patients with rheumatism of the soft tissues of the shoulder were randomized to treatment with meloxicam 7.5 mg and 15 mg per day orally and piroxicam 20 mg per day orally.All treatment groups showed similar efficacy in pain relief on day 7. However, for meloxicam, in comparison with piroxicam, a more rapid onset of action was characteristic in a significantly larger number of patients – they experienced relief of pain on movement for 1–3 days (Fig. 2). The rationale for the earlier onset of pain relief, which was observed in patients in the meloxicam group, is the difference in the pharmacokinetics of the two drugs (meloxicam reaches a stable plasma concentration after 3-4 days of treatment compared to 7-10 days for piroxicam).Moreover, in the meloxicam group, only a few patients discontinued treatment due to the development of adverse reactions [45].

Acute lower back pain, which usually results from abnormal movements or sprains in the lumbar spine, is an extremely excruciating condition that requires rapid analgesia. Treatment with meloxicam at a dose of 15 mg per day and piroxicam at a dose of 20 mg per day provides rapid relief of pain – the average time of onset of analgesia is 40–45 minutes.This treatment was studied in a multicenter, randomized, open-label study of 160 patients with acute low back pain [46]. Both drugs were injected intramuscularly on the first day and then taken orally for the next 7 days. By the end of the study, 82% and 81% of patients who took meloxicam and piroxicam, respectively, had no or slight pain when moving; 53% and 51%, respectively, had no restrictions on daily activities.Results from two multicenter, double-blind studies have shown that 7.5 and 15 mg per day of meloxicam is more effective than placebo and as effective as 150 mg of diclofenac per day for reducing pain associated with acute sciatica [47]. Placebo-controlled studies with diclofenac included 532 and 489 patients, respectively. The rate of reduction in overall pain (assessed by the patient according to the VAS) compared with baseline and on the 7th day of treatment was significantly higher in patients taking meloxicam (in both dosages) compared with those who took placebo, and this indicator in the meloxicam group at a dose of 15 mg per day was significantly superior to that in the placebo group after three days of treatment.In a diclofenac-controlled study, the efficacy in the meloxicam group was similar to that in the diclofenac group. The difference in total pain (estimated by the method of least squares of the mean) for recipients of diclofenac, meloxicam at a dose of 7.5 mg per day and meloxicam at a dose of 15 mg per day was -40 ± 2 (-54%), -40 ± 2 (-52%) and -41 ± 2 (-54%), respectively, on the 7th day and -57 ± 2 (-77%), -57 ± 2 (-75%)
and -56 ± 2 (-73%) – on the 14th day.
Postoperative pain
Non-selective NSAIDs are often used to treat postoperative pain.However, patients who have undergone surgery are at a higher risk of developing gastrointestinal, renal, or hemostatic adverse reactions. Selective COX-2 inhibitors have the advantage of an improved tolerability profile and may be particularly useful in these patients.
In a double-blind, placebo-controlled study, meloxicam is an effective treatment for postoperative pain after abdominal hysterectomy [48]. Thirty-six women who underwent hysterectomy under general anesthesia were randomized to receive rectal meloxicam 15 mg or placebo before surgery.They also received intravenous morphine at the start of surgery and after surgery using a patient-controlled analgesia system (PAS). The mean values ​​of all pain indicators at rest, during movement and coughing (measured by VAS at the 2nd, 4th, 8th, 12th and 24th hours after surgery) were significantly less (by 46%, 29% and 23%, respectively) in patients taking meloxicam compared with those taking placebo. However, there was no significant difference in morphine consumption by the AUP system.In a randomized, double-blind study in patients who underwent surgery for an inguinal hernia, it was found that local infiltrative administration of meloxicam into the subfascial space of the inguinal canal was as effective as intravenous (iv) administration of the same for preventing postoperative pain. doses (7.5 mg) of the drug [49]. There was no significant difference between the two groups in terms of pain levels or consumption of additional analgesics (paracetamol / codeine or fentanyl).As expected, the plasma concentration of meloxicam was significantly lower after local infiltration was performed.
Potential role of meloxicam in cardiovascular protection
A recently published second pilot study of the role of NSAIDs in the treatment of unstable angina (NUT-2) concluded that meloxicam may have a cardioprotective effect in patients with coronary artery disease [50]. The data from this randomized, simple, blinded study led to the conclusion that the administration of meloxicam in conjunction with standard antithrombotic therapy (aspirin and heparin) in patients with acute coronary syndrome without ST-segment elevation led to a significant reduction in the number of cardiovascular complications compared with their number alone. using only aspirin and heparin.The study involved 120 patients who were randomized to receive either standard therapy alone or standard therapy plus meloxicam during their hospital stay and for 30 days after discharge. Treatment with meloxicam was carried out by its intravenous administration (15 mg immediately at the very beginning of the study), and then in the form of oral administration (15 mg per day) for 30 days. During the period of stay in the intensive care unit, there were significantly fewer cases of angina attacks, myocardial infarctions, or death (primary mixed outcome) among patients who took meloxicam compared with those who received only standard therapy (15% versus s 38.3%; p = 0.007).In particular, the recipients of meloxicam were significantly less likely to have recurrent angina pectoris (15% versus 35%; p = 0.02). Similarly, the secondary outcomes in the meloxicam group were better than in the control group, as evidenced by fewer coronary revascularization procedures, myocardial infarction, or death (10% versus 26.7%; p = 0.034). This significant difference between the two groups was observed during the 90-day follow-up period.The significant beneficial effects associated with meloxicam administration may be justified by a decrease in vascular inflammation. Meloxicam was well tolerated; no bleeding or other complications were observed during the observed period.
Despite the limiting conditions of the study (simple blind method, relatively small number of patients, “soft” endpoints that could be influenced by subjective perception of symptoms) [51], these results are encouraging and clearly indicate the need for further research on the potential of meloxicam in cardiovascular therapy. -vascular pathology. Portability
Gastrointestinal tolerance . Selective COX-2 inhibitors have been developed to reduce the risk of gastrointestinal adverse reactions associated with the use of non-selective NSAIDs, while maintaining their therapeutic efficacy [17]. The GI tolerance profile of the selective COX-2 inhibitor meloxicam, as well as its clinical efficacy, has been studied in a series of studies. In particular, two large prospective comparative studies conducted with the participation of patients with OA (the international large-scale study of the safety of meloxicam – MELISSA and the large-scale assessment of the safety and efficacy of COX inhibition therapy – SELECT) showed that treatment with meloxicam is associated with a lower level of GI toxicity compared with treatment with diclofenac or piroxicam [52, 53].In the MELISSA study, 4635 patients were randomized (using a double-blind method) to receive meloxicam 7.5 mg daily and 4688 patients were assigned to diclofenac 100 mg daily; over a 28-day period, the tolerability of the two drugs was compared. The meloxicam group had significantly fewer gastrointestinal adverse reactions compared with the diclofenac group (13% versus 19%; p Another large, randomized, double-blind, 28-day SELECT study compared the tolerability of meloxicam 7.5 mg / day ( n = 4320) and piroxicam at a dose of 20 mg per day (n = 4336).The results were similar to those obtained in the MELISSA study, with the number of meloxicam recipients experiencing adverse GI reactions was lower than among piroxicam recipients (10.3% versus 15.4%; p

Clinical studies were confirmed by the results of a prospective double-blind study in which 44 healthy volunteers participated; it assessed the level of damage to the mucous membrane in the esophagus, stomach and duodenal zone after 4 weeks of treatment with meloxicam at a dose of 15 mg per day, piroxicam at a dose of 20 mg per day, or placebo [55].Patients underwent endoscopic examination at the initial stage and at the 1st stage,
7th and 28th day of treatment. During these periods, biopsies were obtained to assess microscopic lesions of the mucous membrane and to determine the content of prostaglandin E2 (PGE2). Patients in the piroxicam group showed severe macroscopic lesions of the gastric mucosa on day 1 (with a tendency to normalize by day 28); no such lesions were observed in recipients in the meloxicam or placebo group.There were no significant changes in the concentration of PGE2 in mucosal biopsies over time or between groups [55].
The UK Prescribing Safety Monitoring Study analyzed the occurrence of GI adverse events in 19-087 patients who were prescribed meloxicam as therapy between December 1996 and March 1997. According to the data obtained as a result of this study, the number of cases of serious GI complications in patients who did not have risk factors was low [56].All participants received questionnaires with a request to provide information on adverse reactions that occurred within 6 months after the first dose of meloxicam; 50% of these questionnaires were returned. Overall, 203 (1.1%) patients had 252 suspected meloxicam adverse reactions. Serious reactions were very rare, with 20 cases of gastrointestinal bleeding, 7 cases of melena, 5 cases of uncomplicated gastric and duodenal ulcers, and 4 cases of perforated duodenal ulcer reported in GI reactions.During the first month of follow-up, the most common adverse reaction was dyspepsia with a frequency of 28.3 per 1000 patients per month (the frequency decreased during the 2-6 month of observation), while the frequency of bleeding from the upper alimentary canal and gastric ulcer and duodenum during follow-up was 0.4 and 0.3 per 1000 patients per month, respectively. These results confirm the data on the low incidence of gastrointestinal diseases obtained in clinical studies.However, in patients with a history of alimentary canal diseases and in those who were prescribed concomitant intake of gastroprotective drugs, the incidence of dyspepsia, stomach pain and peptic ulcers increased from 2 to 4 times. Therefore, researchers were cautious when prescribing meloxicam in patients who had such risk factors from the gastrointestinal tract [56].
A meta-analysis of all randomized comparative studies of meloxicam and other nonselective NSAIDs, which evaluated the GI tolerability of treatment, published in the 1990-1998s, found that meloxicam showed a more preferable tolerance profile than other NSAIDs [57].In general, patients treated with meloxicam experienced fewer GI adverse reactions and a reduced risk of GI toxicity problems such as dyspepsia, perforation, ulceration, and bleeding. The relative risk of developing GI adverse reactions was 0.64 (95% CI 0.59–0.69) in patients treated with meloxicam compared with those taking other non-selective NSAIDs. As a result of recent meta-analyzes, more accurate estimates of the GI tolerance of meloxicam have been obtained compared to other NSAIDs by involving a very large number of patients in the study [58, 59].Singh and Triadafilopoulos evaluated the incidence of serious gastrointestinal complications (perforations, ulcers, and extensive gastrointestinal bleeding) in patients who participated in clinical trials. We identified 35 studies involving 27,309 patients who received placebo, meloxicam and other non-selective NSAIDs (Table 2) [58]. The results of this meta-analysis confirmed the findings on the favorable tolerability profile of meloxicam. Similar conclusions were obtained by Degner et al, who assessed the relative risk of adverse reactions associated with meloxicam versus the risk of developing them with diclofenac or piroxicam, based on the processing of pooled data from 117-755 patients with rheumatic diseases who took part in 48 clinical trials [59].

It should be noted that although when replacing other non-selective NSAIDs with meloxicam, a relative decrease in the number of GI side reactions is observed, these side effects are not completely excluded, and for a significant part of patients there is a threat of GI toxicity problems if meloxicam is prescribed. Moreover, most of the data regarding the GI tolerability of meloxicam have come from short-term studies. More research is needed to clarify whether and to what extent the GI profile of meloxicam is better than other NSAIDs when used over an extended period. Hepatotoxicity . When prescribing NSAIDs, it is necessary to take into account the possibility of hepatotoxic reactions, which are not as common as GI problems. In general, the number of cases of liver damage associated with taking NSAIDs is 5 per 100–000 people per year, their clinical manifestation depends on the specific drug, the greatest risk is associated with the use of sulindac [60]. Selective COX-2 inhibitors have a low potential for liver disease, possibly even less than conventional NSAIDs [60, 61].According to our data, meloxicam was associated with only one case of liver toxicity (acute hepatitis) [62].
Renal adverse reactions . With the appointment of NSAIDs, renal adverse reactions may occur, such as fluid and electrolyte disturbances, tubulointerstitial nephritis, papillary necrosis, and acute renal failure [63]. Renal adverse reactions due to NSAID treatment can occur in approximately 5% of cases [64]. As a rule, these complications develop due to the decrease in prostaglandin synthesis caused by NSAIDs [65].It is known that in cases of such pathologies as congestive heart failure, liver cirrhosis, hypovolemia, nephrosis or chronic renal failure, the provision of renal blood flow and glomerular filtration depends on the compensatory activity of local COX-associated prostaglandins. Inhibition of COX caused by NSAIDs may influence this compensatory mechanism and contribute to the onset of acute renal failure [65]. Animal model studies and clinical studies have shown that COX-1 and COX-2 are constitutively expressed in the kidney, and both isoforms are involved in the regulation of renal function [66].However, the role of selective inhibition of COX-2 in the onset of renal impairment has not yet been determined. Based on a recent analysis of data from FDA adverse event reports and published clinical data of 122 and 142 cases of renal complications in the United States associated with celecoxib and rofecoxib, respectively, it was concluded that selective COX inhibitors have the same potential for renal toxicity as non-selective NSAIDs [67].According to data obtained in more distant periods, the risk of renal adverse reactions associated with taking meloxicam is not higher than with other NSAIDs, which is confirmed by the results of a meta-analysis conducted by Degner et al., In which it was found that the relative risk of developing renal complications during treatment with meloxicam at doses of 7.5 or 15 mg per day was estimated as 0.87 (95% CI 0.66–1.14) and 1.12 (95% CI 0.61–2.04), respectively – in comparison with the use of diclofenac at a dose of 100 mg per day, as well as 0.68 (95% CI 0.45-1.02) and 0.95 (95% CI 0.56-1.62), respectively – in comparison with the use of piroxicam at a dose of 20 mg per day [59].Since renal complications associated with the use of NSAIDs tend to be most often manifested in the risk group, Bevis and co-authors assessed the tolerance profile of treatment with meloxicam at a dose of 15 mg per day for 4 weeks in 25 patients with rheumatism, in whom renal forms of mild pathology were observed [ 68]. There were no cases of deterioration of renal function after treatment with the drug, which is confirmed by the absence of significant changes in creatinine clearance compared to its initial level.Therefore, it was suggested that meloxicam does not significantly affect the compensatory mechanism caused by the activity of prostaglandins. Researchers have suggested that the pharmacokinetic properties of meloxicam, especially the absence of cumulation, are the reason for its low potential for nephrotoxicity, even in patients with mild renal diseases. During the dispensing phase, the restriction fraction of the protein exceeds 99%. Also, the substance undergoes extensive biotransformation in the liver into inactive metabolites, which are excreted through the biliary and urinary tract [22]. Effect on platelet function and cardiovascular tolerance . Inhibition of platelet aggregation with the use of conventional NSAIDs is one of the factors in the deterioration of the clinical course of GI lesions, which, in turn, increase the susceptibility to hemorrhagic complications. This inhibition is caused by the ability of NSAIDs to block the activity of platelet COX-1, which is responsible for the formation of thromboxane A2 [69]. Since COX-2 is not expressed in platelets, selective inhibitors of COX-2 do not affect platelet aggregation and thus cause fewer hemorrhagic complications, especially in the alimentary canal [17].Some studies have found that meloxicam only partially affects COX-1-dependent platelet function at concentrations that clearly inhibit COX-2 [70-72]. De Meijer et al investigated platelet function parameters in healthy volunteers who took sequentially meloxicam 15 mg per day for 7 days, followed by indomethacin 75 mg per day for the next 7 days. Although serum thromboxane B2 levels were significantly less than baseline after meloxicam treatment (535 ± 233 to 183 ± 62 nmol / L), significant changes in collagen or arachidonic acid-induced platelet aggregation (18.7 ± 1.6 to 19 ± 2.5 Ohm and from 12.2 ± 2 to 11 ± 2.4 Ohm, respectively) were not observed, while treatment with indomethacin decreased the amount of thromboxane B2 and significantly inhibited platelet aggregation.Since inhibition of thromboxane B2 does not correlate with the ability of NSAIDs to affect platelet function, recent studies have examined the direct effect of meloxicam on platelet aggregation and bleeding time in both volunteers and patients with OA [73, 74]. The results of a cross-sectional study conducted by Knijff-Durtmer and co-authors with the participation of patients with RA showed that the administration of meloxicam at a dose of 15 mg per day for 14 days did not have a significant effect on platelet aggregation and bleeding time, whereas with such treatment, naproxen in a dose of 1000 mg per day caused a significant inhibition of platelet aggregation and, as a result, a concomitant significant increase in the bleeding period [73].In a study by Rinder et al., Volunteers were randomized to receive 7.5 doses of meloxicam; 15 or 30 mg per day, indomethacin at a dose of 75 mg per day or placebo for 8 days. No dosage of meloxicam significantly altered platelet aggregation and bleeding time compared with placebo, while significant changes in both parameters were observed after treatment with indomethacin (Table 3) [74].

In the cardiovascular system, thromboxane biosynthesis mainly depends on the activity of platelet COX-1; COX-2 participates in the formation of endothelial prostacyclin.Thus, selective inhibition of COX-2 can inhibit the biosynthesis of prostacyclin by the vascular endothelium without affecting the formation of platelet thromboxane [14]. It has been hypothesized that in patients with a high risk of thrombus formation, selective COX-2 inhibitors may affect the antiplatelet activity of endothelial prostacyclin, thus increasing the risk of thrombotic complications [69]. Taking into account the wide spectrum of biological activity of COX inhibitors, Mukherjee et al., Having placed on one side of this range the best GI tolerance at prothrombotic potential (represented by selective COX-2 inhibitors) and an increased risk of GI complications with cardioprotective effects – on the other (aspirin and naproxen) , made the assumption that, ideally, when choosing a therapy, the position of each NSAID in this row should be determined [75].The effect of NSAIDs on the parameters of the cardiovascular system has a rather complex mechanism, which is beyond the modulation of platelet function. NSAIDs can affect blood pressure in a variety of ways (by affecting the renin-angiotensin system, renal sodium metabolism, and vasodilator / vasoconstrictor factors). According to two meta-analyzes, NSAID intake correlates with a low rise in systolic blood pressure (-5 mm Hg) and a low incidence of hypertension and peripheral edema (1–9%).The incidence of arterial hypertension associated with COX-2 inhibitors was within this range [76]. Other authors found significant differences between celecoxib and rofecoxib in terms of edema (9.5% for rofecoxib versus 4.9% for celecoxib; p = 0.014) or increased systolic blood pressure (17% and 11%, respectively; p = 0.032) in elderly patients with arterial hypertension [77]. The use of NSAIDs has also been associated with a doubling of the risk of hospitalization for congestive heart failure [78].Although meloxicam demonstrates excellent GI tolerance, special studies on its cardiovascular tolerance currently provide too little data to accurately determine the place of the drug in the spectrum of biological activity. A meta-analysis of data obtained from 27–000 patients showed that the incidence of cardiovascular complications with the use of meloxicam is approximately at the same level with the frequency with the use of non-selective NSAIDs [79].As already mentioned, in a pilot study, meloxicam has shown beneficial effects in acute coronary syndrome [50].
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A complete list of references, including 82 items, is under revision.
The article is abbreviated.
Translated by D. Kvitchasty.

The use of four imported drugs has been suspended in Russia, including Tramadol

The Ministry of Health of the Russian Federation has suspended the use of four drugs: Tramadol is an opioid narcotic analgesic, Melbek® is a non-steroidal anti-inflammatory drug, Axosef® is an antibiotic, and Terbinafin-Akrikhin is an antifungal drug.Tramadol is manufactured in India, the rest of the drugs are manufactured in Turkey. The relevant documents are published on the website of the State Register of Medicines grls.rosminzdrav.ru on April 21, 2020.

According to the published information, the Ministry of Health of Russia made a decision to suspend the use of drugs on the basis of letters from the Ministry of Industry and Trade of the Russian Federation, which provided information on the need to suspend the use of drugs.The use of the following medicines will be resumed only after Roszdravnadzor submits the relevant information.

• Tramadol (tramadol) – injection, 50 mg / ml; the holder of the registration certificate LP-003733 dated July 14, 2016 is Rusurofarm LLC (Russia), and the drug is produced at the Indian enterprise Karnataka Antibiotics & Pharmaceuticals Limited.

The use of Tramadol has been suspended since April 17, 2020.Note that on the territory of the Russian Federation there are registered 32 trade names of the drug, which contain tramadol. At the same time, various dosage forms are presented, including tablets, capsules, rectal suppositories and solutions for injection.

• Melbek® (meloxicam) – solution for intramuscular administration, 15 mg / 1.5 ml; the holder of the registration certificate LP-000963 dated October 18, 2011 the company “Nobel Ilach Sanayi ve Ticaret A.NS.” (Turkey), the drug is produced at two sites: in Turkey at the plant “Idol Ilach Dolum Sanayi Ve Ticaret A.Sh.” and in Kazakhstan at the site of JSC Nobel Almaty Pharmaceutical Factory.

According to the information from the state register, there are 56 trade names registered in Russia for meloxicam preparations, of various manufacturers, both Russian and foreign. The use of “Melbek” has also been suspended since April 17.

• Axosef® (cefuroxime) – powder for preparation of a solution for intravenous and intramuscular administration, 250 mg, 750 mg; the drug is produced in Turkey and Kazakhstan (three production sites are indicated), and the holder of the registration certificate LP-001214 dated November 15, 2011is, again, the Turkish company “Nobel Ilach Sanayi ve Ticaret A.Sh.”

Preparations containing cefuroxime as an active ingredient are registered in the Russian Federation 23 trade names. The use of the drug has been suspended since April 17.

• Terbinafine-Akrikhin (terbinafine) – tablets, 250 mg; the drug is produced by the Turkish enterprise Sanovel Pharmaco-Industrial Trading Company, and the holder of the registration certificate LP-000205 dated February 11, 2011is the Russian company AKRIKHIN JSC.

It should be noted that the use of this drug has been suspended since April 16, and there are a very large number of medicines with terbinafine registered in Russia – 59 trade names of various manufacturers, while both imported and Russian pharmaceutical substances are used for their production.

instructions for use (dosage, indications, composition, side effects from the drug)

Special instructions

Patients with gastrointestinal diseases should be monitored regularly.If ulcerative lesions of the gastrointestinal tract or gastrointestinal bleeding occur, Movalis ^® must be canceled.

Gastrointestinal bleeding, ulcers and perforations can occur during the use of NSAIDs at any time, both in the presence of alarming symptoms or a history of serious gastrointestinal complications, or in the absence of these signs. The consequences of these complications are generally more serious in the elderly.

To reduce the risk of developing adverse events from the gastrointestinal tract, the minimum effective dose should be used in the shortest possible short course.

When using the drug Movalis ^® , serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis can develop. Therefore, special attention should be paid to patients reporting the development of adverse events from the skin and mucous membranes, as well as hypersensitivity reactions to the drug, especially if such reactions were observed during previous courses of treatment. The development of such reactions is observed, as a rule, during the first month of treatment.If the first signs of a skin rash, changes in mucous membranes or other signs of hypersensitivity appear, the question of discontinuing the use of Movalis ^® should be considered.

Cases of increased risk of developing serious cardiovascular thrombosis, myocardial infarction, angina attack, possibly fatal, when taking NSAIDs have been described. This risk increases with prolonged use of the drug, as well as in patients with a history of the above diseases and those predisposed to such diseases.

NSAIDs inhibit the synthesis of prostaglandins in the kidneys, which are involved in maintaining renal perfusion. The use of NSAIDs in patients with reduced renal blood flow or reduced BCC can lead to decompensation of latent renal failure. After the withdrawal of NSAIDs, renal function is usually restored to its original level. The most at risk of developing this reaction are elderly patients, patients with dehydration, congestive heart failure, cirrhosis of the liver, nephrotic syndrome or acute renal dysfunction, patients taking diuretics, ACE inhibitors, angiotensin II receptor antagonists, and also patients who have undergone major surgical interventions that lead to hypovolemia.In such patients, diuresis and renal function should be carefully monitored at the beginning of therapy.

The use of NSAIDs in conjunction with diuretics can lead to sodium, potassium and water retention, as well as to a decrease in the natriuretic effect of diuretics. As a result, predisposed patients may experience increased signs of heart failure or arterial hypertension. Therefore, careful monitoring of the condition of such patients is necessary, as well as the maintenance of adequate hydration.Before starting treatment, a study of renal function is necessary.

In the case of combination therapy, renal function should also be monitored.

When using the drug Movalis ^® (as well as most other NSAIDs), an episodic increase in the activity of transaminases or other indicators of liver function in the blood serum was reported. In most cases, this increase was small and transient. If the identified changes are significant or do not decrease over time, Movalis ^® should be canceled and the identified laboratory changes should be monitored.

Weak or malnourished patients may be less likely to tolerate adverse events, therefore, such patients require careful monitoring.

Like other NSAIDs, Movalis ^® can mask the symptoms of an infectious disease.

As a drug that inhibits the synthesis of COX / prostaglandin, Movalis ^® can affect fertility and is therefore not recommended for women with difficulties in conception. In women undergoing examination for this reason, it is recommended to cancel the use of the drug Movalis ^® .

The maximum recommended daily dose of the drug contains 2.45 g of sorbitol. The use of the drug is not recommended for patients with hereditary fructose intolerance.

With the simultaneous use of indirect anticoagulants, ticlopidine, heparin for systemic use, thrombolytic agents, careful monitoring of the effect of anticoagulants is necessary.

It is recommended to control the concentration of lithium during the period of administration of the drug Movalis ^® , when changing the dose of lithium preparations and their cancellation.