The article was published on p. 8-11 (Ukr.)
Non-steroidal anti-inflammatory drugs (NSAIDs), due to their anti-inflammatory, analgesic and antipyretic activity, are today widely used in the treatment of various pathologies, including rheumatic diseases, fevers of various origins, chronic bursitis and tendovaginitis, injuries of the musculoskeletal system, orthopedic manipulations, periodontitis and etc.
More than 30 million people worldwide take NSAIDs daily, and 40% of these patients are over the age of 60 years [1, 2]. NSAIDs are prescribed to approximately 20% of inpatients suffering from diseases of the internal organs [3], and 97% of doctors consider NSAIDs to be important or very important drugs for the treatment of patients with diseases of the joints and spine (Lain L., 2001).
Compound
One ml of Denebol solution contains 25 mg of rofecoxib, tocopherol acetate, centubucridine hydrochloride, methyl carbonate, saline. One Denebol tablet contains 25 or 50 mg of rofecoxib, as well as microcrystalline cellulose, corn starch, betacyclodexphrine, povidone, magnesium stearate, purified talc, sodium propylparaben, sodium methylparaben, colloidal silicon dioxide, brilliant blue, colored tartrazine, dry starch, sodium starch glycolate. One hundred mg of Denebol gel contains 1 g of rofecoxib, 10 g of methyl salicylate, 3 g of linseed oil, 5 g of menthol, 1 g of phenoxyethanol, propylene glycol, butylated hydroxytoluene, polyethylene glycol, carbomer 934, triethanolamine, disodium edetate, isopropyl alcohol, polyoxyl, hydrogenated castor oil, purified water. One Denebola rectal suppository contains 25 mg of rofecoxib and solid fat.
Pharmacological properties
The drug Denebol is an anti-inflammatory drug. Denebol is used to treat diseases of the musculoskeletal system, dentistry, gynecology, and ENT diseases. Cyclooxygenase II, along with cyclooxygenase I, is involved in the formation of mediators of the inflammatory reaction: prostaglandins, prostacyclins and thromboxane, but COX-II is an inducible enzyme and is included in the reaction only in certain situations, most often during inflammation. Denebol blocks cyclooxygenase II, providing anti-inflammatory, analgesic, anti-edematous and antipyretic effects. At the same time, the drug has virtually no effect on the enzyme cyclooxygenase I, which works continuously in the body and performs many physiologically necessary functions. For example, such as regulation of metabolic processes in the tissues of the gastric and intestinal walls, platelets, bronchopulmonary system and others. When taken orally, Denebol is quickly absorbed from the digestive tract, and the bioavailability of the drug is over 90%. The maximum concentration in the blood plasma of Denebol's active ingredient, rofecoxib, is reached two hours after administration and is about 0.300 mcg/ml. Over 80% of rofecoxib in the body forms weak bonds with plasma proteins. It is biotransformed mainly in the liver with the formation of 6 inactive metabolites, which are excreted by the kidneys in the urine (70%). In unchanged form, rofecoxib is excreted from the body through the intestines in the feces. The pharmacokinetics of Denebol in young and elderly patients are no different.
Evolution of NSAIDs:
from non-selective to specific COX-2 inhibitors
The discovery of two isoforms of COX became the promise for the development of new forms of drugs from the class of NSAIDs that have the ability to predominantly suppress the activity of COX-2, selective COX-2 inhibitors: meloxicam, nimesulide, nabumetone, and subsequently - specific COX-2 inhibitors - coxibs. The different activities of modern NSAIDs against COX isoenzymes have made it possible to construct a classification based on the selectivity of the drugs' effects on COX-1 and COX-2. The following groups of drugs were identified [5]: - non-selective COX inhibitors (classical NSAIDs); - selective COX-2 inhibitors (meloxicam, nimesulide, nabumetone); - specific COX-2 inhibitors (coxibs: celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib); - selective COX-1 inhibitors (low doses of acetylsalicylic acid).
Subsequently, another isoenzyme was identified - COX-3, localized in the cells of the cerebral cortex, the influence of which is associated with the analgesic activity of the simple analgesic - paracetamol.
In 1999, the first representative of coxibs appeared on the pharmacological market - celecoxib, released as a specific COX-2 inhibitor; a little later, another representative of coxibs appeared - rofecoxib; in the future - valdecoxib, etoricoxib, lumiracoxib. The mechanism of action of coxibs, in contrast to traditional NSAIDs, is based on selective inhibition of PGs, which, along with the pronounced anti-inflammatory activity of coxibs, ensures a low degree of development of gastrointestinal complications with their long-term use [6].
Indications
Denebol is prescribed for diseases of the musculoskeletal system: acute and chronic periarthritis, rheumatoid arthritis, osteoarthritis, tendonitis, bursitis, as well as injuries to tendons, ligaments and muscles. The drug is effective for thrombophlebitis, pain of various origins (neuralgia, neuritis, osteochondrosis, lumbago, radicular syndrome, myalgia, toothache with pulpitis, migraine, algodismenorrhea), inflammatory processes in the ENT organs (sinusitis, otitis media, laryngitis) and dental practice (gingivitis , stomatitis, pulpitis). It can be used as symptomatic therapy for infectious and inflammatory diseases of the pharynx, trachea and bronchi, urinary system (urethritis, cystitis, cystopyelitis), in ophthalmology and gynecology.
Rofecoxib has the following properties:
- reduces the intensity of pain in osteoarthritis and diseases of the musculoskeletal system; - reduces swelling of joints; - has a chondroneutral effect; - has a high safety profile from the gastrointestinal tract; — possibility of safe use for 6–12 months; manifestation of NSAID gastropathy as a result of taking rofecoxib for 6 months. was 0.01% per 100 patients per year (comparable to that in persons not taking NSAIDs); — possibility of safe use on the part of the cardiovascular system for 6–12 months. at a dose of 25 mg; — does not change platelet function; — prolonged action — taken 1 time/day [8].
This data allows us to recommend Denebol (rofecoxib) for use in the practice of therapists, traumatologists, rheumatologists, gynecologists, dentists and other specialists for the purpose of anti-inflammatory and analgesic therapy for osteoarthritis, rheumatoid arthritis, acute pain syndrome of various origins, algodismenorrhea, toothache, and also in the postoperative period after surgical interventions.
Contraindications
Denebol is contraindicated in cases of development of allergic reactions to salicylates (aspirin) or other non-steroidal anti-inflammatory drugs in the anamnesis, with bronchial asthma, cancer and children under the age of 12 years. The solution for intramuscular injection should not be used in patients with myocardial infarction, stroke, progressive form of atherosclerosis, or malignant arterial hypertension. The drug is not recommended for use by persons with hypersensitivity to rofecoxib or auxiliary components in Denebol.
Special instructions for the use of Rofecoxib
Use with caution in the 1st and 2nd trimester of pregnancy, breastfeeding, with renal failure, asthma, or a history of the “aspirin triad”. In patients at increased risk of impaired renal perfusion, the use of rofecoxib may result in decreased renal blood flow and deterioration of renal function. The highest likelihood of such an effect is observed in patients with a history of severe renal dysfunction, decompensated heart failure, or cirrhosis of the liver. In this category of patients, careful monitoring of renal function is necessary during treatment. In patients with significant dehydration, rehydration is recommended before starting therapy. The risk of developing perforations, ulcers, or bleeding in the upper gastrointestinal tract increases in patients over 65 years of age. During the treatment period, it is necessary to monitor the prothrombin time (especially with combination therapy with anticoagulants).
Directions for use and dosage
Denebol in the form of an injection solution is administered deeply intramuscularly (into the buttock) once a day with an interval of 24 hours.
Intravenous administration of the drug is strictly prohibited! Rofecoxib is recommended for use in an initial dosage of 50 mg per day, which can be reduced to 25 mg depending on the intensity of the inflammatory process and the severity of pain. For osteoarthritis, the effective daily dosage is 12.5 mg. If necessary, it is increased to 25 mg. Intramuscular injections are often used as a short symptomatic introductory course, and after a week the patient is transferred to the tablet form of Denebol and gel. When using several forms of the drug simultaneously, the total daily dosage of rofecoxib should not exceed 50 mg. Denebol courses lasting 4-6 weeks at a dosage not exceeding 25 mg are considered safe. The decision to increase the dose in each case is made purely individually, depending on the severity of the patient’s condition. Denebol in tablet form is used for the treatment of primary dysmenorrhea and pain syndrome in a daily dose of 25 mg. Subsequent doses are taken after 24 hours and may be 12.5 or 25 mg depending on symptoms, but the maximum daily dose should not exceed 25 mg. The medication is taken until the condition is completely relieved, but the course should not exceed three days. Take Denebola tablets regardless of meals and wash them down with a small amount of water. For osteoarthritis, it is recommended to start with 12.5 mg of rofecoxib per day, the course of treatment is from 4 to 6 weeks. Denebol in the form of a gel is applied with light massaging movements to the skin up to 4 times a day. In this case, they use a small volume of gel (1-2 g), comparable in size to a pea, and try to avoid contact of rofecoxib with mucous membranes, eyes and skin defects (wounds). The duration of treatment is determined by the effect achieved. Denebol in the form of suppositories is used rectally to relieve acute pain of inflammatory origin and treat primary dysmenorrhea, one suppository 2 times a day, that is, the maximum daily dose is 50 mg. The duration of treatment is no more than 1.5 months.
Rofecoxib in the family of non-steroidal anti-inflammatory drugs
Rofecoxib is a specific inhibitor of COX-2, has the highest selectivity coefficient (IC50COX-1/IC50COX-2 according to Warner et al.) - 0.004, which is explained by the peculiarities of the stereometric structure of its molecule: the presence of a rigid side chain capable of penetrating into the hydrophilic side cavity molecules of COX-2 and thereby non-competitively block the active center of this isoenzyme [7]. For celecoxib this figure is 0.1, for nimesulide - 0.15, ibuprofen - 10, indomethacin - 33, naproxen - 100. Another important aspect is the fact that the selectivity of rofecoxib is practically independent of the concentration of the drug, which distinguishes it favorably from classic NSAIDs.
Rofecoxib has a pronounced analgesic and anti-inflammatory effect that is superior to traditional NSAIDs. Thus, in a study by Jokhio et al. The analgesic efficacy of rofecoxib and ketoprofen was compared. 165 patients with damage to the ligamentous apparatus, dislocations of the joints of the upper and lower extremities were divided into two equal groups. Group 1 (82 patients) received rofecoxib 25 mg per day orally, group 2 (83 patients) took ketoprofen 200 mg per day. The duration of therapy was 7 days. The effectiveness was assessed taking into account the speed of onset of pain relief and the degree of its severity. The study found that in the group receiving rofecoxib therapy, an analgesic effect was achieved more quickly, which persisted for 24 hours and did not require additional analgesia, in contrast to the group taking ketoprofen, where additional analgesia was required in 7.8% of cases.
A similar study was conducted by M. Petri et al. It involved 306 patients with post-traumatic glenohumeral periarthritis and subacromial bursitis. All patients were divided into 3 groups (102 patients each). Group 1 received rofecoxib at a dose of 25 mg/day, group 2 received naproxen at a dose of 1000 mg/day, and group 3 received placebo. Treatment was carried out for 14 days. At the end of the observation period, only with the use of rofecoxib there was a significantly significant (compared to placebo) reduction in pain severity - on average by 35.0 mm according to VAS. However, the effectiveness of naproxen was not superior to placebo.
A prospective, randomized, double-blind study conducted by M. Broggini (2003) involving 30 patients compared the effectiveness of nimesulide (100 mg), celecoxib (200 mg) and rofecoxib (25 mg) in the symptomatic treatment of osteoarthritis of the knee joint for 7 days [10 ]. Its results demonstrated a faster onset of analgesic action with a pronounced and long-lasting effect in the group of patients taking rofecoxib.
K. Malmstrom et al. [11] conducted a large-scale RCT that examined the comparative effectiveness of a single dose of rofecoxib 50 mg, celecoxib 200 and 400 mg, ibuprofen 400 mg, or placebo in 482 patients who had undergone extraction of at least 2 teeth (3 molars). For the primary outcome measure of total pain relief (TOTPAR) at 8 and 12 hours, all three NSAIDs were superior to placebo, but the advantage in pain relief was in the rofecoxib group.
Thus, according to a number of studies, rofecoxib is superior in its analgesic and anti-inflammatory activity to both classical NSAIDs and coxibs. To date, there are no comparative studies of rofecoxib and etoricoxib, but the undoubted advantage of rofecoxib is the presence of several dosage forms: ampoules, tablets, gel, suppositories, which allows for stepwise therapy, and therefore better control of pain in patients.
Side effects
From the senses and central nervous system: hallucinations, confusion, decreased speed of thought processes, dizziness, drowsiness. From the heart and blood vessels: congestive heart failure, arterial hypertension, disorders of cerebral and coronary blood flow. From the digestive tract: nausea, heartburn, diarrhea, discomfort and pain in the upper third of the abdomen (epigastric region), dyspepsia, vomiting, the appearance of ulcers on the oral mucosa (aphthous stomatitis). From the urinary system: decreased renal function (usually reversible), renal failure. Allergic reactions: angioedema, urticaria, itching, rash. Other: increased levels of AlAt, AsAt, the occurrence of edema of the lower extremities.
Interaction with other drugs
When taking Denebol simultaneously with ACE inhibitors, the effectiveness of antihypertensive therapy is significantly reduced. Rofecoxib should not be used in combination with drugs or products containing caffeine (it increases blood pressure). The use of Denebol during anticoagulant therapy may increase prothrombin time. Rofecoxib increases plasma concentrations of methotrexate. Some antibiotics (rifampicin, rifamycin) can reduce the plasma concentration of rofecoxib by half. Denebol does not affect the pharmacokinetics of drugs such as prednisolone, digoxin, oral contraceptives (norethindrol, ethinyl estradiol), antacids, ketoconazole, cimetidine.
