Treatment of rheumatoid arthritis: a review including newer and experimental anti-inflammatory agents.

Treatment of rheumatoid arthritis is often frustrating for patient and physician alike because of its chronic nature and our lack of knowledge about precise cause. It can be confused by the vast array of anti-inflammatory drugs now available, with new agents being added all the time. We present here an outline for a systematic treatment program that must be tailored to each patient's needs. It emphasizes a broad approach on the part of the physician and indicates that drugs comprise only one part of treatment. We review the drugs currently used in the treatment of rheumatoid arthritis and include discussion of those newer antiinflammatory agents that should be available shortly. A rational scheme for the use of these drugs is proposed.

Anti-inflammatory drugs in experimental atherosclerosis. Part 6. Combination therapy with steroid and non-steroid agents.

The pathological changes which accompany enhanced cholesterol deposition in atherosclerosis include inflammatory responses mediated by the prostaglandin cyclooxygenase and lipoxygenase-leukotriene metabolite of the arachidonic acid cascade. Cortisone suppresses arachidonic acid release, whereas non-steroid anti-inflammatory drugs inhibit principally the cyclooxygenase enzyme. Groups of New Zealand white rabbits were fed a 1% cholesterol diet for 12 weeks. Diets of selected groups were further supplemented daily with the non-steroid anti-inflammatory drugs phenylbutazone (100 mg), oxyphenylbutazone (240 mg), flufenamic acid (100 mg), either singly or in combination with cortisone acetate (10 mg or 5 mg), or 9-alpha-fluorohydrocortisone (30 micrograms or 200 micrograms). Serum lipid levels were measured at 0, 4, 8 and 12 weeks, and atherosclerotic plaque intensity in thoracic aorta was measured at 12 weeks using a planimetric technique: serum cholesterol levels in control groups increased from 38 +/- 5 to 1190 +/- 139 mg/100 ml. Neither the rate of increase nor the final lipid values attained were significantly changed by the non-steroid drugs. The non-steroid drugs reduced plaque coverage by about one third (phenylbutazone 34 +/- 10%, flufenamic acid 36 +/- 11%) compared to controls. In combination therapy, addition of cortisone acetate resulted in further plaque suppression. Cortisone 10 mg + phenylbutazone gave 100% suppression; cortisone 5 mg + phenylbutazone gave 82 +/- 18%, and cortisone 5 mg + flufenamic acid gave 84 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxyphenbutazone--an adjuvant to be used in prevention of adhesions in operations for fertility.

A laparotomy was performed in 40 rats and the cecum was subjected to a standardized trauma. Half the rats were treated with oxyphenbutazone in a dose of 40 mg/kg body weight daily for 14 days. The remaining 20 rats served as controls. All of the rats were killed 2 weeks after the laparotomy, and the number of intraperitoneal adhesions was recorded. There were significantly (P less than 0.001) fewer rats with adhesions in the group treated with oxyphenbutazone than in the control group.

The use of diflunisal in post-operative pain: a report of double-blind comparative trials in patients after meniscectomy.

A series of double-blind randomized trials was carried out in patients suffering from moderate to severe pain after meniscectomy to assess the analgesic effectiveness of diflunisal. In a single-dose study, 150 patients received either diflunisal (125 mg, 250 mg or 500 mg), aspirin (600 mg), or placebo, and hourly assessments were made of pain severity over an 8-hour period. The results showed that 500 mg diflunisal produced comparable relief to aspirin within 3 to 4 hours, but the analgesic effect continued for longer and was still very marked after 8 hours. A multi-dose study in 120 patients receiving doses of diflunisal (375 mg or 500 mg) or placebo confirmed the overall effectiveness of twice daily treatment with diflunisal. In a comparative study against oxyphenbutazone (200 mg t.i.d.), hourly pain scores made on the first post-operative day showed that a single dose of 500 mg diflunisal produced comparable relief over a 12-hour period to that with 2 doses of 200 mg oxyphenbutazone. Overall response to multiple doses was assessed as excellent or good by all the patients receiving diflunisal. Preliminary results are reported on the use of diflunisal in other painful conditions.

A compliance study in general practice of patients switched from phenylbutazone and oxyphenbutazone to naproxen and other non-steroidal anti-inflammatory drugs.

Fifty-nine patients on long-term treatment with phenylbutazone or oxyphenbutazone for chronic rheumatic conditions were switched to treatment with naproxen and followed-up for 6 months in a compliance study. All patients were started on 500 mg naproxen twice daily but adjustment of the dosage was permitted. During the 6 months of the study only 3 patients returned to treatment with phenylbutazone. Of the remaining 56 patients, 45 were still taking naproxen after 6 months, 9 were changed to other non-steroidal, anti-inflammatory drugs and 2 were lost to follow-up. The study demonstrates that in routine general practice, phenylbutazone and oxyphenbutazone can be successfully replaced by less toxic drugs.

Diflunisal in the management of sprains.

A double-blind randomized trial was carried out in 31 patients suffering from acute, minor ligamentous injuries to compare the efficacy of diflunisal in the relief of pain with that of oxyphenbutazone. Patients received either 500 mg diflunisal twice daily or 200 mg oxyphenbutazone 3-times daily for 3 days. The results of subjective assessments showed tha by Day 3 spontaneous pain had either completely resolved or markedly improved in all patients, and that diflunisal was significantly better than oxyphenbutazone on Days 1 and 3 in relieving pain on movement of the joint.

Clinical experiences in the treatment of pain in rheumatology.

Meclofenamic acid is an analgesic endowed with anti-inflammatory properties. Its main activity is the combined inhibition of leukotrienes and prostaglandins synthesis, yet it is also able to antagonize the peripheral effects of prostaglandins. This particular feature explains why the effect of this drug is so fast, especially when administered orally. The pharmacological properties and good tolerability of meclofenamic acid propose the use of this drug for the treatment of various types of pain, particularly at osteoarticular localization. Recent comparative studies with meclofenamic sodium versus placebo, indomethacin, oxyphenbutazone, and diclofenac confirmed that meclofenamate sodium is very effective, significantly reducing pain as well as the subjective and objective symptoms accompanying it. The findings of these studies have also highlighted a particularly favorable safety profile. Our study primarily focused on assessing the effectiveness and tolerability of this drug in 82 patients affected with extraarticular rheumatism localized in various sites. Meclofenamic acid (as a sodium salt) was orally administered in doses of 100 mg twice daily for 2 weeks. The assessment of the drug's clinical effectiveness took into account the various aspects of pain (spontaneous, on motion, due to active contrasted movements) and quantified it using a 5-point rating scale (0 = absence of pain; 5 = very intense pain). At the end of the 2-week observation period, both the investigator and the patient gave their opinion as to the effectiveness and tolerability of the drug. The treatment was found to be highly effective in reducing pain in 59.7% of the patients, regardless of the nature and location of the rheumatic process. Tolerability was rated good-to-excellent in 72% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonsteroid anti-inflammatory drugs in the treatment of immunologic iridocyclitis in the rabbit.

Effectiveness of selected nonsteroid anti-inflammatory drugs was studied on an immunologic model of uveitis. Intensity of inflammatory reactions was assessed on the basis of biochemical parameters (Levels of protein, seromucoid, sialic acid and hydrolytic activity of the aqueous humor) and morphologic criteria pertaining to the anterior eye chamber. All drugs studied diminished intensity of inflammation as judged by biochemical tests, as well as morphologic changes observed with the biomicroscope. Closest correlation was found between hyperemia of the iris, numbers of cells and fibrin in the anterior eye chamber on the one hand, and values of protein and sialic acid in the aqueous humor. Levels of seromucoid and hydrolytic activity were less clearly related to the changes observed with the biomicroscope. Sodium salicylate showed the weakest action, and ibuprofen and oxyphenbutazone were somewhat more effective. However, indometacin showed strongest anti-inflammatory activity.

Nimesulide in the short-term treatment of inflammatory process of dental tissues: a double-blind controlled trial against oxyphenbutazone.

One hundred out-patients with inflammatory process of dental tissues due to tooth extraction, root abscess alveolitis and periodontitis, were randomly assigned, according to a double-blind design, to one of two treatment groups with nimesulide (200 mg/day) or oxyphenbutazone (400 mg/day). By means of a self-rating record, each patient rated his pain, difficulty of chewing, redness and swelling before starting, during and at the end of treatment. Nimesulide and oxyphenbutazone were both well tolerated and effective, but the improvements during the first and the second day of treatment were of greater magnitude in the nimesulide-treated patients. Nimesulide, being well tolerated, rapid acting and effective, could be considered as a drug of choice for the treatment of inflammatory process of dental tissues.

Tanderil/chloramphenicol eye ointment in the treatment of the "Red Eye" seen in general practice.

An open study is reported in which 35 general practitioners treated 128 patients suffering from 'Red Eye' with a new eye ointment containing 10% Tanderil(oxyphenbutazone) and 1% chloramphenicol. One hundred and seventeen patients completed the seven day treatment period, in which time 99 had completed resolution of the symptoms and were discharged, the remaining 18 patients needed a longer period of treatment. Eleven patients failed to complete the study period, of whom 5 patients were subsequently referred to a specialist and 6 had their treatment changed by the general practitioner. Six patients showed signs of allergy to the ointment, all of whom were being treated for allergic conjunctivitis. Seventeen per cent of patients had some difficulty in applying the eye ointment or complained of subsequent blurring of vision.

Drug and non-drug factors influencing adverse reaction to pyrazoles.

Some of the factors influencing the likelihood of the appearance of adverse drug reactions in patients are identified and discussed. Ways of quantifying some of the risks of adverse reactions in different patients are demonstrated. It is pointed out that adverse reaction data can give valuable guidance for both day-to-day patient management and for the initiation or guidance of research projects. In this latter connection, this study highlights the difference in time of onset between aplastic anaemia and agranulocytosis, suggesting different mechanisms of reaction. The majority of adverse reactions occur during the first three weeks of treatment and it is during this time that patients must be most carefully supervised. The old patients should be watched with particular care. It is concluded that age, sex, disease being treated, length of treatment and even the geographical location where the patient lives, can affect the time, type, frequency and outcome of an adverse drug reaction.

[Pyrasanone in the treatment of rheumatism]. / Il pyrasanone nella terapia antireumatica

The results of a set of experiments conducted on a new non-steroid antirheumatic preparation--pyrasanone (Carudol)--are presented and its indications in the general management of the disease are noted. The pharmacokinetics and therapeutic efficacy of the new drug are described. Statistical analysis showed it to be more effective than hexahydropyrazine, diphenylbutazone, indomethacin and oxyphenbutazone. A basic therapeutic approach is suggested in accordance with the pharmacodynamic aspects of the drug and the results observed in a clinical trial on 719 subjects. Pyrasanone has low toxicity and is well tolerated. Due caution in the administration of antirheumatic drugs should nevertheless be maintained during its use.

Cold injuries in Kashmir, December 1971.

A total of 847 cases of cold injury occurred within the short space of 2 weeks during the Indo-Pakistan conflict in Kashmir in December 1971. The management of these cases and their end results are described. A combination of drugs consisting of low-molecular-weight dextran, an anti-inflammatory agent, and a vasodilator was tried with encouraging results. A conservative attitude towards ablation of necrosed tissues paid good dividends.

[Sulindac: Clinical test of a new antiinflammatory agent in rheumatoid arthritis (author's transl)]. / Sulindac: Klinische Prüfung eines neuen Antiphlogisticums bei der chronischen Polyarthritis

Sulindac, a new non steroidal antiinflammatory agent has been compared with acetylsalicylic-acid in a six week controlled double blind study in 28 patients with rheumatoid arthritis. In continuation of this study all patients have been treated with Sulindac up to 18 months. Sulindac has proved to be statistically significant superior to acetylsalicylic-acid as regarding the achieve of pain during the day, of morning stiffness, of gripping of the right hand and evaluation of patients response to the drug. Moreover markedly fewer adverse reactions especially of the gastrointestinal tract were seen. During the following long term study, when 19 patients were treated with Sulindac, a further statistically significant improvement of all controlled parameters up to the complete relief of complaints was observed. A reduction of the daily dose could be established. Laboratory evaluations as well as controlls of EKG and blood pressure showed no evidence of any organ toxicity of this drug.

Mondor's disease. A forgotten cause of anterior chest pain.

A 50-year-old woman sought a rheumatological consultation for anterior chest pain of three weeks duration. The diagnosis of superficial phlebitis of the anterior chest wall (Mondor's disease) was made. This was confirmed thereafter by the pathological report. She was treated with a non-steroidal anti-inflammatory drug Oxyphenylbutazone (Tanderil) and made a prompt recovery.

Systemic treatment of sarcoidosis.

PURPOSE: To compare the evidence base and systemic treatment strategies for sarcoidosis. METHODS: Medline and EMBASE literature search on "sarcoidosis AND treatment", "sarcoidosis AND uveitis AND treatment", and "sarcoidosis AND eye AND treatment". The search was limited to randomized controlled trials (RCTs) and meta-analyses. RESULTS: A total of 19 RCTs for the systemic treatment of extraocular sarcoidosis were identified. The majority were on corticosteroid-oral and inhaled. There were two meta-analyses on corticosteroid, including a Cochrane review. Only two RCTs were indentified for the treatment of intraocular sarcoidosis, one on etanercept, and the other from 1967 on prednisolone or oxyphenbutazone vs. placebo. There were no meta-analyses. Due to the paucity of RCTs other treatment studies were included but these were limited to only a few immunosuppressive agents and on small numbers of patients. CONCLUSION: Limited high-quality evidence exists for the systemic treatment of sarcoidosis, in particular intraocular disease.