[Use of topical non-steroidal anti-inflammatory drugs in aggravated and decompensated arthroses]. / Zur Anwendung von NSAR-Topika bei irritierten und dekompensierten Arthrosen.

Pain in osteoarthritis of the big weight bearing joints is either derived from periarticular ligaments, tendons, fascias, muscles, bursae--periarthropathy as sign of decompensation or from the reactive synovitis with or without effusion. NSAIDs (ibuprofen, diclofenac, indometacin, some salicylates, etofenamate and piroxicam) have demonstrated relevant advantages of the percutaneous route over the systemic one in soft tissue rheumatism. NSAIDs, mentioned above, locally administered as cream, gel or spray, quickly penetrate through the corneal layer of the skin and the site of application, reach highly effective concentrations in subcutis, fascias, tendons, ligaments and muscles, less in joint-capsule and -fluid indicating direct penetration. The blood levels of topical NSAIDs are extremely low with no systemic side effects, especially no gastric toxicity; however, local skin irritation is observed (1 to 2%). In contrast to this, systemic (oral) NSAIDs lead primarily via high blood levels to a lower concentration--only one tenth--in periarticular soft tissues with a high incidence of side effects. In conclusion the percutaneous application of certain NSAIDs has become a well established therapeutic regimen in painful osteoarthritis and in all other inflammatory degenerative and posttraumatic alterations of soft tissue structure.

[Results of efficacy study with diclofenac/orphenadrine infusions in patients with musculoskeletal diseases and functional disorders]. / Ergebnisse einer Anwendungsbeobachtung mit Diclofenac/Orphenadrin-Infusionen bei Patienten mit muskuloskelettalen Krankheiten und Funktionsstörungen.

During a post-marketing surveillance study, 641 patients (age range 18 to 86 years) with painful rheumatic diseases, mostly of vertebral etiology, were given ready-for-use infusions containing a combination of the non-steroid antiphlogistic agent diclofenac (75 mg) and the muscle relaxing agent orphenadrine (30 mg) parenterally for 7 days. The goal of the study was to investigate efficacy, tolerability, and acceptance of this intravenous therapy in wide use in physicians' practices. At the end of treatment, the global evaluation resulted in a score of 1.6 on a scale of 1 (very good) to 4 (insufficient). The tolerability score was 1.3 and the acceptability score was 1.5. Only 20 patients (3.1%) had adverse effects, most of which were of gastrointestinal nature. The medication proved appropriate for use in the treatment of painful spine syndromes, inflammatory osteoarthritis, painful osteoporosis, post-operative conditions, and extra-articular rheumatism and could represent a first step towards multi-factorial therapeutic management of these diseases.

Comparison of tissue and plasma levels of ibuprofen after oral and topical administration.

The penetration and absorption of ibuprofen (CAS 15687-27-1) from a topical gel and oral tablets were tested in an open study, performed in 17 patients with degenerative knee disorders requiring an operation. Patients administered the topical test preparation (ibugel, 3 x 375 mg ibuprofen daily) or the standard oral preparation (2 x 600 mg ibuprofen daily) for 3 days prior to the operation. Samples of blood, synovial fluid, muscle, fasciae and subcutis were obtained during the operation (15 h after the last administration) and analysed for ibuprofen content using a validated HPLC method. Different absorption profiles were observed for topical and oral administration. Oral administration led to higher concentrations in the plasma, synovial fluid and fasciae, while higher levels in the muscle and subcutis were found after topical administration. After topical application, the concentrations in the fasciae, muscle and subcutis were significantly higher than those in the blood plasma and synovial fluid (p < 0.05). Very low levels of ibuprofen were observed in the subcutis after oral administration. This can be explained by the different pathways. This study demonstrated that concentrations of ibuprofen in the various biological samples were still within therapeutically effective levels 15 h after topical or oral administration. By use of an oral comparison group, it has been possible to show that the concentrations in times directly under the site of topical application lie in the same order of magnitude as those found after preoral treatment. Therapy of intra-articular inflammatory and degenerative joint diseases requires oral administration of non-steroidal anti-inflammatory drugs (NSAIDs). However, based on the results of this study, topical therapy with NSAIDs can be recommended for soft tissue rheumatism and periarticular insertion tendinopathia.

[Percutaneous therapy with non-steroidal anti-inflammatory drugs. Pharmacokinetic criteria of effectiveness]. / Perkutane Therapie mit nichtsteroidalen Antiphlogistika. Pharmakokinetische Kriterien der Effektivität.

As in the case of systemically administered drugs, there is also a requirement for reliable kinetic evidence for the clinical effectiveness of local therapeutic NSAIDs. The conditions required for this are discussed, and compared with provisions already existing in EC countries. On the basis of a comprehensive review of the literature, it is shown that among all the locally employed NSAIDs, kinetically reliable and plausible evidence of therapeutic effectiveness is, at present, available only for indomethacin, diclofenac, salicylic acid salts and ibuprofen.

[Percutaneous therapy of painful arthritis]. / Perkutane Therapie der schmerzhaften Arthrose.

Pain in osteoarthrosis of the big weight bearing joints is either derived from periarticular ligaments, tendons, fasciae, muscles, bursae--peri-arthropathy as sign of decompensation--or from the reactive synovitis with or without effusion. NSAIDs systemically administered have been so far considered as first choice medication together with physical therapy. New pharmacokinetic data on the topical, percutaneous application of NSAIDs (ibuprofen, diclofenac, indomethacin, some salicylates and to a lesser degree for etofenamate and piroxicam) have demonstrated relevant advantages of the percutaneous route over the systemic one in soft tissue rheumatism. NSAIDs, mentioned above, locally administered as cream, gel or spray, quickly penetrate through the corneal layer of the skin at the site of application, reach high effective concentrations in subcutis, fasciae, tendons, ligaments and muscles, lesser in joint-capsule and -fluid indicating direct penetration. The blood levels of topical NSAIDs are extremely low with no systemic side effects, especially no gastric toxicity; however, local skin irritation is observed (1 to 2%). In contrast to this, systemic (oral) NSAIDs lead primarily via high blood levels to a much lesser concentration--only one tenth--in particular soft tissues with a high incidence of side effects. In conclusion the percutaneous application of certain NSAIDs has become a well established therapeutic regimen in painful osteoarthrosis and in all other inflammatory degenerative and posttraumatic alterations of soft tissue structures.

[Optimizing the clinical value of polyreactive autoantibodies to double-stranded DNA]. / Untersuchung zur Optimierung der klinischen Wertigkeit polyreaktiver Autoantikörper gegen Doppelstrang-DNS.

The serological characteristic of systemic lupus erythematosus is the presence of antibodies to double stranded (ds) DNA. Raised levels of these antibodies have been found occasionally in patients with other inflammatory rheumatic diseases. Evaluating 67 patients with anti-dsDNA antibodies we searched for additionally immunological features to improve their clinical relevance for connective tissue diseases. We found out that coexistent antinuclear antibodies, antibodies to Sm, U1-nRNP, Ro and La, except in D-penicillamine induced lupus syndrome, were most specific for connective tissue diseases. Permanent antinuclear antibody negative systemic lupus erythematosus may not really exist.

Comparison of naproxen and piroxicam in the treatment of rheumatoid arthritis: a double-blind, crossover study.

A double-blind, crossover study was carried out in 50 patients with rheumatoid arthritis to compare the efficacy and tolerance of single evening doses of 1000 mg naproxen and 20 mg piroxicam. After an initial wash-out period of 1 week, patients received 4-weeks' treatment with one or other of the trial drugs and were then crossed over after a 1-week wash-out period to the alternative medication for a further 4 weeks. Objective assessments of disease activity and patients' and physician's assessments of therapeutic response were made at the end of each wash-out and active treatment period, and at the end of the trial patients and physician were asked to say which of the two active treatments was preferred. Forty-nine patients completed the 10-week trial; one patient discontinued the study while on piroxicam therapy because of side-effects. While both treatments proved effective, naproxen was statistically significantly better than piroxicam for total joint pain, grip strength, duration of morning stiffness, and overall therapeutic response. Naproxen also had a more rapid and more pronounced action than did piroxicam and was selected as the preferred drug by both patients and physicians. Patients taking naproxen reported slightly fewer side-effects than did those taking piroxicam.

[Are inflammation parameters true signs of activity? A contribution to the problem of process activity and progression in chronic polyarthritis]. / Sind Entzündungsparameter echte Aktivitätszeichen? Ein Beitrag zum Problem der Prozess-Aktivität und Progredienz bei der chronischen Polyarthritis.

Among all laboratory parameters used today in the assessment of activity and progression of rheumatoid arthritis erythrocyte sedimentation rate (ESR) can only be recommended reservedly. ESR is influenced by anemia, reduction of plasma fibrinogen, dysproteinemia and by the concentration of acute phase proteins. Quantification of acute phase proteins especially of the C-reactive protein (CRP) correlates best with activity and progression of early forms of rheumatoid arthritis as well as with malignant courses. During the administration of alkylating agents - rise of ESR in spite of clinical improvement and decrease of CRP - and during antimalarials - clinical improvement, decrease of CRP and constant, unchanged ESR - the quantification of CRP turns out to be superior to ESR.

[Effect of cyclophosphamide (Endoxan) on experimental arthritis in rabbits]. / Zur Wirkung von Cyclophosphamid (Endoxan) bei der experimentellen Arthritis des Kaninchens.

The experimental investigation is divided into 3 parts: Firstly, it was assessed that cyclophosphamide (Cp) in different dosages was well tolerated locally when injected into the knee joint of normal rabbits as compared to saline controls on the basis of histology and cell count determination of the injected joints. In a second series of experiments a hyperimmune arthritis (HIA) was produced in rabbits by systemic administration of albumin, complete Freund's adjuvant and intraarticular stimulus by ovalbumin. Histological examination of synovial membranes reveal alterations similar to those of human rheumatoid arthritis on the 7th day after stimulus. Further experiments were aimed at assessing if Cp exerted an inhibitory effect on the 7 day old HIA. Cp in a dosage of 10 mg has been applied intraarticularly in various intervals prior, simultaneously and after the elicitation of HIA. It could be demonstrated that Cp led to a reduction of the number of lymphocytes, plasma cells and fibroblasts in the synovial membrane, the inhibitory effect on fibroblasts was bound to its administration around the point of HIA elicitation, an even stronger inhibition of lymphocytes and plasma-cells was only to be expected when Cp was applied 48 hours after ovalbumin challenge. Unwanted reactions in the course of Cp administration such as superficial and deep necrosis as well as damage of blood vessels in the synovial membrane combined with minor inhibition of lymphocytes and plasma cells were encountered when Cp was injected 120 hours after HIA elicitation. These new experimental results lead to the conclusion that efficacy and unwanted reactions during Cp administration are related to a local activation of the substance in the inflammatory milieu of HIA. Furthermore we were able to demonstrate that even the sole application of Cp if injected shortly before immigration of lymphocytes into the synovial tissue led to a marked suppression of almost all histological parameters of HIA. Our experimental findings strongly support the importance of lymphocytes and plasma cells being inactivated for the successful treatment of adult rheumatoid arthritis. They grow to consider the formation of necrosis and damage of blood vessels as sequelae of too fast a local activation of Cp in the inflammatory tissue.

[Indometacin glucosamide in the therapy of rheumatoid arthritis (author's transl)]. / Indometacin-glucosamid in der Behandlung der chronischen polyarthritis.

40 patients with classical or definite rheumatoid arthritis were included in a double blind trial to assess efficacy and side effects of indometacin (n = 20) versus glucametacin (n = 20). In a daily dose of 420 mg glucametacin proved to be equally potent to 150 mg indometacin daily in its anti-inflammatory activity but showed fewer side effects.

Clinical studies of the interaction between tolmetin and glibenclamide.

Forty patients with diabetes mellitus and rheumatic disorders (rheumatoid arthritis, osteoarthritis, soft-tissue rheumatism) were included in a double-blind trial with the purpose of investigating whether the concomitant administration of tolmetin and glibenclamide leads to an interaction. No significant alterations of blood and urine glucose values could be found in comparison to placebo. Therefore it can be assumed that there is no interaction between these two substances.

[Treatment of osteoporosis with a delayed-action sodium fluoride preparation]. / Zur Behandlung der Osteoporose mit einem protrahiert wirksamen Natrium-Fluorid-Präparat

40 patients with various types of osteoporosis, aged 17 to 76 years, were treated for 12 months with a new NaF-drug (Ossiplex-Retard, film tbl. 25 mg NaF plus 200 mg vitamine C). Daily dosage was 50-100 mg. Clinical symptoms, X-ray-status of the axial skeleton, alkaline serum phosphatase and the consumption of analgetics were used for assessment. 2/3 of the patients with presenile and steroid induced osteoporosis responded well to treatment, while those with osteogenesis imperfecta, idiopathic osteoporosis and plasmocytosis did not show clinical or radiological improvement. In senile osteoporosis, a physiological process of aging, should only be given NaF-treatment, if fractures without callus formation are present. Harmless side effects, (gastrointestinal intolerance in 15% and a painful tendoperiostosis syndrome in 12.5%), necessitated discontinuation of treatment in 3 cases. The NaF-drug with added vitamine C has less side effects than other NaF-containing compounds and should therefore be included as part of the therapeutical regimen of certain types of osteoporosis.