[DGRh recommendations for the implementation of current security aspects in the NSAID treatment of musculoskeletal pain]. / DGRh-Empfehlungen zur Implementierung aktueller Sicherheitsaspekte in die NSAR-Therapie muskuloskelettaler Schmerzen.

NSAIDs exert their anti-inflammatory and analgesic effects by inhibition of COX­2, a key enzyme for proinflammatory prostanoid synthesis. Therapy with NSAIDs is limited by their typical gastrointestinal, cardiovascular and renal side effects, which are caused by inhibition of COX­1 (gastrointestinal toxicity), COX­2 (cardiovascular side effects) or both COX-isoenzymes (renal side effects). Appropriate prevention strategies should be employed in patients at risk. If gastrointestinal risk factors are present, co-administration of a proton pump inhibitor or misoprostol is recommended; in patients with cardiovascular risk, coxibs, diclofenac and high-dose ibuprofen should be avoided. Furthermore, drug interactions and contraindications should be considered. In patients with renal impairment (GFR < 30 ml/min) all NSAIDs must be avoided. Ulcer anamnesis is a contraindication for traditional NSAIDs. Preexisting cardio- or cerebrovascular diseases are contraindications for coxibs. Treatment decisions should be individually based with a continuous monitoring of the risk - benefit ratio and exploitation of non-pharmacological treatment options.

[Recommendations for symptomatic therapy of rheumatic pain with opioid analgetics]. / Empfehlungen zur symptomatischen Therapie mit Opioidanalgetika bei rheumatischen Schmerzen.

The treatment of musculoskeletal pain is often difficult. For this reason opioids are increasingly being used for chronic musculoskeletal complaints despite poor or lacking evidence for their pain relieving and function improving effects. However, side effects are common and can be severe. Opioid-induced hyperalgesia can lead to higher doses and stronger pain and increase the risk of side effects. Long-term treatment of rheumatic pain with opioids should be carried out with caution.

Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations.

It is well documented that the aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant endocrine therapy in postmenopausal women with hormone receptor-positive breast cancer. However, compared with tamoxifen, an elevated incidence of arthralgia has been observed during AI treatment. Concerns have been raised that AI-induced arthralgia may dissuade patients from completing their full AI treatment course, and may also deter physicians from prescribing an AI if they feel that patients may be at risk of permanent joint damage. Patient education about the possibility of experiencing arthralgia, and effective management of symptoms if they appear, are important in helping patients adhere to AI treatment, and consequently improving breast cancer outcomes. In this paper, we discuss the potential mechanisms behind AI-induced arthralgia, review the frequency with which arthralgia occurs, and propose for the first time an algorithm specifically for the treatment of AI-induced arthralgia. As with joint pain in non-breast cancer patients, a sequential approach to disease management is recommended, involving modifying the patient's lifestyle in addition to taking a stratified approach to pharmacological intervention with analgesia and anti-inflammatory medication. Knowing that joint symptoms can be managed in most patients may encourage patient-physician communication and treatment compliance.

[Recommendations for treatment with nonsteroidal anti-inflammatory drugs]. / Antientzündliche Schmerzbehandlung mit klassischen NSAR oder Coxiben. Differenzialtherapie in Abhängigkeit von gastralen und kardialen Risiken.

Recommendations for treatment with NSAIDs that take into account the latest study results must note that both the duration of treatment and the NSAID dose must be kept as small as possible. Elevated gastrointestinal risk is the rationale for the use of selective COX-2 inhibitors in place of conventional NSAIDs, or, where indicated, co-medication with a proton pump inhibitor. A manifest cardiovascular risk is aggravated by the use of coxibs, but probably also by the administration of traditional NSAIDs. Cardioprotective medication in the form of low-dose acetyl salicylic acid can probably reduce the cardiovascular risk, but at the same time increases the gastrointestinal risk. In such cases, proton pump inhibitors can offer some relief. However, the latter have no effect on the situation in the lower gastrointestinal tract. In patients with an elevated cardiovascular risk, the use of coxibs, and probably also NSAIDs for the treatment of pain, is problematical. The decision on what treatment to apply should be made on the basis of a benefit/risk assessment, and consideration should be given to alternative therapeutic strategies.

Improved determination of sulfadiazine in human plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of sulfadiazine in human plasma and human urine was developed and validated. The method involves the acid extraction of drug and internal standard from plasma with ethyl acetate followed by evaporation and reconstitution in mobile phase. Urine samples were simply diluted with purified water. Recovery, linearity, intra- and inter-day variation of sulfadiazine were tested and found appropriate. The quantitation range was 0.0299-15.2 micrograms/ml for plasma samples and 0.578-148.8 micrograms/ml for urine samples. The method is suitable for the quantitation of sulfadiazine from pharmacokinetic studies.

Sensitive determination of nitrofurantoin in human plasma and urine by high-performance liquid chromatography.

A highly sensitive and selective HPLC method was developed and validated for the determination of nitrofurantoin in human plasma and urine. The method involves the liquid-liquid extraction of drug and internal standard from plasma with ethyl acetate followed by evaporation and reconstitution in mobile phase. Urine samples were simply diluted with purified water. UV detection was done at 370 nm. The limit of quantification for nitrofurantoin in plasma was 0.010 micrograms/ml. In urine nitrofurantoin could be quantified down to 0.380 microgram/ml. Linearity was proven over the whole calibration range in plasma (2.48-0.0100 microgram/ml) as well as in urine (187 micrograms/ml-0.380 microgram/ml). The method was validated according to Good Laboratory Practice guidelines and its suitability was demonstrated by analysis of samples from a pharmacokinetic study.

Improved high-performance liquid chromatographic determination of amoxicillin in human plasma by means of column switching.

A highly sensitive and selective HPLC method was developed for the determination of amoxicillin in human plasma. After addition of buffer and internal standard, the sample was ultrafiltered and injected on to a precolumn to remove polar plasma interferences. Detection was effected with a UV detector set at 230 nm. The limit of quantification for amoxicillin was 50.1 ng/ml with an imprecision of 4.2% using 0.25 ml of plasma. Linearity was confirmed over the whole calibration range (25.4-0.0501 micrograms/ml) and the inter-day variation ranged from 2.0 to 4.5%. The method was validated according to GLP guidelines and its suitability was demonstrated by the analysis of several hundred samples in a bioequivalence study. The method can be used to determine pharmacokinetic parameters of amoxicillin in humans after a single oral dose of 500 mg.

Temporomandibular joint function in patients with longstanding rheumatoid arthritis - I. Role of periodontal status and prosthetic care - a clinical study.

PURPOSE: Temporomandibular joint (TMJ) dysfunction in rheumatoid arthritis (RA) occurs in 2 % to 86 % of RA patients. Dental factors possibly contributing to the development of TMJ dysfunction in RA patients have rarely been investigated in controlled studies. The present clinical study aimed 1) to compare patients with active, longstanding RA and healthy control subjects matched for age, sex, periodontal risk factors, dental and prosthetic status in order to obtain data on the prevalence of TMJ dysfunction in dentate RA patients and 2) to investigate a possible relationship between RA activity, general functional state and the severity of TMJ involvement. METHODS: 50 RA patients (38 F, 12 M; 54 +/- 9 years) were compared with 101 control subjects (76 F, 25 M; 54 +/- 11 years) with regard to dental, periodontal and prosthetic status and clinical TMJ findings as measured by the Helkimo indices. Clinical evaluation of RA patients included serological parameters, pain as measured by visual analog scale (VAS), a 28-joint count, a radiological destruction score, a functional status and measurement of grip strength. RESULTS: The sum of carious, missing and filled teeth was similar in both groups. RA patients had more missing teeth (p < 0.01), more gingival bleeding, deeper pockets and more attachment loss (p < 0.0001). They showed no differences with regard to the mean number of occluding pairs of teeth, tooth support, the percentage of dentures, the grade of prosthetic support. 36 % of RA patients had a unilaterally shortened dental arch compared with 11.9 % in controls (p < 0.05). 32 % of RA patients and 27.7 % of the control subjects reported TMJ or facial pain. The mean VAS was 50 +/- 19 for RA patients and 52 +/- 21 for controls. The anamnestic data and the clinical symptoms grouped according to the Helkimo index showed no significant differences between both subject groups. However, the maximal mouth opening capacity in RA patients was significantly lower (40.6 +/- 6.5 mm) than in controls (45.8 +/- 5.5 mm; p < 0.001). Analysis of the Helkimo symptom groups revealed a significantly reduced mobility index in the RA group and impaired TM-joint function in controls (p < 0.05). Grip strength was significantly correlated with mouth opening capacity, TMJ pain with tooth support. CONCLUSION: The prevalence of TMJ dysfunction in dentate patients with longstanding RA does not exceed that of healthy controls when structural risk factors predisposing to the development of temporomandibular dysfunction are taken into consideration. Maintaining adequate tooth support might help to prevent progressive TMJ impairment in the course of disease.

The role of risk factors for periodontal disease in patients with rheumatoid arthritis.

There are conflicting reports whether patients with rheumatoid arthritis (RA) are at a higher risk for periodontal disease (PD). Analogous mechanisms of tissue destruction have been reported for both diseases. This cross-sectional study should quantify PD in patients with longstanding RA and examine a possible association between the two diseases. It should also be investigated whether PD in RA patients could be the result of reduced functional capacity or be amplified by concomitant medical treatment. 50 RA patients were matched for age, sex, smoking and oral hygiene with 101 healthy controls. Data on the medication over the last three years was obtained by questionnaire. Among the rheumatological parameters recorded were a 28-joint-count, C-reactive protein (CRP), grip strength testing, upper extremity function (Keitel Index) and the Larsen-score of radiological joint destruction. The oral examination included the recording of individual oral hygiene measures and sicca symptoms, a modified Approximal Plaque- and Sulcus-Bleeding-Index (SBI), probing depths and clinical attachment loss and the Community Periodontal Index of Treatment Needs. The mean duration of RA was 13 (+/- 7.9) years. RA patients under treatment with disease modifying antirheumatic drugs (DMARDs, n = 46; 92%), corticosteroids (n = 38; 76%) and non steroidal antirheumatic drugs (NSAIDs, n = 43; 86%) had a higher rate of gingival bleeding (+ 50%), probing depth (+ 26%), clinical attachment loss (+ 173%) and number of missing teeth (+ 29%) compared with controls. While no correlation between the rheumatological variables (radiological destruction, functional capacity, grip strength) and the periodontal measurements (SBI, probing depth, clinical attachment loss) could be demonstrated, a positive correlation was observed between the CRP and the periodontal attachment loss (r = 0.32; p <0.05). In spite of a strong correlation between the duration of DMARD- and cortisone-medication and the Larsen-score (r = 0.48 and 0.64; p = 0.0005 and 0.0001, rsp.), no correlation between the duration of pharmacotherapy and the periodontal parameters could be established. Patients with long-term active RA present a substantially higher degree of PD including loss of teeth compared with controls. Functional impairment of the upper extremity might amplify present PD. The longterm use of NSAIDs, corticosteroids and DMARDs shows no connection with the severe PD observed in these patients. Oral hygiene amplifies PD severity and treatment need. Intensive prophylactic measures are required to prevent or reduce the damage of the periodontal tissues in RA patients.

Scientific rationale for specific inhibition of COX-2.

Cyclooxygenase (COX) is the principal enzyme involved in the production of prostaglandins. Inhibition of COX is also the primary mechanism of action of aspirin and other nonsteroidal antiinflammatory drugs (NSAID). Since prostaglandins are important regulators of cellular function, inhibition of prostaglandin production may lead to adverse effects. Two isoforms of COX have been identified, sequenced, and cloned. COX-1 is constitutively produced and is believed to be involved in regulating normal cellular processes, such as gastrointestinal (GI) cytoprotection, vascular homeostasis, and renal function. In contrast, COX-2 -- the inducible form -- is undetectable in most tissues but is present in inflamed tissue. Evidence therefore suggests that the GI toxicity associated with NSAID use is primarily the result of inhibition of COX-1, and antiinflammatory effects are largely due to inhibition of COX-2. A drug that specifically inhibits COX-2 without affecting COX-1 would, theoretically, reduce inflammation without leading to GI side effects. A variety of biologic assays have been developed to characterize the relative activities of NSAID against COX-1 and COX-2. Such in vitro testing has demonstrated that individual NSAID possess different relative inhibitory effects in various tissues. Several NSAID have been reported to show more potent inhibition of COX-2 than of COX-1 in vitro; however, the clinical relevance of differential inhibition of COX isozymes is as yet unknown. Some clinical studies indicating reduced toxicity for these NSAID may, in fact, be attributable to use of these agents at subtherapeutic doses. As yet, no clinically available NSAID has been shown to have significant in vivo effects on COX-2 while sparing COX-1 activity in humans. However, compounds that may be 100 to 300-fold more effective inhibitors of COX-2 and that therefore may have lower risks for toxicity as well as more potent antiinflammatory effects have been developed, but are not yet available for clinical use.

[Diagnosis, therapy and prognosis in systemic autoimmune disorders like lupus erythematosus]. / Diagnose, Therapie und Prognose der Kollagenosen am Beispiel des Lupus erythematodes.

Systemic lupus erythematosus (SLE) is the prototype of a systemic autoimmune disorder, in which immune complexes or cytotoxic antibodies give rise to tissue damage and organ failure, which often results in death. Due to more sensitive diagnostic tools and more sufficient therapeutic methods, the five-year survival rate in patients with systemic lupus erythematosus has improved dramatically during the past decades from less than 50% to 95%. Mortality is still 4 to 5 times higher and is mostly caused by uncontrolled disease flares, infections, and thromboses. Risk factors influencing the course of SLE and favouring the higher mortality are serum antibodies (anti-dsDNA, anticardiolipin, lupus anticoagulant), infections, hypertension, osteoporosis with fractures, cytopenia, renal involvement, higher age at onset, and genetic factors. Morbidity and social consequences are conducted by individual multisystemic disease manifestations.

[Differential analgesic treatment in arthrosis and arthritis]. / Arthrosen und Arthritiden: Schmerztherapie kann Invalidität verhindern. Durchbrechen Sie den Teufels--kreis der Unbeweglichkeit!

The leading symptom of arthrosis and arthritis is pain. As in the case of pharmacotherapy fortumor pain, a stepped approach is also recommended for rheumatic complaints. Mild-to-moderate pain in noninflammatory arthrosis can be ameliorated by paracetamol or low-dose ibuprofen. If inflammation is present, nonsteroidal anti-inflammatory drugs (NSAIDs) must be employed. If this treatment does not suffice to manage systemic arthritis, oral short-acting corticosteroids are applied. Intra-articular corticosteroid injections can be used to individual inflamed active joints. For chronic pain, opioids may be necessary in addition to NSAID treatment. The use of NSAIDs is limited by gastrointestinal side effects. In the case of risk patients, therefore, preventive measures must be taken, and PPI or, instead of NSAIDs, coxibs employed in addition.

[Symptomatic therapy of rheumatic diseases. How they reduce pain and thereby safe costs]. / Symptomatische Therapie rheumatischer Erkrankungen. Wie Sie Schmerzen lindern und dabei Kosten sparen.

The leading symptom of rheumatic diseases is pain. Further common symptoms are swelling, restricted mobility and joint deformation. The aim of treatment is freedom from pain and unrestricted function of the affected parts, together with improved quality of life. Amelioration of pain usually succeeds with the so-called non-steroidal antiinflammatory drugs (NSAIDs). In 10% of the cases, however, these can lead to gastric bleeding and perforation necessitating emergency hospitalization. Approximately 10% of patients with complicated ulcers die. COX-2-inhibitors have an analgesic action equal to that of conventional NSAIDs, but cause appreciably fewer gastrointestinal complications. Comedication of NSAIDs and misoprostol or omeprazole also has a gastric protective effect. Concomitant treatments, provision of aids and relevant information about the disease and its course, help to secure a good outcome. In the last resort, when conservative treatment fails, surgical intervention becomes necessary.

Problem of the atherothrombotic potential of non-steroidal anti-inflammatory drugs.

Treatment of pain in rheumatoid arthritis must take into account the gastrointestinal and cardiovascular risk of individual patients. Adequate results are not yet available, and until they are, treatment recommendations must take into account, not only the more favourable gastrointestinal risk profile of selective COX-2 inhibitors, but also the potential atherothrombotic risk of any NSAID or selective COX-2 inhibitor treatment.