Oxaceprol is a Well-Tolerated Therapy for Osteoarthritis with Efficacy Equivalent to Diclofenac

The therapeutic equivalence and safety of treatment for 21 days with 400 mg t.i.d. oxaceprol (n= 132) and 50 mg t.i.d. diclofenac (n= 131) were assessed in a multicentre, randomised, double-blind study of a mixed population of patients with osteoarthritis of the knee and/or hip. In a per-protocol analysis of efficacy, the mean Lequesne index decreased by 2.5 points in the oxaceprol group (n= 109) and by 2.8 points in the diclofenac group (n= 109). The 95% confidence interval for the end-point difference revealed therapeutic equivalence. This was confirmed by assessments (visual analogue scale) of pain at rest, weight-bearing pain, pain on standing and pain on movement, all of which decreased to a similar extent under both treatments. The pain-free walking time increased in both groups from 10 min to 25 min by the end of the treatment period. Mobility was also increased to a similar extent by both drugs. The physicians assessed treatment as good or very good in 45–46% of patients in both groups. In all patients who received treatment, 28 and 37 adverse events were reported by 25 out of 132 (18.9%) and 33 out of 131 (25.2%) patients treated with oxaceprol and diclofenac, respectively. In 15 patients (11.4%) with 15 adverse events in the oxaceprol group and 25 patients (19.1%) with 27 adverse events in the diclofenac group, a relation to the medication was considered probable. The difference between the groups was statistically significant (p= 0.04106) for the number of these adverse events. Oxaceprol is therapeutically equivalent to diclofenac, but better tolerated than diclofenac in the treatment of osteoarthritis. Received: 15 February 1999 / Accepted: 7 September 1999     

Tissue Concentration of the Active Substance of Voltaren SR 75 in Articular Cartilage, Synovial Membrane and Bone

The tissue concentration of diclofenac sodium, the active substance of Voltaren SR 75 mg tablets, was studied in 10 patients with coxarthrosis. Voltaren SR 75 mg tablets were administered twice daily for 5 days, then prosthetic joint replacement of the hip was performed. Tissue levels of diclofenac were determined by HPLC in specimens of articular cartilage, synovial membrane and bone obtained during surgery. The results demonstrate that diclofenac was present in all three tissue types after 5 days of therapy. Received: 1 March 1999 / Accepted: 25 August 1999     

Valdecoxib is as effective as diclofenac in the management of rheumatoid arthritis with a lower incidence of gastroduodenal ulcers: results of a 26-week trial

OBJECTIVE: To compare the efficacy and upper gastrointestinal (GI) safety of valdecoxib 20 and 40 mg daily with those of diclofenac 75 mg slow release (SR) twice daily in treating rheumatoid arthritis (RA). METHODS: Seven hundred and twenty-two patients with adult-onset RA were enrolled into this 26-week, randomized, multicentre, double-blind, parallel-group study (246 in the valdecoxib 20 mg daily arm, 237 in the valdecoxib 40 mg daily arm and 239 in the diclofenac 75 mg SR daily arm). Acetylsalicylic acid use (< or =325 mg per day) was similar across all groups: 5.4% in the diclofenac group, 5.7% in the valdecoxib 20 mg group and 5.9% in the valdecoxib 40 mg group. Efficacy was measured by the Patient's Assessment of Arthritis Pain [visual analogue scale (VAS)] and the modified Health Assessment Questionnaire (mHAQ) at baseline and at weeks 2, 6, 8, 12, 18 and 26 of treatment, or at early termination. Upper GI safety was evaluated by endoscopy at the end of treatment, which took place no more than 2 days after the last dose of study medication or at early termination. RESULTS: Valdecoxib 20 and 40 mg daily were comparable to diclofenac 75 mg SR twice daily in treating the signs and symptoms of RA. No significant differences were observed between treatment groups with respect to mean changes from baseline in the Patient's Assessment of Arthritis Pain (VAS) or mHAQ. The incidence of gastroduodenal ulcers in patients receiving valdecoxib 20 mg daily (6%) and valdecoxib 40 mg daily (4%) was significantly lower (P < 0.001) than in patients receiving diclofenac 75 mg SR twice daily (16%). Valdecoxib 20 mg daily was also associated with significantly improved GI tolerability (P = 0.035) compared with diclofenac. CONCLUSIONS: Single daily doses of valdecoxib 20 and 40 mg provided efficacy comparable to that of diclofenac, with a superior upper GI safety profile in the long-term treatment of RA patients.     

Efficacy and Safety of a Combination Therapy of Methotrexate, Chloroquine and Cyclophosphamide in Patients with Refractory Rheumatoid Arthritis: Results of an Observational Study with Matched-Pair Analysis

The efficacy and safety of a combination of methotrexate (MTX), chloroquine (CQ) and cyclophosphamide (CYC) were studied in patients with refractory rheumatoid arthritis. A single-centre, matched-pair observational study with prospectively gathered data was performed. Fifty-six patients who had previously failed with MTX were treated with 15 mg MTX per week, 50 mg CYC three times a week and 250 mg CQ per day (group A). A 50% improvement of the swollen joint count was required to continue therapy. Data were compared with the results of the previous MTX therapy in the same group and with a matched-patient cohort receiving MTX monotherapy for the first time (group B). In group A, the combination therapy resulted in a significant decline of the swollen joint count after 1 year, in contrast to the previous MTX monotherapy in the same group. Complete remission of joint swelling was achieved in 13 patients (23%), compared with 26 patients in group B (47%). The median duration of effective combination treatment in group A was significantly longer than preceding therapies with MTX alone (19 vs 13 months, p <0.05). However, patients in group B could be treated for a median of 57.5 months (p <0.0001 compared with group A). Side-effects were comparable in both groups. The applied DMARD combination is safe and beneficial in a significant proportion of patients if MTX monotherapy is ineffective. Received: 6 March 1998 / Accepted: 5 October 1998     

Comparison of aceclofenac with diclofenac in the treatment of osteoarthritis

Summary A multicentre randomised, double-blind, parallel group, general practice study was undertaken to investigate the efficacy and safety of aceclofenac (200 patients, 100mg twice daily and placebo once daily) in comparison with diclofenac (197 patients, 50mg three times daily) in patients with osteoarthritis of the knee. The treatment period of twelve weeks was preceded by a washout period of two weeks duration. At end point, patients in both aceclofenac and diclofenactreated groups exhibited significant improvement in pain intensity (p=0.0001). Although both treatment groups showed significant improvement in all investigators' clinical assessments (joint tenderness, swelling, pain on movement, functional capacity, overall assessment), there were no significant differences between the groups. There was, however, a trend towards greater improvement in complete knee movement and reduced pain on movement with aceclofenac. In patients with initial flexion deformity, aceclofenac was significantly more effective than diclofenac in improving knee flexion after 2–4 weeks of treatment. Patients' subjective assessment of pain relief demonstrated significantly greater efficacy with aceclofenac. At end point, 71% of patients in the aceclofenac group reported improvement in pain intensity as compared to 59% treated with diclofenac (p=0.005). Tolerability of aceclofenac was better than with diclofenac as fewer patients experienced gastrointestinal adverse events. In particular, the incidence of treatment related diarrhoea was less with aceclofenac (1%) than with diclofenac (6.6%). In summary, this study supports a therapeutic role for aceclofenac in arthritis and suggests that it is an alternative NSAID to diclofenac in the treatment of osteoarthritis.     

Efficacy of Methotrexate in the Treatment of Ankylosing Spondylitis: A Three-Year Open Study

The aim of the study was to evaluate the efficacy of methotrexate treatment in patients with ankylosing spondylitis in a 3-year open trial. Seventeen patients, 14 men and three women (mean age 32.7 ± 8.9 years), suffering from ankylosing spondylitis and non-responders to treatment with sulphasalazine, were enrolled in our study. Sixteen of them were evaluable at the end of the study. Methotrexate (7.5–10 mg/week) was administered for 3 years. Efficacy was evaluated on the basis of clinical and laboratory variables, radiographic signs of disease progression and daily dosage of indomethacin. We obtained a good and relatively prompt clinical response except for peripheral arthritis and iridocyclitis; in fact, after 3 months of methotrexate treatment a significant amelioration of the following parameters was observed: visual analogue scale for the evaluation of both night pain and general well-being, Shober’s test, occiput-wall distance, fingertip to floor, erythrocyte sedimentation rate, C-reactive protein level and daily dose of indomethacin. A further improvement was obtained during the subsequent period. Radiographs of the spine and sacroiliac joints did not show any signs of disease progression. Side-effects were a transitory elevation of transaminases (four cases) and slight hypogammaglobulinaemia (one case). Methotrexate treatment may be useful in ankylosing spondylitis, but a combined treatment might be indicated for patients with peripheral arthritis. Received: 26 January 1999 / Accepted: 25 August 1999     

Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis

OBJECTIVE: To determine whether valdecoxib, at chronic arthritis doses, has the characteristics of a cyclo-oxygenase 2 (COX-2) specific inhibitor, as measured by a reduced incidence of upper-gastrointestinal ulceration compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: This double-blind, multicentre, placebo-controlled, parallel-group study compared the incidence of gastroduodenal ulcers associated with valdecoxib 10 mg daily (q.d.) and 20 mg q.d. with that of ibuprofen 800 mg three times daily (t.i.d.) or diclofenac 75 mg twice daily (b.i.d.) when administered over a 12-week period. The incidence of gastroduodenal ulcers was assessed by upper-gastrointestinal endoscopy, performed at baseline and again at the end of week 12 (or at early study termination). Efficacy assessments were performed at baseline and at weeks 2, 6 and 12 using Patient's and Physician's Global Assessments of Arthritis. RESULTS: A total of 1052 osteoarthritis patients were enrolled into the trial. The incidence of gastroduodenal ulcers over 12 weeks was 5% in patients receiving valdecoxib 10 mg q.d., 4% in patients receiving valdecoxib 20 mg q.d., 7% in patients receiving placebo, 16% in patients receiving ibuprofen 800 mg t.i.d. (P <0.05 v. placebo), and 17% in patients receiving diclofenac 75 mg b.i.d. (P <0.05 v. placebo). The incidence of gastroduodenal ulcers at week 12 seen in the ibuprofen 800 mg t.i.d. and diclofenac 75 mg b.i.d. groups was significantly higher than that in the valdecoxib 10 mg q.d. and valdecoxib 20 mg q.d. groups (P <0.05). The incidence rates of gastroduodenal ulcers were not significantly different between the valdecoxib treatment groups or between valdecoxib- and placebo-treated patients. Efficacy responses to valdecoxib 10 mg and 20 mg q.d. were significantly greater than placebo and comparable with both ibuprofen 800 mg t.i.d. and diclofenac 75 mg b.i.d. CONCLUSIONS: The results of the study demonstrate that valdecoxib has an upper-gastrointestinal safety profile typical of a COX-2 specific inhibitor. Overall, the data indicate that administration of valdecoxib offers similar efficacy for the treatment of osteoarthritis but improved upper-gastrointestinal safety compared with the conventional NSAIDs, ibuprofen and diclofenac, based on the significantly lower incidence of gastroduodenal ulcers detected by endoscopy.     

Comparative Tolerability of Paracetamol, Aspirin and Ibuprofen for Short-Term Analgesia in Patients with Musculoskeletal Conditions: Results in 4291 Patients

The aim of this blinded, randomised, multicentre study was to compare the tolerability of aspirin, paracetamol and ibuprofen in common pain resulting from musculoskeletal conditions (MSC) in general practice with patients with other non-MSC pain conditions. Patients took aspirin, paracetamol (both up to 3g daily) or ibuprofen (up to 1.2g daily) for up to 7 days. The main outcome was the rate of significant adverse events (SGAE). Four thousand two hundred and ninety one patients with MSC were evaluable (1436 aspirin, 1423 paracetamol, 1432 ibuprofen) and 4101 (95.5%) were per-protocol. A group of 4342 patients included for other (non-MSC) mild to moderate pain conditions was used for comparison. In the MSC group, SGAE were reported by 20.5% of patients with aspirin, 17.0% with paracetamol and 15.0% with ibuprofen. Ibuprofen was statistically equivalent to paracetamol and better tolerated than aspirin (p<0.000l). Ibuprofen was associated with fewer digestive system AE (4.4%) than aspirin (8.6%, p<0.000l) and paracetamol (6.5%, p<0.02). The non-MSC group showed similar inter-treatment differences, but experienced fewer SGAE. No serious digestive events were observed with any of the three treatments in either group. These results show that in patients with mild to moderate pain resulting from MSC, ibuprofen given in OTC doses for 6 days is as well tolerated as paracetamol and better tolerated than aspirin. Received: 3 January 2001 / Accepted: 18 July 2001     

Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Rofecoxib Phase III Protocol 035 Study Group

OBJECTIVE: To compare the clinical efficacy of rofecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2), with that of diclofenac in patients with osteoarthritis (OA) and to evaluate the safety and tolerability of rofecoxib. METHODS: We performed a randomized, double-blind, active comparator-controlled trial in 784 adults with OA of the knee or hip. Patients were randomized to 1 of 3 treatment groups: 12.5 mg of rofecoxib once daily, 25 mg of rofecoxib once daily, and 50 mg of diclofenac 3 times daily. Clinical efficacy and safety were evaluated over a 1-year continuous treatment period. RESULTS: Rofecoxib at dosages of 12.5 and 25 mg demonstrated efficacy that was clinically comparable to that of diclofenac, as assessed by all 3 primary end points according to predefined comparability criteria. Results from secondary end points were consistent with those of the primary end points. There were small statistical differences favoring diclofenac for 2 of the end points. All treatments were well tolerated. CONCLUSION: Rofecoxib was well tolerated and provided efficacy that was clinically comparable, according to predefined statistical criteria, to that of 150 mg of diclofenac per day in this 1-year study. Specific inhibition of COX-2 provided therapeutic efficacy in OA.     

Early rather than delayed administration of lisinopril protects the heart after myocardial infarction in rats

Background:ACE inhibitors have shown beneficial results in several studies after myocardial infarction (MI). However, this studies have shown conflicting results about the ideal starting time of the ACE inhibitors administration after MI and the importance of infarct size. Objectives: This study was designed to assess the long-term effects of lisinopril on mortality, cardiac function, and ventricular fibrosis after MI, in rats. Methods: Lisinopril (20 mg/kg/day) was given on day 1 or 21 days after coronary occlusion in small or large infarctions. Results: The mortality rate was reduced by 39% in early treatment and 30% in delayed treatment in comparison to the untreated rats. Early treatment reduced cardiac dysfunction in small MIs; however, delayed treatment did not. No statistical difference was observed among the groups for large MIs. No statistical difference was observed among the groups with large or small MIs on myocardial hydroxyproline concentration. Conclusions: Both early and delayed treatments with lisinopril increased survival. Treatment exerts no marked effects on fibrosis; early treatment has exerted beneficial influences on cardiac function whereas delayed treatment had no consistent effects. The protective effect of lisinopril is detectable only in small (< 40% of LV) MIs. Received: 6 May 1999, Returned for 1. revision: 28 May 1999, 1. Revision received: 20 July 1999, Returned for 2. revision: 26 August 1999, 2. Revision received: 28 September 1999, Accepted: 29 September 1999     

Bone mineral density in women with systemic lupus erythematosus

The aim of this cross-sectional study was to determine the prevalence of reduced bone mineral density (BMD) in a group of female SLE patients and to identify factors predictive of reduced BMD. Femoral neck (FN) and lumbar spine (LS) dual-energy X-ray absorptiometry results were evaluated in 79 pre- and postmenopausal women with SLE aged (mean, range) 49 (22–73) years). Variables evaluated were disease duration, SLEDAI, current and cumulative corticosteroid dose, Steinbrocker’s functional classification, use of immunosuppressive agents, and history of fracture due to minor trauma. A T-score of ≤1.0 was found in 61.9% at the LS and 48.3% at the FN, and 18 (23.7%) patients belonged to the category of osteoporosis at LS, compared to only three (5.4%) patients at FN. A statistical difference (P= 0.014) was found when comparing LS BMD in pre- and postmenopausal patients. LS BMD had a significant correlation with daily and cumulative steroid dose (P= 0.016 and 0.031, respectively). There was a significant difference in LS BMD between the daily steroid dose group receiving ≤7.5 and those receiving >7.5 mg/day (P= 0.008), and also in FN BMD comparing groups on 0 and >7.5 mg/day (P= 0.022). There was significant difference in LS and FN BMD between patients in Steinbrocker classes I and III (P= 0.016 and 0.005, respectively). No significant correlation was found in either subgroup between BMD and other studied parameters. We concluded that the prevalence of reduced bone mass at LS is pronounced among postmenopausal women with SLE, in those with a high Steinbrocker functional classification and those on a high daily steroid dose. Therefore, these patients should be considered as a high-risk group deserving regular spinal BMD scans and therapy in time to prevent vertebral fractures. Received: 26 March 2000 / Accepted: 18 September 2001     

A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee

OBJECTIVE: To perform a randomized, double-blind, crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee. METHODS: Patients in 12 ambulatory care settings were eligible if they were age >40 years and if they had Kellgren/Lawrence radiographic grade 2-4 osteoarthritis of the knee or hip and a score of > or =30 mm on a 100-mm visual analog pain scale. Patients were randomized to one of two groups, 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily (each for 6 weeks), and were then crossed over to the other treatment for 6 weeks. A placebo was included in each treatment regimen to enable double blinding. The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Questionnaire. Safety was assessed using a standard form to review adverse events. RESULTS: We enrolled 227 patients, of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods. Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen (P < 0.001). Adverse events were more common when patients took diclofenac + misoprostol (P = 0.046). Diclofenac + misoprostol was rated as "better" or "much better" by 57% of the 174 patients who provided such ratings for both treatment periods, while acetaminophen was rated as "better" or "much better" by 20% of these patients, and 22% reported no difference (P < 0.001). Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores, radiographs, or number of involved joints. CONCLUSION: Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen, although patients with mild osteoarthritis had similar improvements with both drugs. Acetaminophen was associated with fewer adverse events.     

Ginkgo biloba extract EGb 761 attenuates myocardial stunning in the pig heart

Myocardial stunning, a transient contractile dysfunction that appears following a brief period of ischemia, is at least partly due to the production of oxygen-derived free radicals. The objective of the present study was to determine whether the Ginkgo biloba extract EGb761, which has antioxidant properties in vitro, can attenuate myocardial stunning in vivo. Forty-seven anesthetized open-chest farm pigs underwent 10 min of occlusion of the left anterior descending coronary artery (LAD), followed by 3 hours of reperfusion. They were pretreated with either physiological saline, 100 mg or 300 mg of EGb 761 (Protocol I) or 3 mg or 9 mg of ginkgolide B (GkB) (Protocol II). Contractile function was assessed by sonomicrometry. Both doses of EGb 761 significantly improved recovery of contractile function in the reperfused myocardium with segment shortening averaging 23 +/- 5 % of baseline values at 3 hours post-reflow in controls versus 81 +/- 10 % and 57 +/- 12 % in the EGb100 and EGb300 groups, respectively (p < 0.05 vs control in both cases). In contrast, neither dose of GkB improved functional recovery during reperfusion. ESR experiments revealed that EGb761 resulted in a 59 % decrease in myocardial spin-adduct release during reperfusion (p < 0.05 versus control and GkB groups). A significant 28 % decrease (p < 0.05 vs control group) was also obtained in GkB-treated animals. These results indicate that EGb 761 can attenuate myocardial stunning following a brief ischemic insult in the in situ pig heart by an effect that involves a decrease in the formation of free radicals. As the effect of EGb 761 on functional recovery cannot be explained by the presence of GkB, the beneficial action of the extract on myocardial stunning likely involves complementary effects of both its non-ginkgolide and ginkgolide constituents.     

Endoscopic Comparison of the Gastroduodenal Safety and the Effects on Arachidonic Acid Products between Meloxicam and Piroxicam in the Treatment of Osteoarthritis

Our objective was to evaluate the efficacy, the gastroduodenal safety, and the effects on arachidonic acid products of meloxicam, a new acidic enolic non-steroidal anti-inflammatory drug which preferentially inhibits cyclo-oxygenase-2 over cyclo-oxygenase-1, versus piroxicam in patients with osteoarthritis of the knee. Meloxicam 7.5 mg or piroxicam 20 mg daily was administered for 4 weeks in this double-blind parallel-groups randomised study. The efficacy for pain relief of the two tested medications was assessed by means of visual analogue scale and other clinical parameters. Pre- and post-treatment endoscopies were performed, and the findings were scored and recorded. The gastric fluid was aspirated at each time and prostaglandin E₂, thromboxane B₂ and leukotriene B₄ were determined by ELISA. There was no significant difference between the groups regarding the primary efficacy. Changes in endoscopic findings by means of Lanza score showed statistically significant differences between the two treatment groups in favour of meloxicam at all sites – gastric, duodenal and total. Within-group comparisons showed a statistically significant difference (worsening) in gastric and total score with piroxicam, but no significant difference with meloxicam. The frequency of clinically relevant cases (total score >2) also showed a statistically significant worsening in the piroxicam group. The better GI tolerability of meloxicam was also suggested by fewer adverse GI events and no withdrawals due to adverse events compared with piroxicam. The pre-/post-study gastric juice concentration of PGE₂, TXB₂, and LTB₄ in the meloxicam group was 135.2 ± 85.8/71.2 ± 32.2, 116.3 ± 81.7/99.4 ± 107.5 and 388 ± 321/223 ± 98 pg/ml respectively. The pre-/post-study gastric juice concentration of PGE₂, TXB₂ and LTB₄ in the piroxicam group was 105.7 ± 43.1/68.2 ± 34.9, 94.0 ± 50.9/105.9 ± 121.1 and 625 ± 1574/828 ± 1464 pg/ml, respectively. Both meloxicam and piroxicam significantly inhibited gastric PGE₂ levels after 4 weeks’ treatment; however, there was no difference between these two groups. Neither of these medications had an effect on TXB₂. Only meloxicam inhibited LTB₄ concentration significantly, and the between-groups difference was significant. Meloxicam 7.5 mg once daily had better gastrointestinal tolerability and an efficacy comparable to that of piroxicam 20 mg over 4 weeks in patients with osteoarthritis of the knee. Received: 18 April 2000 / Accepted: 17 August 2000     

N-acetyl-beta-d-glucosaminidase Urinary Excretion as an Early Indicator of Kidney Damage in Rheumatoid Arthritis Patients Starting on Parenteral Gold and Depo-Medrone/Placebo Injections

The purpose of the study was to determine the effect of initiation of gold therapy on glomerular and tubular integrity. Urine albumin was used as a marker of glomerular damage. N-acetyl-beta-d-glucosaminidase (NAG) urinary excretion served as an indicator of proximal tubular damage. This study was an adjunct to a clinical trial that investigated the safety and the efficacy of Depo-Medrone during the induction phase of gold therapy. The NAG activities and albumin levels in the urine of 36 patients with active rheumatoid arthritis treated with sodium aurothiomalate weekly up to a total of 1 g were investigated. NAG was assayed in 565 early morning urine samples of these patients at weekly intervals for 24 weeks. The mean NAG level rose from 50.2 nmol/mg of creatinine on entry to peak NAG excretion of 120.4 nmol/mg of creatinine at week 4 and then fell to 56.3 nmol/mg of creatinine at week 24. Urinary albumin was assayed in 252 early morning urine samples at monthly intervals during gold treatment. Values greater than 20 mg/l were observed in 7.5% of urine samples. Microalbuminuria was present in 9% of patients at baseline. Two patients who were withdrawn because of proteinuria and macroalbuminuria had normoalbuminuria on entry. We conclude that raised levels of NAG associated with tubular damage are more frequent than glomerular damage on entry to, and during, treatment with gold salts. Received: 26 January 1998 / Accepted: 27 July 1998     

Intravenous Cyclophosphamide Pulse Therapy for the Treatment of Lung Disease Associated with Scleroderma

Until recently, renal crisis was the most significant cause of morbidity and mortality in patients with scleroderma (SSc). Nowadays, following the introduction of angiotensin-converting enzyme inhibitors used in renovascular hypertension, pulmonary fibrosis and pulmonary hypertension have become the most common causes of death in SSc. Consequently, the early diagnosis and treatment of pulmonary fibrosis is essential to improve morbidity and mortality in SSc patients. The aim of this study was to investigate the effect of intravenous cyclophoshamide pulse therapy in patients with SSc and evidence of active alveolitis assessed on a high resolution computed tomographic (HRCT) scan, and to compare the effect of cyclophosphamide pulse therapy with oral therapy. Sixteen consecutive patients with SSc were allocated alternately to the two treatment groups. Eight patients were treated with monthly cyclophoshamide pulse therapy (750 mg/m²) for 12 months; the other eight patients were treated with oral cyclophosphamide (2–2.5 mg/kg/day) for the same period. All patients received concurrently prednisone (10 mg/day). Pulmonary function tests and HRCT scans were performed before therapy and at 6 and 12 months. In the oral cyclophosphamide group, three patients with a grade I pattern showed regression of disease extent. In the other five patients (one with grade II and four with grade III) the pattern and extent of disease remained stable during the study. No statistical differences were found in forced expiratory volume in 1 s, forced vital capacity and total lung capacity during the study period. The diffusing capacity for carbon monoxide increased significantly between baseline and 12 months (p= 0.043). In the cyclophosphamide pulse therapy group, seven patients with a grade I pattern showed regression of disease extent at 6 months (p= 0.018) and 12 months (p= 0.012). One patient with grade III remained stable during the study. In both groups the regression of the extent of disease estimated on HRCT was due to a decrease in the ground glass appearance. The extent of the reticular appearance remained stable throughout the study. Our results indicate that cyclophosphamide pulse therapy is effective in suppressing active alveolitis (ground glass appearance). Although in this study it is not possible to compare pulse therapy with oral therapy because of the different pattern seen on HRCT between the two groups, it seems that oral therapy is also effective in suppressing active alveolitis. Neither regimen improved pulmonary involvement when the reticular appearance predominated over the ground glass appearance on HRCT. It is concluded that either pulse or oral cyclophosphamide therapy may improve the outcome of SSc patients. Received: 10 November 1998 / Accepted: 4 April 1999     

Role of angiotensin II AT1 and AT2 subtype receptors in the regulation of atrial natriuretic peptide expression in salt-restricted rats

Previous studies have suggested that angiotensin II modulates ANP secretion and this action appears to be largely independent from its hemodynamic effects. In order to explore the contribution of angiotensin II AT₁ (AT₁r) and AT₂ (AT₂r) receptor subtypes in the regulation of cardiac ANP, we studied the effects of selective antanonists of these receptors on ANP mRNA levels in the cardiac chambers of salt-restricted rats. Thirty-one Sprague-Dawley rats (12 weeks-old) weighing 250–350 g were studied during a low salt regimen and randomly assigned to the following treatment groups: AT₁r-blockade (losartan) (10 mg7kg/day) (n = 18), AT₂r-blockade (PD123319) (50 μg/kg/min) (n = 6), Control (salt-restriction) (n = 7). Treatments were maintained for 7 days; subsequently 12 rats from the AT₁r-blockade group were subdivided in to two groups: AT₁r-blockade (losartan+PD123319) (n = 6) and AT₁r-blockade/vehicle (losartan-vehible) (n = 6), and treated for 7 additional days. Systolic blood pressure was significantly reduced by AT₁r-blockade (p < 0.001), while it was not affected by AT₂r-blockade. Concomitant treatment with both antagonists (AT₁r/AT₂r-blockade) restored blood pressure values to baseline (p < 0.001 vs. AT₁r-blockade, p = n.s. vs Control). Atrial ANP mRNA was reduced by AT₁r-blockade (-42%, p < 0.05) and did not change during AT₂r-blockade alone. On the contrary, concomitant treatment with both antagonists resulted in a further significant inhibition of ANP expression (-65% and -36% vs Control and AT₁r-blockade, respectively, both p < 0.05). ANP expression in ventricles was not affected by any of these treatments. Our results demonstrate that angiotensin II tonically modulates cardiac ANP expression in our experimental model. In particular, angiotensin II receptor subtypes AT₁r and AT₂r regulate atrial ANP mRNA levels through a synergic action and independently from blood pressure changes. Received: 26 May 1999, Returned for revision: 17 June 1999, Revision received: 4 August 1999, Accepted: 26 August 1999     

Patients with Fibromyalgia Benefit from Aerobic Endurance Exercise

Fibromyalgia (FM) is a disorder characterised by diffuse widespread musculoskeletal aching and stiffness and multiple tender points [1]. Its pathophysiology is poorly understood. The influence of aerobic endurance exercise on pain in patients with FM was investigated. Twenty-seven patients (25 female, 2 male) participated in a controlled clinical study and performed 12 weeks of jogging, walking, cycling or swimming following a given schedule. Twelve sedentary FM patients (11 female, 1 male) served as controls. Before and after training both the study and the control groups were evaluated spiroergometrically. Tender point pain was quantified by dolorimetry. The painful body surface was estimated by a pain body diagram, and its intensity by a visual analogue scale and a ranking scale. Patients trained for an average of 25 min two to three times a week, with an average intensity of 50% of maximal oxygen uptake (VO_2max). Unlike the control group, the training group exhibited a decrease in heart rate and VO₂ and an increase in respiratory quotient during submaximal workload. Maximal performance capacity and VO_2max remained unchanged, whereas the wattpulse (watt/heart rate) improved at maximal workload. Pain parameters remained unchanged in the control group, but in the training group the mean number of positive tender points (15.4/12.7), the mean pain threshold of the gluteal tender point (2.89 kp/3.50 kp) and the painful body surface (18%/15% body surface) decreased significantly. Subjective general pain condition deteriorated in two patients but improved in 17. Our results suggest a positive effect of aerobic endurance exercise on fitness and well-being in patients with FM. Received: 24 February 1999 / Accepted: 23 September 1999     

THE GASTRODUODENAL SAFETY AND EFFICACY OF THE FIXED COMBINATION OF DICLOFENAC AND MISOPROSTOL IN THE TREATMENT OF OSTEOARTHRITIS

A double-blind, randomized, parallel group study was conductedto compare the gastroduodenal safety and antiarthritic efficacyof a fixed combination of diclofenac 50 mg and misoprostol 200tg with that of a combination of diclofenac 50 mg and placeboin patients with osteoarthritis. Three hundred and sixty-onepatients with no significant gastroduodenal lesions were enrolledand received study medication two or three times daily for 4weeks. Post-treatment endoscopic examination of the gastroduodenalmucosa revealed ulcers in 4% of patients in the diclofenac/placebogroup compared with none in the diclofenacimisoprostol group(P=0.015). There were no clinically or statistically significantdifferences between the two treatment groups in formal assessmentsof osteoarthritis after either 2 or 4 weeks. It was concludedthat diclofenadmisoprostol was associated with significantlyless gastroduodenal damage than diclofenac, whilst being aseffec tive as diclofenac alone in the treatment of osteoarthritis. KEY WORDS: Gastroduodenal safety, Diclofenac, Misoprostol, NSAIDs, Osteoarthritis, Ulcers     

Calcitonin versus Clodronate in the Prevention of Ovariectomy-Induced Osteopenia in Rats

The effects of salmon calcitonin and clodronate were compared in ovariectomised rats. Sixty female Wistar rats (∼260 g in weight) were fed the same diet and had the same living conditions. The rats were divided into the following groups: 15 rats with sham ovariectomy and no drug treatment (Sham-OVX); 45 rats with bilateral ovariectomy subdivided into 15 rats not receiving drug treatment (OVX group), 15 rats treated with subcutaneous salmon calcitonin, 2 U/kg/day every 2 days (OVX + CT group) and 15 rats treated with subcutaneous clodronate, 5 mg/kg/day every 2 days (OVX + Cl group). Sixty days after surgery, the rats were sacrificed and their femurs and fifth lumbar vertebrae were dissected and cleaned of soft tissue. Femur length, vertebral height, and bone mineral content and bone mineral density of the femur and fifth lumbar vertebra by dual-energy X-ray absorptiometry were measured. Calcitonin had a significant and stronger effect in preventing ovariectomy-induced osteopenia in the femur (OVX + CT vs OVX groups, p<0.0001); both calcitonin and clodronate had a significant effect on the fifth lumbar vertebra, which was greater in the calcitonin group (OVX + CT vs OVX + Cl groups, p<0.005). These findings indicate that calcitonin has a protective effect on both the axial (trabecular bone) and peripheral (cortical bone) skeletons, but clodronate only has a protective effect on the axial skeleton. Received: 28 May 1999 / Accepted: 29 July 1999