Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug.

OBJECTIVE: To evaluate the short-term efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis (AS). METHODS: The study was a 6-week randomized, double-blind, placebo-controlled trial with 3 treatment arms: placebo, ketoprofen 100 mg twice daily, and celecoxib 100 mg twice daily. Patients who had AS according to the modified New York criteria, without peripheral synovitis and with active disease (pain > or =40 mm on a 100-mm visual analog scale [VAS] and an increase in pain of at least 30% after nonsteroidal antiinflammatory drug withdrawal) were eligible for study. Primary outcome measures were change in pain intensity (VAS) and change in functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI]). RESULTS: Of the 246 randomized patients, 76 were allocated to receive placebo, 90 ketoprofen, and 80 celecoxib. There were no statistically significant differences between treatment groups at study entry. During the 6 weeks of the study, the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group, with a trend in favor of celecoxib when the 2 active treatments were compared. The mean changes were -13 mm, -21 mm, and -27 mm (P = 0.006) for pain and 1, -6, and -12 (P = 0.0008) for BASFI score in the placebo, ketoprofen, and celecoxib groups, respectively. During treatment, the number of patients reporting epigastric pain was 6 (8%), 13 (14%), and 10 (13%) in the placebo, ketoprofen, and celecoxib groups, respectively. CONCLUSION: The results of this study confirm the clinically relevant antiinflammatory effect of celecoxib at a 200-mg daily dosage, with significant improvement of both pain and function in patients with AS.

Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes.

OBJECTIVE: HOE 901 (Hoechst Marion Roussel, Frankfurt, Germany) is a biosynthetic insulin with a prolonged action. The aim of this study was to compare the effect of the long-acting insulin analog HOE 901 with NPH insulin regarding glycemic control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 333 type 1 diabetic patients were enrolled in this multinational parallel group trial. Subjects were randomized either to two different formulations of HOE 901 (the formulations differed only in zinc content) or to NPH insulin. The study was only partially blinded because patients can distinguish HOE 901 (a clear solution) from NPH (a cloudy suspension). In addition to premeal injections of regular insulin, patients received HOE 901 at bedtime or NPH once daily at bedtime or twice daily in the morning and at bedtime. RESULTS: Fasting plasma glucose levels were significantly lower with HOE 901 (-1.88 mmol/l. P = 0.0005) as were fasting self-monitored blood glucose levels (-0.80 mmol/l, P = 0.0020). HbA1c levels also showed a significant reduction with HOE 901 (-0.14%) versus NPH (P = 0.030). The overall frequency of hypoglycemia did not differ, but the frequency of nocturnal hypoglycemia was significantly (P = 0.0037) lower with HOE 901 (36 vs. 55%). However, this effect on nocturnal hypoglycemia was significant only versus NPH once daily not NPH twice daily. The pattern of adverse events and injection site reactions with HOE 901 was similar to that with NPH. CONCLUSIONS: This study indicates that HOE 901 achieves better control of fasting glucose and HbA1c levels over 4 weeks, and HOE 901 has a possible safety benefit in terms of nocturnal hypoglycemia.

Prevention studies with pentoxifylline: new clinical projects.

Pentoxifylline (PTX) is a methylxanthine derivative whose diverse mechanisms of action are now extensively documented. It may play a role in various diseases via a pharmacologic modification of cytokine dysregulation. Despite many encouraging results in animal models, it has not yet been demonstrated that PTX could have beneficial effects in other diseases than intermittent claudication. We selected three clinical conditions that may benefit from PTX and are trying to clarify its potential for use in these disorders. The use of allogeneic bone marrow transplantation is limited by its toxicity, although this form of therapy is able to cure many hematologic malignancies. We are performing a placebo-controlled trial to evaluate the ability of PTX to decrease transplant-related toxicity. In severe chronic respiratory insufficiency, a study is ongoing to compare the number of infectious exacerbations under PTX or placebo. Finally, we have planned a long-term prevention study in patients with peripheral arterial disease. We present here the rationale and design of these trials.

[Phase I trial of recombinant human granulocyte-macrophage colony stimulating factor. Results in patients with advanced tumors]. / Essai de phase I d'un granulocyte-macrophage colony-stimulating factor (GM-CSF) humain recombinant. Résultats chez des malades atteints de tumeurs solides.

Fourteen patients with advanced solid tumors were included in a phase I trial of recombinant human E coli derived granulocyte-macrophage colony-stimulating factor (GM-CSF) given daily subcutaneously for 10 consecutive days. Dose levels were increased from 250 micrograms/m2 to 500, 750 and 1,000 micrograms/m2. Adverse effects were mainly fever, local irritation, lethargia, arthalgia. Three patients did not complete the 10-day cycle: one patient died due to progressive disease without toxic effects related to GM-CSF, one was withdrawn because of suspicion of pulmonary embolism (not confirmed), one patient had hypotension, not recurring after treatment with GM-CSF. Although the maximum tolerated dose was not reached, the trial was stopped at 1,000 micrograms/m2, considering the satisfactory response and the high white blood cell counts observed with lower dose levels. N-fold increases of leucocyte count ranged between 4.2 and 8.2 for the first dose level (250 micrograms/m2), 4 and 10.1 for 500 micrograms/m2, 8.5 and 12.3 for 750 micrograms/m2 and 5.6 and 8.3 for 1,000 micrograms/m2. Increases of granulocyte, neutrophil and eosinophil counts had a similar pattern with a weaker response at 1,000 micrograms/m2 (two patients who completed the cycle). In contrast, even for the first three levels, no dose response relationship was shown for increases of monocytes (between 2.8 and 12 n-fold whatever the dose), or lymphocytes (between 1.7 and 10.7 n-fold whatever the dose). Decreases of platelets (between 6 and 55%) were observed, followed by a rebound after stopping treatment. No modifications of erythrocyte count were observed. Subcutaneous GM-CSF was well-tolerated up to 1,000 micrograms/m2 during a 10-day course. Hematological effects were observed from the first dose level of 250 micrograms/m2.

GM-CSF instead of autologous bone-marrow transplantation after the BEAM regimen.

Five patients with resistant non-Hodgkin lymphoma (NHL) were given granulocyte-macrophage colony-stimulating factor (GM-CSF, 250 micrograms/m2 daily) after the BEAM pretransplant chemotherapy regimen (carmustine 300 mg/m2, etoposide 1.2 g/m2, cytarabine 800 mg/m2, melphalan 140 mg/m2) because persistent lymphoma cell infiltration of the bone marrow precluded autologous bone-marrow transplantation (BMT). In three patients full haemopoietic reconstitution occurred, with similar kinetics to that seen after autologous BMT. The other two patients died without sustained haemopoietic recovery. GM-CSF may replace autologous BMT in highly selected cases of NHL with progressive disease and bone-marrow involvement.

Pentoxifylline, fibrinogen and leukocytes.

Pentoxifylline has been reported to induce a decrease in plasma fibrinogen level in patients with arteritis. We report here ex vivo experiments in both healthy volunteers and patients with arteritis. In patients we have confirmed the decrease in plasma fibrinogen level during pentoxifylline therapy, and shown that the decrease is correlated with the improvement of the clinical symptoms, whereas no significant modification was noted in the healthy volunteers taking pentoxifylline. Therefore it is suggested that the decrease in fibrinogen induced in patients was due to an indirect mechanism, probably related to the pentoxifylline-induced decrease in TNF synthesis.