Detection of low dose of piroxicam polymorph in pharmaceutical tablets by surface-enhanced Raman chemical imaging (SER-CI) and multivariate analysis.

This study demonstrates, for the first time, the ability of surface-enhanced Raman chemical imaging (SER-CI) combined with multivariate analysis to detect low levels (0.1% (w/w)) of a polymorphic form in a pharmaceutical mixture. In the studied formulation, piroxicam was used as a model molecule to develop this approach. Piroxicam is a widely available non-steroidal anti-inflammatory drug, exhibiting an interesting case of polymorphism, with two most commonly observed forms (ß and α2). In this work, the SERS spectra of piroxicam polymorphic forms ß and α2 are presented. These forms showed clear spectral differences in terms of band position and intensity. From a crystallographic point of view, the difference of exaltation between both forms was correlated with a preferred orientation of crystallites of form α2 making its SERS detection difficult compared to form ß. A preferred orientation of the (1k0) crystallographic planes of α2 was demonstrated in samples, not promoting an appropriate molecular orientation onto the metallic surface. Additionally, a semi-quantitative approach using SER-CI combined with chemometric tools was developed enabling to detect crystallites of form ß below the detection limit of conventional Raman microscopy. The exaltation of the Raman signal in the presence of silver nanoparticles allowed a higher sensitivity and a reduction of the acquisition time by a factor of 6.

Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review.

OBJECTIVE: To report on the effectiveness of cyclophosphamide (CYC) to treat glucocorticoid (GC)-dependent giant-cell arteritis (GCA) and/or severe GC-related side effects. METHODS: Fifteen patients with GCA and treated with CYC were retrieved from the computerized patient-record system. Glucocorticoid dependence was defined as a prednisone dose of >20mg/day for 6 months or >10mg/day for 1 year in order not to relapse. Response to CYC was defined as improved clinical and biological findings. Remission was defined as a sustained absence (>12 months) of active signs of vasculitis at a daily GC dose of <7.5mg. A literature review searched PubMed for all patients diagnosed with GCA and who received CYC. RESULTS: Our 15 patients responded to monthly pulses of CYC, and all experienced a GC-sparing effect, including five patients who discontinued GC long term. At a median follow-up of 43 (range: 14-75) months after CYC, nine (53%) patients were still in remission and six (40%) had relapsed at 6 (3-36) months after the last CYC infusion. Twelve (80%) patients experienced side effects, leading to discontinuation of CYC in two (13%). A literature review retrieved 88 patients who received CYC: 66 for GC-dependent disease, 53 for GC toxicity, and 14 for severe organ involvement. Their median follow-up time was 24 (4-60) months. Among the 88 patients, 74 (84%) were responsive to CYC and 17 (19%) relapsed, although all were receiving a maintenance therapy with immunosuppressive agents (such as methotrexate). Twenty-nine (33%) patients experienced side effects and 11 (12.5%) discontinued treatment. CONCLUSION: Cyclophosphamide is an interesting option for GCA patients with GC-dependent disease or with severe GC-related side effects, especially when conventional immunosuppressive agents have failed.

[Periostitis in systemic necrotizing vasculitides: Study of the 4 cases identified among the 1762 patients of the FVSG database and review of the literature]. / Périostéite au cours des vascularites systémiques nécrosantes : à propos de 4 observations d'une atteinte méconnue et pourtant évocatrice.

BACKGROUND: Periostitis (periosteal new bone formation) is a rare manifestation of systemic necrotizing vasculitis. PATIENTS AND METHODS: We searched the French Vasculitis Study Group (FVSG) database, established in 1980 and containing the data on 1762 patients with a systemic necrotizing vasculitis, i.e., polyarteritis nodosa (PAN), microscopic polyangiitis, Churg-Strauss syndrome or Wegener's granulomatosis, for those with periostitis. Herein, we describe their characteristics and outcomes. RESULTS: Only 4 patients with periostitis were identified. All had limited and localized PAN-like vasculitis, without poor prognosis factors. Periostitis was painful and localized to the lower limbs in all of them and associated with local myositis in 2. Pain and inflammation resolved under corticosteroids in all, but relapses or corticosteroid-dependence ultimately required the adjunction of an immunosuppressant for 3. With a median follow-up of 10 [range: 4-11] years, only 1 developed peripheral neuropathy and none progressed to a more systemic form of vasculitis, i.e., with severe visceral involvement. DISCUSSION AND CONCLUSIONS: Physicians should be aware that periostitis, usually localized, is a potential manifestation of systemic necrotizing vasculitis, especially polyarteritis nodosa. The overall long-term outcome of these patients is good, but relapses or corticosteroid-dependence is frequent.

Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: A prospective randomized study of one hundred twenty-four patients.

OBJECTIVE: To assess the efficacy of systemic corticosteroids alone as first-line treatment of polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA) without poor-prognosis factors as defined by the Five-Factors Score (FFS), and to compare the efficacy and safety of azathioprine versus pulse cyclophosphamide as adjunctive immunosuppressive therapy for patients experiencing treatment failure or relapse. METHODS: This prospective, multicenter, therapeutic trial included 124 patients with newly diagnosed PAN or MPA (FFS of 0) treated with corticosteroids alone. At the time of treatment failure or disease relapse, patients were randomized to receive 6 months of therapy with oral azathioprine or 6 pulses of cyclophosphamide. Analyses was performed according to an intent-to-treat strategy. RESULTS: The mean +/- SD followup period was 62 +/- 33 months. Treatment with corticosteroids alone induced remission in 98 patients; 50 (40%) of these patients had sustained disease remission, 46 (37%) experienced a relapse, and 2 became corticosteroid dependent (daily prednisone dose > or = 20 mg). In 26 patients (21%), treatment with corticosteroids alone failed, and 49 patients (40%) required additional immunosuppression. Among the 39 patients randomized, 13 of 19 achieved remission with cyclophosphamide pulses, and 14 of 20 achieved remission with azathioprine. Among all patients, the 1-year and 5-year survival rates were 99% and 92%, respectively. Six deaths occurred in the cyclophosphamide-treated group compared with 2 deaths in the azathioprine-treated group. Disease-free survival was significantly lower for patients with MPA than for those with PAN (P = 0.046). CONCLUSION: For patients with PAN or MPA with an FFS of 0, overall 5-year survival was good, but first-line corticosteroid treatment was able to achieve and maintain remission in only about half of the patients, and 40% of the patients required additional immunosuppressive therapy. Azathioprine or pulse cyclophosphamide was fairly effective for treating corticosteroid-resistant disease or major relapses.

Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients.

OBJECTIVE: To assess the efficacy of systemic corticosteroids (CS) alone as first-line treatment in patients with Churg-Strauss syndrome (CSS) without poor-prognosis factors, as defined by the Five-Factors Score (FFS), and to compare the efficacy and safety of oral azathioprine (AZA) versus intravenous pulse cyclophosphamide (CYC) as adjuvant immunosuppressive therapy for treatment failure or relapse. METHODS: This multicenter, prospective, randomized, open-label therapeutic trial included 72 patients with newly diagnosed CSS (FFS of 0) treated with CS alone. At treatment failure or relapse, patients were randomized to receive 6 months of oral AZA or 6 pulses of CYC. Analyses were performed according to an intent-to-treat strategy. RESULTS: The mean +/- SD followup was 56.2 +/- 31.7 months. Among the 72 patients studied, 93% achieved remission with CS therapy alone, and 35% relapsed, mainly during the first year of treatment. Among the 19 patients randomized to additional immunosuppression because of treatment failure or relapse, 5 of 10 receiving AZA and 7 of 9 receiving pulse CYC achieved remission, but the difference was not statistically significant. Survival rates in all patients at 1 and 5 years were 100% and 97%, respectively. At the end of followup, 79% of the patients whose disease was in remission required low-dose CS therapy, mainly to control respiratory disease. CS-related adverse events were observed in 31% of the 72 patients. CONCLUSION: In CSS patients with an FFS of 0, survival was excellent, confirming the predictive value of the FFS in this disease. First-line therapy with CS achieved remission in most patients, but relapses were common, and one-third of them required additional immunosuppressive therapy. AZA or pulse CYC was fairly effective in treating CS-resistant disease or major relapses. Over the long term, most patients continued to take oral CS, which might explain the high rate of CS-related adverse events.