Retreatment and maintenance therapy with infliximab in fistulizing Crohn's disease.

OBJECTIVES: Infliximab has clearly demonstrated its efficacy in the short-term treatment of fistulizing Crohn's disease. We present here the results of retreatment and long-term maintenance therapy. PATIENTS AND METHODS: Eighty one consecutive patients with active fistulizing Crohn's disease, in whom previous treatments had failed, were treated with infliximab. All patients received as the initial treatment of 5 mg/kg i.v. infusions (weeks 0, 2, and 6). Those patients who failed to respond after the initial cycle (group 1, n = 25), or those who relapsed after having responded (group 2, n = 13), received retreatment with three similar doses (weeks 0,2, and 6). Those who responded to retreatment were included in a long-term maintenance programme (n = 44), with repeated doses (5 mg/kg i.v. infusions) every eight weeks for 1-2 years. RESULTS: In the initial treatment 56% of the patients responded partially; this response being complete in 44%. In the retreatment, 28% of group 1 (non-responders) presented a complete response, compared to 77% in group 2 (relapsers) (p < 0.0001). In the maintenance treatment, the global response was 88% (39/44). The mean number of doses per patient was 4.4 +/- 2 (range 1-9) with a duration of 36 +/- 12 weeks (range 8-72). Adverse effects were not significantly increased in either treatment. CONCLUSIONS: Both retreatment and long-term maintenance therapy with infliximab, are highly effective and well tolerated in fistulizing Crohn's disease patients.

Mesoporous SBA-15 HPLC evaluation for controlled gentamicin drug delivery.

Mesoporous silica SBA-15 was prepared to evaluate its application as gentamicin drug delivery system. Two procedures were used to evaluate the delivery: calcined powder and disk conformed. The samples were charged with gentamicin sulphate and the experiments were carried out in vitro. No significant difference between powder and disk was observed in the tests. The release profiles exhibited a pronounced initial burst release effect of 60%, followed by a very slow release pattern. A new HPLC method was employed for calculated gentamicin amount in the delivery test. This method requires a small amount of sample, very advisable in these kinds of assays.

In vitro bioactivity of silicon-substituted hydroxyapatites.

Silicon-containing hydroxyapatites were synthesized by the controlled crystallization method. Chemical analysis, N(2) adsorption, Hg porosimetry, X-ray diffraction, scanning electron microscopy-energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy (XPS) were used to characterize the hydroxyapatite and to monitor the development of a calcium phosphate layer onto the surface of the substrate immersed in a simulated body fluid, that is, in vitro bioactivity tests. The influence of the silicon content and the nature of the starting calcium and phosphorus sources on the in vitro bioactivity of the resulting materials were studied. A sample of silicocarnotite, whose structure is related to that of hydroxyapatite and contains isolated SiO(4) (4-) anions that isomorphically substitute some PO(4) (3-) anions, was prepared and used as reference material for XPS studies. An increase of the unit cell parameters with the Si content was observed, which indicated that SiO(4) (4-) units are present in lattice positions, replacing some PO(4) (3-) groups. By using XPS it was possible to assess the presence of monomeric SiO(4) (4-) units in the surface of apatite samples containing 0.8 wt % of silicon, regardless the nature of the starting raw materials, either Ca(NO(3))(2)/(NH(4))(2)HPO(4)/Si(OCOCH(3))(4) or Ca(OH)(2)/H(3)PO(4)/Si(OCOCH(3))(4). However, an increase of the silicon content up to 1.6 wt % leads to the polymerization of the silicate species at the surface. This technique shows silicon enrichment at the surface of the three samples. The in vitro bioactivity assays showed that the formation of an apatite-like layer onto the surface of silicon-containing substrates is strongly enhanced as compared with pure silicon-free hydroxyapatite. The samples containing monomeric silicate species showed higher in vitro bioactivity than that of silicon-rich sample containing polymeric silicate species. The use of calcium and phosphate salts as precursors lead to materials with higher bioactivity.

Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation.

We present the case of a 63-year-old woman who had undergone 7 months of treatment with Nimesulide (100 mg/b.i.d.) for symptomatic osteoarthritis. The patient was admitted to our unit with a clinical picture of progressive jaundice over 3 weeks. Clinical and analytical studies revealed acute liver failure, this being confirmed by liver biopsy, which showed submassive necrosis. Serological tests for different viral agents causing hepatitis were all negative. In addition, she presented a picture of severe haemolytic anaemia resistant to several treatments and needed multiple transfusions. Twenty-three days after admission, the patient presented hepatic encephalopathy and received an orthotopic liver transplant on day 25. The evolution after transplantation was good and the patient continues in good health with no evidence of haemolysis almost 2 years later. Liver toxicity due to Nimesulide is well known, but to our knowledge the occurrence of haemolytic anaemia has not been related to this drug previously. For these reasons, Nimesulide has been restricted or removed from the market in several countries in recent months.

High serum tumor necrosis factor-alpha levels are associated with lack of response to infliximab in fistulizing Crohn's disease.

OBJECTIVES: Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor-alpha (anti-TNF-alpha), has been effective in the treatment of patients with active Crohn's disease and with fistulas. We investigated the effect of infliximab on circulating cytokines and acute phase proteins in patients with fistulas to determine the clinical response to anti-TNF-alpha. METHODS: A total of 36 patients with fistulizing Crohn's disease were selected for study. Serum from patients was drawn before the infusion on day 0 and at wk 2, 4, 6, 8, and 10 after completion of treatment. Circulating concentrations of TNF-alpha, interleukin-1beta (IL-1beta), and IL-6 were measured by ELISA. The functional activity of circulating TNF-alpha was assessed by the WEHI 164 TNF-alpha bioassay. Acute phase proteins were also determined. RESULTS: Elevated TNF-alpha, IL-1beta, IL-6, and acute phase proteins were observed in patients with Crohn's disease. Of the patients with fistulas, 22 (61.1%) responded to treatment. Before receiving infliximab, higher levels of serum TNF-alpha were found in patients who did not respond to infliximab compared with those who did (median interquartile range 26, 0-245 pg/ml; n = 14 vs 0, 0-22 pg/ml, n = 22). Patients showed no change in circulating levels of TNF-alpha during the course of the study. CONCLUSIONS: This treatment produces a clinical improvement in about two-thirds of CD patients with fistulas. The circulating levels of TNF-alpha are associated with the response to infliximab and could help to identify patients who would benefit from anti-TNF-alpha treatment.

Evolution of porosity during in vitro hydroxycarbonate apatite growth in sol-gel glasses.

A bioactive glass of composition (mol %) SiO(2) 58, CaO 36, P(2)O(5) 6 was obtained using the sol-gel method. Changes in porosity during the growth of a hydroxycarbonate apatite (HCA) phase were studied at different stages of the process. The high Ca (II) content led to a higher degree of porosity and enhancement of Ca(2+) released from surface and bulk when the glass was soaked into simulated body fluid (SBF). Saturation of the media (SBF) together with the porosity of the material led to fast growth of HCA on the surface and into the pores.

Influence of composition and surface characteristics on the in vitro bioactivity of SiO(2)-CaO-P(2)O(5)-MgO sol-gel glasses.

Glasses in the system SiO(2)-CaO-P(2)O(5)-MgO were prepared by the sol-gel method. These glasses featured SiO(2) contents in the range 60-80 mol %, 4 mol % of P(2)O(5), and a CaO/MgO molar ratio of 4. Because of their composition and surface properties, all the glasses showed in vitro bioactivity, as evidenced by the formation of an apatite-like layer on their surface when soaked in an acellular medium with ionic composition similar to human blood plasma. An increase in the CaO content of the glasses also caused an increase in their porosity. Higher porosity facilitated the apatite nucleation on the sample surface during the first days of the in vitro test. On the other hand, those glasses with higher SiO(2) content also showed higher surface area values, as well as higher calcium phosphate layer growth rates. For longer soaking periods, the grown layer was analyzed, revealing a two-phase composition: apatite and whitlockite.

A solid-state NMR study of the molecular sieve VPI-5 synthesized in the presence of a CTABr surfactant.

Silicon-free and silicon-rich large-pore aluminophosphate VPI-5, synthesized with various contents of AIPO-H3 impurity, was studied by Bloch decay (BD) and cross polarization (CP) NMR under magic angle spinning (MAS). The 1H-->31P CP peaks were considerably stronger from AIPO-H3 than from VPI-5. A detailed examination of the CP kinetics and a careful comparison of the CP and BD spectra are prerequisites for the unequivocal interpretation of 1H-->31P CP in porous aluminophosphates.

Solid-state NMR study of ordered mesoporous aluminosilicate MCM-41 synthesized on a liquid-crystal template.

A novel mesoporous aluminosilicate MCM-41, synthesized in a liquid-crystal system, was characterized by magic angle spinning NMR. Conventional Bloch decay and cross-polarization spectra were compared. The 27Al spectra showed that the calcined material was highly siliceous, while 29Si NMR proved that it was rich in single and geminal silanol groups. Two kinds of the silanol groups were detected: exchanging and non-exchanging protons with water on the timescale of the 1H experiment. The 13C spectra of the uncalcined material were consistent with the concept of the micellar arrangement of the cetyltrimethylammonium template inside MCM-41.