A phase II study of high-dose celecoxib and metronomic 'low-dose' cyclophosphamide and methotrexate in patients with relapsed and refractory lymphoma

BACKGROUND AND OBJECTIVESRelapsed, histologically aggressive non-Hodgkin lymphoma (NHL) has a poor prognosis; relapsed patients who do not respond to second line therapy or are unfit for BMT have a worse prognosis. Angiogenesis is increased in aggressive NHL and could be targeted by selective cyclooxygenase-2 inhibition and metronomic chemotherapy. We assessed the toxicity of metronomic chemotherapy and the response and progression-free survival in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).PATIENTS AND METHODSWe prospectively studied 41 patients with a diagnosis of relapsed and/or refractory DLBCL who may have received any number of preceding therapies (as long as one included an anthracycline) and were not candidates for bone marrow transplantation. They received oral cyclophosphamide (50mg every day), oral methotrexate (2.5mg 4 times/week) and high-dose oral celecoxib (400mg twice daily) until there was disease progression or unacceptable toxicity.RESULTSAll 41 patients (median age, 56 years) were evaluable for toxicity and response, with a median follow up of 9.1months (range, 4-35 months). At relapse, 51.2% had a high international prognostic index. The treatment protocol was well tolerated with no major toxicities. The most common toxicities were fatigue (61%), nausea (22%), neutropenia (19.5%), and anemia (22%). In 31.7% there was a partial response and 48.8% had stable disease. Progression-free survival was 12 months. The median response duration was 10 months.CONCLUSIONSWe conclude that metronomic chemotherapy can be used for patients with relapsed and or refractory DLBCL with reasonable outcome and acceptable toxicity. Standard approaches such as hematopoietic stem cell transplantation and chemo-immunotherapy combinations should be explored prior to a decision on metronomic chemotherapy

2-Hydroxypropyl-ß-Cyclodextrin Complex with Ketotifen Fumerate for Eye Drops Preparations

Ketotifen fumerate ophthalmic solution is an antihistaminic drug. The aim of this study was to develop a novel aqueous ketotifen eye drop formulation containin ketotifen/2-Hydroxypropyl-β-cyclodextrin complex, which has the ability to enhance the solubility of the drug at the physiological pH (7.4), consequently decreasing the irritation to the eye. Moreover, increaseing the fraction of the unionized drug leads to enhancing the permeability of the drug through the cornea. The stability constant was determined from phase-solubility diagrams and found to be higher with KF/HP-ß-CD complex (29.47 M−1) than KF/ß-CD complex (10.36 M−1). Differential scanning calorimetry (DSC), fourier transform-infrared (FT-IR) spectroscopy and X-ray analysis (X-ray) showed the formation and the physiochemical proporties of the complex. The effect of different additives including; antioxidants, isotonicity adjusting agents and preservatives on the stability of ketotifen fumerate solution were studied. Sodium ascorbate (0.1%w/v) showed a significant increase in the stability of the KF solutoion. Fluid thioglycolate medium and Tryptic Soy Broth were used as a medium to test of sterility of selected formulations to detect aerobic, anaerobic and fungal contamination and verified that no turbidity or surface growth was observed during the incubation period of all tested formulae. Finally, the chemical stability using the stability indicating HPLC assay showed that the stability of the selected formulation were significantly higher in comparison to that of a commercial product (Zaditen® eye drops Novartis Pharma-Egypt) (p>0.05). These results indicate that KF/HP-ß-CD eye drops formulation is a promising (formulation) resulting in enhancing the solability, stability and permeability of the drug.Keywords: Ketotifen Fumerate; 2-Hydroxypropyl-ß-cyclodextrin; Inclusion complex; Solubility; Stability

Sputum epithelial cell-derived neutrophil-activating peptide-78 (ENA-78/CXCL5) in asthmatic children: relation to eosinophil activation

Background: Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) is a chemokine that recruits and activates neutrophils, possesses angiogenic properties and promotes connective tissue remodeling. Thus, it could play a pathogenic role in allergic airway inflammation. Eosinophils are the major source for this chemokine in inflamed airways. Objective: To evaluate sputum ENA-78 expression and its relation to acute asthma exacerbations of varying severity, and eosinophil cationic protein (ECP) as a marker of eosinophil activation, as well as eosinophil counts in blood and sputum. Methods: Sputum ENA-78 and serum ECP were measured by ELISA in 21 children during and after acute asthma exacerbation and 21 healthy matched controls. Patients were subdivided according to exacerbation severity into three equal subgroups; mild, moderate and severe. Results: Sputum ENA-78 was significantly higher in asthmatic children during acute exacerbation than controls (310.1±156.9 pg/ml vs 65.9±11.6 pg/ml, p < 0.0001). It was significantly higher in severe than moderate and in moderate than mild exacerbations, and was negatively correlated to the peak expiratory flow rate. Sputum ENA-78 showed significant positive correlations with serum ECP and eosinophil counts in blood and sputum. By follow up of patients with acute asthma exacerbation till remission of symptoms and signs, sputum ENA-78, serum ECP and eosinophil counts in blood and sputum decreased significantly, but their levels remained significantly higher than the control values. Conclusion: Sputum ENA-78 is increased during acute asthma exacerbation and it positively correlates with exacerbation severity and eosinophil activation. Thus, it may play a role in the evolution of acute asthma exacerbation and may be a future target for new asthma therapeutic modalities.Keywords: Bronchial asthma; chemokines; children; epithelial cell-derived neutrophil-activating peptide-78; eosinophils; eosinophil cationic protein; sputum markersEgypt J Pediatr Allergy Immunol 2007; 5(2): 55-6

Serial changes in the serum levels of leptin, homocysteine, galectin-3, total phospholipids and hexosamines among patients undergoing coronary artery bypass grafting

AbstractBackgroundCoronary artery disease (CAD) is the most common cardiovascular disorder in adults. This study was performed to elucidate the role of active leptin, homocysteine, galectin-3, total phospholipids, total, bound, free hexosamines, free-to-bound hexosamines ratio in the pathogenesis of chronic myocardial ischemia and studying the effect of coronary artery bypass grafting (CABG) on their serum levels.MethodsA prospective case control study was carried out on 100 ischemic heart disease male patients undergoing elective CABG and 25 healthy males. Serum levels of total phospholipids, total and free hexosamines, were estimated using spectrophotometric methods, while, serum levels of active leptin, homocysteine and galectin-3 were estimated using ELISA assay kit.ResultsSignificant higher serum active leptin, homocysteine, galectin-3, free hexosamines and free to bound hexosamines ratio levels preoperatively when compared with the control group (p < 0.01 for all) with significant lowering of their serum levels following CABG (p < 0.01 for all) except for active leptin. Significant lower serum total phospholipids, total and bound hexosamines levels preoperatively when compared with the control group (p < 0.01 for all) with significant elevations in their serum levels following CABG (p < 0.01 for all).ConclusionsHigh active leptin, homocysteine, galectin-3, free and free to bound hexosamines ratio and low total phospholipids, total and bound hexosamines play an important role in the pathogenesis of myocardial ischemia. The serum levels of homocysteine, galectin-3, hexosamines and total phospholipids, but not active leptin are significantly lowered following CABG

Preparation and Biological Evaluation of 99mtc-Sarafloxacin and 99mtc- Danofloxacin Complexes as a Model for Infection Imaging

Infection and inflammation remain a major cause of mortality and morbidity globally. This promotes research into better and more accurate diagnostic and therapeutic methods. This investigation focused on the labeling of sarafloxacin and danofloxacin for infection imaging. The radiolabeled antibiotic 99mTc-sarafloxacin and 99mTc-danofloxacin were assessed as an infection imaging agent in a mouse model. 99mTc-sarafloxacin and 99mTc-danofloxacin were obtained at pH 11 with a radiochemical yield of 96, 90%, respectively by adding 99mTc to 1 mg sarafloxacin or danofloxacin in the presence of 50 μg SnCl2.2H2O. Biodistribution studies in mice were carried out in experimentally induced infection in the left thigh using Staphylococcus aureus. Both thighs of the mice were dissected and counted, and the ratio of bacterial infected thigh/contralateral thigh was then evaluated. 99mTc-sarafloxacin and 99mTc-danofloxacin showed high uptake (T/NT=3.8±0.1 and 4.9±0.1, respectively) in the infectious lesion and abscess to normal muscle ratio indicating that 99mTcsarafloxacin and 99mTc-danofloxacin could be used for infection imaging

Preparation and Biological Evaluation of 99mtc-Sarafloxacin and 99mtc- Danofloxacin Complexes as a Model for Infection Imaging

Infection and inflammation remain a major cause of mortality and morbidity globally. This promotes research into better and more accurate diagnostic and therapeutic methods. This investigation focused on the labeling of sarafloxacin and danofloxacin for infection imaging. The radiolabeled antibiotic 99mTc-sarafloxacin and 99mTc-danofloxacinwere assessed as an infection imaging agent in a mouse model. 99mTc-sarafloxacin and 99mTc-danofloxacin were obtained at pH 11 with a radiochemical yield of 96, 90%, respectively by adding 99mTc to 1 mg sarafloxacin or danofloxacin in the presence of 50 μg SnCl2.2H2O. Biodistribution studies in mice were carried out in experimentally induced infection in the left thigh using Staphylococcus aureus. Both thighs of the mice were dissected and counted and the ratio of bacterial infected thigh/contralateral thigh was then evaluated. 99mTc-sarafloxacin and 99mTc-danofloxacin showed high uptake (T/NT=3.8±0.1 and 4.9±0.1, respectively) in the infectious lesion and abscess to normal muscle ratio indicating that 99mTcsarafloxacin and 99mTc-danofloxacin could be used for infection imaging.Key words: sarafloxacin/ danofloxacin/ Technetium-99m/ Infection/ inflammation/ Diagnosi

On the SigmaN cusp in the pp -> pK+Lambda reaction

Measurements of the $pp \to pK^+\Lambda$ reaction at $T_p$ = 2.28 GeV have been carried out at COSY-TOF. In addition to the $\Lambda p$ FSI and $N^*$ resonance excitation effects a pronounced narrow structure is observed in the Dalitz plot and in its projection on the $p\Lambda$-invariant mass. The structure appears at the $pp \to$N$K^+\Sigma$ threshold and is interpreted as $\Sigma$N cusp effect. The observed width of 20 MeV/$c^2$ is substantially broader than anticipated from previous inclusive measurements. Angular distributions of this cusp structure are shown to be dissimilar to those in the residual $pK^+\Lambda$ channel, but similar to those observed in the $pK^+\Sigma^0$ channel

On the Production of π+π+\pi^+\pi^+ Pairs in pp Collisions at 0.8 GeV

Data accumulated recently for the exclusive measurement of the $pp\to pp\pi^+\pi^-$ reaction at a beam energy of 0.793 GeV using the COSY-TOF spectrometer have been analyzed with respect to possible events from the $pp \to nn\pi^+\pi^+$ reaction channel. The latter is expected to be the only $\pi\pi$ production channel, which contains no major contributions from resonance excitation close to threshold and hence should be a good testing ground for chiral dynamics in the $\pi\pi$ production process. No single event has been found, which meets all conditions for being a candidate for the $pp \to nn \pi^+\pi^+$ reaction. This gives an upper limit for the cross section of 0.16 $\mu$b (90% C.L.), which is more than an order of magnitude smaller than the cross sections of the other two-pion production channels at the same incident energy

Phenomenological study on the pˉN→NˉNππ\bar p N\to \bar NN\pi\pi reactions

We extend our recent phenomenological study of $pN \to NN\pi\pi$ reactions to the $\bar{p}N \to \bar{N}N\pi\pi$ reactions for anti-proton beam momenta up to 3.0 GeV within an effective Lagrangian approach. The contribution of $N^*(1440)$ with its $N\sigma$ decay mode is found to be dominant at the energies close to threshold for $\bar NN\pi^+\pi^-$ and $\bar NN\pi^0\pi^0$ channels. At higher energies or for $p\bar n\pi^-\pi^-$ and $\bar NN\pi^\pm\pi^0$ channels where $N^*(1440)\to N\sigma$ mode cannot contribute, large contributions from double-$\Delta$, $\Delta(1600) \to N^*(1440)\pi$, $\Delta(1600) \to \Delta\pi$ and $\Delta(1620) \to \Delta\pi$ are found. In the near-threshold region, sizeable contributions from $\Delta \to \Delta\pi$, $\Delta \to N\pi$, $N \to \Delta\pi$ and nucleon pole are also indicated. Although these results are similar to those for $pN\to NN\pi\pi$ reactions, the antinucleon-nucleon collisions are shown to be complementary to the nucleon-nucleon collisions and may even have advantages in some aspects. The PANDA/FAIR experiment is suggested to be an excellent place for studying the properties of relevant $N^*$ and $\Delta^*$ resonances.Comment: 14 pages+7 figure