Preliminary bioequivalence of an oral integrating film formulation containing meloxicam with a suspension formulation in beagle dogs.

The oral disintegrating film (ODF) has advantages over suspension and tablet. These include convenience of administration, patient compliance, and accurate dosing. We evaluated the bioequivalence between the ODF and the meloxicam suspension by using a crossover design with a 3-week washout period. Six healthy male beagle dogs were randomized to receive both formulations of meloxicam, 2 mg. Plasma meloxicam concentrations were measured at the same times. From the start until maximum concentration, the initial absorption of the ODF meloxicam formulation was more rapid (2.08 ± 1.56 hr) as compared to the suspension (3.33 ± 1.03 hr). Mean elimination half-lives were 28.77 ± 4.01 and 32.85 ± 9.79 hr for the ODF and the suspension, respectively. Bioequivalence of the ODF was confirmed, based on the relative ratios of geometric mean concentrations (and 90% confidence intervals within the range of 80%-125%) for a maximum concentration of 101.05% (88.59-115.25), for the area under the plasma concentration-time curve (AUC) to the last sampling time of 96.07% (87.06-115.25), and for AUC to infinity of 92.65% (86.76-98.94). The meloxicam ODF may be used as an alternative to suspension formulations in the treatment of inflammatory joint diseases and painful musculoskeletal disorders.

Preparation and characterization of metformin hydrochloride controlled-release tablet using fatty acid coated granules.

Metformin hydrochloride (MFM) is often used as a controlled-release (CR) tablet to reduce dosing frequency. However, the MFM CR tablet contains significant amounts of excipients and the tablet size is also large. Dosing convenience and patient compliance can be increased by reducing the size of the CR tablets. The aim of this study was to prepare and evaluate the MFM controlled-release tablet (MFM-CRT) using two types of release modulators, inner and outer. The MFM-CRT was prepared by coating the MFM granules using a binder solution containing aluminum stearate (ALS) as the inner release-modulator, and polyethylene oxide (PEO) as the outer release-modulator. The dispersion stability of the binder solution was optimized by the dispersion analyzer. The MFM-CRT was evaluated for dissolution rate and tablet volume. Additionally, dissolution behavior and dissolution kinetics of the MFM-CRT were analyzed using micro-computed tomography (micro-CT). Although the optimal MFM-CRT showed no difference in the release rate as compared to the commercially available product of Glucophage® XR 500 mg (f2 value: 72), the length of the long axis was reduced by 6 mm and the weight was reduced by about 27%. We expect patient compliance to improve because of effective sustained release and volume reduction of MFM-CRT.

Tumor necrosis could reflect advanced disease status in patients with diffuse large B cell lymphoma treated with R-CHOP therapy.

Tumor necrosis (TN) can lower responsiveness to chemotherapy and confer basic resistance to anti-cancer therapy. We investigated the association of TN with poor clinical features and outcome in diffuse large B cell lymphoma (DLBCL). We examined the presence or absence of TN in 476 DLBCL patients of who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Eighty-nine (18.7 %) patients had TN at diagnosis. Patients with TN had a progression-free survival (PFS) and overall survival (OS) of 39.3 and 46.7 %, whereas patients without TN had a PFS and OS of 73.4 and 82.6 %. Adverse clinical factors of poor Eastern Cooperative Oncology Group performance status ≥ grade 2 (p = 0.005), elevated lactate dehydrogenase ratio >1 (p < 0.001), advanced Ann Arbor stage (p = 0.002), and bulky disease (p = 0.026) were more prevalent in the TN group than the non-TN group. Cox regression model analysis revealed TN as an independent prognostic factor for PFS and OS in DLBCL (PFS, hazard ratio [HR] = 1.967, 95 % confidence interval [CI] = 1.399-2.765, p < 0.001; OS, HR = 2.445, 95 % CI = 1.689-3.640, p < 0.001). The results indicate that TN could reflect adverse clinical features and worse prognosis in DLBCL patients receiving R-CHOP therapy.

Preparation and Evaluation of Inhalable Amifostine Microparticles Using Wet Ball Milling.

The conventional dosage form of Ethyol® (amifostine), a sterile lyophilized powder, involves reconstituting it with 9.7 mL of sterile 0.9% sodium chloride in accordance with the United States Pharmacopeia specifications for intravenous infusion. The purpose of this study was to develop inhalable microparticles of amifostine (AMF) and compare the physicochemical properties and inhalation efficiency of AMF microparticles prepared by different methods (jet milling and wet ball milling) and different solvents (methanol, ethanol, chloroform, and toluene). Inhalable microparticles of AMF dry powder were prepared using a wet ball-milling process with polar and non-polar solvents to improve their efficacy when delivered through the pulmonary route. The wet ball-milling process was performed as follows: AMF (10 g), zirconia balls (50 g), and solvent (20 mL) were mixed and placed in a cylindrical stainless-steel jar. Wet ball milling was performed at 400 rpm for 15 min. The physicochemical properties and aerodynamic characteristics of the prepared samples were evaluated. The physicochemical properties of wet-ball-milled microparticles (WBM-M and WBM-E) using polar solvents were confirmed. Aerodynamic characterization was not used to measure the % fine particle fraction (% FPF) value in the raw AMF. The % FPF value of JM was 26.9 ± 5.8%. The % FPF values of the wet-ball-milled microparticles WBM-M and WBM-E prepared using polar solvents were 34.5 ± 0.2% and 27.9 ± 0.7%, respectively; while the % FPF values of the wet-ball-milled microparticles WBM-C and WBM-T prepared using non-polar solvents were 45.5 ± 0.6% and 44.7 ± 0.3%, respectively. Using a non-polar solvent in the wet ball-milling process resulted in a more homogeneous and stable crystal form of the fine AMF powder than using a polar solvent.

Usefulness of spleen volume measured by computed tomography for predicting clinical outcome in primary myelofibrosis.

Although splenomegaly is major characteristic of primary myelofibrosis (PMF), splenomegaly has been devalued due to a less reliable method based on physical examination (PEx). We evaluated whether spleen volume (SV) on CT would accurately predict clinical outcomes in PMF. A total of 188 patients were enrolled. SV was quantitated by the automatic volume software. In ROC curve, the SV predicted prognosis more accurately than spleen length by PEx (p < 0.001). The ideal cut-off value was 378.1 cm(3) for SV, which was divided into high- and low-volume status. Patients with low SV status had superior leukemia-free survival and overall survival compared to high SV status (p < 0.001, p < 0.001) In the Cox analysis, old age ≥65 years (p = 0.004, p = 0.001), low Hemoglobin <10.0 g/dL (p = 0.023, p = 0.021), high WBC counts ≥25 × 10(9)/L (p = 0.003, p = 0.006), peripheral blasts ≥1 % (p = 0.029, p = 0.020), unfavorable cytogenetic abnormalities (p = 0.025, p = 0.028), and high SV status (p = 0.004, p = 0.003) were independently associated with survivals. SV measured by CT was important for predicting survival in patients with PMF.

Incidence and prognostic impact of DNMT3A mutations in Korean normal karyotype acute myeloid leukemia patients.

BACKGROUND: DNA methyltransferase 3A (DNMT3A) mutation was recently introduced as a prognostic indicator in normal karyotype (NK) AML and we evaluated the incidence and prognostic impact of DNMT3A mutations in Korean NK AML patients. METHODS: Total 67 NK AML patients diagnosed during the recent 10 years were enrolled. DNMT3A mutations were analyzed by direct sequencing and categorized into nonsynonymous variations (NSV), deleterious mutations (DM), and R882 mutation based on in silico analysis results. Clinical features and prognosis were compared with respect to DNMT3A mutation status. RESULTS: Three novel (I158M, K219V, and E177V) and two known (R736H and R882H) NSVs were identified and the latter three were predicted as DMs. DNMT3A NSVs, DMs, and R882 mutation were identified in 14.9%-17.9%, 10.3%-10.4%, and 7.5% of patients, respectively. DNMT3A mutations were frequently detected in FLT3 ITD mutated patients (P=0.054, 0.071, and 0.071 in NSV, DMs, and R882 mutation, resp.) but did not affect clinical features and prognosis significantly. CONCLUSIONS: Incidences of DNMT3A NSVs, DMs, and R882 mutation are 14.9%-17.9%, 10.3%-10.4%, and 7.5%, respectively, in Korean NK AML patients. DNMT3A mutations are associated with FLT3 ITD mutations but do not affect clinical outcome significantly in Korean NK AML patients.

Evaluation of a colorimetric antifungal susceptibility test by using 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride.

A colorimetric antifungal susceptibility test was performed using 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride. Among 24 strains of Candida species, no trailing growth was found. In 22 and 20 strains, the MICs obtained in the colorimetric assay were within two dilutions of those obtained by the National Committee for Clinical Laboratory Standards method for ketoconazole and itraconazole, respectively.

The clinical significance of antibody screening test including Dia+ panel cell in Asian-Mongoloid populations.

The Di(a) antigen is well known as one of the antigens with low incidence among Caucasians; however, it has been discovered with a relatively higher incidence among Mongoloid populations. Thus, it has been speculated that the incidence of unexpected antibody against the Di(a) antigen might be relatively higher among these populations. Hemolytic transfusion reactions (HTRs) and hemolytic disease of the newborns (HDNs) caused by anti-Di(a) have been reported sporadically. However, there has been no prospective study on the incidence of anti-Di(a) in Mongoloid populations particularly. The authors conducted a series of antibody screening tests on 11,219 Korean individuals for 25 months, by using three kinds of screening cells including Di(a) cell. Anti-Di(a) was detected in 8 patients, seven of whom had a history of transfusions or were multigravida. The incidence of anti-Di(a) measured in this study was higher than expected, ranked third among unexpected antibodies identified during the period of the study, so it is strongly recommended that the Di(a+) panel cell must be incorporated into antibody screening test for safer transfusion in Asian-Mongoloid populations.

Plasmodium vivax malaria complicated by hemophagocytic syndrome in an immunocompetent serviceman.

We describe a 23-year-old retired military officer who was immunocompetent but diagnosed with hemophagocytic syndrome (HPS) by Plasmodium vivax infection. Initially, the patient was suspected to have toxic hepatitis related to heavy drinking. But abnormal hematologic findings required a further bone marrow examination and the diagnosis of HPS was made. Antimalarial chemotherapy then brought complete remission. Plasmodium falciparum, a species causing more severe malarial infection, was listed as one of the major causes of HPS. However, P. vivax was not mentioned, and only one case was reported in the literature. In this study, we suggest that P. vivax malaria should be included in the differential diagnosis of HPS, even in an immunocompetent person.