The Impact of Hot Melt Extrusion and Spray Drying on Mechanical Properties and Tableting Indices of Materials Used in Pharmaceutical Development

The impact of melt extrusion (HME) and spray drying (SD) on mechanical properties of hypromellose acetate succinate (HPMCAS), copovidone, and their formulated blends was studied and compared with that of reference excipients. Tensile strength (TS), compression pressure (CP), elastic modulus (E), and dynamic hardness (H_d) were determined along with Hiestand indices using compacts prepared at a solid fraction of ～0.85. HPMCAS and copovidone exhibited lower H_d, lower CP, and lower E than the reference excipients and moderate TS. HPMCAS was found to be highly brittle based on brittle fracture index values. The CP was 24% and 61% higher for HPMCAS after SD and HME, respectively, than for unprocessed material along with a higher H_d. Furthermore, the TS of HPMCAS and copovidone decreased upon HME. Upon blending melt-extruded HPMCAS with plastic materials such as microcrystalline cellulose, the TS increased. These results suggest that SD and HME could impact reworkability by reducing deformation of materials and in case of HME, likely by increasing density due to heating and shear stress in a screw extruder. A somewhat similar effect was observed for the dynamic binding index (BI_d) of the excipients and formulated blends. Such data can be used to quantitate the impact of processing on mechanical properties of materials during tablet formulation development.     

Haploidentical vs autologous hematopoietic stem cell transplantation in patients with acute leukemia beyond first remission

This is a retrospective comparison of partially mismatched related donor transplantation (PMRDT) and autotransplantation (ABMT) in advanced acute leukemia. Patients underwent T-cell-depleted PMRDT (n=164) or ABMT (n=131) for acute myeloid leukemia (n=130) or acute lymphoblastic leukemia (n=165). Fewer PMRDT patients were in remission (29 vs 85%; P<0.0001). The 5-year cumulative incidence of transplant-related mortality (TRM) was 52% after PMRDT and 16% after ABMT (P<0.0001). The 5-year cumulative incidence of relapse was 32% after PMRDT and 54% after ABMT (P=0.006). The actuarial unadjusted 5-year disease-free survival (DFS) was 16% after PMRDT and 30% after ABMT. In Cox's regression analysis, PMRDT (P<0.0001) and age >15 years (P=0.002) were associated with higher TRM, active disease (P=0.0021), ABMT (P=0.0074) and male sex (P=0.011) with higher relapse, and age >15 years (P=0.0007) and PMRDT (P=0.047) with lower DFS. Amongst second remission patients, TRM was higher after PMRDT (P=0.0003), relapse was higher after ABMT (P=0.034), and 5-year DFS was comparable (32% ABMT and 25% PMRDT). ABMT, if feasible, may be preferable to PMRDT in advanced acute leukemia patients since lower relapse after PMRDT is offset by higher TRM. If an autograft is not feasible because of nonavailability of autologous cells or very advanced disease, PMRDT is a potential alternative.     

Impact of cytogenetics on the outcome of autotransplantation for acute myeloid leukemia in first remission: is the benefit of intensive pretransplant therapy limited to patients with good karyotypes?

A total of 81 adults with acute myeloid leukemia (AML) (47% favorable karyotypes) were autografted in first remission after melphalan-total body irradiation, having received 0 (n=7), 1 (n=19), 2 (n=51), or 3 (n=4) consolidation chemotherapy cycles before harvest. The cumulative 5-year incidences of relapse and transplant-related mortality were 37 and 17%, respectively. The actuarial 5-year probability of disease-free survival (DFS) was 46%. In Cox analysis, favorable karyotypes, increasing numbers of consolidation cycles (0 vs > or =1 or 1 vs >1), and higher nucleated cell doses were associated with lower relapse rates and higher DFS. Patients with favorable karyotypes benefited from every additional cycle of consolidation therapy (0 vs > or =1 as well as 1 vs >1). Among patients with other karyotypes, while the benefit of one cycle of consolidation was clear (0 vs > or =1), there was no obvious beneficial impact of further consolidation therapy (1 vs >1). Administration of consolidation chemotherapy prior to harvest is essential in AML. While it is possible to enhance the benefit of consolidation with favorable karyotypes by delivering two cycles, its usefulness is limited in others. In them, it may be worthwhile exploring alternatives not normally used in AML (eg high-dose cyclophosphamide) that could have antileukemic effects while permitting mobilization of stem cells.     

Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'?

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.     

Impact of previous high-dose therapy on outcome after allografting for multiple myeloma

We describe a single centre experience of 33 patients allografted for multiple myeloma, of which 28 received matched sibling marrow, one haploidentical family donor marrow and four matched but unrelated donor marrow. Median follow-up after transplant is 27 months, and 13 patients are currently alive. One out of four patients with an unrelated donor survives and 12 out of 28 (42.8%) with matched sibling donors. Four patients were unevaluable because of early death (相似文献   

Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma

Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production.     

Structure–Function Analysis of Liver Flavin Monooxygenase 3 that Drives Trimethylaminuria in Humans

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Mutations in human flavin monooxygenase-3 (hFMO3) enzyme have been implicated in the rare autosomal recessive...     

Lipid abnormalities in coronary heart disease: a population-based case-control study

BACKGROUND: We performed a case-control study to estimate lipid-cholesterol fractions in patients with coronary heart disease and compared them with population-based controls. METHODS AND RESULTS: A total of 635 newly diagnosed patients with coronary heart disease (518 males and 117 females) and 632 subjects (346 males and 286 females) obtained from an ongoing urban coronary heart disease risk factor epidemiological study were evaluated. Age-specific lipid values (total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, and total:high-density lipoprotein cholesterol ratio) were compared using the t-test. Age-adjusted prevalence of dyslipidemia as defined by the US National Cholesterol Education Program was compared using the Chi-square test. In all the age groups, and in both males and females, levels of total and low-density lipoprotein cholesterol were not significantly different. In males, the high-density lipoprotein cholesterol (mg/dl) was significantly lower in patients with coronary heart disease as compared to controls in the age groups 30-39 years (35.1+/-11 v. 43.7+/-9), 40-49 years (39.0+/-10 v. 47.1+/-8), 50-59 years (38.9+/-11 v. 43.8+/-9) and 60-69 years (38.6+/-11, v. 42.8+/-7) (p<0.05). In females, high-density lipoprotein cholesterol was less in the age groups 30-39 years (30.2+/-9 v. 40.7+/-9), 50-59 years (39.7+/-12 v. 44.7+/-8) and 60-69 years (35.6+/-11 v. 42.2+/-9). The level of triglycerides was significantly higher in male patients in the age groups 40-49 years (195.3+/-96 v. 152.8+/-78), 50-59 years (176.7+/-76 v. 162.9+/-97), 60-69 years (175.5+/-93 v. 148.1+/-65) and >70 years (159.8+/-62 v. 100.0+/-22); and in female patients in the age group 30-39 years (170.8+/-20 v. 149.9+/-9) (p<0.05). The total:high-density lipoprotein cholesterol ratio was significantly higher in all age groups in male as well as female patients with coronary heart disease (p<0.05). CONCLUSIONS: An age-adjusted case-control comparison showed that the prevalence of hypertension, diabetes, high total cholesterol (> or =200 mg/dl) (males 48.8% v. 20.2%; females 59.8% v. 33.4%) and high low-density lipoprotein cholesterol (> or =130 mg/dl) (males 42.1% v. 15.0%; females 52.1% v. 31.0%) was significantly more in cases than in controls. The prevalence of low high-density lipoprotein cholesterol (<35 mg/dl) (males 39.6% v. 6.2%; females 39.3% iv 9.5%), high total:high-density lipoprotein ratio (> or = 5.0) and high triglycerides (> or =200 mg/ dl: males 39.6%, v. 10.2%; females 17.1% v. 11.9%) was also significantly higher in cases (p<0.05).