Purpose: Spray-freeze drying (SFD) is a recently applied method to develop pharmaceutical powders. This study aimed to analyze the competence of Trehalose, Mannitol, Lactose, and Sorbitol instability and aerosolization of Immunoglobulin G (IgG) via SFD.
Methods: Induced soluble aggregates were quantified at 0 and 3?months, and 45?°C using size-exclusion chromatography. Conformation and thermogravimetric assessments were done by Fourier transform infrared spectroscopy and differential scanning calorimetry. Laser light scattering was performed to determine the particle sizes. Aerodynamic features were characterized by twin stage impinger and scanning electron microscopy.
Results: Although sugars/polyols preferably stabilized IgG following the process, storage stabilization was achieved in Trehalose, Trehalose-Lactose, Lactose, and Trehalose-Mannitol-based powders with soluble aggregates <5%. The conformation of antibody was preserved with β sheet content from 66.28% to 76.37%. Particle sizes ranged from 5.23 to 8.12?µm. Mannitol exhibited the best aerodynamic behavior, fine particle fraction (FPF: 70%) but high degree of protein aggregation during storage.
Conclusions: SFD could favorably stabilize antibody using Trehalose and its combination with Lactose and Mannitol, and also, Lactose alone. Sorbitol disturbed IgG powder recovery. Incorporation of other types of excipient is required for efficient respiratory delivery of IgG molecules. 相似文献
We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca alkaloids such as Vincristine (VCR), Vinblastine (VBL) and Vinorelbine (VNR). Additionally, BV6 acts in concert with DOX or VCR to suppress long-term clonogenic growth. While BV6 causes rapid downregulation of cellular IAP (cIAP)1 protein and nuclear factor-kappaB (NF-κB) activation, DOX/BV6- or VCR/BV6-induced apoptosis occurs independently of NF-κB or TNFα signaling, since overexpression of dominant-negative IκBα superrepressor or the Tumor Necrosis Factor (TNF)α-blocking antibody Enbrel fail to block cell death. Mechanistic studies reveal that Receptor-interacting protein (RIP)1 is required for DOX/BV6-, but not for VCR/BV6-induced apoptosis, since transient or stable knockdown of RIP1 or the pharmacological RIP1 inhibitor necrostatin-1 significantly reduce apoptosis. By comparison, VCR/BV6-mediated apoptosis critically depends on the mitochondrial pathway. VCR/BV6 cotreatment causes phosphorylation of BCL-2 during mitotic arrest, enhanced activation of BAX and BAK and loss of mitochondrial membrane potential (MMP). Additionally, overexpression of BCL-2 profoundly suppresses VCR/BV6-induced apoptosis. Thus, BV6 sensitizes NB cells to chemotherapy-induced apoptosis via distinct initial signaling mechanisms depending on the chemotherapeutic drug. These findings provide novel mechanistic insights into Smac mimetic-mediated chemosensitization of NB. 相似文献
Visceral leishmaniasis (VL) as one of the most important human parasitic disease is endemic in some parts of Iran. Several cases of VL have been reported recently in the Ilam Province. The current study aimed to assess the present status of human VL in the region.
Methods:
A random cluster sampling method was used to collect 456 serums samples from the children up to 12 years of age and 10% of adults living in urban and rural areas of the province. All the collected serum samples were tested by direct agglutination test (DAT) to detect anti- Leishmania infantum antibodies.
Results:
Of the examined 456 serum samples with direct agglutination test (DAT), only 21 (0.43%) sera showed anti- Leishmania antibodies at titers 1:400 and higher. Distribution of anti- Leishmania antibodies titers were: 1:400(n=4), 1:800(n=11), 1:1600(n=3), 1:3200(n=1), and 1:6400(n=1). Individuals with titers ≥1:3200 showed clinical signs and symptoms such as fever and splenomegaly. The highest and lowest seropositivity were observed in the age groups of 5–9 and >15 years old, respectively. There were no significant difference between the rate of seropositivity in males and females.
Conclusion:
VL with a low prevalence circulates in some parts of Ilam province, particularly in the southern parts. Complementary studies should be needed to find animal reservoir hosts and vectors. Furthermore, health systems and physicians should pay particular attention to the disease. 相似文献
Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.
Methods
The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan–Meier analysis.
Results
The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HRPFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HROS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.
Conclusions
Discrepancies between preclinical success and clinical failure may be due to the patients'' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response. 相似文献
The aim of this study was to assess the effectiveness of a multimodal exercise program to increase trunk muscle morphology and strength in older individuals, and their associated changes in functional ability. Using a single‐blinded parallel‐group randomized controlled trial design, 64 older adults (≥60 years) were randomly allocated to a 12‐week exercise program comprising walking and balance exercises with or without trunk strengthening/motor control exercises; followed by a 6‐week walking‐only program (detraining; 32 per group). Trunk muscle morphology (ultrasound imaging), strength (isokinetic dynamometer), and functional ability and balance (6‐Minute Walk Test; 30 second Chair Stand Test; Sitting and Rising Test; Berg Balance Scale, Multi‐Directional Reach Test; Timed Up and Go; Four Step Square Test) were the primary outcome measures. Sixty‐four older adults (mean [SD]; age: 69.8 [7.5] years; 59.4% female) were randomized into two exercise groups. Trunk training relative to walking‐balance training increased (mean difference [95% CI]) the size of the rectus abdominis (2.08 [1.29, 2.89] cm2), lumbar multifidus (L4/L5:0.39 [0.16, 0.61] cm; L5/S1:0.31 [0.07, 0.55] cm), and the lateral abdominal musculature (0.63 [0.40, 0.85] cm); and increased trunk flexion (29.8 [4.40, 55.31] N), extension (37.71 [15.17, 60.25] N), and lateral flexion (52.30 [36.57, 68.02] N) strength. Trunk training relative to walking‐balance training improved 30‐second Chair Stand Test (5.90 [3.39, 8.42] repetitions), Sitting and Rising Test (1.23 [0.24, 2.23] points), Forward Reach Test (4.20 [1.89, 6.51] cm), Backward Reach Test (2.42 [0.33, 4.52] cm), and Timed Up and Go Test (?0.76 [?1.40, ?0.13] seconds). Detraining led to some declines but all outcomes remained significantly improved when compared to pre‐training. These findings support the inclusion of trunk strengthening/motor control exercises as part of a multimodal exercise program for older adults. 相似文献