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91.
CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells 总被引:2,自引:0,他引:2
Harata M Soda Y Tani K Ooi J Takizawa T Chen M Bai Y Izawa K Kobayashi S Tomonari A Nagamura F Takahashi S Uchimaru K Iseki T Tsuji T Takahashi TA Sugita K Nakazawa S Tojo A Maruyama K Asano S 《Blood》2004,104(5):1442-1449
Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) have poor prognosis despite intensive therapeutic intervention. Recently, imatinib, a BCR-ABL tyrosine kinase inhibitor, has been proven to be an effective treatment for Ph(+) ALL, but nearly all patients rapidly acquire resistance. High-dose imatinib administration might overcome this resistance; however, systemic toxicities would likely limit this approach. Therefore, a new delivery system allowing for the specific targeting of imatinib is urgently needed. Because almost all Ph(+) ALL cells express CD19 on their surface, we have developed an immunoliposome carrying anti-CD19 antibody (CD19-liposomes). The internalization efficiency of the CD19-liposomes approached 100% in all Ph(+) ALL cells but was very low in CD19(-) cells. The cytocidal effect of imatinib-encapsulated CD19-liposomes (imatinib-CD19-liposomes) on Ph(+) ALL cell lines and primary leukemia cells from patients with Ph(+) ALL was much greater than that of imatinib with or without control liposomes. Importantly, the imatinib-CD19-liposomes did not affect the colony formation of CD34(+) hematopoietic cells, even at inhibitory concentration of free imatinib. Taken together, these data clearly demonstrate that the imatinib-CD19-liposomes induced specific and efficient death of Ph(+) ALL cells. This new therapeutic approach might be a useful treatment for Ph(+) ALL with fewer side effects than free imatinib. 相似文献
92.
Yoshiko Tomita Emma Hansson Florent Mazuir Gustaf J Wellhagen Qing Xi Ooi Enrica Mezzalana Atsushi Kitamura Daisuke Nemoto Sbastien Bolze 《CTS Clinical and Translational Science》2022,15(4):1014
Imeglimin is an orally administered first‐in‐class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m2 were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration‐time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15–45 ml/min/1.73 m2, and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment. Study Highlights
- WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
- WHAT QUESTION DID THIS STUDY ADDRESS?
- WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
- HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
93.
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96.
Three cases of ceroid granulomas of the female genital system are presented, involving the cervix in two and lesions in the ovaries and bowel serosa in the other. Ceroid granulomas are unusual and interesting lesions formed when suitable substrates accumulate within macrophages to such an extent that a relative lack of biological antioxidants results and auto-oxidation and conversion to ceroid is favoured. This may occur in the setting of haemorrhage and necrosis, whether from tumour necrosis or associated with endometriosis. Other sources of lipids and lipoproteins include bile, meconium and vernix caseosa. 相似文献
97.
Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides 总被引:24,自引:7,他引:24 下载免费PDF全文
T Ooi M Oobatake G Némethy H A Scheraga 《Proceedings of the National Academy of Sciences of the United States of America》1987,84(10):3086-3090
A method is described for the inclusion of the effects of hydration in empirical conformational energy computations on polypeptides. The free energy of hydration is composed of additive contributions of various functional groups. The hydration of each group is assumed to be proportional to the accessible surface area of the group. The constants of proportionality, representing the free energy of hydration per unit area of accessible surface, have been evaluated for seven classes of groups (occurring in peptides) by least-squares fitting to experimental free energies of solution of small monofunctional aliphatic and aromatic molecules. The same method has also been applied to the modeling of the enthalpy and heat capacity of hydration, each of which is computed from the accessible surface area. 相似文献
98.
Studies have shown that patients with rheumatoid arthritis (RA) in the Middle East have delayed diagnosis and low disease-modifying
anti-rheumatic drug (DMARD) utilization. We describe the characteristics and treatments of consecutive RA patients presenting
to a new musculoskeletal clinic in Dubai, United Arab Emirates (UAE). Demographic and clinical data were collected over a
10-month period at the first visit to our clinic for patients meeting the American College of Rheumatology (ACR) criteria
for RA. A total of 100 patients were seen: (average ± SD) age 42.2 ± 12.3 years; female 87%; Arabs 38%, Indian 36%, Caucasian
and others 26%; 73% rheumatoid-factor positive; years since diagnosis: 3.9 ± 5.7; lag time between symptom onset to diagnosis
1.2 ± 1.3 years and lag time to first DMARD was 1.6 ± 2.0 years. Mean tender joint count was 8.9 ± 7.9, mean swollen joint
count 9.0 ± 7.6, mean patient’s global assessment of disease activity 57.4 ± 25.0 mm, mean ESR 33 ± 25 mm/h, mean DAS28 5.2 ± 1.6,
physician global assessment 55.0 ± 23.8. Only 43% were on DMARDs (25% MTX, 5% TNF blockers). Among the patients who were not
on DMARD, only 28.1% had disease duration less than 1 year (p = <0.01). Erosions were present in 55.2% of patients with available X-rays, and deformities in 26% of patients. There were
no racial differences in disease characteristics. The UAE has a unique population with many races residing in the country.
Among the first 100 consecutive patients seen at our clinic, there were no significant differences in disease characteristics
with the majority of the patients having very active disease, delayed diagnosis, and not being treated with DMARDs.
Footline: RA in the United Arab Emirates 相似文献
99.
100.
Association of ambient air‐pollution levels with acute asthma exacerbation among children in Singapore 总被引:1,自引:0,他引:1
BACKGROUND: Air-pollution levels have been shown to be associated with increased morbidity of respiratory diseases. METHODS: Data for ambient air-pollutant levels, meteorologic factors, and hospitalization or emergency room (ER) visits for acute asthma in Singapore children over a 5-year period (1990-4) were obtained and analyzed for associations by time-series methods. RESULTS: Throughout this period, the annual mean and 24-h mean levels for sulfur dioxide (SO2), nitrogen dioxide (NO2), and total suspended particles (TSP) and maximum 1-h daily average for ozone were generally within the air-quality guidelines established by the World Health Organization (WHO). However, positive correlation between levels of each of these pollutants and daily ER visits for asthma was observed in children aged 3-12 years, but not among adolescents and young adults (13-21 years old). The association with SO2 and TSP persisted after standardization for meteorologic and temporal variables. An adjusted increase in 2.9 ER visits for every 20 microg/m3 increase in atmospheric SO2 levels, lagged by 1 day, was observed on days when levels were above 68 microg/m3. With TSP, an adjusted increase of 5.80 ER visits for every 20 microg/m3 increase in its daily atmospheric levels, lagged by 1 day, was observed on days with levels above 73 microg/m3. Similar results were also obtained after controlling for autocorrelation by time-series analysis. CONCLUSIONS: These associations were observed even though the overall levels of all pollutants were generally within the air-quality guidelines established by the WHO. These findings suggest that asthmatic children are susceptible to increased levels of air pollutants, particularly SO2 and TSP, although the ambient levels are generally within "acceptable" ranges. 相似文献