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《Journal of pharmaceutical sciences》2019,108(10):3425-3433
This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation. 相似文献
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Fereydoun DAVATCHI Mahmood AKBARIAN Farhad SHAHRAM Abdolhadi NADJI Farhad GHARIBDOOST Ahmad‐Reza JAMSHIDI 《International journal of rheumatic diseases》2006,9(1):60-63
Aim: To evaluate the overall effect of disease modifying anti‐rheumatic drug (DMARD) combination therapy in daily practice. Methods: In a retrospective study, 161 consecutive files of patients who attended regular follow‐up sessions, seen from 1998, were analysed. Their data were extracted at baseline, 6 months, 1, 2, 3, 4 and 5 years. American College of Rheumatology ACR70 criteria was chosen for the evaluation of the global result. DMARD combination was methotrexate (7.5–15 mg weekly) and chloroquine (150 mg daily), with low‐dose prednisolone (less than 10 mg daily). In cases of remission, methotrexate was gradually tapered, then prednisolone. Chloroquine was discontinued after 1 year if no recurrence occurred at low‐dose (150 mg every other day). In cases of recurrence at any stage, the treatment scheme was stepped back. Results: The data of 161 patients were analysed. One hundred and six were rheumatoid factor positive (RF+) (66%). ACR 70 for all patients at 6 months follow‐up was 72.5% (95% CI = 7.0); at 1 year, 75.8% (95% CI = 6.7); at 2 years, 72.2% (95% CI = 7.2); at 3 years, 78.9% (95% CI = 6.6); at 4 years, 78.4% (95% CI = 6.9); and at 5 years, 70.6% (95% CI = 8.5). Conclusion: The classical DMARD combination therapy, when used with adequate low‐dose prednisolone, gave an ACR70 response from 71–79%. The efficacy of the treatment did not fade over time. RF– patients did better than RF+ patients, but the difference was not statistically significant. 相似文献
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Masafumi Kumano Hideaki Miyake Isao Hara Junya Furukawa Atsushi Takenaka Masato Fujisawa 《International journal of urology》2007,14(4):336-338
BACKGROUND: The objective of this study was to evaluate the efficacy and safety of first-line high-dose chemotherapy (HDCT) combined with peripheral blood stem cell transplantation (PBSCT) for patients with advanced extragonadal germ cell tumors (EGGCT). METHODS: Six male patients with advanced non-seminomatous EGGCT were treated with HDCT combined with PBSCT following 2-3 cycles of conventional-dose induction chemotherapy. The regimens used for HDCT were carboplatin, etoposide and ifosfamide (ICE) in five patients and ICE plus paclitaxel (T-ICE) in one patient, and that for induction therapy was cisplatin, etoposide and bleomycin (PEB) in all patients. As a rule, HDCT was continuously administered until alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin normalized (beta-HCG). RESULTS: Following 1-6 courses of HDCT (median, 4 courses), beta-HCG and AFP were normalized in all patients, and five and one patient were diagnosed as showing partial remission and stable disease, respectively. Five patients underwent surgical resection of residual tumors after HDCT, yielding necrotic tissue in two, mature teratoma in two, and viable cancer tissue in one, and the surgical margin was negative in all patients. At a median follow-up of 36 months, five patients were alive and disease-free, whereas the remaining one died of disease progression. Although all patients had grade 3 hematological toxicity, there was no treatment-related death by combining PBSCT. CONCLUSIONS: First-line HDCT with PBSCT could be safely administered to patients with advanced EGGCT, and the antitumor effect of this treatment was comparatively favorable. First-line HDCT therefore may represent an attractive option for patients with advanced EGGCT. 相似文献
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Tsuneharu Miki Yoichi Mizutani Hideyuki Akaza Seiichiro Ozono Taiji Tsukamoto Toshiro Terachi Katsusuke Naito Norio Nonomura Isao Hara Osamu Yoshida The Japan Blood Cell Transplantation Study Group for Testicular Germ Cell Tumor 《International journal of urology》2007,14(1):54-59
OBJECTIVE: Standard chemotherapy shows relatively low long-term survival in patients with poor-risk testicular germ cell tumor (GCT). First-line high-dose chemotherapy (HD-CT) may improve the result. High-dose carboplatin, etoposide, ifosfamide chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) was investigated as first-line chemotherapy in patients with advanced testicular GCT. METHODS: Fifty-five previously untreated testicular GCT patients with Indiana 'advanced disease' criteria received three cycles of bleomycin, etoposide and cisplatin (BEP) followed by one cycle of HD-CT plus PBSCT, if elevated serum tumor markers were observed after three cycles of the BEP regimen. RESULTS: Thirty patients were treated with BEP alone, because the tumor marker(s) declined to normal range. Twenty-five patients received BEP and HD-CT. One patient died of rhabdomyolysis due to HD-CT. Three and six (13% and 25%) out of 24 patients treated with BEP and HD-CT achieved marker-negative and marker-positive partial responses, respectively. The other patients achieved no change. Fifteen (63%) are alive and 14 (58%) are free of disease at a median follow-up time of 54 months. Severe toxicity included treatment-related death (4%). CONCLUSIONS: HD-CT with peripheral stem cell support can be successfully applied in a multicenter setting. HD-CT demonstrated modest anticancer activity for Japanese patients with advanced testicular GCT and was well tolerated. This regimen might be examined for further investigation in randomized trials in first-line chemotherapy for patients with poor-risk testicular GCT. 相似文献
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Zakiya Al-Lamki Eileen Thomas Nagwa El-Banna Norman Jaffe 《Pediatric blood & cancer》1995,24(2):137-140
We report an unusual case of anaphylaxis and hepatitic dysfunction in a child with the administration of the twenty-third course of high-dose methotrexate. The latter had been used as an adjuvant to prevent pulmonary metastases and the prior 22 courses had been well tolerated. An attempt to reinstate methotrexate after the twenty-third course was again followed by a similar reaction. © 1995 Wiley-Liss, Inc. 相似文献
8.
外源性核苷能抵消抗代谢药对肿瘤细胞的杀伤作用;核苷转运抑制剂潘生丁则能阻断核苷的这种抵消作用,从而增强抗代谢药的细胞毒性。本研究证明,胸苷和次黄嘌呤可明显抵消氨甲蝶呤对L1210细胞的杀伤作用,潘生丁则能有效地阻断核苷的抵消作用;潘生丁和两性霉素B合用可明显增强氨甲蝶呤对小鼠S180肉瘤的抑制作用,但不增强氨甲蝶呤对动物的毒性。提示潘生丁有可能应用于肿瘤联合化疗。 相似文献
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10例椎管内转移癌病人曾长期使用大剂量镇痛药难以奏效,而少数病例便采用硬膜外腔注射吗啡2~4mg疼痛缓解仅1h。采用硬膜外腔灌注氨甲喋呤配伍高渗盐水,使抗癌药直接与肿瘤接触,几分钟内杀死癌细胞,加之高渗盐水能促使肿瘤和神经干脱水,肿瘤体积缩小和破坏,改善局部动脉缺血和组织水肿,从而减轻或消除肿瘤对神经根的压迫,缓解和消除神经痛。 相似文献
10.
E Christophers† CEM Griffiths‡ G Gaitanis‡ P van de Kerkhof§ 《Journal of the European Academy of Dermatology and Venereology》2006,20(8):921-925
BACKGROUND: Conventional systemic therapies and phototherapy for psoriasis are limited by safety concerns that may preclude long-term treatment with these agents. OBJECTIVES: To estimate the unmet need for safe and effective treatments for psoriasis. METHODS: A survey was conducted at three psoriasis outpatient clinics in Europe. Male and female patients of any age with psoriasis requiring more than topical treatment were eligible to participate in the survey. Patient data were obtained from patients' answers to a questionnaire as well as by a chart review of each participating patient. The survey questionnaire addressed various aspects of psoriasis, including demographics and disease characteristics, treatment history, pre-existing medical conditions, and patient satisfaction with treatments received. RESULTS: A total of 301 patients participated in the survey, with approximately 100 patients from each centre. Nearly 90% of patients had received at least one systemic therapy or phototherapy for psoriasis, with 39% of patients receiving three or more. Ultraviolet B (UVB), methotrexate, psoralen plus ultraviolet A (PUVA), retinoids and cyclosporin were the most commonly used agents. Inadequate response, reported by patients as no change or worsening of disease with treatment, ranged from 10% to 50%. Contraindications to conventional systemic therapies were reported by 9-22% of patients. A substantial number of patients (42%) were not satisfied with these therapies. CONCLUSIONS: This survey highlights the unmet need for safe and effective therapies for moderate to severe psoriasis. 相似文献