Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

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.     

Risk factors associated with delayed methotrexate clearance and increased toxicity in pediatric patients with osteosarcoma

High‐dose methotrexate (HD‐MTX; 12 g/m²) is part of standard therapy for pediatric osteosarcoma (OS). Risk factors associated with MTX toxicity in children with OS are not well defined. We investigated the association between peak MTX levels (four‐hour) and delayed MTX clearance or treatment toxicity. Information was retrieved from electronic medical records of 33 OS patients treated with HD‐MTX at Texas Children's Hospital from 2008 to 2015. We found that the four‐hour MTX level did not contribute to toxicity or delayed MTX clearance. We demonstrated that certain demographic characteristics are associated with delayed clearance and increased toxicity.     

DMARD combination therapy in rheumatoid arthritis: 5‐year follow‐up results in a daily practice setting

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.     

First-line high-dose chemotherapy combined with peripheral blood stem cell transplantation for patients with advanced extragonadal germ cell tumors

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.     

Long-term results of first-line sequential high-dose carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell support for patients with advanced testicular germ cell tumor

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.     

Acute urticaria and hepatitis complicating high-dose methotrexate therapy

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.     

芍药总甙和甲氨蝶呤治疗类风湿关节炎的疗效和安全性

类风湿关节炎９０例（男性１８例，女性７２例，年龄４７±ｓ１２ａ），随机分为芍药总甙（ＴＧＰ）６０例，１．８ｇ／ｄ，分３次ｐｏ，甲氨喋呤（ＭＴＸ）每同ｐｏ１次１５ｍｇ，２药均４ｗｋ为一个疗程，连用３个疗程。服药的ｗｋ４，８，１２，ＴＧＰ的总有效率分别为４５％，６０％和６３％，ＭＴＸ的总有效率分别为５３％，６７％和７０％，２组相比无显著差异（Ｐ＞０．０５）。ＴＧＰ的不良反应（２８％）低于ＭＴＸ（５７％）。     

潘生丁增强氨甲蝶呤的抗肿瘤作用

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。