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.     

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。     

椎管内转移癌病人氨甲喋呤配伍高渗盐水硬膜外灌注治疗顽固性疼痛的临床探讨

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。     

The unmet treatment need for moderate to severe psoriasis: results of a survey and chart review

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.     

Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy

BACKGROUND: Concomitant methotrexate (MTX) therapy of oral corticosteroid (CS)-dependent asthmatics has been shown to spare CS therapy, but the mechanism is unknown. In a previous report, we showed that MTX increases T cell inhibition by CS. In this report we focus on effects of MTX on immunoglobulin concentrations and their possible clinical relevance. OBJECTIVE: To monitor changes in circulating leucocytes and Ig in a group of these patients during MTX therapy, and to relate these changes to clinical 'response' as defined by oral CS reduction. METHODS: Sixteen severe asthmatics dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high dose inhaled CS were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. Prednisolone dosages were maintained constant for 12 weeks then reduced systematically over the next 16 weeks provided that asthma control did not deteriorate. Patients were classified a priori as 'responders' or 'non-responders' to MTX (reduction of initial oral prednisolone requirement by >or=50% or <50%, respectively). Patients were followed-up for a further 12 weeks after MTX withdrawal. Serum Ig and differential blood leucocyte counts were measured at baseline, 12, 28 and 40 weeks. RESULTS: MTX therapy allowed significant, but individually variable, reductions in oral prednisolone dosages (P<0.00001) without alteration of lung function or symptoms. This was associated with significant reductions in mean serum concentrations of Ig of all classes, which reversed following MTX withdrawal. Reductions in IgE and IgG were significantly greater in the MTX 'responders' as compared with 'non-responders', and changes in IgE, IgG and IgM correlated with changes in prednisolone requirements. Differential blood leucocyte counts showed no significant variation. CONCLUSION: MTX therapy reduced oral CS requirements in these severe asthmatics to a degree which correlated with reduced circulating Ig but not lymphopaenia, suggesting a possible cause and effect relationship. These reductions might also contribute to the documented incidence of opportunistic infection in these circumstances.