Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation

Purpose: Lometrexol [(6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate] is the prototype folate antimetabolite that targets the de novo purine synthesis pathway. Early phase I trials were confounded by cumulative myelosuppression that prevented repetitive administration. Subsequent preclinical and clinical studies suggested that coadministration of folic acid might favorably modulate lometrexol toxicity without eliminating potential antitumor activity. We set out to determine if concurrent folic acid would allow administration of lometrexol on a weekly schedule, and, if so, to identify an appropriate dose combination for phase II trials. Pharmacokinetic and metabolism studies were undertaken in an attempt to improve our understanding of lometrexol pharmacodynamics. Methods: Patients with advanced cancer received daily oral folic acid beginning 7 days before lometrexol and continuing for 7 days beyond the last lometrexol dose. Lometrexol was administered by short i.v. infusion weekly for 8 weeks. Scheduled lometrexol doses were omitted for toxicity of more than grade 2 present on the day of treatment, and dose-limiting toxicity was prospectively defined in terms of frequency of dose omission as well as the occurrence of severe toxic events. Plasma and whole blood total lometrexol contents (lometrexol plus lometrexol polyglutamates) were measured in samples taken just prior to each lometrexol dose. Results: A total of 18 patients were treated at five lometrexol dose levels. The maximum tolerated dose was identified by frequent dose omission due to thrombocytopenia and mucositis. The recommended phase II dose combination is lometrexol 10.4 mg/m² per week i.v. with folic acid 3 mg/m² per day orally. One patient with melanoma experienced a partial response, and three patients, two with melanoma and one with renal cell carcinoma, experienced stable disease. Lometrexol was not detectable in any predose plasma sample tested. The total red blood cell content of lometrexol increased over several weeks and then appeared to plateau. Conclusions: Weekly administration of lometrexol is feasible and well-tolerated when coadministered with daily oral folic acid. The nature of the interaction between natural folates and lometrexol that renders this schedule feasible remains unclear. A definition of dose-limiting toxicity that incorporated attention to dose omissions allowed efficient identification of a recommended phase II dose that reflects the maximum feasible dose intensity for a weekly schedule. Lometrexol is a promising, anticancer agent. Received: 21 January 1999 / Accepted: 26 August 1999     

Operative revision of non-functioning filtering blebs with 5-fluorouracil to regain intraocular pressure control

PURPOSE: To determine the efficacy of extensive microsurgical needling revision of failed filtering blebs followed by serial 5-fluorouracil subconjunctival injections. METHODS: Thirty-six eyes of 34 consecutive patients with progressive open-angle glaucoma refractory to topical therapy submitted to needling revision as a major procedure. All patients required multiple antiglaucoma medications preoperatively, and had completely flat or densely encapsulated filtering blebs. All patients underwent elaborate needling revision (limbus to superior rectus >8 mm diameter, >3 mm elevation, entry-site sutured with 8-0 vicryl and bleb reformed via paracentesis with viscoelastic) in the operating room, followed by serial 5-fluorouracil. The patients were followed for up to 6 months postoperatively. The main outcome measures were intraocular pressure (IOP) and the number of antiglaucoma medications used. RESULTS: Thirty-one eyes (86%) maintained mean IOP below 15 mmHg postneedling without medication. Overall the mean IOP postneedling was >9 mmHg lower than medicated preoperative levels (P < 0.0001). IOP reduction in encapsulated blebs was marginally superior to that in flat blebs. CONCLUSIONS: Extensive needling revision in the operating room is safe, straightforward, and produces reproducible restoration of filtering function.     

Antimetabolites and cancer: emerging data with a focus on antifolates

Antimetabolites, especially antifolates, play an important role in the treatment of a variety of both malignant, and non-malignant diseases, such as rheumatoid arthritis, and bacterial and parasitic infections. Recently, new antimetabolites have become an area for anticancer drug expansion. Gemcitabine has emerged as an important new agent in several tumour types, including non-small cell lung cancer, pancreatic, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also been developed; raltitrexed and pemetrexed are now commercially available for the treatment of mesothelioma, non-small cell lung cancer and other solid cancer types. This review will describe the most recent findings and their potential clinical applications.     

固相萃取-高效液相色谱法测定人乳中甲氨蝶呤的含量

目的:建立胎盘植入产妇术后人乳中甲氨蝶呤含量测定的固相萃取-高效液相色谱法。方法:乳汁样品经C18固相萃取小柱提取后进样测定,色谱柱为Agilent ZOBAX SB-C18(4.6 mm×250 mm,5μm)柱,流动相为0.05%醋酸溶液-乙腈(88∶12),流速为1.0 mL.min-1,检测波长为306 nm。结果:乳汁中甲氨蝶呤在0.5～5μg.mL-1浓度范围内线性关系良好,高、中、低浓度的方法回收率分别为99.8%,100.9%,99.1%;RSD均小于10%。日内和日间精密度均小于5.8%。结论:本方法专属性强,灵敏度高,操作简便,适用于乳汁中甲氨蝶呤含量的测定。     

Intra-lesional 5 fluorouracil for the management of recurrent pterygium

Aim

Recurrence is the most common complication arising from pterygium surgery. The aim of this study was to investigate the effectiveness of 5 fluorouracil (5FU) in halting the recurrence of pterygium after surgical excision.

Methods

A retrospective review of patients treated for pterygium recurrence was carried out. Patients with recurrent (secondary) pterygium were treated with multiple weekly intra-lesional injections of 0.1–0.2 ml (2.5–5 mg) 5FU post-operatively depending on the size of the recurrence. The treatment was started within 1 month from the date of recurrence. The time from surgery to start of recurrence, previous treatment modalities, and number of recurrences were documented. The number of injections required to induce arrest of progression and/or regression of vascularity and fleshiness of the pterygium and any complications related to 5FU treatment were examined.

Results

Fifteen eyes from 14 patients with recurrent pterygium treated with intra-lesional 5FU injections were analysed. Three of the 15 eyes had undergone a secondary excision and 12 had undergone a primary excision. In all, 93.3% of patients showed regression of the fibrovascular tissue (thickness and vascularity) and arrest of progression following a dose of 0.1–0.2 ml (2.5–5 mg) 5FU. Twelve eyes required three injections or fewer, whereas one patient required eight injections. This beneficial effect was maintained over an average follow-up period of 17 months. No complications from 5FU were observed.

Conclusion

The use of weekly intra-lesional 5FU injections for the treatment of recurrent pterygium is safe and effective in limiting the progression and inducing the regression of recurrent pterygium. The number of injections can be tailored according to clinical need.     

药物治疗瘢痕疙瘩的应用研究

瘢痕疙瘩是一种难治性的异常瘢痕,目前药物治疗是一种比较常规的方法。作者查阅了国内外近年的相关文献资料进行分析与综述,阐述各类药物治疗瘢痕疙瘩的机制和临床应用情况。临床使用最广泛的药物包括皮质类固醇激素、抗代谢药、免疫调节剂、类维生素A。另外钙通道阻滞剂、抗组胺药等对治疗瘢痕疙瘩也有一定的疗效。药物在治疗和预防瘢痕疙瘩复发方面有重要的用途和意义。     

Pharmacotherapy of scleritis: current paradigms and future directions

Introduction: Scleritis is an inflammatory condition affecting the eye wall that may be associated with a number of systemic inflammatory diseases. Because scleritis can be refractory to standard treatment, knowledge of the body of available and emerging therapies is paramount and is reviewed here.

Areas covered: This review focuses on both traditional and emerging therapies for noninfectious scleritis. The authors cover the mechanisms of action and potential adverse effects of each of the treatment modalities. In addition, a summary of the significant MEDLINE indexed literature under the subject heading ‘scleritis', ‘treatment', ‘immunomodulator' will be provided on each therapy, including commentary on appropriate use and relative contraindications. Novel treatments and potential drug candidates that are currently being evaluated in clinical trials with therapeutic potential will also be reviewed.

Expert opinion: While oral nonsteroidal anti-inflammatory drugs and oral corticosteroids are widely used, effective, first-line agents for inflammatory scleritis, refractory cases require antimetabolites, T-cell inhibitors, or biologic response modifiers. In particular, there is emerging evidence for the use of targeted biologic response modifiers, and potentially, for local drug delivery.     

Pemetrexed in advanced non-small-cell lung cancer

Importance of the field: Current therapeutic options for advanced non-small-cell lung cancer (NSCLC) yield relatively modest improvements in survival leading to an ongoing search for new active treatment agents. In the past decade, pemetrexed has had an increasingly established role in the treatment of advanced NSCLC in both first- and second-line settings.

Areas covered in this review: Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of pemetrexed in the treatment of advanced NSCLC are described. Peer-reviewed publications on the development of pemetrexed and its clinical use in NSCLC were reviewed (1995 – 2009).

What the reader will gain: Pemetrexed is a multitargeted antifolate cytotoxic agent. Key Phase II and Phase III trials are described that have shown pemetrexed's efficacy in both the first- and second-line treatment of advanced NSCLC. The efficacy of pemetrexed seems to vary between squamous and nonsquamous histologies. Possible reasons for this are explored. Additionally, the potential role of pemetrexed in maintenance therapy is discussed.

Take home message: Pemetrexed is an effective treatment for advanced NSCLC, with an overall favorable toxicity profile. There is growing evidence that, in patients treated with pemetrexed, nonsquamous tumors have improved outcomes compared to squamous cell tumors. Pemetrexed may also have a role in maintenance therapy for NSCLC.     

Contradictory antitumor efficacies produced by the combination of DNA attacking drugs and polyamine antimetabolites

The antitumor effects of two polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when combined with cis-diamminedichlroplatinum (CDDP) or mitomycin C (MMC), were studied using human gastric cancer cells xenotransplanted into nude mice. DFMO 1000 mg/kg and MGBG 50 mg/kg were given intraperitoneally for 6 successive days, while CDDP 3 mg/kg or MMC 2 mg/kg was given every second day. Although DFMO and MGBG plus MMC did suppress the tumor growth, the combination with CDDP led to no suppression, and rapid growth occurred after the cessation of therapy. The inhibition of tumoral DNA biosynthesis and a decline in polyamine levels, were also not observed. The polyamine antimetabolites when used with CDDP did not produce the desired antitumor efficacy, even though the platinum concentration in the tumor tissue was high. On the contrary, however, DFMO and MGBG when combined with MMC did suppress tumor growth, inhibited DNA biosynthesis, and tissue polyamine levels were low. These results suggest that though CDDP and MMC belong to a similar category of DNA attacking, bifunctional alkylating agents, the findings of these two drugs are contradictory. Here, the mechanism of action no doubt plays a contributory role.