Topical delivery of 5-fluorouracil (5-FU) by 3-alkylcarbonyloxymethyl-5-FU prodrugs

The 3-alkylcarbonyloxymethyl-5-fluorouracil (3-ACOM-5-FU) prodrugs have been characterized by their solubilities in isopropyl myristate (S(IPM)) and partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)). Estimated S(AQ) values have been obtained from S(AQ) = S(IPM)/K(IPM:AQ.) The abilities of the prodrugs to deliver total 5-FU species from IPM suspensions through hairless mouse skin (J(i)) have been evaluated in diffusion cell experiments. All of the prodrugs were much more soluble in IPM than 5-FU, and the propionyloxymethyl (C2) member of the series was almost twice as soluble in pH 4.0 buffer. Except for the acetyloxymethyl (C1) member of the series, the 3-ACOM-5-FU prodrugs exhibited greater S(IPM) and S(AQ) values than the corresponding 1-alkylcarbonyloxymethyl (1-ACOM-5-FU) prodrugs. The 3-ACOM-5-FU prodrugs that exhibited greater S(IPM) and S(AQ) values than the 1-ACOM-5-FU prodrugs also exhibited greater J(i) values, except for the C2 member. The C2 member also gave the largest error in predicting J(i) using the transformed Potts-Guy equation. All of the 3-ACOM-5-FU prodrugs delivered more 5-FU as a percentage of J(i) than the 1-ACOM-5-FU prodrugs but were not more effective as a series at targeting dermal as opposed to transdermal delivery.     

Activated protein C in patients with septic shock: a consecutive case series

Background: The recommendation to restrict the use of activated protein C (APC) to patients with severe sepsis and the highest risk of death originates from large trials that were subject to major exclusion criteria. Objective: To investigate the effect of APC on prognosis in ??real world?? patients. Method: Consecutive case series at tertiary care hospital including 63 adults with septic shock and multi-organ failure treated with APC (24 mcg/kg/h) for up to 96?h in addition to standard care. Results: Median APACHE score was 35 (quartiles, 29?C41), mean number of failing organs was 4 (quartiles, 4?C5), and overall 30-day mortality was 48%. Independent predictors of 30-day mortality risk were the number of failing organs and number of antibiotics given. Risk of dying was significantly lower if compared with the mortality rates expected per APACHE II score category (P for trend per 5-point increment <0.001). This association was most prominent in patients with an APACHE II score of 30?C44. Intracranial or major bleeding during APC treatment did not occur. Conclusion: These findings support the view that targeting APC treatment to patients with septic shock and a very high risk is a sound and safe approach. However, due to lack of consistent evidence from randomized studies APC was recently removed from the market.     

Topical delivery of 5-fluorouracil (5-FU) by 1,3-bisalkylcarbonyl-5-FU prodrugs.

The solubilities in isopropyl myristate (S(IPM)) and pH 4.0 buffer (S(AQ)) and the partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)) have been measured for a series of 1,3-bisalkylcarbonyl-5-fluorouracil prodrugs (1,3-AC-5-FU). The 1,3-AC-5-FU prodrugs were each over 500 times more soluble in IPM, but all members of the series, whose solubilities could be estimated, were much less soluble in pH 4.0 buffer than 5-FU. The abilities of the 1,3-AC-5-FU prodrugs to deliver total 5-FU species through hairless mouse skin from IPM suspensions (J(i)) were also measured. The 1,3-diacetyl derivative 2, which exhibited the highest S(AQ) in the series, gave the highest J(i) value. Although the series of 1,3-AC-5-FU prodrugs was generally effective at increasing J(i) (three to ten times), the best 1,3-AC-5-FU prodrug was not as effective as the best 1- or 3-alkylcarbonyl-5-FU prodrug (1- or 3-AC-5-FU) at increasing J(i) and their ability to increase the concentration of total 5-FU species in the skin was generally less than that of the 1-AC-5-FU prodrugs, but greater than that of the 3-AC-5-FU prodrugs. Thus, the 1-AC-5-FU prodrugs remain the best prodrugs with which to enhance the topical delivery of 5-FU.     

Formulation and characterization of Paclitaxel, 5-FU and Paclitaxel + 5-FU microspheres

The purpose of this study was to compare the combination (Paclitaxel + 5-FU microspheres) with a single drug chemotherapy (Paclitaxel and 5-FU microspheres) against metastatic breast cancer cell line (MDA-MB 435 S). The physicochemical characteristics of the microspheres (i.e. encapsulation efficiency, particle size distribution, in vitro release, thermal characteristics) were studied. The results demonstrated that the encapsulation efficiency of Paclitaxel was high (90%) when the drug was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microparticles with or without 5-fluorouracil (5-FU). However, the encapsulation efficiency of 5-FU was low (19%) and increased to 30% when the drug was encapsulated with Paclitaxel. The mean particle size of microspheres was 2.5microm and were spherical in shape. The in vitro release of both 5-FU and Paclitaxel from the microspheres was relatively fast initially followed by a slower and more controlled release. The cytotoxic activity of Paclitaxel microspheres was far greater compared to either the microspheres containing 5-FU + Paclitaxel or 5-FU alone. Overall results demonstrated that incorporation of Paclitaxel or 5-FU in microspheres enhances the cytotoxicity in more controlled manner compared to that of free drugs and also that careful consideration should be made when combining drugs acting in different phases of cell cycle.     

Augmentation with olanzapine in TCA-refractory depression with melancholic features: a consecutive case series

Using an 8-week, open label study design, we report the effect of augmentation strategy with olanzapine in hospitalized depressive patients with melancholic features who had insufficient response to a tricyclic antidepressant (TCA), amitriptyline. Subjects were hospitalized patients meeting the criteria of DSM-IV major depressive disorder with melancholic features who had been suffering from residual symptoms after treatment of amitriptyline. After study entry, olanzapine was added to amitriptyline and the dose was adjusted according to patients' clinical condition. Data were analyzed using an intent-to-treat methodology, with last observation carried forward. Paired t-test was adopted to assess the data from baseline to endpoint. Of 26 patients who enrolled in this study, 23 patients completed the trial and 3 patients dropped out. The mean dose of olanzapine was 6.5 (SD = 2.4) mg/day. The mean score of Montgomery-Asberg Depression Rating Scale (MADRS) was significantly decreased from 33.6 (SD = 3.5) to 20.8 (SD = 9.1) during this study (37.9% from baseline) (p < 0.001). Ten patients (38.5%) were considered as responders (50% or greater reduction in MADRS scores from baseline). These results suggest that augmentation with olanzapine in TCAs-resistant melancholia may be effective and well tolerated. We cannot draw any conclusion with certainty from the open-label, uncontrolled clinical trial. Double blind, controlled trial is needed to confirm this preliminary finding.     

Acute Encephalopathy Attributed to 5-FU

Acute encephalopathy attributable to 5-fluorouracil (5-FU) is rare. A patient experienced this reaction associated with a continuous 5-FU infusion. The etiology of the event remains uncertain, but it is generally reversible and does not preclude retreatment with 5-FU at reduced dosages. Steroids and thiamine may expedite neurologic recovery.     

5-氟尿嘧啶及其衍生物的研究进展

尿嘧啶的氟化类似物5-FU是一种抗代谢物,它对很多实体肿瘤有较好活性。5-FU抗肿瘤活性是通过干扰DNA合成和mRNA翻译来实现的。然而,由于5-FU具有非特异性细胞毒性,故采用5-FU治疗的患者表现出多种副作用。为了改善这些缺点,研究者们对5-FU的结构展开了大量的修饰工作。文章综述了5-FU的作用机理以及药代动力学情况,介绍了5-FU的几种新型修饰衍生物。最后,对提高5-FU衍生物生物利用度的研究进展进行了综述,为5-FU衍生药物的合理使用提供了理论依据。     

5-氟尿嘧啶纳米级给药系统研究进展

目的介绍近年来5-氟尿嘧啶纳米级给药系统的研究进展。方法查阅近几年国内外有关文献并进行整理分析。结果5-氟尿嘧啶纳米级给药系统具有控释性、靶向性等优点,并显现出良好的抗动物肝癌模型效果。结论5-氟尿嘧啶纳米级给药系统为癌症的有效治疗带来新的突破。     

5-氮杂-2-脱氧胞苷提高结肠癌SW620细胞株对5-FU的化学敏感性

目的 探讨5-氮杂-2-脱氧胞苷(5-aza-CdR)可能增强结肠癌SW620细胞株对5-氟尿嘧啶(5-FU)化学敏感性的作用.方法 分别用不含药物组(A组)、5-aza-CdR(B组)、5-FU(C组)以及5-aza-CdR联合5-FU(D组)作用人结肠癌SW620细胞株后,光镜下观察细胞形态学改变,MTT法测定细胞的生长情况和流式细胞术检测细胞凋亡.结果 A、B、C、D组细胞存活率分别为100％、(65.85±0.95)％、(45.14±1.44)％、(30.18±0.89)％;B、C、D组细胞存活率均明显低于A组(P＜0.05),D组低于B、C组(P＜0.05).A、B、C、D组细胞凋亡率分别为(4.50±0.61)0％、(16.80±0.57)％、(12.66±0.43)％、(42.07±0.85)％;与A组比较,B、C、D组引起细胞凋亡增加(P＜0.05);与B组、C组比较,D组促进细胞凋亡作用更明显(P＜0.05).结论 5-aza-CdR在体外提高了结肠癌SW620细胞对5-FU的化学敏感性.     

Short incubation PDT versus 5-FU in treating actinic keratoses

The efficacy of photodynamic therapy (PDT) using broad area treatment with 5-aminolevulinic acid (ALA) has not been compared to topical 5-fluorouracil (5-FU) in the treatment of actinic keratoses (AK). The purpose of this study was to compare the efficacy and tolerability of PDT using short incubation time, broad area treatment with ALA plus activation with either blue light or laser light to topical 5-FU in the treatment of AK of the face and scalp. Thirty-six subjects with AK of either the face or scalp were randomized to receive either application of ALA for 1 hour followed by activation with blue light or pulsed dye laser or topical 5-FU. Efficacy was evaluated by grading AK lesions and photoaging signs. Tolerability was assessed by scoring crusting/erosions, erythema and stinging/burning. Treatment with PDT using ALA plus blue light was as effective as topical 5-FU in clearing AK. PDT using ALA plus laser light was the least effective treatment. All treatments made improvements in the signs of photoaging. Both PDT treatments were better tolerated than 5-FU. In conclusion, broad area PDT treatment with ALA plus activation with blue light appears to be as effective as 5-FU in the treatment of AK. ALA plus laser light is somewhat less effective than the above therapies. Efficacy could likely be improved with further study of laser parameters and incubation times.     

Medical care consumption in a phase III trial comparing irinotecan with infusional 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer after 5-FU failure

We evaluated economic implications of treatment with irinotecan, following a RCT which demonstrated significantly increased survival at 1 year with irinotecan (45%) compared to infusional 5-fluorouracil (5-FU) (32%) in patients with metastatic colorectal cancer. Medical care consumption data were collected prospectively alongside the trial, with 256 patients followed for a median of 10 months. Follow-up was prolonged beyond treatment failure and medical care consumption was not protocol driven, enabling a realistic evaluation of economic implications. Medical care consumption associated with chemotherapy administration was lower with irinotecan as compared with infusional 5-FU. The cumulative number of days in hospital due to treatment toxicity and cancer complications, which is the key cost driver, was 14.4 (95% CI: 10.7-18.1) with irinotecan versus 17.5 (95% CI: 11.7-23.3) with infusional 5-FU. Thus, the survival benefit with second-line irinotecan compared to infusional 5-FU in patients with advanced colorectal cancer was achieved without increasing medical care consumption.     

Nonlinear pharmacokinetic characteristics of 5-fluorouracil (5-FU) in colorectal cancer patients

Summary The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37°C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma.A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination.The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. These findings suggest the possibility of pulmonary clearance of 5-FU.     

Quality of Life in Patients With Metastatic Colorectal Cancer Receiving Chemotherapy: A Randomized,Double-Blind Trial Comparing 5-FU versus 5-FU With Leucovorin

We compared health-related quality of life (HQL) measures in 210 patients with metastatic colorectal cancer who were receiving equitoxic regimens of weekly 5-fluorouracil (5-FU) plus leucovorin (LV) or 5-FU alone in a multicenter, placebo-controlled, double-blind, randomized trial. The HQL was assessed during the first 120 days of treatment by the patient-generated functional living index-cancer (FLIC) questionnaire. Also assessed were clinician-generated measures to evaluate physical functioning and suffering: Karnofsky performance status (KPS), body weight, disease symptoms, and hospitalization. No significant difference was detected between treatment groups in HQL or in any measurement of efficacy or toxicity. The number of patients hospitalized was similar in both groups, 35 patients receiving 5-FU-LV, 32 receiving 5-FU-placebo, but those receiving 5-FU-LV were hospitalized longer (450 vs 315 total days). The KPS improved or stabilized in 23% and 37% of patients, respectively. Overall, FLIC scores significantly improved in 27% or remained stable in 62% of all patients; disease symptoms improved in 19–49%; a weight increase of 2 kg or more occurred in 27%. A change in FLIC was not associated with tumor response or improvement in pain, but a decline in FLIC was associated with improved survival. An improvement in KPS or weight was associated with tumor response and strongly correlated with survival. Improvement of pain was associated with a stable or increase in weight, and worsening of pain correlated with lack of tumor response.     

A Physiologically Based Pharmacokinetic Analysis of Capecitabine,a Triple Prodrug of 5-FU,in Humans: The Mechanism for Tumor-Selective Accumulation of 5-FU

Purpose. To identify the factors governing the dose-limiting toxicity in the gastrointestine (GI) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans. Method. The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measured experimentally in vitro to construct a physiologically based pharmacokinetic model. Sensitivity analysis for each parameter was performed to identify the parameters affecting tissue 5-FU concentrations. Results. The sensitivity analysis demonstrated that (i) the dihydropyrimidine dehydrogenase (DPD) activity in the liver largely determines the 5-FU AUC in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) the metabolic enzyme activity in the GI and the DPD activity in liver are the major determinants influencing exposure to 5-FU in the GI. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges. Conclusions. It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine administration are tumor-specific activation by dThdPase, the nonlinear elimination of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors.