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PubMed1997

Phase I-II study of gamma interferon and 5-fluorouracil for patients with metastatic renal cell carcinoma

We have completed a phase I/II trial to evaluate the toxicity and efficacy of the combination of gamma interferon and 5-fluorouracil in metastatic renal cell carcinoma. Gamma interferon was administered at a weekly dose of 100 micrograms. 5-fluorouracil was given as a 5 day continuous infusion days 1-5 of each 21 day cycle. In the phase I portion of the trial, the gamma interferon dose was held constant, while the 5-fluorouracil was escalated from 500 to 800 mg/m2/day. Serum neopterin and beta 2 microglobulin were measured prior to and 48 hours after each dose of gamma interferon for the first six weeks of treatment. Dose limiting toxicity was not encountered in the phase I part of the trial; therefore the phase II study was initiated at the 800 mg/m2/day dose of 5-fluorouracil. No responses were seen among 34 patients treated on the phase II trial. Forty-six percent of patients experienced disease stabilization and the remainder progressed through treatment. In the phase I trial, increments in neopterin and beta 2 microglobulin levels differed significantly between patients treated with lower and higher doses of 5-fluorouracil. We conclude that the addition of 5-fluorouracil to gamma interferon does not appear to enhance the cytokines clinical activity. Incremental increases in macrophage activation markers with escalating 5-fluorouracil doses suggests a role for 5-fluorouracil beyond its usual proposed cytotoxic activity and warrants further investigation into potential immunologic effects of this drug.

Journal Article↗

PubMed1985

Topical fluorouracil. Pharmacokinetics in normal rabbit eyes.

Postoperative subconjunctival fluorouracil injections may be a useful adjunct to standard glaucoma filtering surgery in eyes that are at high risk of failure. Topical administration would be preferable to subconjunctival administration; however, there are no data on the ocular penetration of topically applied fluorouracil. Consequently, we investigated the pharmacokinetics of topically administered fluorouracil labeled with carbon 14 in normal rabbit eyes. One drop (approximately 2.4 mg) of fluorouracil resulted in the following concentrations at 0.5 and six hours, respectively: 17.3 and 0.9 micrograms/g of conjunctiva; 24.3 and 1.3 micrograms/g of cornea; 14.6 and 0.2 micrograms/mL of aqueous; 0.8 and 0.5 microgram/g of lens; 1.1 and 0.3 microgram/g of vitreous; and 0.2 and less than 0.1 microgram/mL of serum. Three drops (approximately 7.2 mg) of fluorouracil resulted in the following concentrations at 0.5 and eight hours, respectively: 589.8 and 1.3 micrograms/g of conjunctiva; 502.9 and 1.8 micrograms/g of cornea; 199.6 and 0.8 micrograms/mL of aqueous; 6.2 and 0.5 micrograms/g of lens; 6.8 and 0.5 micrograms/g of vitreous; and 1.3 and 0.2 microgram/mL of serum. Since a fluorouracil concentration of 0.2 microgram/mL inhibits rabbit conjunctival fibroblast proliferation in cell culture by 50%, these data suggest that topically applied fluorouracil achieves sufficient levels in the ocular compartments and tissues to have potential therapeutic applications.

Administration, Topical↗

PubMed1980

Pharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils in plasma and ascites fluid after oral administration in mice.

Pharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils was examined in mice bearing sarcoma 180. The alkylcarbamoyl derivatives were absorbed rapidly as intact form through the gastrointestinal tract and distributed into ascites fluid. Concentration-x-time (C-x-t) values of 5-fluorouracil formed in plasma and ascites fluid decreased in order by extension of the carbon chain of the alkyl moiety. C-x-t value of 5-fluorouracil formed in ascites fluid after hexylcarbamoyl derivative was higher than that in plasma. Antitumor activity of the compounds was correlated with both maximum concentration (Cmax) and C-x-t values of 5-fluorouracil formed and Cmax of total (intact form plus 5-fluorouracil formed) in ascites fluid (P < 0.01), and with C-x-t values in ascites fluid and Cmax and C-x-t values of 5-fluorouracil formed in plasma (P < 0.05). Alkylcarbamoyl structure was valuable for rapid absorption through the gastrointestinal tract and blood-ascites barrier and for maintenance of 5-fluorouracil level in plasma and ascites fluid.

Administration, Oral↗

PubMed1985

Gas-liquid chromatographic analysis of fluoropyrimidine nucleosides and fluorouracil in plasma and urine.

A gas-liquid chromatographic method employing on-column alkylation and a nitrogen-sensitive detector was developed for the analysis of 5-fluoro-2'-deoxyuridine, 5-fluorouridine, and 5-fluorouracil in plasma and urine. Samples (0.72 ml) containing the fluoropyrimidine and internal standard (5-chloro-2'-deoxyuridine for nucleoside analyses and 6-methyluracil for 5-fluorouracil analyses) were prepared for gas-liquid chromatography by sequential cation-exchange and anion-exchange column chromatography. Recoveries of fluoropyrimidines were 71-95% over the concentration ranges studied. The dried eluate from the anion-exchange column was dissolved in p-tolyltrimethylammonium hydroxide in methanol before gas-liquid chromatographic analysis. Columns packed with either 3% SP-2100 on Supelcoport or 3% OV-1 on Gas-Chrom Q were suitable for nucleoside analyses; a column packed with 0.75% Carbowax 20M-5% KOH on Chromsorb G was used for 5-fluorouracil analyses. The fluoropyrimidine nucleosides were well separated from each other and from the potentially interfering endogenous compounds 2'-deoxyuridine and uridine; 5-fluorouracil was well separated from uracil. Linear standard curves (peak area ratio method) were obtained for plasma containing 0.025 to 20 micrograms FdUrd (0.1 to 81 microM) or 0.05 to 1.0 microgram FUrd (0.2 to 3.8 microM), and for urine containing 0.2 to 1.0 microgram (0.8 to about 4 microM) of the nucleosides. Standard curves for 5-fluorouracil (1.5 to 7.9 microM) and 2'-deoxyuridine (0.9 to 4.4 microM) were also linear. A measurable amount of 5-fluorouracil, equivalent to 4 to 7% of the 5-fluoro-2'-deoxyuridine injected, was formed from the nucleoside on the gas-liquid chromatographic column, requiring correction of 5-fluorouracil concentrations measured in the presence of 5-fluoro-2'-deoxyuridine.

Animals↗

PubMed1988

Patterns of haemopoietic recovery after stress--II. Treatment with fluorouracil.

The mouse haemopoietic system is not permanently damaged by repeated injections of cytotoxic fluorouracil. It contains approximately normal numbers of nucleated femoral and spleen colony-forming cells (CFUs) after seven monthly injections of the drug and normal numbers of high proliferation potential colony-forming cells (HPP-CFC) after five serial injections. Furthermore, the mouse is fully fertile after seven injections of fluorouracil. The mouse recovers quickly after treatment because it regenerates from cells which were not killed by the drug. Within 14 days of treatment with fluorouracil there are almost twice the normal number of femoral macrophage and high proliferation potential colony-forming cells (M-CFC and HPP-CFC). These numbers then fall but are returning to normal 6 weeks after the drug was administered. In this quick recovery the response of the haemopoietic system differs from its response to the loss of blood cells caused by sub-lethal irradiation, or lethal irradiation, or treatment with busulphan. When mice are treated twice with fluorouracil, the second injection 14 days after the first, the number of femoral M-CFC two days after the second injection, is 16-fold the number in controls, but the number of femoral HPP-CFC is only twice the number in controls. When the interval between the two injections is 21 days, the number of femoral M-CFC is almost 8% of that of mice treated once, but the number of HPP-CFC is 67%. The characteristic response of each type of cell to repeated treatment with fluorouracil is probably due to the number of its precursors which are killed by the drug and to the interval between successive injections. A second injection of fluorouracil, 28 days after the first, speeds the growth rate of HPP-CFC. Their doubling time is 6 h shorter than that of mice treated once. Haemopoietic tissue from mice treated repeatedly with fluorouracil can only outgrow normal marrow under certain conditions. The nature of these conditions and the mechanisms involved are discussed in the light of contradictory findings.

Animals↗

PubMed1994

Combination therapy with radiation, mitomycin C, and 5-fluorouracil in EMT6 tumors.

PURPOSE: The primary purpose of these studies was to assess whether concomitant treatment with 5-fluorouracil increased the cytotoxicity of radiation, mitomycin C, or the combination of these two agents to cells in solid tumors. METHODS AND MATERIALS: All studies were performed using EMT6 mouse mammary tumor cells. In vitro studies used exponentially-growing monolayers. In vivo studies used solid EMT6 tumors growing in BALB/c Rw mice. The effects of treatment on tumors or cultures were assessed using clonogenic assays which considered both the colony forming abilities of the intact cells and the numbers of cells in the cultures or tumors. RESULTS: EMT6 cells in vitro were killed effectively by 5-fluorouracil. The cytotoxicity increased as the drug concentration increased from 1 microM to 1 mM or as the treatment time increased from 1 to 48 hr. However, 5-fluorouracil was only marginally active against solid EMT6 tumors: treatment with doses of up to 400 micrograms/gm killed less than 50% of the tumor cells, regardless of whether the drug was given as an injection or an infusion over 48 hr and regardless of the time between injection of the drug and assay of cell survival. Treatment with 5-fluorouracil produced only a statistically insignificant increase in the effect of 15 Gy of x-rays, whether the drug was given by injection or infusion over 48 hr. Both injection of 200 micrograms/g 5 FU and infusion of 100 micrograms/g 5-fluorouracil decreased the cytotoxicity of 6 micrograms/g of MC to cells in solid tumors. Injection of 200 micrograms/g of 5-fluorouracil decreased the cytotoxic effects of a regimen combining 6 micrograms/g MC plus 15 Gy of x-rays. CONCLUSION: In this solid tumor system, a regimen combining single doses of mitomycin C and x-rays was more effective in killing the tumor cells than was the same regimen combined with 5-fluorouracil.

Animals↗

PubMed1992

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer.

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1-3, N1-2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and fluorouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased according to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2, fluorouracil = 375 mg/m2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2 and fluorouracil = 500 mg/m2 (level 2), 69 patients at cyclophosphamide = 75 mg/m2, epirubicin = 60 mg/m2, and fluorouracil = 500 mg/m2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 70 mg/m2, and fluorouracil = 500 mg/m2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Randomized, controlled study of low-dose 5-fluorouracil in primary trabeculectomy.

PURPOSE: To report a randomized clinical trial of postoperative subconjunctival injections of low-dose 5-fluorouracil in patients undergoing primary trabeculectomy. METHODS: In a prospective, randomized clinical trial, 40 eyes of 40 patients were randomized to the low-dose 5-fluorouracil group and received three subconjunctival injections of 5 mg each over 11 postoperative days, and 40 eyes of 40 patients were randomized to trabeculectomy without 5-fluorouracil. RESULTS: Mean (+/-SD) preoperative and 1-year postoperative intraocular pressures in the 5-fluorouracil group were 26.9 (+/-9.5) and 15.3 (+/-5.8) mm Hg, respectively. In the control group these were 25.9 (+/-8.1) mm Hg, and 15.8 (+/-5.1) mm Hg, respectively. The patients who received 5-fluorouracil had a mean reduction in intraocular pressure of 11.5 (+/-9.1) mm Hg at a median follow-up of 52.3 weeks. The control group had a mean reduction in intraocular pressure of 10.2 (+/-8.7) mm Hg at a median follow-up of 52.6 weeks. These differences were not statistically significant. CONCLUSIONS: Three postoperative subconjunctival 5-fluorouracil injections of 5 mg each after trabeculectomy in eyes at low risk for failure had no statistically or clinically significant effect on reduction of intraocular pressure with 1-year follow-up. Enhancement of success in this group of patients may require a larger total dose of 5-fluorouracil.

Adult↗

PubMed1993

A prospective trial of intraoperative fluorouracil during trabeculectomy in a black population.

In a study population of black Africans with advanced glaucoma in Ghana we conducted a prospective study of intraoperative 5-fluorouracil alone. Eyes undergoing trabeculectomy were randomly selected either to receive or not receive a single intraoperative application of 5-fluorouracil (50 mg/ml for five minutes). Fifty-five eyes had a mean follow-up of 282 days (minimum, 92 days). Twenty of 24 eyes (83%) in the 5-fluorouracil group vs 12 of 31 eyes (39%) in the control group had postoperative intraocular pressure of 20 mm Hg or less with or without medical therapy (P = .01). Eleven of 24 eyes (46%) in the 5-fluorouracil group and five of 31 eyes (16%) in the control group had intraocular pressure of 15 mm Hg or less (P = .02). Without medical therapy, 17 of 24 eyes (71%) in the 5-fluorouracil group and ten of 31 eyes (32%) in the control group had intraocular pressure of 20 mm Hg or less (P = .02). The overall complications were similar in the two groups. In this population, intraoperative 5-fluorouracil markedly improved the ability of trabeculectomy to lower intraocular pressure. We recommend that intraoperative 5-fluorouracil be considered in glaucoma surgery with poor prognosis as an alternative to postoperative subconjunctival injections when multiple injections are not feasible.

Adult↗

PubMed1988

A randomized comparison of doxifluridine and fluorouracil in colorectal carcinoma.

In a randomized study 52 patients with advanced colorectal cancer and measurable lesions were treated with doxifluridine 4000 mg/m2 or fluorouracil 450 mg/m2 i.v. on 5 consecutive days over 3 weeks. None had prior fluoropyrimidines except two who received adjuvant fluorouracil. Partial responses with a duration ranging from 259 to 406 days were observed in five patients treated with doxifluridine and two patients treated with fluorouracil. Toxic reactions were evaluated in 88 doxifluridine courses and 105 fluorouracil courses. The most frequent adverse effects were neurotoxicity (48% of patients) and mucositis (43%) for doxifluridine, leukopenia (48%) and nausea/emesis (37%) for fluorouracil. Mucositis, diarrhea, nausea, emesis and skin reactions were observed in both treatment groups. Fluorouracil produced neurotoxic effects in 26% of patients. Reversible cardiac dysfunctions were observed in four patients treated with doxifluridine, expressed by ectopic ventricular beats (2) precordial pains (1) and ventricular fibrillation (1). This latter toxicity justified the premature interruption of the study. Doxifluridine is an active agent in colorectal cancer. Compared to fluorouracil it produces, when used i.v., a lower myelosuppression and a greater incidence of neurological and cardiac toxicity.

Adenocarcinoma↗

PubMed1996

Tiazofurin enhances the anabolism and toxicity of 5-fluorouracil.

Tiazofurin, a clinically active anticancer agent, is undergoing additional clinical testing in combination with other agents. We found that tiazofurin is an effective biochemical modulator of 5-fluorouracil anabolism. Pretreatment of cultured L1210 cells with tiazofurin at concentrations of 1-100 microM results in an increase in the rate of conversion of 5-fluorouracil to phosphorylated metabolites. Concentrations of tiazofurin effective in increasing 5-fluorouracil anabolism cause a corresponding increase in the 5-phosphoribosyl-1-pyrophosphate pool. Studies in mice show that tiazofurin increases the lethal toxicity of 5-fluorouracil and increases the antitumor effectiveness of low doses of 5-fluorouracil: however, the combination is not more effective than an optimal dose of 5-fluorouracil given alone. These results indicate that caution should be exercised in the concurrent use of tiazofurin with other drugs, particularly 5-fluorouracil, that require 5-phosphoribosyl-1-pyrophosphate for activation or that are affected by a decrease in pyrimidine nucleotide synthesis.

Animals↗

PubMed1994

Liquid scintillation spectrometry of 5-fluorouracil in cervical tissue following in vitro surface application of a bioadhesive cervical patch.

The potential use of bioadhesive technology for the treatment of cervical intraepithelial neoplasia was investigated. A cervical patch was designed containing 5-fluorouracil in a bioadhesive matrix and polyvinyl chloride as the backing layer. The concentration of 5-fluorouracil at specified tissue depths from the cervical surface was determined in vitro in relation to the ability of the drug to reach precancerous foci in cervical crypts up to 4 mm below the tissue surface. Thus, tissue was exposed to drug-loaded patches spiked with 5-fluorouracil-6-3H and subsequently sectioned to obtain tissue slices at different depths. The concentration of 5-fluorouracil was determined by liquid scintillation spectrometry. Drug penetration into cervical tissue exceeded a depth of 5.5 mm. Furthermore, the concentration in the tissue depended on the drug loading in the patch. Patches containing 10 and 20 mg of 5-fluorouracil produced a linear drug gradient that was established after a 4 hour application of the patch and persisted over 24 hours. However, patches containing 3.5 mg of 5-fluorouracil displayed signs of drug exhaustion after 24 hours. The penetration characteristics of 5-fluorouracil through cervical tissue using the cervical patch delivery system were sufficiently favourable to warrant further clinical investigations.

Adhesives↗

PubMed2000

Minimal toxicity to myeloid progenitor cells of weekly 24-hr infusion of high-dose 5-fluorouracil: direct evidence from colony forming unit-granulocyte and monocyte (CFU-GM) clonogenic assay.

Although very high doses of 5-fluorouracil was used in the weekly 24-h infusion, high-dose 5-fluorouracil (2600 mg/m2/week) and leucovorin (500 mg/m2/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit-granulocyte and monocyte clonogenic assay; and 2 representative modes of 5-fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5-fluorouracil in the bone marrow to be 200-400 microM and 1-2 microM for the 30 min. infusion (600-900 mg/m2) and the 24 hr-infusion (1000-2000 mg/m2) regimens, respectively. The results of our colony-forming unit-granulocyte and monocyte clonogenic assay showed that 24-hr exposure to 5-fluorouracil (2 microM) and 30 min. exposure to 5-fluorouracil (100 microM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.

Adolescent↗

PubMed1998

The addition of paclitaxel to continuous infusion 5-fluorouracil is an active regimen for metastatic breast cancer.

Metastatic breast cancer is commonly thought to be incurable. Treatment advances have resulted in increased response rates, although such responses are often more palliative than curative. A regimen of continuous infusion 5-fluorouracil (5FU) or continuous infusion 5-fluorouracil with paclitaxel was studied in patients with metastatic breast cancer and measurable disease. The induction therapy preceded high-dose ifosfamide, carboplatin, and melphalan in a phase I-II trial. Eighty-seven patients were enrolled in the trial. Forty-five received continuous infusion 5-fluorouracil as induction and 42 received 5-fluorouracil and paclitaxel. The single-agent, continuous infusion 5-fluorouracil cohort had one complete response (2%) and eight partial responses (18%). The combination continuous infusion 5-fluorouracil and 3-hour paclitaxel regimen produced four complete responses (10%) and 17 partial responses (40%). The combination regimen of continuous infusion 5-fluorouracil with bolus paclitaxel was well tolerated and with a 50% response rate, is an active regimen for women with metastatic breast cancer.

Adult↗

PubMed2003

5-Fluorouracil as chemoadjuvant for primary pterygium surgery: preliminary report.

PURPOSE: To investigate the safety and efficacy of intraoperative application of 5-fluorouracil as an adjuvant in primary pterygium surgery and to evaluate the effect of postoperative subconjunctival 5-fluorouracil injections on the recurrent pterygium. METHODS: Of 25 consecutive white patients, 28 eyes with primary pterygium underwent pterygium excision with intraoperative application of 5-fluorouracil (25 mg/mL for 3 minutes). The superior and inferior conjunctiva was approximated to cover the scleral bed within 1 mm of the limbus. Recurrence of pterygium was defined as postoperative fibrovascular growth more than 1 mm onto the cornea. Eyes with recurrence less than 2 mm were treated with subconjunctival 5-fluorouracil injections. RESULTS: After a mean follow-up of 14.1 +/- 3.9 months (mean +/- standard deviation), 7 recurrences (25%) were observed. All recurrences were detected within 12 months. In 4 of 7 recurrences, the fibrovascular growths were less than 2 mm. We, therefore, performed subconjunctival 5-fluorouracil injections. In 3 (75%) of 4 recurrences, the fibrovascular growths became atrophic. No serious complications were observed during and after the surgery. However, superficial punctate keratitis, pain, and hyperemia were detected in all patients in the early postoperative period. As a result, of 28 eyes, 4 (14%) had unacceptable cosmetic results and growing recurrences. CONCLUSIONS: This study suggests that intraoperative applications of 5-fluorouracil is both efficient and safe in the treatment of primary pterygium. Additionally, postoperative subconjunctival 5-fluorouracil injections may prevent the progression of fibrovascular tissue.

Adult↗

PubMed1994

Pharmacokinetic characteristics of 5-fluorouracil and mitomycin C in intraperitoneal chemotherapy.

Eight patients with malignancies confined to the peritoneal space participated in this study. Five hundred milligrams 5-fluorouracil or 10 mg mitomycin C was diluted in 1 L saline. The mixed solution was injected intraperitoneally through the semi-permanent peritoneal catheter. Blood and peritoneal fluid were collected after injection. 5-Fluorouracil concentrations in the peritoneal fluid were 1000 times those in serum, while mitomycin C concentrations were 100 times those in serum. Areas under the concentration vs time curve (AUC) were calculated by the trapezoidal method with extrapolation to infinity. The ratio of peritoneal fluid AUC to serum AUC was about 1400 for 5-fluorouracil and 80 for mitomycin C. Patterns for the absorption and elimination from systemic circulation were similar for both compounds. Drug concentrations in the peritoneal fluid and serum were analysed according to the compartment model. The half-life in the peritoneal fluid (t1/2p) and the rate constant from the peritoneal fluid to the systemic circulation (ka) were nearly equal for both 5-fluorouracil and mitomycin C (t1/2p, 1.0 h for 5-fluorouracil and 1.3 h for mitomycin C; ka 0.71 h-1 for 5-fluorouracil and 0.68 h-1 for mitomycin C), although the apparent volume of distribution (Vds/F) and clearance in the peritoneal cavity (CLp) for mitomycin C (78 L m-2 and 1.8 L h-1 m-2) were about twice the values for 5-fluorouracil (149 L m-2 and 0.8 L h-1 m-2).

Absorption↗

PubMed1999

Dystrophic psoriatic fingernails treated with 1% 5-fluorouracil in a nail penetration-enhancing vehicle: a double-blind study.

BACKGROUND: Topically applied nail therapeutics need to permeate the nail plate to reach the nail bed or nail matrix and exert their potential beneficial effect at these locations to obtain a therapeutic benefit. So far only topically applied 5-fluorouracil on affected nails of psoriatic patients has been shown to produce a notable clearance. Vehicle formulations enhancing nail permeation processes are thought to increase the concentration of the active agent and therefore therapeutic efficacy, possibly enabling the use of a low concentration of the active agent thereby lowering the incidence of adverse effects. OBJECTIVE: This study was designed to verify whether a recently developed nail penetration enhancer in a lotion formulation, Belanyx((R)) (urea, propylene glycol), improves the efficacy of a low concentration of 5-fluorouracil (1%) in psoriatic fingernail lesions. METHODS: In a randomised, double-blind, left-right study the efficacy of 1% 5-fluorouracil in the Belanyx vehicle was compared to the vehicle preparation Belanyx in dystrophic fingernails of 57 psoriatic patients. Both preparations were applied in a once daily regimen for 12 weeks. Responses and adverse effects of one selected target nail were recorded at screening, at baseline and at weeks 2, 4, 8 and 12 of treatment with a final assessment at week 16: 4 weeks after the end of treatment. As parameter of efficacy was chosen the total nail area severity (NAS) score, consisting of the separate parameters nail pitting area, number of nail pits, subungual keratosis, onycholysis, oil spots and the various scores of overall improvement. RESULTS: The efficacy of 1% 5-fluorouracil in lotion and that of the vehicle in suppressing the parameters of dystrophy were shown to be similar at the end of treatment (p = 0.063) or follow-up (p = 0.130). Both preparations produced statistically significant improvements (p </= 0.05) for almost all assessed parameters after 12 weeks of treatment and after the 4 weeks of follow-up. For Belanyx lotion this applied to the nail pitting area, the number of nail pits, subungual keratosis, onycholysis and oil spots. The investigators' and patients' opinion of overall improvement of severity as well as the total NAS score of one target nail likewise showed a statistically significant improvement at the end of treatment and at the end of the observation period (p </= 0.05). With the 1% 5-fluorouracil lotion the same statistically significant improvements were obtained in all of the assessed symptoms with the exception of the number of pits and onycholysis at week 12 and week 16. Possible treatment-related adverse effects were established in 6 patients showing inflammation and infection (3 patients) or discoloration (5 patients); 3 patients on 5-fluorouracil lotion showed onycholysis. CONCLUSION: Addition of 1% 5-fluorouracil to the nail permeation enhancer Belanyx does not increase the efficacy of the active agent in psoriatic nail dystrophy of this study population. The obtained results also suggest that Belanyx lotion can be used in this indication since it has shown a favourable efficacy-safety ratio.

Adult↗

PubMed1995

Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer.

PURPOSE: To determine the effectiveness of fluorouracil plus levamisole administered postoperatively to patients with resected stage II (Dukes' B2) colon cancer. PATIENTS AND METHODS: This randomized controlled clinical trial (INT-0035) was performed by National Cancer Institute-sponsored cancer clinical trials cooperative groups. Patients were assigned to observation only or to fluorouracil (450 mg/m2 intravenously [IV] daily for 5 days and, beginning at 28 days, weekly for 48 weeks) plus levamisole (50 mg orally three times daily for 3 days repeated every 2 weeks for 1 year). Cancer recurrence, survival, and treatment side effects were assessed. RESULTS: Three hundred eighteen eligible patients were analyzed with a median follow-up time of 7 years. Fluorouracil plus levamisole reduced the recurrence rate by 31%, although this trend was not statistically significant (P = .10). A total of 87 patients died: 43 on observation and 44 on fluorouracil plus levamisole. Disparity between effects on recurrence rate and overall survival is partially explained by a higher rate of non-colon cancer-related deaths on fluorouracil plus levamisole (15 v seven) and by the effects of salvage surgery with curative intent. Of seven patients with recurrence who were rendered disease-free by salvage surgery, six were on the observation arm. As was observed in patients treated with fluorouracil plus levamisole for stage III disease, toxicity was acceptable and compliance was excellent. CONCLUSION: Fluorouracil plus levamisole is tolerable and accepted as standard surgical adjuvant therapy for patients with stage III colon cancer, but the data from this study in stage II patients suggest a decreased relapse rate without a significant improvement in survival.

Adenocarcinoma↗