摘要:

This review focuses on ways to ameliorate diagnosis and treatment of cancer-related pain with currently available knowledge and methods. The first part Indicates how to improve pain assessment and diagnosis in the cancer patient. The second part evaluates current views for adequate pain management based on evidence of double-blind analgesic trials in cancer-related pain and deals with misconceptions in established symptomatic therapy.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Maximum androgen blockade, a relatively recent development in the treatment of prostate cancer, combines medical or surgical castration with antiandrogen therapy. A large randomized study comparing the non-steroidal antiandrogen, bicalutamide, with flutamide, each in combination with luteinizing hormone-releasing hormone (LHRH) analogs, showed that after a median follow-up of 49 weeks, the time to treatment failure was significantly longer for the bicalutamide patients compared with the flutamide patients (p=0.005). After a median follow up of 95 weeks, bicalutamide in combination with LHRH analog therapy produced at least equivalent efficacy with flutamide in combination with LHRH analog therapy in terms of time to treatment failure and equivalent efficacy in terms of survival. The tolerability profile of bicalutamide, as based on reported findings and a literature review, Indicates a superior tolerability to that of currently available antiandrogens, particularly with respect to diarrhea with a low Incidence of treatment-related withdrawals.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Pre-clinical data have demonstrated synergy between 5-fluorouracil (5-FU) and Interferon (IFN)-α in colon cancer cell lines. In 1989 the first small single-Institution phase II study with this combination in advanced colorectal cancer showed a response of 81% with substantial toxicity, whereas IFN-α alone was virtually inactive. Ten published phase II studies including 175 evaluable patients have demonstrated a response rate of 2.3%. 5-FU alone has been used extensively and is moderately active with response rates of 10–11% in 1148 patients evaluated by the Advanced Colorectal Cancer Meta-analysis Project in 1992 and 1994. Eleven subsequent phase II studies with 5-FU + IFN-α published over the period of 1990–1994 on 548 patients showed a response rate of 28% with 2% toxic deaths. Recently, nine phase III clinical trials Including 1727 randomized patients have compared 5-FU + IFN-α to some standard therapies, most often treatment regimens based on 5-FU + leucovorin. Except for one study Involving 105 patients, the rest of the phase III studies have demonstrated either no difference (six studies) or significantly worse results (two studies showing substantial toxicity with IFN-α+5-FU). Several studies are ongoing, but results are not likely to change. In conclusion, after a period of high hopes, the combination of 5-FU + IFN-α does not seem to fulfill the original expectations. It is costly, It is toxic and it is not effective. New treatment strategles must be developed If progress is to be obtained.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

It was our Intention to verify If Increases of granulocyte colony stimulating factor (G-CSF) dose were able to reduce treatment delays due to leukopenia in our weekly regimen of clsplatin (40 mg/m2), epidoxorublcin (35 mg/m2), SS-leucovorin (250 mg/m2 and 5-fluorouracil (500 mg/m2), usually supported by G-CSF at a dose of 5 μg/kg. Forty five patients with advanced gastric carcinoma (30 males and 15 famales; median age 64 years) were randomized to receive three different doses of G-CSF (5, 8 and 10 μ/kg) by s.c. Injection. We did not observe any difference in the mean value of neutrophil counts at each of the 8 weeks of treatment; while we registered a higher incidence of severe neutropenia (3) in pattents receiving higher G-CSF doses: two patients in the group at 5 μg/kg, four in the group at 8 μg/kg and seven in the group at 10 μg/kg. Furthermore, low doses of G-CSF allowed a similar number of chemotherapeutic administrations in the eight study weeks. The results arising from our study do not seem to support the use of higher doses of G-CSF, at least in not such a weekly regimen.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Proionged exposure to 5-fluorouracil (5-FU) is effective for gastrointestinal mallgnancy (GIM) and it is considered synergistic or additive to concurrent radiotherapy. Oral 5-FU (OF) could represent an easy therapy. The present study prospectively tested the toxicity and effectiveness of OF in GIM by means of 5-FU mannitol-coated tabiets (MCT) at 275 or 225 mg/m2/day according to the patients age (65 years cut-off) for a period of 4 weeks every 7 weeks. Also the drug given over 5 days a week for 4 weeks was studied to assess OF toxicity over a time corresponding to that used in standard radiotherapy. Quality of life (LQ) was analyzed. Patients were 27 Individuals (20 males), aged 43–70 years, pretreated with radiotherapy (four patients) or I.v. 5-FU-based chemotherapy (five patients), and with progressive malignancy of colorectum (six patients), stomach (five patients), pancreas (four patients) and liver (two patients). The total number of cycles was 91 and 16 patients had more than two cycles. Myelotoxicity was consistently absent; other toxicities greater than WHO grade 1 were: nausea (grada 2 in four patients), diarrhes (grade 2 in six and grade 3 in 11), palmar erithema (grade 2 in one), brown-turning skin (grade 2 in one) and CNS (grade 2 in one). Diarrhea was less frequent (p=0.007) in gastric and in colorectal than in pancress and liver cancer patients. in the 10 patients given the drug of 5 days a week, diarrhea was practically absent. LQ was above 90%. Fourteen patients (51%) had total arrest of disease, and 2 among 16 colorectal cancer patients had PR (12.5%). in conclusion, the MCT-OF was tolerated and as effective as the classic i.v. 5-FU at non-myelosuppressive dose. The MCT-OF dose recommended for further studies is 275 mg/m2/day (or 225 above 65 years) for 4 weeks followed by a 2 week rest period.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The potential for hepatic enzyme induction by bicalutamide (`Casodex‘) was assessed in an open study in prostate cancer patients. A single, oral dose of antipyrine 1000 mg was given before and after 12 weeks' bicalutamide therapy [once daily 50 mg (n=7) or 150 mg (n=11)] and its pharmacokinetics and metabolism were determined. Plasma or saliva samples were taken for the measurement of antipyrine concentration. Urine samples were assayed for antipyrine and Its three major metabolites. With bicalutamide 50 mg, plasma antipyrine concentrations were maximal between 2 and 4 h after administration, declined in a log-linear manner and were unaffected by bicalutamide therapy; with bicalutamide 150 mg, saliva antipyrine concentrations were maximal between 2 and 4 h, declined in a log-linear manner, and were also unaffected by bicalutamide therapy. Antipyrine half-life was 16.3% shorter after bicalutamide 50 mg (p < 0.05); a small decrease (13.5%) in half-life after bicalutamide 150 mg was not statistically significant. A small reduction (18.6%, p < 0.05) in the AUC® for antipyrine was noted after bicalutamide 150 mg. A statistically significant reduction in antipyrine recovery was seen with the lower bicalutamide dose (23.7%, p < 0.05). The statistically significant changes were small in absolute terms and showed no dose-response relationship. Bicalutamide does not significantly Induce the hepatic enzymes responsible for antipyrine metabolism and has no obvious potential for producing clinically significant drug Interactions due to enzyme Induction.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Vinblastine at doses ranging from 0.2 to 6 mg/kg body weight was administered I.p. to mice in the absence or presence of the drugs PSC 833, cyclosporin A, mefloquine, quinidine and dipyridamole, all compounds that modulate the multidrug resistance pump and thus increase the accumulation of this cytotoxin in drug-resistant cells in cell culture. In the absence of modulators, vinblastine accumulated in tissues to different extents— Howest in brain, highest in pancreas and intestine. The extent of accumulation was directly proportional to the vinblastine dose in the range 0.2–6 mg/kg body weight. Both at high and low vinblastine doses, all the modulators except quinidine increased the ability of liver, kidney, intestine and lung to accumulate vinblastine by up to 5-fold, and with the further exception of mefloquine, also increased vinblastine levels in pancreas. Only dipyrida-mole had a marked effect also in brain. Cyclosporin A provided effective increases in the tissue distribution of vinblastine at plasma concentrations similar to those needed to block the multidrug pump in the case of cells in cell culture. For mefloquine, plasma concentrations three or four times higher were neededin vivothan were found to be effective in cell culture. The mouse system provides a quick and rellablein vivomethod to assay modulators before they are tested in the clinic.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The intratumoral distribution of cisplatin was studied in terms of platinum concentrations In tissue pleces and Immunohistochemically detected cisplatin-DNA adducts in xenografted tumors on nude mice. Heterogeneities in drug distribution were calculated as standard deviations and coefficients of variation. A three-dimensional image of adduct distribution was produced which showed regions with low adduct levels to be topographically connected also in three dimensions. A model was presented for investigating the potential Influence of vascularization and cell proliferation on intratumoral adduct distribution by using different immunohistochemical stainings of parallel tissue sections. A weak but significant correlation was found between claplatin-DNA adducts and proliferation, which might indicate that the drug uptake and adduct formation is Increased in proliferating cells.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

So far, all animal pharmacokinetic studies of paclitaxel, which used analytical procedures based on HPLC, have not been sensitive enough to quantify drug levels below 500 ng/ml. Consequently, the interpretation of the results is restricted because drug levels of paclitaxel as low as at least 50 nM (43 ng/ml) are relevant for the pharmacology of this drug. We recently described an accurate and very sensitive method based on HPLC for the determination of paclitaxel and the metabolites 3'-p-hydroxypaclitaxel (I), 6a-hydroxypaclitaxel (II) and 6a,3'-p-dihydroxypaclitaxel (III) in a wide variety of biological matrices. We have now implemented this methodology in a comprehensive pharmacokinetic study in female FVB mice. Previous pharmacokinetic studies in humans demonstrated a large steady-state volume of distribution, indicating that the drug is widely distributed into tissues. Comprehensive tissue distribution studies may, therefore, be helpful in providing more insight into possible relationships between plasma levels, drug levels in tissues and toxicity. Paclitaxel, formulated in Cremophor EL and ethanol (1:1, v/v), was given as a single I.v. bolus dose of 2, 10 and 20 mg/kg to female FVB mice. Except for the brain, the distribution of paclitaxel to all other tissues in the female mice was substantial and maximum drug levels were achieved within 0.5 or 1 h. A marked non-linear increase in the area under the concentration-time curve (AUC) in plasma was observed, which was not paralleled by a proportional increase in the tissue AUC levels. It is postulated that this effect may be related to the substantial amounts of Cremophor EL administered concurrently. The recovery of paclitaxel in the feces (0–96 h) was reduced from 58% at the 2 mg/kg does level to 44% at the 20 mg/kg dose level. Small amounts of metabolites 1 and II were detected in the gut, liver and gall bladder, but not in the systemic circulation or any other tissue. Metabolite III was not detected. Metabolites I and II are likely excreted directly into the bile, and since their recovery in the feces accounts for about 25% of the administered dose, their formation thus represents an important pathway of detoxification.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Rh(I) complexes adsorbed on polymers, as a way to Improve their transport and solubility properties, were studied as antitumor agents. The binding constants of the complexes to the polymer were evaluated in order to determine the conditions for maximum association to the vehicle. The toxicity of the pure complexes and those bound were determinedin vivousing female mice. [Rh(NBD)(2,4N))CIO4, complex A; where NBD = norbor-nadlene, (2,4N)=3,3‘-dimethylene-2,2’-di-1,8-nephyridine, was investigated on primary solid tumors and ascltic tumors. [Rh(NBD)(3,4N)]CIO4, complex B; where (3,4N)=3,3′-trimethylene-2,2′-di-1,8-nephthyridine, was investigated on ascltic tumors. These Rh(I) complexes appear to be promising drugs because of their solubility in aqueous polymer, which make them easler to handle in comparison with the neutral species. These complexes show a similarity to clsplatin by reducing tumor growth and by increasing the survival life span of mice. Poly (oxyethylene) was used to solubillze these poorly water-soluble compounds and to stabilize the compounds in the solution before injection. These studies suggest that both complexes, A and B, are good candidates for tumor control growth and increase the survival time.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID