Effects of some antineoplastic drugs (vincristine, doxorubicin and epirubicin) on human platelet aggregation

The effects of some antineoplastic drugs (vincristine, doxorubicin and epirubicin) on collagen- and ADP-induced human platelet aggregation are investigated. Platelet rich plasma (PRP) and platelet poor plasma (PPP) from healthy male and female donors were used. The PRP was adjusted with analogous PPP to 300,000 platelets/microliters. Platelet aggregation was studied according to Born's turbidimetric technique using an Aggrecorder II PA 3220 with collagen at a concentration of 10 micrograms/ml and ADP at a concentration of 30 microM. Vincristine, doxorubicin and epirubicin significantly (p < 0.01) inhibited collagen- and ADP-induced platelet aggregation. The vincristine induced inhibition was higher than that induced by doxorubicin or epirubicin. The effects of doxorubicin and epirubicin were more intense on ADP-induced platelet aggregation than on the collagen induced one. Moreover, the doxorubicin inhibition of ADP-induced platelet aggregation was greater than the epirubicin one. In conclusion, our study shows that vincristine, doxorubicin and epirubicin inhibit human platelet aggregation. The present results may improve the therapeutic use of these drugs since it has been clearly shown that drugs with antiplatelet activity could block metastases.     

Control of emesis by intravenous granisetron in breast cancer patients treated with 5-FU, epirubicin and cyclophosphamide

Granisetron, a potent and selective 5-hydroxytryptamine receptor (5-HT3) antagonist was reported to be an effective antiemetic agent both in animal studies and in patients given highly emetogenic chemotherapy. A sample of 43 patients with breast cancer was accrued from September to November 1992 in a phase II study to assess the efficacy of granisetron in patients receiving FEC (5-FU, epirubicin, cyclophosphamide). Each patient received 3 mg intravenous granisetron as a single dose just prior to chemotherapy. Oral metoclopromide was prescribed to each patient as a rescue anti-emetic. The emetic episodes and degree of nausea were evaluated on a daily basis. Good control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) was in the range 77%-98% and 77%-93% respectively. There was a complete response (no emetic episodes throughout the 6-day period) in 16 patients (37.2%). Onset of emesis tends to occur on day 1 and tend to subside after day 3; 85% of patients had onset of emesis in the first 2 days after chemotherapy. Control of emesis and nausea tends to improve after day 3, which could be the result of the reduced emetogenicity of the combination FEC with time. Altogether, 77% had good control of acute emesis; control of delayed emesis was better with 84% achieving a major response on day 2 after chemotherapy, which improved to more than 90% after day 4. Granisetron was generally tolerated with headache being the most common side-effect followed by constipation and flushing. This study suggests that granisetron is an effective and well-tolerated anti-emetic agent, which deserves randomised trials to elucidate its efficacy further.     

Effects of granisetron and its combination with dexamethasone on cisplatin-induced delayed emesis in the ferret

1. Granisetron and its combination with dexamethasone for the treatment of delayed emesis following cisplatin (CDDP) administration were investigated using ferrets. 2. CDDP-induced emesis was significantly inhibited in both the granisetron group and the combined granisetron and dexamethasone group during the acute and delayed phase in terms of total emesis, latency to first emesis and duration of emesis. 3. Food and water consumption in the combined group of ferrets was significantly increased as compared with the CDDP control group. 4. 5-Hydroxytryptamine (5-HT) level was increased in the ileum and the 5-hydroxyindole acetic acid (5-HIAA) level was increased in the area postrema of ferrets after 3 days of CDDP administration. It is suggested that the antiemetic activity of granisetron and/or dexamethasone is not related to 5-HT levels in delayed emesis. 5. Both granisetron and its combination with dexamethasone are effective in CDDP-induced emesis, but combination treatment is more effective than granisetron alone for the duration of emesis in the delayed phase.     

A randomized comparison of the efficacy and toxicity of epirubicin and doxorubicin in the treatment of patients with non-Hodgkin's lymphoma

BACKGROUND: Combination chemotherapy consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B) has been frequently used for the treatment of non-Hodgkin's lymphoma. This randomized study was undertaken to assess the efficacy and toxicity of this regimen when either doxorubicin or epirubicin was used as the anthracycline drug. METHODS: Between April 1989 and December 1993, 211 previously untreated patients with intermediate grade and high grade non-Hodgkin's lymphoma were randomized to receive either doxorubicin (n=106) or epirubicin (n=105) with the MACOP-B regimen. These patients were followed through December 1996. Numerous clinical features predictive of response and survival were analyzed. Cardiac and noncardiac toxicity in the two treatment arms were compared. RESULTS: The median age of the patients was 48 years. Complete remission was experienced by 122 patients (58.3%); 62 patients (58.5%) achieved complete remission in the doxorubicin arm and 60 (58.1%) in the epirubicin arm. Response rates, time to treatment failure, relapse data, and overall survival were comparable between the two arms. Morbidity due to mucositis, vomiting, peripheral neuropathy, and cardiotoxicity were also comparable. The overall mortality was 10%. Mortality due to neutropenic sepsis was considerably higher among patients who received epirubicin (10 patients) than among those who received doxorubicin (5 patients). Cardiac evaluation revealed no difference in toxicity between the two arms. CONCLUSIONS: Epirubicin was as effective as doxorubicin in terms of patients' responses to therapy. There was no difference in cardiotoxicity between the two treatment arms. However, in this study, the mortality due to neutropenic sepsis was significantly higher among patients treated with epirubicin.     

Effects of doxorubicin and/or cilostazol on cancer cells during liver regeneration after two-thirds hepatectomy in rats

We report on a 12-year-old girl with postthoracotomy neuropathic pain. A variety of treatments for the pain were ineffective. The symptoms resolved following the institution of therapy with gabapentin.     

Confidence intervals or surfaces? Uncertainty on the cost-effectiveness plane

Although cost-effectiveness analysis is not new, it is only recently that economic analysis has been conducted alongside clinical trials. Whereas in the past economic analysts most often used sensitivity analysis to examine the implications of uncertainty for their results, the existence of patient-level data on costs and effects opens up the possibility of statistical analysis of uncertainty. Unfortunately, ratio statistics can cause problems for standard statistical methods of confidence interval estimation. The recent health economics literature contains a number of suggestions for estimating confidence limits for ratios. In this paper, we begin by reviewing the different methods of confidence interval estimation with a view to providing guidance concerning the most appropriate method. We go on to argue that the focus on confidence interval estimation for cost-effectiveness ratios in the recent literature has been concerned more with problems of estimation than with problems of decision-making. We argue that decision-makers are most likely to be interested in one-sided tests of hypothesis and that confidence surfaces are better suited to such tests than confidence intervals. This approach is consistent with decision-making on the cost-effectiveness plane and with the cost-effectiveness acceptability curve approach to presenting uncertainty due to sampling variation in stochastic cost-effectiveness analyses.     

Effects of irregular preparatory intervals on reaction time in schizophrenia.

2 experiments attempted to (a) confirm previous observations that the slope of the negative relationship between reaction time (RT) and the length of the preparatory interval (PI) was steeper in schizophrenic than in normal Ss, and (b) investigate the effects of the PI on one trial on RT to the subsequent trial (PPI). The results show that the curves relating the PI with RT are significantly steeper for the patients even when differences in "baseline" RT level are controlled. Also, the detrimental effects of long PPIs are much greater for the schizophrenics. The data suggest that instead of establishing a generalized preparatory set, the schizophrenic Ss simplify the task by basing their pattern of preparation largely on the just preceding trial. (17 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Simultaneous determination of epirubicin, doxorubicin and their principal metabolites in human plasma by high-performance liquid chromatography and electrochemical detection

A method is described which permits the trace analysis of 10 chlorobenzenes in aqueous samples. Chlorobenzenes were extracted from water samples by solid-phase extraction with a C18 cartridge and analysis was carried out by gas chromatography-mass spectrometry in the selected-ion monitoring mode. The recovery and precision of the method were evaluated by extraction of spiked reagent-grade water at concentration levels of 0.1, 1.0 and 10.0 micrograms/l. This method was applied to the determination of chlorobenzenes in tap, ground and river water. By preparing 200 ml of environmental water samples, the detection limits of the compounds studied were in the range of 0.010-0.042 microgram/l.     

Comparison of epirubicin and doxorubicin cardiotoxicity induced by low doses: evolution of the diastolic and systolic parameters studied by radionuclide angiography

This article reports on the effect of dietary modification on changes in eating patterns and serum lipids among hypercholesterolemic persons aged 40-59 years with no evidence of coronary heart disease in Mae Sot District, Tak Province, between 1995 and 1996. A total of 381 persons with total cholesterol levels > or = 240 mg/dl and triglyceride levels < 400 mg/dl were educated, counseled, and followed-up by the mobile health team at the health centres in the communities. The team comprised both hospital personnel (a physician, a health educator, and public health nurses) and the health centre workers. Of the 381 study persons, 331 (86.9%) completed the one-year follow-up. The participants at one-year follow-up were more likely than at baseline to reduce intakes of dietary fat and cholesterol, whereas, there was an increased intake of vegetables and fruits. The mean total cholesterol level significantly decreased from 258.9 mg/dl at baseline to 236.1 mg/dl at one-year follow-up (p < 0.01), giving an 8.8 per cent reduction. The mean change in low-density lipoprotein cholesterol levels was a 26.0 mg/dl decrease (p < 0.01), yielding a 15.1 per cent fall. The mean high-density lipoprotein cholesterol level increased from 44.6 mg/dl at baseline to 46.8 mg/dl at one-year follow-up (p < 0.01). The proportion of those who had a body mass index of < 25 slightly increased from 70.7 per cent at baseline to 72.5 per cent at one-year follow-up. The dietary intervention program by the mobile team may be useful for lowering serum cholesterol among the rural population with hypercholesterolemia.     

Use of granisetron in patients refractory to previous treatment with antiemetics

Since a high tissue penetration of dirithromycin (D) has been assessed in early studies, the aims of this study were to determine D concentrations in bronchial mucosa and secretions in patients suffering from an acute exacerbation of chronic bronchitis (AECB), to compare intra-individual bronchial mucosa and secretion concentrations and to relate bronchial concentrations of D and clinical efficacy. The main inclusion criteria were comprised of (1) AECB, defined by the presence of an increase in dyspnea, sputum production and change in sputum purulence, and (2) clinical indication of fiberoptic bronchoscopy allowing performance of bronchial biopsies. All patients were treated with a 500-mg once-daily D dose for 5 days. Patients were randomly divided into three groups, according to sampling times (24, 48 and 72 h after the last dose). Tissue concentration analyses were performed by one blinded microbiologist (microbiological agar diffusion assay). The results showed: (1) 37 out of the 46 patients (80.4%) had a favorable response to treatment at the time of fiberoptic bronchoscopy (14 cured, 23 improved); (2) bronchial mucosa concentrations were high in all groups, and (3) mean values at 24, 48 and 72 h after the last dose were respectively 6.51 +/- 1.44, 6. 61 +/- 2.7, 5.67 +/- 1.02 mg.kg-1; no statistical difference was observed between the groups. In bronchial secretions collected simultaneously, concentrations were lower, i.e. 1.26 +/- 0.3, 0.61 +/- 0.12, 0.84 +/- 0.12. Significant associations were observed between bronchial mucosa and secretion concentrations (r = 0.71, p = 0.0001), and between clinical response and bronchial concentrations (p = 0.03, Kruskall-Wallis test). In conclusion, these results may confirm the clinical significance of tissue concentrations measured in bronchial tissues of patients with AECB.     

In vivo effects of tumor necrosis factor-alpha or flavone acetic acid in combination with doxorubicin on multidrug-resistant B16 melanoma

BACKGROUND: A soft pancreas with a main pancreatic duct (MPD) with normal diameter has been considered a high risk for pancreatic anastomotic leakage because of a relatively high output of pancreatic juice, but data are lacking. METHODS: An attempt was made to assess the relationship between the consistency of the pancreas, MPD diameter, pancreatic juice output, and pancreatic leakage after partial pancreatoduodenectomy. The pancreatic parenchyma was classified as of soft, intermediate, and hard consistency in 70 consecutive patients undergoing operation (groups 1, 2, and 3, respectively) by one surgeon. The MPD diameter was determined by means of endoscopic pancreatography or abdominal ultrasonography. Pancreatic juice output was measured for 21 days after operation by using a catheter inserted into the MPD. Anastomotic leakage was identified radiologically by using contrast medium. RESULTS: The mean (SD) pancreatic juice output during a period of 10 days (postoperative days 5 to 14) was 1554 (1073) ml in group 1 (n = 29), 1513 (1060) ml in group 2 (n = 13), and 187 (220)ml in group 3 (n = 28) (groups 1 and 2 versus group 3, p < 0.0001). The MPD diameter was 3.0 (1.6) mm in group 1, 5.9 (2.5) mm in group 2, and 6.6 (2.6) mm in group 3 (group 1 versus groups 2 and 3, p = 0.0001). Anastomotic leaks occurred in four (14%) patients in group 1, three (23%) in group 2, and none in group 3 (p < 0.05). CONCLUSIONS: Patients with a pancreatic parenchyma with an intermediate or normal consistency produced more pancreatic juice and had a higher leak rate.     

Effects of intra-abdominal pressure on pharmacokinetics and tissue distribution of doxorubicin after intraperitoneal administration

Increased hydrostatic pressure in solid tumor nodules decreases the penetration of chemotherapy into cancerous tissue. This is true for both i.v. and i.p. chemotherapy. The purpose of this study was to determine the influence of increasing intra-abdominal pressures on the pharmacokinetics and tissue distribution of doxorubicin administered i.p. Four groups of 10 Sprague Dawley rats were given i.p. doxorubicin (4 mg/kg) during 60 min combined with no pressure (control), 10, 20 and 30 mm Hg pressures. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled. Two other groups of 10 rats received the same dose of i.p. doxorubicin during 10 min combined with no pressure and 30 mm Hg pressure. At the end of experiments animals were sacrificed and tissue samples were collected. Doxorubicin concentrations in peritoneal fluid, plasma and tissues were determined by HPLC. Pharmacokinetic studies showed that increased intra-abdominal pressures of 10, 20 and 30 mm Hg did not alter peritoneal fluid AUCs, the plasma AUCs and the peak ratios of i.p. doxorubicin when compared to the control group (no pressure). A subset analysis of high intra-abdominal pressure groups (20 and 30 mm Hg) versus control group showed statistically significant differences in peritoneal fluid AUCs, plasma AUCs and AUC (peritoneal fluid/plasma) ratios. For all groups, the highest tissue concentrations of doxorubicin were found in tissues associated with the parietal peritoneum: the bladder, the abdominal wall and the diaphragm. After 10 min of i.p. chemotherapy, the group treated with 30 mm Hg pressure showed a significant increase of doxorubicin concentrations in these tissues as compared to the control group. This significant increase of tissue doxorubicin concentrations was not found after 60 min of pressure with i.p. chemotherapy; prolonged intra-abdominal pressure was associated with a high incidence of intestinal ischemia. In conclusion, intra-abdominal pressure of 20 and 30 mm Hg significantly decreased the AUC ratios of i.p. doxorubicin but concomitantly increased tissue uptake of doxorubicin in bladder, diaphragm and abdominal wall during the first 10 min of i.p. administration. These findings may have significance in the design of improved strategies to increase tissue concentrations of chemotherapy delivered by an i.p. route.     

Oral combination antiemetics in patients with small cell lung cancer receiving cisplatin or cyclophosphamide plus doxorubicin

BACKGROUND: Intravenous antiemetic combinations containing a 5-HT3 receptor antagonist (like metoclopramide, ondansetron, or granisetron) with dexamethasone have become the standard therapy for the treatment of acute chemotherapy-induced vomiting. Intravenous antiemetics, however, can be more costly and take more time to prepare and deliver, and therefore are not preferred for home, outpatient, or office use. The objective of this study was to determine the antiemetic activity and safety of the oral combination antiemetic regimen of metoclopramide, dexamethasone, and diphenhydramine in patients with small cell lung cancer receiving standard outpatient chemotherapy programs. METHODS: Fifty-two patients receiving initial cisplatin (60 mg/m2) or cyclophosphamide (600-1500 mg/m2) plus doxorubicin (30-45 mg/m2) received an oral regimen of metoclopramide (3 mg/kg x 2 then 2 mg/kg x 2 or 4 doses), dexamethasone (20 mg) and diphenhydramine (50 mg x 2 or 3 doses) (oral MDD), beginning 30 minutes before chemotherapy. RESULTS: Vomiting was prevented in 15 of 21 (76%) patients (95% confidence interval [CI], 53%-92%) receiving cisplatin and 21 of 31 (71%) individuals (95% CI, 52%-86%) given cyclophosphamide plus doxorubicin. Adverse effects were mild and transient and included sedation, loose stools, akathisia, and hiccoughs. CONCLUSIONS: The oral MDD antiemetic regimen prevented acute emesis in 73% of the patients entered and was well tolerated in this population of patients with small cell lung cancer.     

环氧合酶-2抑制剂对白血病细胞HL-60的化疗增敏作用及机制

目的 观察环氧合酶-2(COX-2)抑制剂塞来昔布对白血病细胞株HL-60的化疗增敏作用,并对其机制进行初步探讨.方法 MTT法评估塞来昔布、多柔比星及二者联合对HL-60细胞的生长抑制效应;流式细胞术(FCM)检测细胞的凋亡;反转录聚合酶链反应(RT-PCR)检测Survivin基因的表达;Western blotting检测Survivin蛋白的表达.结果 多柔比星联合塞来昔布5和10μmol/L对HL-60细胞的半数抑制浓度(IC50)分别为0.25及0.16μg/ml,明显低于多柔比星单用的IC50(0.48μg/ml);多柔比星0.10μg/ml联合10 μmol/L塞来昔布下调Survivin基因mRNA及蛋白的表达;联合塞来昔布5和10 μmol/L的凋亡率[分别为(13.07±1.66)%及(22.36±1.84)%]较多柔比星0.10μg/ml单用[(5.72±1.25)%]明显增加(P<0.01).结论 COX-2抑制剂塞来昔布对白血病细胞株HL-60具有明显的化疗增敏作用,其初步机制涉及下调Survivin的表达,增加细胞凋亡.     

Cyclophosphamide and fluorouracil combined with mitoxantrone versus doxorubicin for breast cancer: superiority of doxorubicin

PATIENTS AND METHODS: We conducted a randomized, multicenter study of intravenous cyclophosphamide 500 mg/m2 plus fluorouracil 500 mg/m2 combined with either mitoxantrone (Novantrone, Lederle Cyanamid Canada Ltd, Willowdale, Ontario) 10 mg/m2 (CNF) or doxorubicin (Adriamycin, Adria Laboratories of Canada Ltd, Mississauga, Ontario) 50 mg/m2 (CAF) every 3 weeks in advanced breast cancer. RESULTS: The response rate in 249 randomized patients was 36% with CNF (44 of 121) and 48% with CAF (62 of 128) (P = .054), with complete remissions in 10 patients (8.3%) on CNF and in 13 (10.2%) on CAF. If only fully assessable patients are considered, the response rate was 48% (44 of 91) with CNF and 60% (62 of 103) with CAF (P = .098). At time of analysis, all except 10 patients (one CNF and nine CAF) had died. The median survival time with CAF was longer than with CNF (15.2 v 10.9 months; P = .003), and time to progression was also longer with CAF (5.3 v 3.2 months; P < .03). Survival differences remained significant (P = .006) if patients who failed to meet all eligibility criteria were excluded. Favorable prognostic factors for survival in a Cox regression model included good performance status (P < .0001); less than two organ systems involved by tumor (P < .0001); no involvement of lung, liver, or brain (P < .003); involvement of bone or bone marrow (P < .009), prior surgery for breast cancer (P < .006); being premenopausal (P < .03); > or = 3 years from diagnosis until randomization on this study (P < .03); and treatment with CAF (P < .03). Alopecia > or = grade 3 was reported in 55% of patients with CAF and 12% of patients with CNF (P < .001), while other > or = grade 3 toxicities did not differ significantly. Priestman-Baum quality-of-life assessment was comparable on the two study arms. CONCLUSION: In patients with advanced breast cancer, CAF was associated with longer survival than was CNF, with an increase in alopecia, but not in other toxicities.     

Initial high anti-emetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles

We have reported previously that the anti-emetic efficacy of single agent 5HT3 antagonists is not maintained when analysed with the measurement of cumulative probabilities. Presently, the most effective anti-emetic regimen is a combination of a 5HT3 antagonist plus dexamethasone. We, therefore, assessed the sustainment of efficacy of such a combination in 125 patients, scheduled to receive cisplatin > or = 70 mg m(-2) either alone or in combination with other cytotoxic drugs. Anti-emetic therapy was initiated with 10 mg of dexamethasone and 3 mg of granisetron intravenously, before cisplatin. On days 1-6, patients received 8 mg of dexamethasone and 1 mg of granisetron twice daily by oral administration. Protection was assessed during all cycles and calculated based on cumulative probability analyses using the method of Kaplan-Meier and a model for transitional probabilities. Irrespective of the type of analysis used, the anti-emetic efficacy of granisetron/dexamethasone decreased over cycles. The initial complete acute emesis protection rate of 66% decreased to 30% according to the method of Kaplan-Meier and to 39% using the model for transitional probabilities. For delayed emesis, the initial complete protection rate of 52% decreased to 21% (Kaplan-Meier) and to 43% (transitional probabilities). In addition, we observed that protection failure in the delayed emesis period adversely influenced the acute emesis protection in the next cycle. We conclude that the anti-emetic efficacy of a 5HT3 antagonist plus dexamethasone is not maintained over multiple cycles of highly emetogenic chemotherapy, and that the acute emesis protection is adversely influenced by protection failure in the delayed emesis phase.     

Intonation of musical intervals by musical intervals by deaf subjects stimulated with single bipolar cochlear implant electrodes

Aqueous alcoholic mallow flower extracts were analyzed both by HPTLC-densitometry in the reflectance mode at 530 nm and by reversed-phase HPLC with gradient elution. For the mallow flower anthocyanins the best chromatographic resolution was obtained by HPLC, which revealed only two main compounds, confirmed by FAB-MS: malvidin 3,5-O-diglucoside (malvin) and malvidin 3-O-(6"-O-malonylglucoside)-5-O-glucoside. The HPTLC densitometric method on cellulose plates provides accuracy, reproducibility and selectivity for the quantitative analysis of the anthocyanins and this method was shown to be much more sensitive than the HPLC-DAD system, at 530 nm. Both methods give comparable quantitative results for total anthocyanins when applied to mallow flowers from two different sources: Italy and Albania.