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Protracted
Treatment with Tegafur and Low Dose Oral Leucovorin in Patients
with Advanced Colorectal CarcinomaM Nogué et al ,Cancer 83:254-8, 1998
Protracted oral administration of tegafur (TG) and leucovorin (LV) attempts to simulate the continuous infusion of 5-fluorouracil, with a higher intracellular folate pool. In a prior dose-finding study with a fixed TG dose of 0.75 g/m2/day for a period of 21 days and continuous oral LV, the recommended dose of LV was 45 mg/day in 28-day cycles.Thirty-nine patients with histologic confirmation of adenocarcinoma of the colon or rectum, either advanced or metastatic disease, and who were not candidates for radical treatment were included in a Phase II study using this schedule.One hundred sixty-three cycles of chemotherapy were delivered (median, 4 cycles per patient). Toxicity was observed in the form of diarrhea, which was severe in 12 patients (30.7%). Grade 3 (according to the World Health Organization criteria) oral mucositis was recorded in 7 patients (18%). Asthenia was severe in 10% of the patients. Recuperation from toxicity was rapid and managed primarily on an outpatient basis. Two complete (5.1%) and 13 partial (33.3%) responses were observed, with a global response index of 38.5% (95% confidence interval, 23.2-53.6%). The median overall survival was 11.3 months.The results of this study show that an all-oral regimen of tegafur and leucovorin can obtain biochemical modulation, with a significant response rate, in patients with advanced colorectal carcinoma. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.
COMMENTS:
(1) This is a Phase II study of oral TG and folinic acid in patients with advanced or metastatic colorectal carcinoma, with the goal of analyzing the efficacy and confirming the toxic profile of this schedule. The main advantage expected of an all-oral regimen of biochemical modulation was avoiding the need for frequent administration of intravenous treatment associated with the use of 5-FU and folinic acid.
(2) Overall response of 38% is comparable favorably with respect to intravenous modulation schedules and additional 30% of patients achieved stable disease. Therefore, a high proportion of patients with CRC received some therapeutic benefit that lasted > 7 months.Whether a longer treatment duration may result in more prolonged benefit or not? .
(3) The TG dose reduction made the administration of successive treatments in these patients possible without further complications. This explains the lower percentage of toxicity per administered cycle compared with the toxicity per patient. The practically nonexistent hematologic toxicity, as well as the appearance of cutaneous toxicity in the form of hand-foot syndrome in 33% of patients, is very similar to results obtained in protracted, continuous 5-FU administration.
(4) This is a simple treatment schedule with oral administration which can achieve results similar to more complex intravenous administration schedules, with an improvement in quality of life for these patients. To assess the possible advantage of an all-oral regimen over intravenous schedules, a randomized trial comparing this regimen with standard intravenous modulation is warranted.
Impact of Cilostazol
on Intimal Proliferation After Directional Coronary AtherectomyE Tsuchikane et al, [Am Heart J 135(3):495-502, 1998]
| Cilostazol, a novel platelet aggregation inhibitor, inhibits intimal proliferation in animal models. We randomly assigned 41 patients with lesions suitable for directional coronary atherectomy to the cilostazol group (200 mg/day) or the aspirin (250 mg/day) group. Medication was started before directional coronary atherectomy and was continued to a 6-month follow-up. Serial quantitative coronary angiography and intravascular ultrasound study were performed. Baseline characteristics were not different between the two groups. However, the minimal lumen diameter at follow-up was larger (2.33 ± 0.60 mm vs 1.81 ± 0.68 mm, p = 0.016) and the percent diameter stenosis (24.5% ± 16.6% vs 40.9% ± 21.0%, p = 0.010) was smaller in the cilostazol group. The change in vessel area was not different, but the percent plaque area at follow-up was smaller in the cilostazol group (55.7% ± 11.2% vs 64.5% ± 14.5%, p = 0.044). The restenosis rate was significantly lower in the cilostazol group (0% vs 26%, p = 0.020). We conclude that cilostazol appears to have an inhibitory effect on intimal proliferation after directional coronary atherectomy and may reduce restenosis. [Am Heart J 135(3):495-502, 1998] |
| COMMENTS: Although this was a prospective study, the number of patients enrolled was only 39. Although it was randomized, it was not a double-blind trial asit was intended to investigate the drug's efficacy as a preliminary study. Only two-dimensional IVUS measurements were used to observe vessel cross-sections without making use of three-dimensional algorithms showing the entire lesion. Choosing DCA as the device resulted in a change in vessel diameter (a change in VA as measured by IVUS). To measure the effect of cilostazol on postangioplasty neointimal proliferation, a better protocol may have been to analyze follow-up data after stenting, a procedure in which restenosis is thought to result largely from neointimal proliferation and not from vascular remodeling.Cilostazol's efficacy in controlling subacute thrombosis after stenting has not yet been established. To confirm the drug's efficacy in reducing restenosis, a carefully designed, large-scale, multicenter, double-blind randomized study is required in which conventional balloon angioplasty or other devices, especially stents, are used.Although there are weak points, this study demonstrates that cilostazol may be able to inhibit neointimal proliferation and thereby reduce the restenosis rate after PTCA. |
Angioplasty (versus
non surgical management) for intermittent claudicationFowkes FGR, Gillespie IN (Source: http://som.flinders.edu.au/fusa/cochrane/cochrane/revabstr/g11@in~1.htm)
To determine if angioplasty of arteries in the leg is more effective than non surgical therapy or no therapy in patients with mild to moderate intermittent claudication. Trials were identified using the search strategy of the Peripheral Vascular Diseases Review Group, reviewing reference lists in papers and conference proceedings, and corresponding with selected authors. Trials were selected for inclusion by one reviewer and comprised only trials of mild or moderate intermittent claudication in which patients were randomly allocated to angioplasty or conservative treatment. Lesions amenable to angioplasty had to be demonstrated on angiography or duplex scanning. Data from each trial were obtained by one reviewer and included the following outcomes: treadmill walking distances, ankle brachial pressure index, duplex scanning results, complications of angioplasty and quality of life. Data were obtained from two trials. At six months of follow up, mean ankle brachial pressure indices were higher in the angioplasty groups than control groups, WMD 0.17 (95% CI 0.11, 0.24). In one trial, walking distances were greater in the angioplasty group, but in the other trial in which controls underwent an exercise programme, walking distances did not show a greater improvement in the angioplasty group. At two years of follow up in one trial the angioplasty group were more likely to have a patent artery, OR 5.5 (95% CI 1.8, 17.0) but not a significantly better walking distance or quality of life. In the other trial, long term follow up at six years demonstrated no significant differences in outcome between the angioplasty and control groups. These limited results suggest that angioplasty may have had a short term benefit, but this may not have been sustained. Further large scale trials are required. Meanwhile, widespread use of angioplasty for mild to moderate claudication cannot be recommended.
COMMENT: The Cochrane Peripheral Vascular Disease Group has done several reviews on the topic of PVD and this review showed that angioplasty may have short term benefit. The most important recommendation should be exercise to all suitable patients. Garlic, Vitamin E, steroid sex hormones, antilipidemic agents have been tried for treatment of PVD but no sufficient evidence to support therapies.
Ticlopidine updateAustralian Adverse Drug Reactions Bulletin 1998;17(2):6.
Ticlopidine (Ticlid) is an inhibitor of platelet aggregation used in the prevention of stroke in patients with known vascular disease who are intolerant of or unresponsive to aspirin. It is also frequently used in association with the implantation of vascular stents. In the two year period to February 1998, ADRAC has received 110 reports of suspected adverse reactions in association with ticlopidine. Most (77) implicated ticlopidine as the sole suspected drug cause of the reaction. Ages ranged from 33 to 85 (median 67) years. For the 97 reports which provided the information, onset occured within the first month in 72% of cases with only 3 reports documenting onset after three months. The major adverse reactions are white cell disorders, and haemorrhagic reactions which may be due to thrombocytopenia or platelet dysfunction.
Agranulocytosis (19 reports) and neutropenia (17) comprised one third of the total reports on ticlopidine. These white cell disorders were sometimes accompanied by fever/rigors (7), pharyngitis (4), mouth ulcers (3), hepatitis (2), thrombocytopenia (3) or anemia (2). Four of the reports of agranulocytosis were accompanied by bone marrow biopsy reports documenting maturation arrest of myeloid precursors consistent with a drug-induced aetiology. Of the 36 reports of white cell disorders, 22 patients had recovered and 14 had not recovered at the time the reports were submitted. There were no fatalities. In addition to the three reports of thrombocytopenia with a white cell disorder, there were 7 other cases of thrombocytopenia. Three were accompanied by purpura including one case which involved a rectal hemorrhage. Another case had concomitant haematuria and haemolysis. There have also been overseas reports of thrombotic thrombocytopenic purpura in association with ticlopidine. There were four other reports of hemorrhagic effects not related to thrombocytopenia, consisting of one report each of haemorrhagic colitis, pulmonary haemorrhage (with cardiac failure, diffuse bleeding noted at bronchospy_, purpura, and unspecified life threatening haemorrhage (with purpura).
Prescribers should be aware that ticlopidine may be associated with blood dyscrasias, particularly neutropenia or agranulocytosis which may be of sudden onset. The product information for ticlopidine warns that the period of maximum risk is from 3 weeks to 3 months after starting therapy. Patients should be advised to report promptly any occurrence of fever, chills, sore throat and/or mouth ulcers which may indicate neutropenia or agranulocytosis. Prolonged or unusual bleeding, bruising, purpura or dark stools may indicate thrombocytopenia or platelet dysfunction. If any of these occur ticlopidine should be withdrawn immediately.
COMMENTS: There were 277 reports of adverse drug reactions according to TOXILINE database. The adverse reactions include fatal neutropenia, fatal aplastic anaemia, severe bone marrow aplasia, severe aplastic anaemia, severe chronic diarrhea, neutropenia, thrombocytopenia, pancytopenia, thrombotic thrombocytopenic purpura, agranulocytosis, hemoptysis, acute interstitial nephritis, lymphocytic colitis, cholestatic hepatitis (jaundice), etc...There were 368 reports of ticlopidine and side effects searched at MEDLINE database and the number of search results indicated neutropenia (52 ), throbocytopenia (63 ) and agranulocytosis (51 ). Healthcare professionals must be aware of the possibility of severe neutropenia and death caused by ticlopidine, even when the manufacturers' monitoring guidelines are followed. A complete blood cell count should be performed every 2 weeks during the first 3 months of therapy to check for leucopenia.
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