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HEMATOLOGIC TOXICITY OF DRUGS USED IN CARDIOVASCULAR-DISEASE

POSTGRADUATE MEDICINE 1979年第1期65卷 165-+页

作者： MISSRI, J HARVARD UNIV SCH MED BOSTON MA 02115 USA NEW ENGLAND DEACONESS HOSP BOSTON MA 02215 USA

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关键词：贫血溶血性/化学诱导抗心律失常药/副作用抗心律失常药/代谢抗体生成抗高血压药/副作用抗高血压药/代谢自身抗体/免疫学血液/药物作用心血管疾病/药物疗法利尿药/副作用利尿药/代谢红细胞膜/代谢溶血/药物作用长期医疗中性粒细胞减少/化学诱导血小板减少/化学诱导人类

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Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial

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BLOOD 2000年第8期96卷 2723-2729页

作者： Robak, T Blonski, JZ Kasznicki, M Blasinska-Morawiec, M Krykowski, E Dmoszynska, A Mrugala-Spiewak, H Skotnicki, AB Nowak, W Konopka, L Ceglarek, B Maj, S Dwilewicz-Trojaczek, J Heilmann, A Urasinski, I Zdziarska, B Kotlarek-Haus, S Potoczek, S Grieb, P Med Univ Lodz Copernicus Mem Hosp Dept Hematol PL-93513 Lodz Poland Med Univ Dept Hematol Lublin Poland Jagiellonian Univ Dept Hematol Krakow Poland Inst Hematol & Transfusiol Warsaw Poland Med Acad Warsaw Dept Hematol Warsaw Poland Univ Gdansk Sch Med Dept Hematol PL-80952 Gdansk Poland Pomeranian Univ Med Dept Hematol Szczecin Poland Med Univ Dept Hematol Wroclaw Poland Polish Acad Sci Med Res Ctr Warsaw Poland

The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m(2) per day for 5 consecutive days or Chi 12 mg/m(2) per day and P 30 mg/m(2) per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received ChI+P as a first-line treatment. OR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with ChI+P (12% and 57%, respectively) (P = .001), Progression-free survival was significantly longer in the 2-CdA-treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to ChI+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than ChI+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the ChI+P-treated group (40%;P = .02), Death rates have so far been similar in patients treated with 2-CdA (20%) and with ChI (17%), The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively). (C) 2000 by The American Society of Hematology.

关键词：苯丁酸氮芥/投药和剂量克利屈滨/投药和剂量无病生存用药计划表发病率感染/流行病学感染/病因学寿命表中性粒细胞减少/化学诱导中性粒细胞减少/流行病学波兰/流行病学泼尼松/投药和剂量前瞻性研究缓解诱导存活率血小板减少/化学诱导血小板减少/流行病学治疗结果女(雌)性人类男(雄)性中年人

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Atypical antipsychotic-induced neutropenia in dogs

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TOXICOLOGY AND APPLIED PHARMACOLOGY 1999年第3期155卷 227-236页

作者： Lorenz, M Evering, WE Provencher, A Blue, JT Lewis, HB Hazelette, JR Rajagopalan, P Meunier, PC Car, BD Dupont Co Stine Haskell Res Ctr Safety Assessment Newark DE 19714 USA AHDL Endocrine Diag Sect Lansing MI 48909 USA Cornell Univ New York State Coll Vet Med Ithaca NY 14853 USA Med Management Int VetSmart Portland OR 97230 USA Dupont Merck Pharmaceut Co Expt Stn Wilmington DE 19880 USA

DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects through selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtypes. Clozapine therapy is clinically associated with severe granulocytopenia in a small subset of patients. In the course of a 3-month toxicity study in dogs, severe neutropenia, thrombocytopenia, marked myeloid and erythroid left-shifted bone marrow hyperplasia with increased erythrophagocytosis, positive Coombs' tests, and hypergammaglobulinemia occurred in individual females dosed with 30 mg/kg/day of DMP 406. Related but less severe changes were also observed in males. Sera or purified immunoglobulins from affected and control dogs were tested in methylcellulose-based, canine hematopoietic colony-forming unit (CFU) assays with or without DMP 406, Neither size nor number of erythroid or myeloid CFUs differed between cultures containing control or affected dog serum components. Sera from individual affected dogs but not controls resulted in moderate numbers of fibroblast-like CFUs, suggesting DMP 406-associated marrow stromal cell-modifying, serum activities to be present. DMP 406 alone resulted in a concentration-dependent reduction of erythroid and myeloid CFUs with an approximate IC50 of 3.0 mu g/mL. Taken together, DMP 406-induced granulocytopenia and bone marrow dyscrasia appear likely to result from both immune-mediated and direct drug-induced myelotoxicity. (C) 1999 Academic Press.

关键词：抗精神病药/毒性苯二氮|艹卓|类/毒性骨髓细胞/药物作用细胞分裂/药物作用培养基条件性造血干细胞免疫球蛋白类/代谢中性粒细胞减少/血液中性粒细胞减少/化学诱导中性粒细胞减少/免疫学中性粒细胞减少/病理学脾/药物作用脾/代谢脾/病理学干细胞/药物作用动物狗女(雌)性男(雄)性

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CYCLOPHOSPHAMIDE-ASPARAGINASE-VINCRISTINE-PREDNISONE INDUCTION THERAPY IN CHILDHOOD ACUTE LYMPHOCYTIC AND NONLYMPHOCYTIC LEUKEMIA

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CANCER 1976年第3期37卷 1243-1247页

作者： KOMP, DM GEORGE, SL FALLETTA, J LAND, VJ STARLING, KA HUMPHREY, GB LOWMAN, J SOUTHWEST ONCOL GRP OPERATIONS OFF SUITE 201 3500 RAINBOW BLVD KANSAS CITY KS 66103 USA

A remission-induction regimen for childhood leukemia using cyclophophamide, asparaginase vincristine and predinosone (CAVP) was compared to standard vincristine-predinisone (VP) induction. The more intensive regimen was associated with a lower complete remission rate (81% vs 93%) and a higher early death rate from infection (15% vs 5%) for acute lymphocytic leukemia. In contrast, complete remission was achieved in 58% of children with acute nonlymphocytic leukemia treated with CAVP compared to 18% for VP. Early death rates were similar (27% vs 25%). These observations corroborate previous studies in childhood nonlymphocytic leukemia showing activity for asparaginase. Preliminary analysis of remission duration and survival for responders shows no advantage for those who survived the more intensive induction.

关键词：天冬酰胺酶/治疗应用环磷酰胺/治疗应用药物疗法联合白血病/药物疗法白血病/死亡率白血病淋巴样/药物疗法白血病淋巴样/死亡率淋巴细胞减少/化学诱导中性粒细胞减少/化学诱导泼尼松/治疗应用缓解自行长春新碱/治疗应用儿童人类

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Clinical and economic considerations of empirical antibacterial therapy of febrile neutropenia in cancer

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PHARMACOECONOMICS 1999年第4期16卷 343-353页

作者： Dranitsaris, G Princess Margaret Hosp Ontario Canc Inst Dept Pharmaceut Serv Toronto ON M5G 2M9 Canada

Febrile neutropenia is a condition that can develop in patients with cancer following the administration of myelosuppressive chemotherapy or radiation therapy. The current standard of patient management involves the empirical use of a combination of antibacterials or a single broad spectrum agent to offer extensive antibacterial coverage of both Gram-positive and Cram-negative microorganisms. Over the past 25 years, febrile neutropenia has changed from a condition that was fatal in over 50% of patients to a condition with an infection-related mortality rate of less than 10%. A major reason behind these extraordinary advances in patient care has been the many well-designed randomised trials of empirical antibacterial therapy that have been conducted over this period of ti me. In contrast to this finding, a review of the literature revealed limited economic data on the empirical treatment of febrile neutropenia in patients with cancer. Therefore, there is a definite need to conduct more pharmacoeconomic research in this area and to develop methods of implementing the findings of such studies.

关键词：抗菌药/经济学抗菌药/治疗应用细菌感染/并发症细菌感染/药物疗法细菌感染/经济学细菌感染/病因学药物疗法联合/经济学药物疗法联合/治疗应用发热/药物疗法发热/经济学发热/病因学肿瘤/并发症肿瘤/经济学中性粒细胞减少/化学诱导中性粒细胞减少/药物疗法中性粒细胞减少/经济学人类

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EFFECTS OF CYTOTOXIC AND IMMUNOSUPPRESSIVE AGENTS ON IMMUNE SYSTEM

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POSTGRADUATE MEDICINE 1975年第7期58卷 67-74页

作者： BODEY, GP HERSH, EM VALDIVIESO, M FELD, R RODRIGUEZ, V UNIV TEXAS MD ANDERSON HOSP & TUMOR INSTDEPT DEV THERAPEUTICSHOUSTONTX 77025

Numerous studies have shown that antitumor agents have considerable toxicity. However, these agents have substantially benefited many cancer patients. It is hoped that as our understanding of drug mechanisms of action... 详细信息

关键词：抗菌药/药理学抗菌药/治疗应用抗体生成/药物作用抗肿瘤药/投药和剂量抗肿瘤药/药理学药物疗法联合超敏反应迟发型/免疫学免疫/药物作用免疫抑制法免疫抑制剂/药理学淋巴细胞减少/化学诱导中性粒细胞减少/化学诱导人类

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Colony-stimulating factors stimulate some treatments, continue to evolve

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JOURNAL OF THE NATIONAL CANCER INSTITUTE 1999年第3期91卷 210-212页

作者： Volkers, N

Reports on the continued development of the colony-stimulating factors G-CSF and GM-CSF. Research on the factors; Major impact of CSF on the practice of oncology; Use of G-CSF and GM-CSF; Obstacles for a wider embrace... 详细信息

关键词：抗肿瘤药/投药和剂量粒细胞集落刺激因子/治疗应用粒细胞巨噬细胞集落刺激因子/治疗应用肿瘤/药物疗法肿瘤/治疗中性粒细胞减少/化学诱导中性粒细胞减少/病因学中性粒细胞减少/预防和控制人类

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Phase I trial of carboplatin, paclitaxel, etoposide, and cyclophosphamide with granulocyte colony stimulating factor as first-line therapy for patients with advanced epithelial ovarian cancer

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GYNECOLOGIC ONCOLOGY 2000年第2期77卷 271-277页

作者： Tung, N Berkowitz, R Matulonis, U Quartulli, M Seiden, M Kim, Y Niloff, J Cannistra, SA Beth Israel Deaconess Med Ctr Program Gynecol Med Oncol Boston MA 02215 USA Beth Israel Deaconess Med Ctr Div Gynecol Oncol Boston MA 02215 USA Harvard Univ Sch Med Dana Farber Partners Canc Care Boston MA 02115 USA

Objectives. The goal of this study was to determine the maximally tolerated doses (MTDs) of carboplatin, paclitaxel (Taxol), etoposide, and cyclophosphamide (CTEC) with granulocyte-colony stimulating factor (G-CSF, Filgrastim) support as first-line chemotherapy in women with advanced epithelial ovarian cancer (EOC). Methods. Newly diagnosed patients with either stage IV EOC, or stage III EOC and any amount of gross residual tumor after surgical debulking were eligible to receive six cycles of CTEC over five different dose levels in this phase I trial (planned 21-day cycle length). Paclitaxel, carboplatin, and cyclophosphamide were administered intravenously on Day 1, and oral etoposide was administered on Days 1, 2, and 3. G-CSF was administered beginning Day 4. Results. Twenty patients received a total of 98 cycles of CTEC over the five dose levels evaluated. Bone marrow suppression was the major toxic effect, with grade 4 neutropenia and thrombocytopenia being observed in 25 and 23% of cycles, respectively. The overall incidence of febrile neutropenia was 10%, and no toxic deaths occurred. No grade IV thrombocytopenia or febrile neutropenia was observed once the carboplatin dose was reduced from AUC of 7 to 5. Nonhematologic toxicity was generally mild (grade 2 or less). Dose-limiting toxicity was not observed at the highest dose level evaluated in this study, preventing assignment of the MTD. The clinical complete response rate was 92%, although 15 of 16 evaluable patients have progressed with a median progression-free interval of 4 months (range, 2-11 months). One patient remains disease-free 9 months from the completion of CTEC. Conclusions. The CTEC regimen is well tolerated and highly active. Although the MTD was not reached in this study, the short median progression-free interval suggests that this regimen is unlikely to be superior to standard treatment with paclitaxel and carboplatin, Strategies to optimize the development of future combination chemothera

关键词：卡铂/投药和剂量癌/药物疗法癌/病理学环磷酰胺/投药和剂量无病生存剂量效应关系药物依托泊甙/投药和剂量粒细胞巨噬细胞集落刺激因子/投药和剂量中性粒细胞减少/化学诱导中性粒细胞减少/预防和控制卵巢肿瘤/药物疗法卵巢肿瘤/病理学紫杉酚/投药和剂量紫杉烷类血小板减少/化学诱导血小板减少/预防和控制治疗结果女(雌)性人类中年人

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ANALYSIS OF TREATMENT IN CHILDHOOD LEUKEMIA .2. TIMING AND TOXICITY OF COMBINED 6-MERCAPTOPURINE AND METHOTREXATE MAINTENANCE THERAPY

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BRITISH JOURNAL OF HAEMATOLOGY 1976年第2期33卷 179-188页

作者： MACLENNAN, ICM KAY, HEM FESTENSTEIN, M SMITH, PG The Members of the Working Party are as follows: Professor J. M. Hutchison (Chairman) Professor R. M. Hardisty (Secretary) Dr K. D. Bagshawe Dr J. M. Bridges Professor Neville Butler Dr J. M. Chessells Dr P. F. Deasy Dr P. M. Emerson Dr H. W. Everley Jones Dr D. I. K. Evans Dr D. M. T. Gairdner Dr D. A. G. Galton Dr R. J. Guyer Dr C. B. Howarth Dr E. M. Innes Dr P. Morris Jones Dr H. E. M. Kay Dr T. J. McElwain Dr I. C. M. MacLennan Dr J. Martin Professor I. C. S. Normand Mr P. G. Smith Dr J. Stuart Dr E. N. Thompson and Dr M. L. N. Willoughby.

The 1st and 2nd Medical Research Council UKALL trails showed that alteration in the timing of methotrexate and 6-mercaptopurine maintenance therapy for the treatment of acute lymphoblastic leukemia can markedly change drug induced toxicity. Maintenance chemotherapy in both trials used a similar total dosage of these drugs but the timing of their administration was different in the 2 schedules. Serial analysis of leukocyte count showed that the UKALL I regimen caused considerably more neutropenia than UKALL II but UKALL II was associated with prolonged lymphopenia which was not characteristic of UKALL I. Analysis of deaths in remission in these 2 trials showed some correlation with these findings. Deaths in complete remission were compared with the known prognostic features of age and presenting white cell count. Of the 350 patients achieving remission, 63% had the good prognostic features of being less than 13 yr of age and having a white cell count below 20 .times. 109/l at presentation. Twelve out of the 26 deaths in this group occurred in patients in 1st remission. In the remaining 128 patients who lacked one or both of these good prognostic features, only 1 out of 56 deaths recorded to date occurred during remission.

关键词：药物疗法联合白血病淋巴样/药物疗法白血病淋巴样/死亡率白细胞计数淋巴细胞淋巴细胞减少/化学诱导甲氨蝶呤/治疗应用甲氨蝶呤/毒性中性粒细胞减少/化学诱导中性白细胞缓解自行时间因素儿童儿童学龄前人类婴儿婴儿新生

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The effects of IB4, a monoclonal antibody to the CD18 leukocyte integrin on phorbol myristate acetate (PMA)-induced polymorphonuclear leukocyte (PMN) accumulation and endothelial injury in rabbit lungs

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INFLAMMATION 1999年第1期23卷 51-62页

作者： Meurer, RD Forrest, MJ MacIntyre, DE Merck Res Labs Dept Pharmacol Rahway NJ 07065 USA

A model of acute lung injury induced by intravenous phorbol myristate acetate (PMA) is described. The model is characterized by the accumulation of polymorphonuclear leukocytes (PMNs) and a hemorrhagic edema in bronchoalveolar lavage (BAL) fluid when measured 6 h following the administration of PMA (60 mu g/kg, i.v.). It was also determined that PMA induces acute leukopenia and neutropenia which were maximal at 5 min following the injection of PMA and were sustained for at least 6 h, with circulating leukocyte numbers returning to control values by 24 h. The extents to which the inflammatory and systemic changes induced by PMA were dependent on the surface expression on leukocytes of the beta 2-integrins was assessed by comparing responses to PMA in control animals and animals pretreated with the anti-CD18 monoclonal antibody IB4. The administration of IB4 (1 mg/kg, i.v.) 15 min before PMA did not alter the time course or extent of PMA-induced leukopenia and neutropenia. In contrast IB4 administration (0.1 to 1 mg/kg) produced a dose dependent inhibition of PMN accumulation and plasma extravasation measured in BAL fluid. IB4 (1 mg/kg) completely inhibited PMA evoked increases in plasma extravasation (94.5 +/- 1.7%, N = 4) and hemorrhage (95.2 +/- 2.1%, N = 4) whereas PMN accumulation in BAL fluid was inhibited by 77.8 +/- 3.8% (mean +/- SEM, N = 4). Thus, a small, but reproducible, component of the PMA-induced PMN accumulation was not inhibited using this regimen of IB4 administration. If IB4 administration was delayed for 3 h post injection of PMA and bronchoalveolar lavage performed 3 h later, the extents of PMN accumulation and edema formation were similar to those observed 3 h following PMA challenge in control animals not dosed with IB4. This suggests that administration of IB4 during an ongoing inflammatory response is capable of preventing the further development of inflammatory changes and further supports the therapeutic potential of CD18 blockade in condit

关键词：抗体单克隆/药理学抗原 CD18/免疫学细胞运动/药物作用内皮血管/药物作用内皮血管/病理学白细胞计数/药物作用中性粒细胞减少/化学诱导中性粒细胞减少/病理学中性白细胞/药物作用中性白细胞/生理学十四酰佛波乙酯/药理学动物女(雌)性兔

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