|
�。�1）與5-氟尿嘧啶（5-FU）合用提高5-FU的療效
在DNA合成過程中dUMP需要在胸苷酸合成酶（TMPS）的作用下接受四氫葉酸的 甲基形成dTMP。而5-FU進入體內先轉變?yōu)榉蜞奏っ撗鹾塑账�，抑制胸苷酸合成酶的作用。在反應過程中，TMPS、四氫葉酸和dUMP三者形成一個過渡性的復合物，反應結束后復合物分解，釋放出二氫葉酸、TMPS和dTMP。但給予5-FU后形成的三聯復合物不能分解，TMPS的功能受到抑制，不能生成dTMP。氟尿嘧啶脫氧核苷酸與酶的結合力與四氫葉酸的濃度成正比，提高四氫葉酸的濃度可加強5-FU對TMPS的抑制作用。
臨床上，5-FU與CF的合用常見于各種消化道的惡性腫瘤，如胃癌、大腸癌等。有作者研究發(fā)現，在晚期大腸癌患者中，單用5-FU與5-FU、CF合用的有效率存在顯著性差異（11%和23%，P<0.001）。但CF與5-FU合用時的劑量卻一直存在爭議，多數隨機對照研究提示低劑量（20mg/m2）與高劑量（200-500mg/m2）相比療效上無顯著性差異。
�。�2）大劑量氨甲蝶呤（MTX）的解救治療
氨甲蝶呤與葉酸的結構相似，并與二氫葉酸還原酶具有較高的親和力，它可在細胞內競爭性地與二氫葉酸還原酶相結合，阻斷二氫葉酸轉變?yōu)樗臍淙~酸，從而抑制DNA的合成。CF進入體內后，通過四氫葉酸還原酶轉變?yōu)樗臍淙~酸，從而有效的拮抗MTX的作用。因此外源性的給予CF可以越過MTX所作用的部位，使正常的生化反應能夠繼續(xù)進行起到解救作用。
所謂大劑量MTX是指每次的劑量比常規(guī)劑量大100倍以上（一般為2-5g/m2），一般靜脈輸注4-6小時，使一段時間內血中藥物濃度達到較高水平，促使MTX進入細胞內的濃度達到10-5 M以上的有效濃度。另一方面，血藥濃度提高后，還可使MTX擴散到血供較差的實體瘤中，并能通過血腦、血眼和血睪屏障。因此，大劑量MTX與常規(guī)劑量相比療效更好。
但是大劑量MTX治療也可以引起嚴重的不良反應，如骨髓抑制、嚴重的黏膜炎、腎功能衰竭、消化道反應、肝功能損害等。因此，MTX治療后一段時間必須采取解救措施。
�。�3）藥代動力學
CF口服后幾乎可被全部吸收，在肝臟及腸黏膜被代謝�？赏ㄟ^血腦屏障。靜脈或肌肉注射后半衰期為6小時。80-90%的藥物經腎臟排泄，5-8%的藥物經糞便排泄。
3.不良反應
極少發(fā)生過敏反應。大劑量應用后可出現胃腸功能紊亂、失眠、抑郁或煩躁.
4.用法用量
�。�1）與5-FU合用時的最合適劑量目前尚不清楚，常規(guī)的方法是200-500mg/m2，在5-FU之前靜脈輸注2小時，隨后靜脈應用5-FU，一般連用5天，21-28天重復治療。
�。�2）用于大劑量MTX的解救治療。
可采用肌肉注射、靜脈注射、靜脈輸注和口服等方法。因為CF幾乎可以被完全吸收，因此不同的用藥途徑對CF的作用影響不大。CF解救一般在大劑量MTX治療后2-18小時（最晚不超過24小時）開始，劑量為6-12mg/m2，隨后每隔3-6小時重復同樣劑量給藥，一般解救應持續(xù)到72小時以上或血中MTX的濃度降到10-7M的安全值以下。如果MTX的毒性較大或血藥濃度較高時，CF的解救時間應適當延長至5-7天，劑量也應加大。
CF解救治療的同時，還要水化、堿化尿液、并給予一定的支持治療。
參考文獻
1.Zofran （ondansetron hydrochloride） injection and tablets product information. Glaxo Wellcome Oncology/HIV in : Physicians' desk reference, 52nd ed, Montvale, NJ, Medical Economics Company, 1998,1177-1183.
2.Kytril （granisetron hydrochloride） injection and tablets product information. Smithkline Beecham Pharmaceuticals in : Physicians' desk reference, 52nd ed, Montvale, NJ, Medical Economics Company, 1998,2836-2840.
3. de Bruijn KM. Tropisetron : a review of the clinical experience. Drugs, 1992, 43 （suppl 3）: 11-22.
4.Fischer V, Baldeck J-P, Tse FL. Pharmacokinetics and metabolism of the 5-hydroxytryptamine antagonist tropisetron after single oral doses in humans. Drug Metab Dispos, 1992, 20:603-607.
5.周際昌，徐兵河，周愛萍. 恩丹西酮（齊魯）預防非順鉑化療所致嘔吐的III期臨床研究。中華腫瘤雜志，1997，19（6）：460-462.
6.Perez EA, Lembersky B, Kaywin P,et al. Intravenous （IV） granisetron vs ondansetron in the prevention of cyclophosphamide-doxorubicin-induced emesis in breast cancer patients: a double blind crossover study. Proc Am Soc Clin Oncol, 1996,15:543 （abstract 1764）.
7.Pion JM, Fournier C, Darloy F, et al. Oral granisetron vs oral ondansetron, a comparative double-blind cross-over multicenter study of preventive anti-emetic in moderately emetogenic chemotherapy, by the French Northern Oncology Group （FNOG）. Proc Am Soc Clin Oncol, 1996,15:530（abstract 1715）.
8.Perez EA, Hesketh P,Sandbach J, et al. Comparison of single dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randimized parallel study. J Clin Oncol, 1998,16:754-760.
9.張頻，馮奉儀，何友兼等.萘西雅注射劑預防化療藥物所致胃腸反應的臨床研究。中華腫瘤雜志，2000，22（1）：70-73.
10. Navari R, Gandara D,Hesketh P,et al. Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin induced emesis. J Clin Oncol, 1995,13:1242-1248.
11. Gralla RJ, Navari RM, Hesketh PJ, et al .Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy. J Clin Oncol, 1998,16:1568-1573.
12. The Italian group for antiemetic research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med,2000,342:1554-1559.
13. Lofters WS, Pater JL, Zee B, et al. Phase III double-blind comparison of dolasetron mesylate and ondansetron and an evaluation of the additive role of dexamethasone in the prevention of acute and delayed nausea and vomiting due to moderately emetogenic chemotherapy. J Clin Oncol,1997,15:2966-2973.
14. 徐兵河，周際昌，周愛萍.恩丹西酮（齊魯）預防順鉑所致嘔吐的III期臨床研究。中華腫瘤雜志，1997，19（5）：358-361.
15. Crawfold J,Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer （r-metHuG-CSF）.N Engl J Med ,1991,325:164-170.
16. 馮奉儀，周立強.基因重組人粒細胞/巨噬細胞集落刺激因子防治腫瘤化療所致的白細胞減少。中華腫瘤雜志1998，20（6）：451-453.
17. Maher D, Green M, Bishop J, et al. Randomized, placebo controlled trial of filgrastim （r-metHuG-CSF） in patients with febrile neutropenia （FN）following chemotherapy（CT）. Proc Am Soc Clin Oncol, 1993,12:434（abstr）.
18. Kemp G, Rose P, Lurain J ,et al. Amifostine pretreatment for protection against cyclophophamide-induced and cisplatin-induced toxicities: Results of a randomized control trail in patients with advanced ovarian cancer. J Clin Oncol, 1996,14:2101-2112.
19. Hortobagyi GN, Theriault RL, Porter L,et al. Efficacy of pamidronate in reducing skeletal complications in patients with breasr cancer and lytic bone metastases. N Engl J Med, 1996,335:1785-1791.
20. Patterson AHG, Powel TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol,1993, 11: 59-65.
21. Van Holten-Verzantvoort ATM, Kroon HM, Bijvoet OLM, et al. Palliative pamidronate treatment in patients with bone metastases from breast cancer. J Clin Oncol,1993,11:491-498.
22. Kanis JA, Powles T, Paterson AHG, et al. Clodronate decrease the frequency of skeletal metastases in women with breast cancer. Bone, 1996,19: 663-667.
23. Van Holten-verzantrvoort AT, Hermas J, Beex LV, et al. Does supportive pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patient? Eur J Cancer, 1996,32A:450-454.
24. Loyama, Uchida T, Takanuki F,et al. Pharmacokinetics of recombinant human interleukin-11（rhIL-11） in healthy male subjects. Br J Clin Pharmacol, 1997,43:571-578.
25. Tepler I, Elias L, Smith II JW,et al. A randomized placebo-controlled trial of recombinant human interliukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood, 1996,87（9）:3607-3614.
26. Isaacs C, Robert NJ, Bailey FA, et al. Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin. J Clin Oncol, 1997,15（11）:3368-3377.
上一頁 [1] [2] [3]
... |
