Comparative Analysis of Adriamycin Toxicity between Continuous Infusion and Bolus Infusion
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Objective To compare the adriamycin(ADM) toxicities of cardiac,liver,blood and digestive system when administered by continuous infusion(CI) and bolus infusion(BL) in malignant tumor.Methods 70 cases of malignancy patients are divided into 2 groups to receive either 72～96 hour continuous infusion of ADM(CI group,60～90 mg/m2,n=35) or 30-minute bolus infusion of ADM(BL group,50～60 mg/m2,n=35).The toxicities in cardiac,liver,blood and digestive system were observed.Results When the total dose of ADM was over 400 mg/m2,there was a significant difference in cardiac toxicity between these two groups(P0.05).The liver toxicity was different between these two groups when the total dose of ADM was between 200～300 mg/m2(P0.05) and was more significantly different when it was over 300 mg/m2.There was also a markedly difference in the toxicity of digestive system(P0.01).But was not in blood toxicity(P0.05).Conclusion Compared with ADM bolus infusion,ADM continuous infusion can reduce the toxicity cardiac,liver and digestive system,but has no influence on blood toxicity.Keywords:
Bolus (digestion)
Cardiac toxicity
Continuous Infusion
Liver toxicity
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In 75 children with mainly lymphoid malignancies, adriamycin was used as part of the treatment. Three groups were distinguished: group I (n = 18), with an adriamycin dose of 30 mg/m2 as bolus; group II (n = 30), with a dose of 100 mg/m2 divided over 2 subsequent days; and group HI (n = 27), with a dose of adriamycin of 100 mg/m2 given as a 24-h infusion. The tolerance of the low dose was the best. In group III small differences in the tolerance were observed. The recovery of the white blood cell count showed a delay in the infusion group, whereas the bolus injection group showed more vomiting. Severe vascular lesions occurred in the infusion group. The use of 24-h infusions of adriamycin is feasible when central venous accesses or totally subcutaneous intravenous devices are used. According to the literature, when long-term invasions of adriamycin are used, the risk of cardiomyopathy is diminished, without influencing the antitumor activity of adriamycin.
Bolus (digestion)
Intravenous bolus
Continuous Infusion
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The hepatic extraction ratios (EH) of adriamycin (ADR) and mitomycin C (MMC), which were administered clinically by an intra-hepatic arterial route, were measured in rats to clarify the disposition of ADR and MMC in liver. EH values of ADR and MMC were determined by comparing the femoral arterial and hepatic venous plasma concentrations at steady state during continuous intravenous administration. The EH value of ADR in rats at each infusion rate of 2, 10 and 50 micrograms/kg/min, was 0.290, 0.286 and 0.251, respectively. There was no significant difference between the EH values (p > 0.05). The systemic clearance (CLtot) at each infusion rate was 108, 77.6 and 72.9 ml/min/kg, respectively. The EH value of MMC in rats at each infusion rate of 2.5, 7.5 and 25 micrograms/kg/min, was 0.332, 0.358 and 0.360, respectively. There was no significant difference between the EH values, the same as for ADR. The systemic clearance (CLtot) at each infusion rate was 38.3, 36.1 and 35.3 ml/min/kg.
Mitomycin C
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It has been proved that vital signs of organism can be influenced by heat infusion and the thermochemotherapy with Adriamycin (ADM) is more effective than the general chemotherapy in inhibiting extraneous rabbit VX-2 cells. Intermittent thermochemotherapeutic infusion and continuous thermochemotherapeutic infusion with ADM were performed respectively on the rabbits to evaluate the effectiveness and safety of intermittent thermochemotherapeutic intra artery infusion by comparing their respiration rate, heart rate, body temperature, and the ADM concentration in VX-2 carcinoma.VX-2 tumor models were established in the hind legs of 30 New Zealand rabbits, and then they were divided into three groups (10 in each group) randomly. 100 ml saline and ADM in room temperature were infused, 100 ml saline and ADM in 60 degrees C were intermittently infused, and 100 ml saline and ADM in 60 degrees C were continuously infused into the tumor nutrient arteries, which were confirmed by DSA, of the rabbits in each group respectively. During the infusion, the 43-45 degrees C lasting time of the tumor tissues in the two 60 degrees C infusion groups was measured. After the infusion,the respiratory rate,heart rate,body temperature,and the concentration of ADM within the tumors were determined.The concentration of ADM was 7.115+/-2.180 microg/ml in the room temperature infusion group,17.213+/-1.657 microg/ml in the 60 degrees C continuous infusion group, and 16.545+/-3.426 microg/ml in the 60 degrees C intermittent infusion group. There was no significant difference between the 60 degrees C intermittent infusion group and the 60 degrees C continuous infusion group (P >0.05), while there was significant difference between the 60 degrees C intermittent infusion groups and the room temperature infusion group,so was between 60 degrees C continuous infusion groups and the room temperature group (P< 0.05). The 43-45 degrees C lasting time was 22.53+/-1.44 minutes in the continuous infusion group and 24.31+/-2.45 minutes in the intermittent infusion group. There was no significant difference between these two groups (P >0.05). There was no significant difference in the respiration rate, heart rate, and body temperature between the 60 degrees C intermittent infusion group and the room temperature infusion group (P >0.05).Compared with continuous infusion, intermittent thermochemotherapy intra artery infusion is a more effective and safer interventional thermochemotherapy.
Respiratory Rate
Continuous Infusion
Lagomorpha
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Furosemide delivery rate in the nephron has been reported to be one of the major determinants of diuretic response. In a randomized, crossover double-blind study in eight healthy volunteers, we tested this hypothesis by comparing continuous intravenous infusion of furosemide (infusion rate, 4 mg/hr) during 8 hours after administration of an intravenous loading dose of 8 mg (total dose, 40 mg) with an intravenous bolus injection of 40 mg furosemide. During the study days subjects were rehydrated with isovolumetric amounts of fluid. Mean total urinary volume (Vur), sodium (UNa), potassium, and chloride excretion after 8 and 24 hours were significantly greater after treatment with continuous furosemide infusion when compared with bolus injection, whereas total urinary furosemide excretion showed no differences (Vur bolus versus Vur infusion, 5270 versus 6770 ml/8 hours; UNa bolus versus UNa infusion, 314 versus 430 mmol/8 hours; both p < 0.001). These findings strongly support the concept of the furosemide delivery rate into the nephron as a determinant of diuretic efficiency. Clinical Pharmacology and Therapeutics (1992) 51, 440–444; doi:10.1038/clpt.1992.44
Bolus (digestion)
Crossover study
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Citations (59)
Objective Effectiveness of two kinds of thermochemotherapy infusion from intraarterial approach were studied in the grafted liver VX2 tumors of rabbit.Methods VX2 tumor model was established in 30 Newzland rabbit's livers.Percutaneous transfemoral hepatic arterial catheterization with fixation of the cathether tip inside the feeding vessel was carried out under DSA guidance.All 30 rabbits were divided into three groups(n=10 in each group),normal temperature 100 ml saline+Adriamycin(ADM)infusion(group 1),60℃100 ml saline+ADM continuous perfusion(group 2)and 60℃100 ml saline+ADM intermittent perfusion(group 3).After the perfusion,the lasting time periods of 43-45℃for tumor tissue of group 2 and 3 together with the concentrations of ADM within tumor's tissue were measured.Results Concentrations of ADM were shown as(12.013±2.237)μg/ml,(17.622±1.368)μg/ml,and(11.519±1.225)μg/ml for group 2, group 3 and group 1 respectively.60℃intermittent perfusion vs 60℃continuous perfusion showed P＜0.05, 60℃continuous pefusion vs normal temperature perfusion also showed P＞0.05. 43-45℃period lasting time (min)for 60℃continuous pefusion vs 60℃intermittent pefusion were(4.1±2.7)min and(11.3±3.3)min respectively,the latter was three times more than the former.There were no differences shown betwen the temperature,respiration and heart rate of group 2 and group 3.Conclusion Intermittent intraarterial perfusion thermochemotherapy is a more effective interventional management among all thermochemotherapies.
Arterial perfusion
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Although continuous hepatic artery infusions (CHAI) of (FUDR) Floxuridine have been effective in reducing the size of colorectal hepatic metastases the toxicity of the infusions have been high with almost a quarter of the patients developing biliary sclerosis. Techniques to lower toxicity, yet continue the beneficial antitumor effects, are being investigated. One suggested strategy is to change the flow pattern of the continuous infusion from a constant rate to a day cycled pattern. In this infusion a continuous rate is given over a 24 hour period with 60% of the infusion delivered between 3 PM and 9 PM and the least amount of infusion delivered between 3 AM and 9 PM. Previous research has suggested that this day cycle pattern will lower the toxicity of the infusion. This experiment is a test of "day cycled" continuous hepatic artery infusions in rats bearing hepatic metastases from a colon adenocarcinoma. Previous research from our laboratory has shown a lowered toxicity when the constant infusion was replaced with the day cycled pattern. In the present study 10 rats with hepatic adenocarcinoma metastases were placed on constant CHAI of FUDR at 10mg/kg/day for 14 days. There was an 80% mortality from chemotherapy toxicity and a 90% objective response rate. Nine other rats were treated with "day cycled" CHAI of FUDR at 15mg/kg/d. There was no mortality in this group and the objective response rate was 90% as in the previous group. This study demonstrated that "day cycled" CHAI of FUDR was substantially less toxic and that the antitumor effect was identical to the constant infusion.
Floxuridine
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It is difficult to administer an effective dose of cyclosporin A (CsA), a potent inhibitor of P-glycoprotein, to prevent multiple drug resistance due to its side effect. We herein evaluated the efficacy of concomitant use of this agent and complete hepatic venous isolation and charcoal hemoperfusion (HVI.CHP). Dogs were divided into two groups; group I (n = 4), intraarterial infusion of only adriamycin (ADM) and group II (n = 4), intraarterial infusion of CsA and ADM. In both groups, ADM was intraarterially administered for 10 minutes under HVI.CHP. In addition, in group II, CsA infusion (0.3 mg/min.kg) was initiated 20 min prior to the start of ADM infusion and maintained for 30 min. The AUC (micrograms.min/ml) of ADM were 21.2 +/- 8.6 (mean +/- SD) and 28.4 +/- 10.3 in groups I and II, respectively, at prefilter (hepatic venous level) and 8.1 +/- 4.6 and 4.8 +/- 3.8, respectively, at postfilter, showing an effective drug elimination in both groups. The Cmax (micrograms/ml) were 14.1 +/- 2.2 at prefilter, 2.4 +/- 0.5 at postfilter, and 3.4 +/- 1.2 in systemic level. These results indicated that HVI.CHP allowed the high-dose CsA infusion required for P-gp inhibition in the liver and could reduce extraregional CsA leakage.
Hemoperfusion
Concomitant
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Bolus (digestion)
Continuous Infusion
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The relationship between platinum concentration in tissues, free CDDP concentration in plasma and infusion rate was investigated in order to determine the optimal intra-arterial infusion rate of CDDP for chemotherapy of cervical carcinoma. Platinum concentrations in uterus were in the same level in the intravenous infusion groups independent of the infusion rate. In the intra-arterial infusion groups, platinum concentrations in the uterus increased as the infusion rate decreased from 24 to 0.8 mg/hr, although Cmax and AUC were decreased. Platinum concentrations in the ovary supplied by another artery were not influenced by the intra-arterial infusion rate. It is suggested that uptake of CDDP in the targeted tissues can be increased by control of intra-arterial infusion rate.
Arterial blood
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Using a fluorometric assay, mean drug levels of Adriamycin were significantly higher in the normal canine liver following bolus injection of this drug via the hepatic artery or portal vein as compared to hepatic tissue levels following systemic intravenous administration (P < 0.001). However, the variations in tissue levels observed after hepatic artery (+/- 16.8 mcg/gm tissue) or portal vein (+/- 21.1 mcg/gm) infusion were significantly wider than those observed after systemic (+/- 1.3 mcg/gm) administration (P = 0.03). Using C14-labeled drugs, regional infusion of Adriamycin through the hepatic artery or portal vein resulted in significantly higher mean drug levels in the liver than after systemic intravenous administration, but the difference was more pronounced with bolus infusion of the drug than 1-hour infusion. 5-FU bolus or 1-hour infusion in the hepatic artery resulted in significantly higher mean drug levels in the liver compared to peripheral intravenous administration, but this was not so with the 3-hour infusion. The above experiments confirm previous studies that regional chemotherapy results in higher drug levels in the regional tissues compared to systemic administration. They also: (1) demonstrate the spotty drug distribution in the regional tissues after regional administration, a potentially correctable problem, and (2) suggest that the advantage of intra-arterial infusion may be more pronounced within a certain range of infusion times.
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