Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

[Methods of preventing phlebitis induced by infusion of fosaprepitant].

At our hospital, we use aprepitant for nausea and vomiting when administering highly emetic anticancer agents, according to "Guidelines for the Appropriate Use of Antiemetic Agents" given by the Japan Society of Clinical Oncology. We initiated the intravenous administration of fosaprepitant for better compliance compared with aprepitant; however, we observed phlebitis after the infusion of fosaprepitant. Therefore, we investigated measures to reduce phlebitis associated with the infusion of fosaprepitant. For the first premedication, fosaprepitant (150 mg) was dissolved in 100 mL of saline and administered for 30 minutes; 1 of 2 patients showed grade 4 phlebitis. For the modified premedication, fosaprepitant, dexamethasone, and 5- HT(3) antagonist were dissolved in 100 mL of saline and administered for 30 minutes. The modified premedication was administered to a total of 27 patients; 5 patients developed mild phlebitis (grade 1), but infusion could be continued by treating their phlebitis with a hot pack. We used a combination of dexamethasone and 5-HT(3) antagonist with fosaprepitant as a modified premedication in order to avoid drug-induced vascular damage, which resulted in the pH decreasing to 6.20-7.55 (close to neutral) and a shorter infusion time.

[The role of the pharmacist in the proper use of antibacterial drugs].

Treatment of infections is a team medical care operation, utilizing the coordinated expertise of many different professionals. Among these, the duty of the pharmacist, as a drug specialist, is considered to be related to the proper use of antibacterial drugs. When selecting an antibacterial drug, it is important to understand the severity and infection source of the patient, and consider drug susceptibility and tissue transitivity based on the antibiogram at the hospital. Moreover, consideration of the specific clinical conditions of pregnant or nursing women, and children, as well as any organ dysfunctions, is required to determine the appropriate antibacterial drug and its proper use. The dosage and administration method of the selected antibacterial drug are determined based on factors such as PK-PD parameters and organ dysfunction of the patient. For drugs requiring TDM, implementation of TDM, determination and evaluation of efficacy, and suggestions to change the antibacterial drug, its dosage, or administration method when needed, are all considered to play a part in the treatment of infection. The duty of the pharmacist is to promote the proper use of antibacterial drugs and participate in the treatment of patients. Moreover, since the proper use of an antibacterial drug and effective use of PK-PD parameters lead to prevention of the emergence of resistant bacteria, we would like to contribute to the preservation of antibacterial drugs as well.

Effect of corticosteroids on phlebitis induced by intravenous infusion of antineoplastic agents in rabbits.

PURPOSE: Phlebitis caused by intravenous infusion of antineoplastic agents is one of the critical problems when anticancer therapy is prolonged. We have already reported that both rapid infusion and dilution of the injection solution were effective methods for reducing phlebitis caused by vinorelbine (VNR) in rabbits. The aim of this study was to explore other practical methods for preventing phlebitis caused by VNR and doxorubicin (DXR) in a rabbit model. VNR is often used with cisplatin, and dexamethasone (DEX) has been co-administered for prevention of cisplatin-induced nausea. DXR is used with prednisolone (PSL) in the CHOP regimen for the treatment of non-Hodgkin's lymphoma. Therefore, the present study investigated the prevention of phlebitis due to VNR with DEX and that due to DXR with PSL. METHODS: VNR and DXR were diluted with normal saline to prepare test solutions at concentrations of 0.6 mg/mL and 1.4 mg/mL, respectively. Each test solution was infused into the auricular veins of rabbits. Two days after VNR infusion and three days after DXR infusion, the veins were evaluated histopathologically. The effect of DEX on VNR-induced phlebitis was evaluated by infusion of DEX before or after VNR. The effect of PSL on DXR-induced phlebitis was similarly evaluated by co-infusion of PSL. RESULTS: The histopathological features of phlebitis caused by the antineoplastic agents differed between VNR and DXR: VNR did not cause the loss of venous endothelial cells, but caused inflammatory cell infiltration, edema, and epidermal degeneration. In contrast, DXR caused the loss of venous endothelial cells and chrondrocyte necrosis. Pre-treatment and post-treatment with DEX significantly decreased VNR-induced phlebitis compared with the control group and pre-treatment was particularly effective. Co-infusion of PSL also significantly decreased phlebitis caused by DXR, but its effect was less marked. CONCLUSION: The present findings suggested that pre-treatment with DEX may be a useful method for preventing phlebitis due to VNR, and that co-infusion of PSL has the potential to prevent phlebitis caused by DXR.

Methods of preventing vinorelbine-induced phlebitis: an experimental study in rabbits.

PURPOSE: In order to identify methods for preventing phlebitis caused by intravenous administration of vinorelbine (VNR), we established a procedure for estimating the severity of phlebitis in an animal model. METHODS: Four different factors (administration rate, dilution, flushing, and infusion of fat emulsion) were evaluated for alleviation of phlebitis caused by VNR infusion. VNR was diluted with normal saline to prepare test solutions with concentrations of 0.6 mg/mL or 0.3 mg/mL for infusion into the auricular veins of rabbits. Two days after VNR infusion, the veins were subjected to histopathological examination. RESULTS: VNR did not cause obvious loss of venous endothelial cells, the most sensitive and common feature of phlebitis, but VNR infusion led to inflammatory cell infiltration, edema, and epidermal degeneration. Tissue damage was significantly decreased by shortening the administration time and by diluting the VNR solution for infusion from 0.6 mg/mL to 0.3 mg/mL. However, there was no effect of flushing with normal saline after VNR infusion, while treatment with fat emulsion before and after VNR infusion only had a minimal effect. CONCLUSION: Rapid infusion and dilution are effective methods of reducing phlebitis caused by the infusion of VNR, but the efficacy of flushing with normal saline or infusion of fat emulsion was not confirmed.

Considerations on prevention of phlebitis and venous pain from intravenous prostaglandin E(1) administration by adjusting solution pH: in vitro manipulations affecting pH.

Prostaglandin E(1) (PGE(1); Alprostadil Alfadex) is a potent vasodilator and inhibitor of platelet aggregation used to treat patients with peripheral vascular disease. The main adverse effects of intravenous PGE(1) administration, phlebitis and venous pain, arise from the unphysiologically low pH of infusion solutions. When PGE(1) infusion solutions with a pH value greater then 6 are used, phlebitis and venous pain are considered to be avoidable. Beginning with a PGE(1) infusion solution with pH greater than 6, we add the amount of 7% sodium bicarbonate needed to bring the solution to pH 7.4 if phlebitis or venous pain develops. In the present study we established a convenient nomogram showing the relationship between the titratable acidity of various infusion solutions and the volume of 7% sodium bicarbonate required to attain pH 7.4 for preventing the phlebitis and venous pain associated with PGE(1) infusion.