Study on the method to avoid infusion-site adverse events following chemotherapeutic treatment with epirubicin and fosaprepitant using immortalized human umbilical vein endothelial cells.

The combination of intravenous Proemend® containing fosaprepitant meglumine, a prodrug for fosaprepitant (FAP), and Tween 80 and chemotherapy with anthracyclines, such as epirubicin (EPI), can cause infusion-site adverse events in clinical practice. In immortalized human umbilical vein endothelial (HUEhT-1) cells, the cytotoxic effects of FAP, EPI, diluted Proemend with culture medium and Tween 80 alone, and a combination of FAP and EPI, were evaluated using the WST-1 cell viability assay. FAP, EPI and diluted Proemend exhibited cytotoxicity in a concentration-dependent manner and marked synergic cytotoxicity was observed between FAP and EPI. The washing of the cell surface following incubation with diluted Proemend containing FAP and Tween-80 eliminated the synergic cytotoxicity of EPI applied thereafter. These results indicated that washing of the infusion-site vascular tissue following intravenous Proemend administration via intravenous tube flushing with an efficient amount of saline may reduce the infusion-site adverse events, which are caused by the combined use of FAP and EPI.

Study on the infusion-site adverse events and vascular distribution of epirubicin in chemotherapy with epirubicin and fosaprepitant.

In breast cancer patients on a fluorouracil-epirubicin (EPI)-cyclophosphamide (FEC) regimen and intravenous fosaprepitant (FAP) during chemotherapy, infusion-site adverse events such as vascular pain and induration and/or phlebitis are observed. In the present study, adverse events induced by the FEC regimen and FAP, a prodrug of aprepitant (AP), were studied based on the vascular tissue distribution of EPI in rats. Rats were treated with intravenous FAP (3 mg/kg, 10 min-constant rate infusion) or oral AP (3 mg/kg) and then intravenous EPI (1 mg/kg, 5 min-constant rate infusion) as follows: FAP-S Group, FAP and then EPI was infused from the same site on the jugular vein; FAP-D Group, FAP and then EPI was infused from different jugular veins (left and right); and AP Group, AP was administered orally and EPI was infused from the jugular vein. Concentrations of EPI in vascular tissue at the EPI infusion sites and opposite sites of the jugular vein (left and right, respectively) were measured at 30 min and 24 h after EPI infusion. Histological observation of the EPI infusion site was also made separately. In rats, the tissue concentrations of EPI at the infusion site in the FAP-S group were higher than those in the FAP-D and AP groups. Inflammation and necrosis were observed at the EPI infusion-site vascular tissue of the FAP-S group, but not of the FAP-D and AP groups. These findings could aid the development of an approach to avoid infusion-site adverse events in anthracycline-based chemotherapy in the clinical practice.

Reduction in the rate of postoperative delirium by switching from famotidine to omeprazole in Japanese hepatectomized recipients.

BACKGROUND: Hepatectomy is a highly invasive procedure with a high probability of postoperative delirium. Treatment with antiulcer drugs is indispensable after hepatectomy for anastomotic ulcer management. The clinical pathway for hepatectomy was reviewed and the antiulcer drug used was switched from famotidine, a H2-receptor antagonist, to omeprazole, a proton pump inhibitor, owing to the pharmacist's intervention. METHODS: Hepatectomized recipients over 65 years of age, except in the cases of laparoscopic surgery and intensive care unit entry, were treated with famotidine injections (10 patients) or omeprazole injections (11 patients), and the incidence rates and severity of delirium were compared between the famotidine and omeprazole groups. The delirium after hepatectomy was assessed using the Japanese version of the NEECHAM confusion scale. RESULTS: The incidence rates of delirium were 90% in the famotidine group and 27.3% in the omeprazole group. Four out of 9 recipients in the famotidine group were injected with haloperidol to treat for delirium, but no recipients needed this treatment in the omeprazole group. CONCLUSIONS: Compared with famotidine, the use of omeprazole was found to be effective in reducing the incidence rate and severity of postoperative delirium in patients undergoing hepatectomy. Pharmacists should actively strive to mitigate the risks of delirium.

Elevation in 5-FU-induced apoptosis in head and neck cancer stem cells by a combination of CDHP and GSK3ß inhibitors.

BACKGROUND: Cancer stem cells (CSCs) are involved in both tumourigenesis and in tumour recurrence after therapy. In head and neck squamous cell carcinoma (HNSCC), there are two biologically different CSC phenotypes both of which express high levels of CD44 but differ in their expression levels of epithelial-specific antigen (ESA). One phenotype is CD44(high)/ESA(high) and has epithelial features (Epi-CSCs), while the other is CD44(high) /ESA(low), has undergone epithelial to mesenchymal transition (EMT-CSCs), has mesenchymal features and is migratory (Biddle et al., 2011). CSCs are resistant to therapeutically induced apoptosis but the molecular mechanisms by which they develop apoptotic resistance remains unclear. However, glycogen synthase kinase 3ß (GSK3ß) contributes to regulation of both the self-renewal and switching of these two CSC phenotypes (Shigeishi et al., 2013). METHODS: CD44(high) /ESA(low), CD44(high) /ESA(high) and CD44(low) cells were FACS sorted from the HNSCC cell line LUC4, and 5-FU-induced apoptosis was analysed by Annexin V staining followed by flow cytometry analysis. RESULTS: CD44(high) /ESA(low) cells exhibited marked resistance to 5-FU-induced apoptosis and had high expression of dihydropyrimidine dehydrogenase (DPD). The DPD inhibitor, 5-chloro-2, 4-dihydroxypyridine (CDHP) significantly enhanced 5-FU-induced apoptosis of CD44(high)/ESA(low) cells. Inhibition of GSK3ß induced CD44(high) /ESA(low) cells to undergo mesenchymal-to-epithelial transition (MET) to CD44(high)/ESA(high) cells and pre-existing CD44(high) /ESA(high) cells to differentiate. Apoptosis induced by 5-FU was thus facilitated. Combination of both CDHP and GSK3ß inhibitors markedly enhanced 5-FU-induced apoptosis of CD44(high) /ESA(low) cells. CONCLUSIONS: Our results suggest potentially new approaches for the elimination of the therapy resistant HNSCC CSC population.

Interaction of magnesium oxide with gastric acid secretion inhibitors in clinical pharmacotherapy.

PURPOSE: Magnesium oxide (MgO), a short-term osmotic laxative, is converted into MgCl2 under acidic condition in the stomach and then Mg(HCO3)2 in the intestinal tract, where Mg(HCO3)2 induces the water exudation into the intestine. This indicates that the laxative effect of MgO could be attenuated under the suppressed gastric acid secretion. In this study, the possible interaction of MgO with gastric acid secretion inhibitors was evaluated by using electronic patient records of MgO dosage levels. METHODS: Defecation was controlled with MgO alone in some patients after colon surgery (n = 67) and after total gastric resection (n = 4). Some other patients were treated with a combination use of MgO and H2 receptor antagonist (H2RA) (n = 14) or proton pump inhibitor (PPI) (n = 27). The possible drug interaction of MgO with H2RA or PPI was evaluated by comparing dosage levels of MgO used in controlling defecation. RESULTS: In controlling defecation, the daily dosage levels of MgO in patients taking H2RA or PPI and patients with total gastric resection were significantly higher than those patients taking MgO alone after colon surgery. The ratios of good constipation control (controlled well at the dosing level of 1,000 mg MgO) in patients taking H2RA or PPI were significantly lower than that in patients treated with MgO alone. In an in vitro study, the solubility of MgO at pH 4.5 was quite low, as compared with that at pH 1.2. CONCLUSIONS: When patients received H2RA or PPI, the laxative effect of MgO is decreased possibly due to the low solubility of MgO at the higher gastric pH and less generation of MgCl2 and Mg(HCO3)2. Higher dosing level of MgO or another laxative should be used in patients taking H2RA or PPI, as well as the case of patients with total gastric resection.

Plasma leptin concentration in dogs with diabetes mellitus.

The plasma leptin concentration was evaluated in dogs with diabetes mellitus. Twenty normal and sixteen diabetic dogs were divided into nonobese and obese groups based on body condition score, respectively. The obese normal dogs had significantly higher plasma leptin concentrations than the nonobese normal dogs, whereas there was no significant difference between the nonobese and obese diabetic dogs. In addition, the plasma leptin concentration in the obese diabetic dogs was significantly lower than that in the obese normal dogs. In conclusion, the plasma leptin concentrations in the diabetic dogs were affected by factors other than adiposity.

Prevention of irinotecan-induced diarrhoea by oral carbonaceous adsorbent (Kremezin) in cancer patients.

Irinotecan (CPT-11) treatments induce severe diarrhoea at a rate of >40%. In clinical trials, we evaluated the preventing effects of oral alkalization, which has been reported previously, and oral carbonaceous adsorbent (Kremezin trade mark ) on diarrhoea possibly induced by CPT-11. Evaluation was made by counting the maximum number of bowel motions in each patient. Five patients out of 7 treated with CPT-11 had bowel motions of >5 times daily, and maximum number of bowel motions reached 20 times in 1 patient. Oral alkalization (2 g sodium bicarbonate, 2 g magnesium oxide and 300 mg ursodeoxycholic acid daily for 4 days) decreased bowel motions from 20 to 8 thereafter in the patient. Maximum number of bowel motions in other 3 patients treated in a combination of CPT-11 and oral alkalization was <3. Oral adsorbent (2 g Kremezin x 3 times, during and after CPT-11 treatment) also decreased maximum number of bowel motions from 7 (without oral adsorbent) to 3 in 1 patient. Also, the maximum number of bowel motions in other 3 patients treated with oral adsorbent was <3 (p<0.05, vs CPT-11 alone). Effect of oral Kremezin on plasma concentrations of CPT-11 and its related compounds after a 1-h CPT-11 infusion, evaluated in a patient, was small. These results suggested that the oral Kremezin is effective in ameliorating CPT-11-induced diarrhoea without decreasing much the plasma clearance of CPT-11.

Possible mechanism for pharmacokinetic interaction between lidocaine and mexiletine.

OBJECTIVE: Our objective was to elucidate the mechanism of pharmacokinetic interaction between lidocaine and mexiletine, because an unexpected increase in plasma lidocaine concentration accompanied by severe side effects was observed when mexiletine was administered to a patient with dilated cardiomyopathy. METHODS: Plasma concentrations of lidocaine, its major metabolites, and mexiletine were measured in a patient with dilated cardiomyopathy. The lidocaine-mexiletine interaction was evaluated by examination of the effects of mexiletine on plasma concentration and the tissue distribution of lidocaine in rabbits in vivo, as well as on the in vitro lidocaine binding to phosphatidylserine, a binding constituent for weakly basic drugs. RESULTS: Plasma lidocaine concentrations increased significantly when the oral dose of mexiletine was increased. This pharmacokinetic interaction was not attributable to a metabolic interaction as evaluated by plasma lidocaine metabolites concentrations. In rabbits, mexiletine seemed to decrease the total plasma clearance of lidocaine, resulting in increased plasma lidocaine concentrations. Mexiletine significantly reduced the tissue distribution of lidocaine to the kidneys and lungs. A strong displacing effect of mexiletine on the binding of lidocaine to phosphatidylserine was observed in vitro. CONCLUSIONS: A drug interaction derived from the displacement of lidocaine from tissue binding sites by mexiletine that resulted in the increased plasma lidocaine concentrations was shown. This observation had implications for loading doses and acute effects of lidocaine in the concurrent therapy of lidocaine and mexiletine.