Tomoyuki Enokiya

Changes in the pharmacokinetics of teicoplanin in patients with hyperglycaemic hypoalbuminaemia: Impact of albumin glycosylation on the binding of teicoplanin to albumin.

There is large interindividual variability in serum teicoplanin (TEIC) concentrations after administration of a loading dose, and the factors that influence the pharmacokinetics of TEIC are disputed. The aim of this study was to clarify changes in the pharmacokinetics of TEIC that occur in patients with hyperglycaemia as well as the impact of albumin glycosylation on the pharmacokinetics of TEIC. This study consisted of retrospective and prospective investigations. The pharmacokinetic parameters of TEIC were retrospectively compared between patients receiving TEIC treatment. Ninety-four patients were divided into four groups according to their serum albumin and blood glucose concentrations [(i) hyperglycaemic hypoalbuminaemia (albumin<3.0g/dL) (n=16); (ii) non-hyperglycaemic hypoalbuminaemia (n=29); (iii) hyperglycaemic normoalbuminaemia (albumin≥3.0g/dL) (n=9); and (iv) non-hyperglycaemic normoalbuminaemia (n=40)]. In addition, the concentration of glycosylated albumin was prospectively determined in 28 patients. At 12h after administration of a loading dose, patients with hyperglycaemic hypoalbuminaemia displayed significantly lower serum TEIC concentrations (P<0.05) and higher TEIC volume of distribution (Vd) (P<0.05) than the other three groups, whereas TEIC clearance did not differ significantly among the groups. In addition, the percentage of glycosylated albumin was significantly correlated with the association constant (Ka) of TEIC for albumin (r=0.53, P=0.004) and the Vd (r=0.41, P=0.031). These results suggest that hyperglycaemic hypoalbuminaemia lowers the serum TEIC concentration, which is attributable to the decreased Ka and increased Vd of TEIC by albumin glycosylation.

Co-administration of proton pump inhibitors ameliorates nephrotoxicity in patients receiving chemotherapy with cisplatin and fluorouracil: a retrospective cohort study

PurposeThe nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP-induced nephrotoxicity.MethodsWe analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury.ResultsThe rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan–Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033).ConclusionsThese findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy.

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non–small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

Arbekacin treatment of a patient infected with a Pseudomonas putida producing a metallo-beta-lactamase

Treatment of infections caused by multidrug-resistant Pseudomonas species is difficult because few antibiotics active against such organisms are available. Arbekacin, a relatively new aminoglycoside, is effective against Pseudomonas spp. in vitro. However, no clinical report on arbekacin treatment of a human infection with a multidrug-resistant Pseudomonas has appeared to date. We encountered a case of pneumonia caused by a Pseudomonas strain producing a metallo-beta-lactamase; the patient was successfully treated with arbekacin. A 69-year-old male presented to our hospital experiencing cardiac arrest after rescue from water. Spontaneous circulation had earlier resumed after brief application of cardiopulmonary resuscitation. The patient was subjected to induced hypothermia. He experienced severe acute respiratory distress syndrome. The patient regained consciousness on day 8 post-admission. Episodes of ventilator-associated pneumonia were recorded on days 5 and 12. The causative organism was a strain of Pseudomonas putida that produced a metallo-beta-lactamase. Combination therapy with arbekacin and levofloxacin successfully resolved the pneumonia. The patient was transferred to another hospital on day 37 to undergo further rehabilitation. Strains of P. putida producing metallo-beta-lactamases have become more widespread in recent years. Colistin is traditionally the drug of last resort to treat infections with multidrug-resistant Pseudomonas. However, colistin use is associated with a very high frequency of adverse effects, and the costs of such therapy are not covered by the Japanese health insurance system. Our results indicate that arbekacin is an efficient alternative to multidrug-resistant Pseudomonas.

Two cases of life-threatening arrhythmia induced by risperidone: evaluation of risperidone and 9-hydroxy-risperidone concentrations

Case 1: A 20‐year‐old woman suffering a suspected overdose was transported to the hospital. She presented bradycardia with wide QRS waves and QT prolongation, followed by cardiac arrest. Extracorporeal cardiopulmonary resuscitation was implemented, improving circulation. Risperidone and 9OH‐RIS levels were 9.6 ng/mL and 127.6 ng/mL, respectively. Case 2: A 54‐year‐old woman was hospitalized for femoral fracture and underwent surgery. Her electrocardiogram showed bradycardia and complete AV block. Risperidone and 9OH‐RIS levels were 3.2 ng/mL and 61.4 ng/mL, respectively.

Use and effectiveness of prothrombin complex concentrate in an emergency department: a review of 15 cases

Hemostatic management of patients on oral anticoagulant therapy with critical bleeding continues to be a major challenge. The present study aimed to validate the efficacy, safety, and optimal dosage of prothrombin complex concentrate for rapidly normalizing elevated international normalized ratio (INR) values and achieving control of hemorrhage at an emergency department in Japan.

Effect of lipid emulsion infusion on paliperidone pharmacokinetics in the acute overdose rat model: A potential emergency treatment for paliperidone intoxication

&NA; Paliperidone prolongs cardiac repolarization in a concentration‐dependent manner. Meanwhile, continuous infusion of intravenous lipid emulsion (ILE) has been established as a detoxification therapy for lipophilic drugs. However, this change in pharmacokinetics of various drugs following ILE administration remains to be clarified. Our objective is to clarify the effect of continuous infusion of ILE on the pharmacokinetics of overdosed paliperidone in rats. Paliperidone (20 mg/kg) was administered orally to free‐moving male Wistar rats. Continuous infusion (initial loading dose: 4 ml/kg for 10 min, followed by 4 ml/kg/h for 12 h) of ILE or acetated Ringers solution (AR) was initiated 30 min after paliperidone administration. Plasma concentration profile of paliperidone was monitored for 12 h after administration. The plasma concentration and tissue/plasma concentration ratios of paliperidone were compared between ILE and AR groups. The rat group infused with ILE showed a higher area under the concentration–time curve (mean [S.D.]: 6102 [900.9] vs. 3407 [992.1] ng h ml−1, p = 0.02) and longer elimination half‐time (t1/2) (4.1 [0.9] vs. 2.2 [0.4] h, p = 0.02) compared with the AR group. Tissue/plasma concentration ratios of paliperidone were lower in ILE rats than in AR rats (1.98 [0.70] vs. 3.82 [1.47] in the heart, p = 0.04; 0.28 [0.29] vs. 1.27 [0.58] in the brain, p < 0.001). In conclusion, continuous infusion of ILE would reduce tissue distribution and prolonged the t1/2 of paliperidone in rats. These results suggest that continuous infusion of ILE has potential as an emergency treatment for acute paliperidone intoxication. Graphical abstract Figure. No caption available.