Comparison of hemostatic effect and safety between epinephrine and tramazoline during nasotracheal intubation: a double-blind randomized trial.

BACKGROUND: Nasal bleeding is the most common complication during nasotracheal intubation (NTI). To reduce nasal bleeding, the nasal mucosa is treated with vasoconstrictors (epinephrine [E] or tramazoline [T]) prior to NTI. This study aimed to determine whether E or T is more effective and safe for reducing nasal bleeding during NTI. METHODS: This study was preregistered on UMIN-CTR after being approved by the IRB of the School of Dentistry at Aichi Gakuin University. Written consent was received from all the patients. Total 206 patients aged 20-70 years and classified as 1-2 on American Society of Anesthesiologists-physical status were scheduled to undergo general anesthesia with NTI. At last, 197 patients were randomly divided into two groups and treated with either E (n = 99; 3 patients were discontinued) or T (n = 98; 2 patient were discontinued). After induction of general anesthesia, each patient's nasal mucosa was treated using either E or T. The E used in this study was BOSMIN® SOLUTION 0.1% (Daiichi-Sankyo Co., Ltd., Tokyo), and the T used in this study was TRAMAZOLIN Nasal Solution 0.118% AFP, (Alfresa Pharma Corporation, Osaka). E was diluted five times according to the package insert (final concentration of E = 0.02%), and T was used in its original solution. After 2 min, NTI was performed via the right nostril. Primary outcome were the presence of nasal bleeding (if bleeding was recognized at the posterior pharyngeal wall via nasal cavity during intubation, it was defined as bleeding) and the degree of bleeding (classified as none, mild, moderate, or severe). Secondary outcomes were arrhythmia, and hemodynamic (mean atrial pressure and heart rate) changes associated with vasoconstrictors. RESULTS: The presence of bleeding was comparable in both groups (12.5%, E; 14.5%, T; P = 0.63). No significant difference between the groups regarding the degree of bleeding (P = 0.78) was observed, with most patients having no bleeding (n = 84, E; n = 82, T). No severe bleeding and no arrhythmias induced by vasoconstrictor were observed in the two groups. CONCLUSIONS: Nasal treatment with E or T shows no difference in nasal bleeding during NTI. Although no arrhythmia associated with E was observed in this study, it has been reported in literature. Therefore, as frequency and degree of nasal bleeding were comparable, nasal treatment with T could reduce the risk of NTI. TRIAL REGISTRATION: UMIN-CTR (Registration No. UMIN000037907 ). Registered (05/09/2019).

Postoperative Anaemia Is a Risk Factor for Bleeding-Related Event in Thromboprophylaxis Using Fondaparinux Sodium Injection after Total Knee or Hip Arthroplasty.

Bleeding is a life-threating side effect of thromboprophylaxis with fondaparinux sodium (FPX) injection. The purpose of this retrospective study was to assess the risk factor for bleeding-related event following thromboprophylaxis with FPX after total knee arthroplasty (TKA) or total hip arthroplasty (THA). Adult patients undergoing TKA or THA at a single university hospital were administered FPX for thromboprophylaxis by subcutaneous injection of 1.5 or 2.5 mg per day. The risk factor for bleeding-related event was identified by propensity score-adjusted multivariate logistic analysis, and survival analysis was performed retrospectively in consideration of the identified risk factors. Two hundred and twenty-six patients who underwent TKA (n = 62) or THA (n = 164) were enrolled. Anaemia on postoperative day (POD) 1 was identified as a risk factor for bleeding-related event (odds ratio: 3.75, 95% confidence interval: 1.02-24.5, p = 0.04). Eighty of 226 patients were selected using a propensity score matching and patients with anaemia on POD1 in this population had a significantly higher incidence of bleeding-related event than those without anaemia (p = 0.0016, Ghen-Breslow-Wilcoxon test; p = 0.0015, log-rank test). These results suggest that anaemia on POD1 is an independent risk factor for bleeding-related event following thromboprophylaxis with FPX after TKA or THA.

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats.

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.

Evaluation of Medication Adherence and Pharmacokinetics of Dasatinib for Earlier Molecular Response in Japanese Patients With Newly Diagnosed Chronic Myeloid Leukemia: A Pilot Study.

BACKGROUND: Tyrosine kinase inhibitors markedly improve the survival for patients with chronic myeloid leukemia (CML). However, a decrease in adherence leads to undesired therapeutic outcomes. In this study, the relationships among adherence, pharmacokinetics, response, and adverse effects for dasatinib treatment were prospectively investigated. METHODS: This study was a prospective cohort study of patients with newly diagnosed CML at 4 general hospitals and 1 university hospital. Patients started to receive dasatinib 100 mg once daily. A Medication Event Monitoring System was used to assess medication adherence and the medication possession ratio during the 12 months. Plasma concentrations of dasatinib were measured using liquid chromatograph-tandem mass spectrometry (LC-MS/MS), and therapy responses were assessed at 3, 6, and 12 months after treatment. RESULTS: Ten patients were included. An extremely high medication adherence for dasatinib was observed; the median medication possession ratio was 99.4%. All 9 CML patients with breakpoints in the major BCR-ABL achieved major molecular response (MMR; major BCR-ABL transcript level below 0.1% on the International Scale) within 12 months, and 5 achieved MMR within 6 months. The receiver operating characteristic curve analysis revealed that the cutoff value for the dasatinib area under the concentration-time curve was 336.1 ng × h/mL (accuracy 88.9%, sensitivity 80.0%, specificity 100%, and receiver operating characteristic curve-area under the concentration-time curve 0.800) for achieving MMR within 6 months. Two patients had interrupted dasatinib treatment because of pleural effusion and diarrhea with intestinal edema, respectively. These edematous adverse events developed after plasma dasatinib Cmin surpassed 3.0 ng/mL. CONCLUSIONS: A Medication Event Monitoring System was applied for the direct evaluation of oral dasatinib adherence for the first time, and the clinical effect of dasatinib was investigated under the strict monitoring of patient adherence. Although this study had a small sample size, the plasma concentration monitoring of dasatinib is considered to be useful to predict an earlier molecular response with fewer edematous adverse events.

The effect of various dilute administration of rocuronium bromide on both vascular pain and pharmacologic onset: a randomized controlled trial.

BACKGROUND: Rocuronium bromide (RB) is known to cause vascular pain. Although there have been a few reports that diluted administration causes less vascular pain, there have been no studies investigating diluted administration and the onset time of muscle relaxation. Therefore, we examined the influence of diluted administration of RB on the onset time of muscle relaxation and vascular pain. METHODS: 39 patients were randomly assigned to three groups: RB stock solution 10 mg/ml (Group 1), two-fold dilution 5 mg/ml (Group 2), or three-fold dilution 3.3 mg/ml (Group 3). After the largest vein of the forearm was secured, anesthesia was induced by propofol and 0.6 mg/kg of RB was administered. The evaluation method devised by Shevchenko et al. was used to evaluate the degree of vascular pain. The time from RB administration until the maximum blocking of T1 by TOF stimulation was measured. RESULTS: There was no significant difference in escape behaviors of vascular pain among the three groups, and the onset time of muscle relaxation was significantly slower in Group 3 than in Group 1 (p = 0.033). CONCLUSION: Our results suggested that it is unnecessary to dilute RB before administration if a large vein in the forearm is used. TRIAL REGISTRATION: UMINCTR Registration number UMIN000026737 . Registered 29 Mar 2017.

Usefulness of Airway Scope for intubation of infants with cleft lip and palate-comparison with Macintosh laryngoscope: a randomized controlled trial.

BACKGROUND: Airway Scope (AWS) with its plastic blade does not require a head-tilt or separate laryngoscopy to guide intubations. Therefore, we hypothesized that its use would reduce the intubation time (IT) and the frequency of airway complication events when compared with the use of Macintosh Laryngoscope (ML) for infants with cleft lip and palate (CLP). METHODS: The parents of all patients provided written consents; we enrolled 40 infants with CLP (ASA-PS 1). After inducing general anesthesia using sevoflurane and rocuronium, we performed orotracheal intubations using either AWS (n = 20) or ML (n = 20), randomly. We define the duration between manual manipulation using cross finger for maximum mouth opening and the first raising motion of the chest following intubation by artificial ventilation as "IT;" further, the measured IT as primary outcomes. Airway complications were considered secondary outcomes. Moreover, we looked for associations between IT and the patient's characteristics: extensive clefts, age, height, and weight. We used the Mann-Whitney test and Fisher's exact probability test for statistical analysis; p < 0.05 was considered as statistically significant. RESULTS: The mean IT was 31.5 ± 8.3 s in AWS group and 26.4 ± 8.9 s in ML group. Statistical significant difference was not found in IT between the two groups. The IT of AWS group was statistically related to extensive clefts. Airway complications were detected in ML group. CONCLUSION: AWS could be useful for intubation of infants with CLP; it required IT similar to that required using ML, with a lower rate of airway complications. TRIAL REGISTRATION: UMIN-CTR Registration number UMIN000024763 . Registered 8 November 2016.

Comparison of disinfection effect between benzalkonium chloride and povidone iodine in nasotracheal intubation: a randomized trial.

BACKGROUND: Nasotracheal intubation can potentially result in microbial contamination from the upper respiratory tract to the lower respiratory tracts. However, an ideal nasotracheal disinfection method is yet to be determined. Therefore, we compared the disinfection effects between benzalkonium chloride and povidone iodine in nasotracheal intubation. METHODS: Overall, this study enrolled 53 patients aged 20-70 years who were classified into classes 1 and 2 as per American Society of Anesthesiologists-physical status and were scheduled to undergo general anesthesia with NTI. Patients who did not give consent (n = 2) and who has an allergy for BZK or PVI were excluded from the study. The patients were randomly divided into two groups on the basis of the disinfection method: BZK (n = 26, one patient was discontinued intervention) and PVI (n = 25). 50 patients were assessed finally. The subjects' nasal cavities were swabbed both before (A) and after disinfection (B), and the internal surface of the endotracheal tube was swabbed after extubation (C). The swabs were cultured on Brain heart infusion agar and Mannitol salt agar. The number of bacteria per swab was determined and the rates of change in bacterial count (B/A, C/B) were calculated. The growth inhibitory activity of the disinfectants on Staphylococcus aureus were also investigated in vitro. RESULTS: Although the initial disinfection effects (B/A) were inferior for benzalkonium chloride compared with those for povidone iodine, the effects were sustained for benzalkonium chloride (C/B). In the in vitro growth inhibitory assay against S. aureus, benzalkonium chloride showed higher inhibitory activity than povidone iodine. CONCLUSION: Although both disinfectants were inactivated or diffused/diluted over time, benzalkonium chloride maintained the threshold concentration and displayed antimicrobial effects longer than povidone iodine; therefore, benzalkonium chloride appeared to show a better sustained effect. Benzalkonium chloride can be used for creating a hygienic nasotracheal intubation environment with sustained sterilizing effects. TRIAL REGISTRATION: UMIN-CTR (Registration No. UMIN000029645 ). Registered 21 Oct 2017.

Incidence and Risk Factors of Postoperative Delirium following Pancreatic Surgery: Does the Administration of TJ-54 Reduce the Incidence of Delirium.

PURPOSES: To clarify the incidence and risk factors of postoperative delirium in patients following pancreatic surgery, and the impact of yokukansan (TJ-54) administered to reduce delirium. METHODS: Fifty-nine consecutive patients who underwent pancreatic surgery (2012.4-2013.5) were divided into 2 groups: TJ-54 group: patients who received TJ-54 (n = 21) due to insomnia and the No-TJ-54 group: patients who did not receive TJ-54 (n = 38), and the medical records including the delirium rating scale - Japanese version (DRS-J) were retrospectively reviewed. RESULTS: Postoperative delirium occurred in 2 patients (9.5%) in the TJ-54 group and in 4 (10.5%) patients in the No-TJ-54 group (p = 0.90). The DRS-J on 5 days after surgery was lower in the TJ-54 group than in the No-TJ-54 group (rough p = 0.006), however, without any statistically significant differences with the Bonferroni correction. As for the hospital cost, there was no difference between the TJ-54 and the No-TJ-54 groups (p = 0.78). History of delirium was identified as an independent risk factor of postoperative delirium. CONCLUSION: The patients with preoperative insomnia, who were treated with TJ-54, did not have a higher incidence of postoperative delirium, compared to those without preoperative insomnia. The patients who had a history of delirium have an increased risk of postoperative delirium and should be cared for and treated prophylactically to prevent it.

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers.

Lansoprazole, a proton pump inhibitor, potently inhibits human organic anion transporter, hOAT3 (SLC22A8). Lansoprazole has an asymmetric atom in its structure and is clinically administered as a racemic mixture of (R)-and (S)-enantiomers. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT3 and its homolog, hOAT1. In the present study, the stereoselective inhibitory effect of lansoprazole was evaluated using hOAT1-and hOAT3-expressing cultured cells. hOAT1 and hOAT3 transported [14C]p-aminohippurate and [3H]estrone-3-sulfate (ES) with Michaelis-Menten constants of 29.8 ± 4.0 and 30.1 ± 9.0 µmol/L respectively. Lansoprazole enantiomers inhibited hOAT1- and hOAT3-mediated transport of each substrate in a concentration-dependent manner. The IC50 value of (S)-lansoprazole against hOAT3-mediated transport of [3H]ES (0.61 ± 0.08 µmol/L) was significantly lower than that of (R)-lansoprazole (1.75 ± 0.31 µmol/L). In contrast, stereoselectivity was not demonstrated for the inhibition of hOAT1. Furthermore, (S)-lansoprazole inhibited hOAT3-mediated transport of pemetrexed and methotrexate (hOAT3 substrates) more strongly than the corresponding (R)-lansoprazole. This study is the first to demonstrate that the stereoselective inhibitory potency of (S)-lansoprazole against hOAT3 is greater than that of (R)-lansoprazole. The present findings provide novel information about the drug interactions associated with lansoprazole.

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.

[Postoperative Analgesia for Video-assisted Thoracoscopic Surgery--Continuous Intravenous Infusion of Fentanyl Combined with Intercostal Nerve Block v.s. Continuous Epidural Analgesia].

BACKGROUND: Epidural analgesia or paravertebral block is widely used in postoperative analgesia for video-assisted thoracic surgery (VATS). We investigated the efficacy of the continuous intravenous infuion of fentanyl combined with intercostal nerve block, in comparison with the continuous epidural analgesia. METHODS: Forty-one patients received a bolus of 0.375% ropivacaine 6-10 ml through the epidural catheter placed at the T5-9 at the end of surgery. Then, continuous epidural infusion of 0.2% ropivacaine at a rate of 4 or 6 ml x hr(-1) was started (Group E). 44 patients received intercostal nerve block at three insertion points of thoracoscopy (using 0.75% ropivacaine 3-4 ml, respectively) at the end of surgery. Then, continuous intravenous infusion of fentanyl at a rate of 0.5 µg x kg(-1) x hr(-1) was started (Group F). The efficacy of post-operative analgesia was evaluated by additional analgesic requirements. RESULTS : There was no significant difference in the additional analgesic requirements between the two groups. However, the additional analgesics were required significantly earlier in Group E than Group F (P < 0.05). CONCLUSIONS: Continuous intravenous infusion of fentanyl combined with intercostal nerve block is effective in the postoperative analgesia for VATS, as well as continuous epidural analgesia.

Delayed elimination half-life of amlodipine in a case of drug overdose.

A 75 year-old-female was transferred to our ICU by an ambulance for refractory hypotension. The patient was suspected to have acute amlodipine (AML) overdose based on the information obtained from patient's family. Serum AML concentration was 355.6 ng/mL on the 1st hospital day. The patient's blood pressure was gradually elevated by intravenous administration of noradrenaline, calcium chlo- ride and insulin, and the patient was transferred to another hospital on the 9th hospital day. The analysis of serum AML concentration showed delayed elimination half life in the early period after the inges- tion. It was thought that decrease in the hepatic clearance of AML by the saturation of metabolism could contribute to the delayed elimination. Severe AML overdose may cause prolonged elimination half-life.

Olopatadine, a non-sedating H1 antihistamine, decreases the nocturnal scratching without affecting sleep quality in atopic dermatitis.

We have demonstrated for the first time that a second-generation antihistamine ameliorates nocturnal scratching behavior in atopic dermatitis patients using a modified wristwatch-type acoustic scratching counting system that we have recently developed. We also analyzed the sleep quality by simultaneous recording of electroencephalogram, and found that sleep quality was unaffected.

Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation.

BACKGROUND: Blood tacrolimus (TAC) concentration delivered via intravenous administration is known to be influenced by genetic polymorphism of CYP3A5 and interaction with triazole antifungal agents. However, interindividual variability of blood TAC concentration is as of yet still difficult to predict during the early stages of hematopoietic stem cell transplantation (HSCT). This study was conducted to assess the wide variability of blood TAC concentrations because of the hepatic metabolic activities of CYP3A and CYP2C19 in HSCT recipients. METHODS: This study is a single-institute prospective study that includes 21 adult patients who underwent HSCT and received 24 hours continuous intravenous administration of TAC at the Mie University Hospital between January 2009 and March 2014. After HSCT, the changes in blood TAC concentration/dose (C/D) ratio and TAC dose reduction from initial dose were investigated. RESULTS: Significant differences between HSCT recipients with CYP3A5*1 allele and CYP3A5*3/*3 genotype were observed with respect to the median TAC C/D ratio on day 14 (563 versus 742 ng/mL per mg/kg, P < 0.01) and day 21 (672 versus 777 ng/mL per mg/kg, P < 0.05) after HSCT. Concomitant administration of voriconazole (VRCZ), but not of lansoprazole, was found to significantly increase the median TAC C/D ratio on day 14 (557 versus 723 ng/mL per mg/kg, P < 0.01). Possession of the CYP3A5*3/*3 genotype (day 14: odds ratio, 32.2; day 21: odds ratio, 33.0; P < 0.05) and concomitant administration of VRCZ (day 14: odds ratio, 37.8; P < 0.05) were found to be independent risk factors, which significantly contributed to an increased TAC C/D ratio. In HSCT recipients with CYP3A5*3/*3 genotype (78.0%), the median TAC dose ratio (day 21/day -1) was significantly lower compared with HSCT recipients with the CYP3A5*1 allele (94.1%), whereas VRCZ administration itself had no significant influence. Interestingly, in HSCT recipients with CYP2C19*1/*1, we found that the influence of VRCZ on the TAC dose ratio (85.7%) was relatively mild, even in a recipient with CYP3A5*3/*3. CONCLUSIONS: In HSCT recipients, the variability of intravenous TAC concentration in the blood could be explained in part by the genetic variation of CYP3A5. The study results also strongly imply that the magnitude of hepatic interaction between TAC and VRCZ is affected by the genetic polymorphism of both CYP3A5 and CYP2C19 genes.

[Effects of Sevoflurane or Desflurane Anesthesia on Perioperative Delirium in Elderly Patients Undergoing Surgical Repair of Hip Fracture].

BACKGROUND: Perioperative delirium increases the morbidity and mortality in elderly patients. The present retrospective study was carried out to evaluate whether desflurane or sevoflurane has influence on the incidence of perioperative delirium. METHODS: In 30 patients above 75 years of age undergoing surgical procedure, anesthesia was maintained with sevoflurane (group S), and with desflurane (group D). The incidence of perioperative delirium was obtained retrospectively from their medical chart The delirium was diagnosed with the Richmond agitation-sedation scale. RESULTS: The incidence of perioperative delirium on postoperative day (POD) 1-3 was not significantly different between group D and group S. The patients in group D were discharged earlier about 10 days compared with those group S. CONCLUSIONS: Desflurane anesthesia is same as sevoflurane regarding perioperative delirium in elderly patients. Shorter hospitalization in group D was achieved for 10 days compared with those in group S, due to the lower incidence of delirium on POD 3 and 5 in group D.

Carboplatin-induced severe hypersensitivity reaction: role of IgE-dependent basophil activation and FcεRI.

Basophil activation was observed in patients with a history of carboplatin-induced severe hypersensitivity reaction (HR). However, the precise mechanism by which carboplatin induces basophil activation and the associated surrogate markers remains to be elucidated. To investigate whether IgE-dependent mechanisms, including the overexpression of FcεRI, participate in carboplatin-induced basophil activation, 13 ovarian cancer patients were enrolled: 5 with a history of carboplatin-induced severe hypersensitivity reaction within the past 2 years, and 8 with no such history. The expression levels of FcεRI, IgE, and CD203c on basophils were measured using a flow cytometer. Immunoglobulin E-dependent basophil activation was evaluated by testing for IgE passive sensitization using lactic acid, and by testing for phosphatidylinositol 3-kinase inhibition, using wortmannin. In three patients positive for carboplatin hypersensitivity, pretreatment with wortmannin almost completely inhibited carboplatin-induced basophil activation (P < 0.05). In a healthy control subject, whose own IgE showed no response to carboplatin, acquired reactivity to carboplatin when exposed to plasma from patients positive for carboplatin hypersensitivity. This did not occur when the same experiment was carried out using plasma from the patients negative for carboplatin hypersensitivity. Moreover, pretreatment with omalizumab, a monoclonal anti-IgE antibody, almost completely blocked carboplatin-induced basophil activation in the plasma of patients positive for carboplatin hypersensitivity. On further investigation, the HR-positive group had significantly higher levels of FcεRI compared with the negative group (P < 0.05). In conclusion, an IgE-dependent mechanism incorporating FcεRI overexpression participates in carboplatin-induced severe HR. These results establish the relevance of monitoring the pharmacodynamic changes of basophils to prevent carboplatin-induced severe HR.

Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia.

Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38 µM. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.

Model-Informed Vancomycin Dosing Optimization to Address Delayed Renal Maturation in Infants and Young Children with Critical Congenital Heart Disease.

Ensuring safe and effective drug therapy in infants and young children often requires accounting for growth and organ development; however, data on organ function maturation are scarce for special populations, such as infants with congenital diseases. Children with critical congenital heart disease (CCHD) often require multiple staged surgeries depending on their age and disease severity. Vancomycin (VCM) is used to treat postoperative infections; however, the standard pediatric dose (60-80 mg/kg/day) frequently results in overexposure in children with CCHD. In this study, we characterized the maturation of VCM clearance in pediatric patients with CCHD and determined the appropriate dosing regimen using population pharmacokinetic (PK) modeling and simulations. We analyzed 1,254 VCM serum concentrations from 152 postoperative patients (3 days-13 years old) for population PK analysis. The PK model was developed using a two-compartment model with allometrically scaled body weight, estimated glomerular filtration rate (eGFR), and postmenstrual age as covariates. The observed clearance in patients aged ≤ 1 year and 1-2 years was 33% and 40% lower compared with that of non-CCHD patients, respectively, indicating delayed renal maturation in patients with CCHD. Simulation analyses suggested VCM doses of 25 mg/kg/day (age ≤ 3 months, eGFR 40 mL/min/1.73 m2 ) and 35 mg/kg/day (3 months < age ≤ 3 years, eGFR 60 mL/min/1.73 m2 ). In conclusion, this study revealed delayed renal maturation in children with CCHD, could be due to cyanosis and low cardiac output. Model-informed simulations identified the lower VCM doses for children with CCHD compared with standard pediatric guidelines.

Comparative Efficacy and Safety of Standard and Biweekly Trifluridine/Tipiracil Regimen in Patients With Colorectal Cancer.

BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC. PATIENTS AND METHODS: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29). RESULTS: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999). CONCLUSION: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event.

MicroRNA-145 post-transcriptionally regulates the expression and function of P-glycoprotein in intestinal epithelial cells.

P-glycoprotein (P-gp/MDR1) is a multispecific efflux transporter regulating the pharmacokinetics of various drugs. Although P-gp expression in the small intestine is elevated after liver ischemia-reperfusion (I/R) injury, the regulatory mechanism remains to be clarified. MicroRNAs (miRNAs) play an important role in the post-transcriptional regulation of the expression of drug transporters. Here, we investigated the intestinal expression profile of miRNAs after liver I/R and the role of miRNAs in the post-transcriptional regulation of P-gp in intestinal epithelial cells. Microarray analysis showed that microRNA-145 (miR-145) level was decreased in the small intestine of I/R rats. This downregulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 3'-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 3'-UTR reporter plasmid in HEK293 cells showed that luciferase activity was decreased by the overexpression of miR-145, and the deletion of miR-145 binding site within MDR1 3'-UTR abolished this decreased luciferase activity. The downregulation of miR-145 in Caco-2 cells, an epithelial cell line derived from human colon, increased P-gp expression and efflux activity of rhodamine 123, but not MDR1 mRNA level. These findings demonstrated that miR-145 negatively regulates the expression and function of P-gp through the repression of mRNA by direct interaction on the 3'-UTR of MDR1 mRNA. In addition, the downregulation of miR-145 should significantly contribute to the elevated intestinal P-gp expression after liver I/R. Our results provide new insight into the post-transcriptional regulation of intestinal P-gp.