[Influence of the Use of a Closed System Drug Transfer Device on the Preparation Time of Anticancer Drugs].

A closed system drug transfer device (CSTD) helps to minimize unnecessary exposure of healthcare workers such as pharmacists to hazardous drugs. One of the concerns in using CSTDs to prepare anticancer drugs is their influence on preparation time. Therefore, we compared the time needed to prepare anticancer drugs with the CSTDs NEOSHIELD® and BD PhaSeal® system and with an injection needle. In the comparison of NEOSHIELD® and an injection needle, the preparation time of the liquid formulations of the cytotoxic drugs irinotecan, eribulin, cisplatin, docetaxel, and paclitaxel was significantly shorter with the injection needle and that of gemcitabine was significantly shorter with NEOSHIELD®, but that of oxaliplatin, carboplatin, and doxorubicin was not significantly different between the two methods; the preparation time of the liquid formulations of the molecular-targeted drugs atezolizumab, obinutuzumab, cetuximab, daratumumab and vorhyaluronidase alfa, nivolumab, ramucirumab, and rituximab was significantly shorter with NEOSHIELD® and that of bevacizumab and pembrolizumab was significantly shorter with the injection needle; and the preparation time of the lyophilized formulation of cytotoxic and molecular-targeted drugs was not significantly different between the two methods. In the comparison of NEOSHIELD® and BD PhaSeal® system, the preparation time of cyclophosphamide and ifosfamide was significantly shorter with NEOSHIELD®, but that of bendamustine was not significantly different between the two CSTDs. In conclusion, these results suggest that the preparation time with CSTDs may be similar to or shorter than that with an injection needle, depending on the type of CSTD and the drug formulation and type.

Differences in kinetics of tacrolimus concentration after letermovir discontinuation by type of concomitant azole antifungal.

Letermovir is commonly used for CMV prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Pharmacokinetic studies have shown an increase in tacrolimus exposure among healthy volunteers who took letermovir. However, studies in HCT recipients are needed because these patients are typically using concomitant antifungals with different degrees of CYP3A4 inhibition that may further interact with tacrolimus pharmacokinetics. In this study, we retrospectively evaluated the kinetics of tacrolimus concentration after letermovir discontinuation by type of concomitant azole antifungal in 57 HCT recipients. The median fold change in tacrolimus concentration-to-dose (C/D) ratio after discontinuing letermovir was 0.64 (range 0.43-0.99) with fluconazole and 1.10 (range 0.59-1.73) with voriconazole (p < 0.001). The tacrolimus C/D ratio decreased ≥ 30% after discontinuing letermovir (p < 0.001) in 66% of patients on fluconazole and 9% on voriconazole. Among patients whose tacrolimus C/D ratio decreased ≥ 30%, three (9%) patients in the fluconazole group and one (4%) in the voriconazole group experienced worsening of GVHD. Careful monitoring of tacrolimus concentration is important after letermovir discontinuation to avoid worsening of GVHD due to decreased tacrolimus concentration.

Drug interaction between letermovir and voriconazole after allogeneic hematopoietic cell transplantation.

Letermovir has been approved for the prevention of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HCT). Letermovir is a cytochrome P450 (CYP) 2C19 inducer. Voriconazole, which is a broad-spectrum triazole antifungal agent, is mainly metabolized by CYP2C19. Thus, voriconazole trough concentration may decrease due to the drug interaction between voriconazole and letermovir. This study aimed to clarify the effects of letermovir on voriconazole trough concentration in allogeneic HCT recipients. We retrospectively examined voriconazole trough concentration in 24 allogeneic HCT recipients who had letermovir for prevention of CMV infection. The median voriconazole C/D ratios significantly decreased after starting letermovir from 0.25 L/kg to 0.11 L/kg (p < 0.01), and increased after discontinuing letermovir from 0.15 L/kg to 0.24 L/kg (p = 0.02). The median fold change of voriconazole trough concentration during letermovir administration was 0.40. Our results suggest that voriconazole trough concentration decreases when voriconazole is combined with letermovir in allogeneic HCT recipients. Therefore, close therapeutic drug monitoring of voriconazole trough concentration is warranted in allogeneic HCT recipients after starting or discontinuing letermovir.

Normal aging induces PD-1-enriched exhausted microglia and A1-like reactive astrocytes in the hypothalamus.

Hypothalamic aging is considered to be critical for systemic aging, and the accumulation of "exhausted glial cells" in the hypothalamus may contribute to brain dysfunction. In this study, we used normal aging mice and investigated aging-specific transcriptional identities of microglia and astrocytes in the hypothalamus. We confirmed that normal aging promoted anxiety, induced impairment of motor coordination and reduced physical strength of muscle in mice. To investigate the senescence of hypothalamic glial cells, we isolated CD11b-positive microglia and ACSA-2-positive astrocytes from the hypothalamus of aged mice using magnetic-activated cell sorting (MACS). The mRNA level of p16INK4A was dramatically increased in the hypothalamic microglia of aged mice compared to young mice. Furthermore, the expression of programmed cell death 1 (PD-1) as well as A1-like astrocyte mediators in the hypothalamic microglia was dramatically induced by aging, indicating that normal aging may produce PD-1-enriched "exhausted microglia" in the hypothalamus. Furthermore, neuroinflammatory A1-like reactive astrocytes with a p16INK4A-positive senescent state were predominantly detected in the hypothalamus of aged mice. Exhausted microglia were also detected in the prefrontal cortex of aged mice, whereas astrocytic neuroinflammation was milder than that observed in the hypothalamus, even with p16INK4A-positive senescence. These results suggest that the production of PD-1-enriched exhausted and senescent microglia and neuroinflammatory A1-like reactive astrocytes in the hypothalamus may partly contribute to aging-related emotional and physical dyscoordination.

Nausea and vomiting during post-transplantation cyclophosphamide administration.

Post-transplantation cyclophosphamide (PTCy) is a new method to prevent graft-versus-host disease after allogeneic hematopoietic cell transplantation. Although the use of dexamethasone is recommended as prophylaxis against chemotherapy-induced nausea and vomiting (CINV) for patients who receive high-dose cyclophosphamide, corticosteroids cannot be used during PTCy administration to exploit depletion of alloreactive T cells. Thus, CINV may not be adequately controlled in this situation. We retrospectively examined antiemetic efficacy of the combination of a 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA) and a NK1 receptor antagonist (NK1 RA) in 36 patients who received PTCy, and compared this efficacy with that of the same combination together with dexamethasone in 27 patients conditioned with cyclophosphamide and total body irradiation (CY/TBI). The proportion of patients who had no vomiting during the acute phase of PTCy administration was 81%, and was lower than 100% in the CY/TBI group (p = 0.02). Our results suggest that prevention of CINV using 5-HT3 RA and NK1 RA during PTCy administration is suboptimal and that addition of antiemetic is necessary in patients who receive PTCy.

Accuracy of predicting the vancomycin concentration in Japanese cancer patients by the Sawchuk-Zaske method or Bayesian method.

BACKGROUND: In cancer patients treated with vancomycin, therapeutic drug monitoring is currently performed by the Bayesian method that involves estimating individual pharmacokinetics from population pharmacokinetic parameters and trough concentrations rather than the Sawchuk-Zaske method using peak and trough concentrations. Although the presence of malignancy influences the pharmacokinetic parameters of vancomycin, it is unclear whether cancer patients were included in the Japanese patient populations employed to estimate population pharmacokinetic parameters for this drug. The difference of predictive accuracy between the Sawchuk-Zaske and Bayesian methods in Japanese cancer patients is not completely understood. OBJECTIVE: To retrospectively compare the accuracy of predicting vancomycin concentrations between the Sawchuk-Zaske method and the Bayesian method in Japanese cancer patients. METHODS: Using data from 48 patients with various malignancies, the predictive accuracy (bias) and precision of the two methods were assessed by calculating the mean prediction error, the mean absolute prediction error, and the root mean squared prediction error. RESULTS: Prediction of the trough and peak vancomycin concentrations by the Sawchuk-Zaske method and the peak concentration by the Bayesian method showed a bias toward low values according to the mean prediction error. However, there were no significant differences between the two methods with regard to the changes of the mean prediction error, mean absolute prediction error, and root mean squared prediction error. CONCLUSION: The Sawchuk-Zaske method and Bayesian method showed similar accuracy for predicting vancomycin concentrations in Japanese cancer patients.

Comparison of valproate and levetiracetam for the prevention of busulfan-induced seizures in hematopoietic stem cell transplantation.

Anticonvulsant administration is the standard of care for prevention of busulfan-induced seizures (BIS) in hematopoietic stem cell transplantation (HSCT). While valproate interacts with other drugs, including carbapenem antibiotics, levetiracetam has no known clinically significant interactions. Only a few reports have discussed the use of levetiracetam for the prevention of BIS in HSCT recipients. This retrospective study aimed to evaluate the efficacy and safety of valproate and levetiracetam for BIS prophylaxis in adult HSCT recipients. We identified patients who received valproate or levetiracetam to prevent BIS at the National Cancer Center Hospital from December 2015 to November 2017. Ninety-one patients were analyzed (valproate group 45; levetiracetam group 46). No BIS occurred in either group. The pattern of anticonvulsant-related adverse events was similar in both groups, except for a higher incidence of rash in the valproate group. Carbapenem antibiotics were more frequently used in the levetiracetam group than in the valproate group. In conclusion, valproate and levetiracetam are effective and safe for the prophylaxis of BIS. Levetiracetam may be more useful in patients colonized with extended-spectrum beta-lactamase-producing bacteria due to its lack of any clinically significant drug-drug interactions.

Bortezomib and dexamethasone for multiple myeloma: higher AST and LDH levels associated with a worse prognosis on overall survival.

BACKGROUND: Bortezomib offers a novel approach to the treatment of multiple myeloma producing rapid control. The aim of this study was to investigate the outcomes of bortezomib and dexamethasone-treated patients with multiple myeloma. METHODS: We conducted a retrospective study of 44 consecutively-treated multiple myeloma patients with bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of a 21-day cycle or 1.3 mg/m(2) intravenously 1, 8, 15, and 22 of every 35-day cycle) and dexamethasone. RESULTS: The median time to progression, progression free survival time, and overall survival time in the treatment groups was 14.9, 14.9, and 38.3 months, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of AST and LDH might be worse. CONCLUSIONS: Our results indicate that the treatment of multiple myeloma with bortezomib and dexamethasone is feasible.

[Prospective study of biotin treatment in patients with erythema due to gefitinib or erlotinib].

Gefitinib anderlotinib, which are epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs), have been usedfor the treatment of inoperable andrecurrent non-small cell lung cancer(NSCLC)patients. These drugs are known to cause a skin rash, one of the major side effects, at a high frequency. Biotin is a water-soluble vitamin, andit belongs to the vitamin B family. It is well known that biotin deficiency increases the risk of skin dermatitis. We administered biotin to four patients with skin rash, all of whom were treatedwith either gefitinib or erlotinib andwere unable to be treatedby a steroid ointment alone. In all patients, administration of biotin reduced the skin rash. Surprisingly, in 2 patients in whom EGFR-TKI therapy was discontinued because of the skin rash, the administration of biotin allowed for long-term gefitinib or erlotinib treatment. Biotin may be considereduseful for the treatment of skin rash causedby EGFR-TKIs. Further trials may be needed to confirm the value of biotin in this setting.

[A case of paclitaxel-induced peripheral neuropathy successfully treated with pregabalin].

Were port a 51-year-old male left renal pelvic cancer patient with paclitaxel (PTX)-induced peripheral neuropathy, which was successfully treated with pregabalin. From June 2010, a gemcitabine/PTX (GP) regimen was used as third-line treatment. In order to relieve the PTX-induced peripheral neuropathy, pregabalin (75mg/day, at night) was administered from day 6 of the 16th course. Moreover, pregabalin was increased to 150mg/day from day 12 of the course. Sensory neurotoxicity after the administration of pregabalin was decreased from CTCAE (version 4. 0) grade 3 to 1 at day 19 of the course. Therefore, there is a possibility that the PTX -induced peripheral neuropathy may be improved by pregabalin administration. Further trials may be needed to confirm the value of pregabalin.

[A case of neurotoxicity reduced with pregabalin in R-CHOP chemotherapy for diffuse large B-cell lymphoma].

When performing R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)for diffuse large B-cell lymphoma(DLBCL), neurotoxicity of vincristine(VCR)is the serious dose-limiting factor.Pregabalin is one of the first-line treatments for painful diabetic peripheral neuropathy in many countries, and we have administered it to relieve the neurotoxicity associated with adverse effects of VCR in a DLBCL patient treated with the R-CHOP regimen.A 49-year-old man with kidney DLBCL had surgery performed.Afterward, the R-CHOP regimen was introduced.In order to relieve the neurotoxicity of VCR, pregabalin was used from day 8 in the second course.The severity of sensory neurotoxicity after the administration of pregabalin was improved from CTCAE(v4.0)grade 3 to grade 1.Therefore, there is a possibility that VCR-induced neurotoxicity is relieved by pregabalin.Further trials are needed to confirm the value of pregabalin.

Evidence for creatine biosynthesis in Müller glia.

In high-energy metabolic tissues like the retina, creatine may play an important role in energy storage and in transmission of phosphate-bound energy substrates. To prove this, we investigated creatine synthesis in Müller glia. We also characterized the localization of the creatine synthetic enzyme, S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT) in the retina. Reverse transcription-polymerase chain reaction analysis revealed that L-arginine:glycine amidinotransferase and GAMT mRNAs were expressed in the retina and the Müller cell line, TR-MUL5. [(14)C]Creatine was detected after incubation of isolated rat retina or TR-MUL5 cells with [(14)C]glycine, L-arginine and L-methionine, suggesting creatine synthesis in Müller glia. Western blot analysis also revealed expression of GAMT protein in the rat retina and TR-MUL5 cells. Furthermore, confocal immunofluorescent microscopy of dual-labeled rat retinal sections demonstrated co-localization of GAMT with glutamine synthetase. Taken together, the results of the present study indicate creatine synthesis in Müller glia, implying an important role of creatine in energy metabolism in the retina.

Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-retinal barrier.

The purpose of this study was to elucidate the mechanisms of blood-to-retina creatine transport across the blood-retinal barrier (BRB) in vivo and in vitro, and to identify the responsible transporter(s). The creatine transport across the BRB in vivo and creatine uptake in an in vitro model of the inner BRB (TR-iBRB2 cells) were examined using [(14)C]creatine. Identification and localization of the creatine transporter (CRT) were carried out by RT-PCR, western blot, and immunoperoxidase electron microscopic analyses. An in vivo intravenous administration study suggested that [(14)C]creatine is transported from the blood to the retina against the creatine concentration gradient that exists between the retina and blood. [(14)C]Creatine uptake by TR-iBRB2 cells was saturable, Na(+)- and Cl(-)-dependent and inhibited by CRT inhibitors, suggesting that CRT is involved in creatine transport at the inner BRB. RT-PCR and western blot analyses demonstrated that CRT is expressed in rat retina and TR-iBRB2 cells. Moreover, using an immunoperoxidase electron microscopic analysis, CRT immunoreactivity was found at both the luminal and abluminal membranes of the rat retinal capillary endothelial cells. In conclusion, CRT is expressed at the inner BRB and plays a role in blood-to-retina creatine transport across the inner BRB.