A Reactive Metabolite of Clozapine Induces Hematopoietic Toxicity in HL-60 Cells Undergoing Granulocytic Differentiation through Its Effect on Glutathione Metabolism.

Clozapine is an atypical antipsychotic with several advantages over conventional antipsychotics, in addition to its well-known efficacy in treatment-resistant schizophrenia. However, the high risk of agranulocytosis associated with clozapine therapy limits its clinical application. Clozapine bioactivation to an unstable protein-reactive metabolite, identified as a nitrenium intermediate, has been implicated in cytotoxicity toward neutrophils. Clozapine affects myeloid precursor cells rather than neutrophils; however, the impact of its reactive metabolite on myeloid precursor cells undergoing granulocytic differentiation remains unclear. Herein, we used hydrogen peroxide (H2O2) to generate the reactive metabolite and compared reactive metabolite-induced cytotoxicity between HL-60 cells undergoing granulocytic differentiation and differentiated HL-60 cells. In addition, we examined the role of oxidative stress in this type of cytotoxicity. The reactive metabolite of clozapine induced rapid cytotoxicity in HL-60 cells undergoing granulocytic differentiation, but not in differentiated HL-60 cells, with the metabolite exhibiting more potent cytotoxicity than clozapine. No cytotoxicity was observed following incubation with olanzapine, a structural analog of clozapine, even after exposure of the drug to H2O2. The reactive metabolite of clozapine decreased the levels of reduced glutathione, while addition of reduced glutathione attenuated the reactive metabolite-induced cytotoxicity. These findings indicate that glutathione metabolism plays a role in the hematopoietic toxicity induced by the reactive metabolite of clozapine. Oxidative stress may potentially increase susceptibility to the hematopoietic toxicity induced by the reactive metabolite of clozapine.

Subcapsular hepatic hematoma as a complicating cardiac surgery.

An 80-year-old woman was hospitalized for aortic valve insufficiency, paroxysmal atrial fibrillation, and ascending aortic aneurysm. She underwent aortic valve replacement, pulmonary vein isolation, left atrium appendectomy, and ascending aorta replacement. She developed a subcapsular hepatic hematoma during the surgery. The patient was managed conservatively and discharged successfully.

Survey of chemotherapy-induced nausea and vomiting in patients with urothelial carcinoma.

Chemotherapy-induced nausea and vomiting (CINV) can cause anorexia, weight loss and deterioration of patient quality of life. It is one of the most unpleasant adverse effects of chemotherapy treatment regimens. For the optimal treatment of gastrointestinal symptoms during urothelial carcinoma chemotherapy, the present study investigated the association between gastrointestinal symptoms and therapeutic effects of gemcitabine plus platinum [cisplatin (GC) or carboplatin (GCa)] therapies. The incidence and frequency of nausea/vomiting with GC split therapy (gemcitabine, 1,000 mg/m2 on days 1 and 8; split-dose cisplatin, 35 mg/m2 on days 1 and 8; 21-day schedule) and GCa therapy [gemcitabine, 750-1,000 mg/m2 on days 1, 8 and 15; carboplatin, area under the blood concentration-time curve=5 mg min/ml (Calvert formula) on day 2; 28-day schedule] were lower compared with those of GC therapy (gemcitabine, 1,000 mg/m2 on days 1, 8 and 15; single-dose cisplatin 70 mg/m2 on day 2; 28-day schedule). However, no differences in therapeutic outcomes were observed among therapies. GCa therapy, regardless of renal function, and GC split therapy demonstrated significant increases compared with GC therapy in alleviating gastrointestinal symptoms associated with cancer chemotherapy in patients with urothelial carcinoma. Overall, these results suggested that split-dose cisplatin administration or the use of carboplatin instead of cisplatin may be useful in patients who experience CINV without compromising treatment effectiveness.

[Endovascular Therapy for Kinking of an Open Stent Graft after Stanford Type A Acute Aortic Dissection Repair:Report of a Case].

This is the case of 50s female with Stanford type A acute aortic dissection who underwent emergent total arch replacement. The aortic arch was transected just distal to the left subclavian artery, followed by the insertion of J Graft Frozenix into the descending aorta. No blood pressure gradient was observed between the radial and femoral arteries immediately after the operation. Nevertheless, intermittent claudication was observed after a week. Ankle-brachial index( ABI) measurement was calculated at 0.7 in both legs. Computed tomography (CT) revealed a kinking of the non-stented part of the endograft. Subsequently, thoracic endovascular aortic repair( TEVAR) was performed. As a result, ABI measurement normalized and lower limb pain disappeared. Three years after, CT showed that the endograft expanded satisfactorily. In deployment of J Graft Frozenix, the non-stented part should be kept as short as possible. For kinking, TEVAR should be considered the initial treatment option.

Thoracic endovascular aortic repair of a ruptured acute type B aortic dissection presenting with right hemothorax: a case report and review of the literature.

Ruptured acute type B aortic dissection is a life-threatening condition with a high mortality rate. Right hemothorax secondary to this condition is extremely rare. Herein, we report a successful treatment of a ruptured acute type B aortic dissection via thoracic endovascular aortic repair in a 45-year-old man who initially presented with right hemothorax. Contrast-enhanced computed tomography confirmed massive right hemothorax and acute type B aortic dissection in which the primary entry was located just below the left subclavian artery. Moreover, a possible rupture site in the descending aorta at the level of Th6 was identified. We then performed an endovascular aortic repair with left subclavian artery open surgical debranching. His postoperative course was uneventful. The patient did not have any complications at a 6-month follow-up.

Multiple nicotinic acetylcholine receptor subtypes regulate social or cognitive behaviors in mice repeatedly administered phencyclidine.

Habitual smoking in patients with schizophrenia (SCZ) is considered to improve their own psychoses or to develop a vulnerability to psychological dependence on (-)-nicotine ([-]-NIC) by stimulating nicotinic acetylcholine receptors (nAChRs) in the central nervous system. In the present study, we investigated whether habitual smoking is due to get therapeutic effect or to psychological dependence and which nAChR subunits are associated with them using mice that were repeatedly administered phencyclidine (PCP: 10 mg/kg/day, s.c. for 14 days) as SCZ-like model mice. Mice that were repeatedly administered PCP showed impairments in social or cognitive behaviors; decreased expression of α7 and/or α4 nAChR subunits in the prefrontal cortex (PFC); and increased expression of α7, α4, and ß2 nAChR subunits in the nucleus accumbens (NAc). These changes were attenuated by repeated administration of (-)-NIC. The attenuating effects on behavioral impairments were prevented by a selective α7 nAChR antagonist and a selective α4ß2 nAChR antagonist. At non- or weak effective dose by themselves, co-administration of (-)-NIC (0.03 mg/kg) and risperidone (0.03 mg/kg) showed synergistic effects on behavioral impairments in PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC in the PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC and attenuating effect on haloperidol-induced catalepsy in the PCP-administered mice. Our findings suggest that habitual smoking in SCZ might be attributed to get therapeutic and reduce side effects mediated by α7 and α4ß2 nAChR activation by (-)-NIC.

Involvement of nicotinic acetylcholine receptors in behavioral abnormalities and psychological dependence in schizophrenia-like model mice.

The smoking incentive in patients with schizophrenia (SCZ) depends on stimulation of nicotinic acetylcholine receptors (nAChRs) in the central nervous system. To detect potential predictor genes for nicotine responses in SCZ, we explored common factor using research data in human and animal samples. In lymphoblastoid cell lines from SCZ, the mRNA expression level of α7 nAChR subunit was decreased. In SCZ-like model mice of phencyclidine (PCP; 10 mg/kg/day, subcutaneously for 14 days)-administered mice, the mRNA expression level of α7 nAChR subunit and protein expression level of α7 or α4 nAChR subunit were significantly decreased in the prefrontal cortex during PCP withdrawal. Protein, but not mRNA, expression levels of α7, α4, and ß2 nAChR subunits were significantly increased in the nucleus accumbens. Acute (-)-nicotine [(-)-NIC: 0.3 mg/kg, s.c.] treatment attenuated impairments of social behaviors and visual recognition memory. These effects of (-)-NIC were completely blocked by both methyllycaconitine, a selective α7 nAChR antagonist, and dihydro-ß-erythroidine (DHßE), a selective α4ß2 nAChR antagonist. (-)-NIC did not induce conditioned place preference, but enhanced sensitivity to methamphetamine-induced hyperactivity. These findings suggest that α7 nAChR is associated with development of disease and is implicated in the therapeutic effect of nicotine in SCZ. The smoking incentive in SCZ might be attributed to treat their own symptoms, rather than a result of (-)-NIC dependence, by stimulating α7 and/or α4ß2 nAChRs.

[Effect of Non-alcoholic Beverage Intake in Children on Alcoholic Beverage Drinking and Smoking].

　The early intake of alcohol and/or nicotine in childhood or adolescence is one of risk factors for alcohol and/or nicotine dependence in adult. Recently, non-alcoholic beverages with less than 0.00% alcohol are on sale for adults as substitutes for alcoholic beverages without strict legal limitations. However, it is unclear whether non-alcoholic beverages could be a risk factor in drinking and smoking in childhood or adolescence. The purpose of the present survey is to clarify the effect of non-alcoholic beverage intake in children on alcoholic beverage drinking and smoking. We examined as follows: the experience of alcoholic or non-alcoholic beverage intake, and of smoking in elementary school pupils and/or their family members, and interest in or motivation for drinking and smoking in the pupils. As a result, the percentage of alcoholic or non-alcoholic beverage intake, and of smoking in the pupils were 16.8% or 21.9%, and 0.3%, respectively. The number of family members took the alcoholic or non-alcoholic beverage was larger in the pupils took it compared to the pupils did not take it. In the pupils who experienced the non-alcoholic beverage intake, interest in or motivation for drinking alcoholic beverages and/or smoking is higher than in those who did not. These findings indicate that non-alcoholic beverage intake is related to drinking and smoking. We will introduce drug abuse prevention education on the risk of drug dependence among childhood or adolescents based on the findings of this survey.

Retrospective survey and evaluation of first-line antibiotics for chemotherapy-induced febrile neutropenia in patients with acute myeloid leukemia.

Patients with acute leukemia are susceptible to chemotherapy-induced severe myelosuppression, and therefore are at a high risk for febrile neutropenia (FN). In such cases, the use of broad-spectrum antibiotics such as fourth-generation cephalosporins and carbapenems is recommended as first-line antimicrobial treatment; however, the effectiveness of these agents in patients with acute myeloid leukemia (AML) has not been investigated in detail. We retrospectively examined and evaluated the effectiveness of first-line antibiotic treatment regimens for chemotherapy-induced FN in patients with AML in Japanese Red Cross Nagoya Daiichi Hospital. The evaluated first-line treatment regimens were as follows: cefozopran (CZOP) + amikacin (AMK) in 38 cases, cefepime (CFPM) alone in 2 cases, CFPM + AMK in 2 cases, piperacillin (PIPC) + AMK in 2 cases, and CZOP alone in 1 case. Additionally, prophylactic antifungal agents were administered in all cases. Markedly effective, effective, moderately effective, and ineffective responses occurred in 31.1%, 8.9%, 8.9%, and 51.1%, respectively, of the treated cases. The response rate, defined as the combination of markedly effective and effective outcomes, was 40.0%. In 11 cases, impairment of renal functions were observed, and they were associated with combination treatments including AMK; nine of these were associated with a glycopeptide. The combination of CZOP with AMK (84.4%) was the most commonly used first-line treatment for FN in patients with AML; carbapenem or tazobactam/PIPC has never been used for treatment of such cases. Our findings demonstrate that fourth-generation cephems will be an effective first-line treatment for FN in patients with AML in our hospital.

An Analysis of Behavioral and Genetic Risk Factors for Chemotherapy-Induced Nausea and Vomiting in Japanese Subjects.

There are individual differences in the frequency of chemotherapy-induced nausea and vomiting (CINV) in cancer patients. We investigated the individual variability in susceptibility to CINV with focus on both behavioral factors and genetic factors in Japanese cancer patients. We performed a prospective study to investigate the association between patient attributes (backgrounds and habits as well as gene polymorphisms) and anorexia, nausea, or vomiting in 55 Japanese cancer patients undergoing chemotherapy at Nagoya University Hospital. We found that gender (female), use of non-steroidal anti-inflammatory drugs, susceptibility to motion sickness, and anxiety were associated with the frequency of CINV. Gene polymorphisms of rs1076560 (dopamine D2 receptor gene), rs6766410 (serotonin 5-HT3C receptor gene) and rs4680 (catechol-O-methyltransferase gene) were also associated. Our data suggest that these attributes may thus be risk factors for CINV. Our results provide novel information that can be used to predict the incidence of CINV in Japanese patients undergoing chemotherapy; this can help provide a substantial improvement in supportive care for patients with different types of cancer.

Association of axitinib plasma exposure and genetic polymorphisms of ABC transporters with axitinib-induced toxicities in patients with renal cell carcinoma.

PURPOSE: Axitinib is a selective tyrosine kinase inhibitor of VEGF receptors, approved for advanced renal cell carcinoma (RCC). Associations between axitinib plasma exposure, genetic polymorphisms of ABC transporters and axitinib-induced toxicities have not been adequately explored. METHODS: Twenty RCC patients treated with axitinib were enrolled in this study. Blood samples were collected 0, 0.5, 1, 2, 4, and 6 h after administration of axitinib on day 1 and at steady state. Plasma concentrations of axitinib were analyzed by UPLC-MS/MS. The ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) genetic polymorphisms were determined by real-time PCR. RESULTS: ABCB1 haplotype was associated with increased dose-adjusted area under the plasma concentration-time curve (AUC) of axitinib at steady state. The incidence of fatigue during therapy was associated with high AUC0-6 of axitinib (P = 0.013). The treatment period without discontinuation or dose reduction due to adverse events in patients with high AUC0-6 of axitinib was significantly shorter than for those with low AUC0-6 (P = 0.024). No significant differences were found in the frequency of adverse events among the ABCG2 genotype and ABCB1 haplotype groups. CONCLUSIONS: Our results have demonstrated that adverse events leading to discontinuation or dose reduction in axitinib were associated with increased axitinib plasma exposure, but not directly with genetic polymorphisms of ABC transporters. Therefore, measurement of steady state axitinib plasma concentrations may be useful in avoiding adverse events in axitinib therapy.

Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells.

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100µM) and doxorubicin (0.2µM) decreased the cell survival rate, but olanzapine (1-100µM) did not. Under granulocytic differentiation for 5days, clozapine, even at a concentration of 25µM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation.

Genotype frequencies for polymorphisms related to chemotherapy-induced nausea and vomiting in a Japanese population.

BACKGROUND: Genotype frequencies for chemotherapy-induced nausea and vomiting (CINV)-related polymorphisms have not yet been reported for Japanese subjects. METHODS: We analyzed 10 genotype frequencies for following polymorphisms associated with the development of CINV: serotonin 5-HT3 receptors (HTR3); neurokinin-1 receptors (Tachykinin-1 receptors, TACR1); dopamine D2 receptors (DRD2); and catechol-O-methyltransferase (COMT). RESULTS: All polymorphisms were successfully genotyped in 200 Japanese subjects and were in Hardy-Weinberg equilibrium. Almost all genotype frequencies were similar to those in the HapMap database or in the previous reports, while frequencies for the Y192H polymorphism in TACR1 were different in Japanese subjects from those in a previous report. CONCLUSIONS: The present study revealed genotype frequencies for polymorphisms, which were related to the appearance of CINV in Japanese subjects. Individual therapy based on genotype variations for each race is needed to allow cancer patients to undergo chemotherapy more safely and to understand etiology of CINV.

A retrospective study to identify risk factors for somnolence and dizziness in patients treated with pregabalin.

BACKGROUND: Pregabalin is a therapeutic drug for neuropathic pain that is associated with somnolence and dizziness. These adverse events are often experienced shortly after initiating pregabalin, and may lead to treatment discontinuation. The purpose of this study was to explore factors that influence the incidence of somnolence and dizziness induced by pregabalin, and to identify patients at higher risk of adverse events. METHODS: A retrospective analysis was conducted of patient characteristics (age, gender, renal function, initial daily dose of pregabalin, co-administration of strong opioids and hypnotics) and the incidence of somnolence and dizziness during the first week of pregabalin treatment. An electronic chart was used to collect data from 204 inpatients prescribed pregabalin at Nagoya University Hospital from June 2011 to November 2012. RESULTS: Among 36 patients who regularly received strong opioids, 18 (50.0 %) reported somnolence or dizziness during the first week of pregabalin treatment. The remaining 168 patients did not regularly receive strong opioids, and 25 (14.9 %) had an adverse event. In multivariate analysis, age (≧65 years, adjusted odds ratio: 2.507, 95 % CI: 1.164-5.397, p = 0.019) and regular co-administration of strong opioids (adjusted odds ratio: 5.507, 95 % CI: 2.460-12.328, p < 0.001) correlated with somnolence or dizziness. CONCLUSIONS: These data suggest that age (≧65 years) and co-administration of strong opioids are risk factors for somnolence or dizziness during pregabalin treatment for neuropathic pain. More careful dose titration is recommended for elderly patients and those receiving concomitant strong opioids.

A fatal case of infantile malignant osteopetrosis complicated by pulmonary arterial hypertension after hematopoietic stem cell transplantation.

Infantile malignant osteopetrosis (IMO) is a rare and fatal autosomal recessive condition characterized by a generalized increased in bone density. Hematopoietic stem cell transplantation (HSCT) is the only effective and rational therapy with achieving long-term disease-free survival. However, complications with HSCT for IMO remain unclear. Here we describe a male infant with IMO, carrying two novel mutations in the T-cell immune regulator 1 (TCIRG1) gene. The TCIRG1 gene encodes the a3 subunit of vacuolar H(+)-ATPase that plays an essential role in the resorptive function of osteoclasts. Direct sequencing of all 20 exons of the TCIRG1 gene revealed a single nucleotide change in exon 11 (c1305 G > T), which causes the substitution of Asp (GAT) for Glu (GAG) at position 435, and a two-nucleotide deletion in exon 16 (c1952-1953 del CA), causing a frame-shift mutation. However, the functional consequence of each mutation remains to be determined. Allogeneic HSCT was performed in the patient at the age of nine months. Donor engraftment was achieved, and abnormal bone metabolism and extramedullary hematopoiesis were corrected. Graft-versus-host disease was mild (grade I). However, the patient died of complication of pulmonary arterial hypertension at seven months after the HSCT. Postmortem examination revealed prominent vascular wall thickening of the pulmonary artery and macrophage infiltration to alveoli. It should be noted that a patient with IMO has a risk for pulmonary arterial hypertension, and the evaluation of pulmonary arterial flow should be included in the assessment of each patient with IMO even after HSCT.

Simultaneous surgical correction of pectus excavatum and cardiac disease in two adults.

Thoracic reconstruction in patients with pectus excavatum with concomitant cardiac or aortic surgery poses a major clinical challenge. The report describes two cases of adult patients undergoing simultaneous surgical correction of cardiac disease and sternal deformity using one of two different techniques: a sterno-turnover method preserving the rectus muscle or a sternal elevation method with A-O plates.

The risk factors of severe acute kidney injury induced by cisplatin.

OBJECTIVES: We reported that the KDIGO (Kidney Disease: Improving Global Outcomes) criteria could stratify the risk of mortality in acute kidney injury (AKI) caused by cisplatin. The purpose of this study was to investigate risk factors of severe cisplatin-induced AKI (CIA). METHODS: From January 2006 to December 2012, we identified Japanese cancer patients who were treated with cisplatin as a first-line chemotherapy at Nagoya University Hospital. Serum creatinine levels were used to define CIA. RESULTS: We evaluated 1,721 patients treated with cisplatin. In multivariable analysis, cisplatin dosages/m(2) [odds ratio (OR) 1.019] or diagnosis of cancer stage 4 (OR 1.797) were risk factors of moderate CIA. History of diabetes mellitus (OR 3.454), history of cardiovascular disease (OR 3.612) or diagnosis of cancer stage 4 (OR 2.610) were risk factors of severe CIA. CONCLUSIONS: Diabetes mellitus, cardiovascular disease and advanced cancer increased the risk of severe CIA. As severe CIA shortens the survival period, we should consider whether the use of cisplatin benefits these patients.

Fasudil is a superior vasodilator for the internal thoracic artery in coronary surgery.

BACKGROUND: The internal thoracic artery (ITA) is a very useful conduit for coronary artery bypass artery (CABG), with excellent long-term patency. With the purpose to dilate the ITA graft and increase graft free flow (GFF) intraoperatively, we evaluated the usefulness of intraluminal injection of fasudil, a Rho-kinase inhibitor, in comparison to the conventional graft dilating agent, papaverine. METHODS: Between June 2011 and January 2012, 30 patients with ischemic heart disease who underwent isolated CABG using ITA were enrolled. The patients were randomly assigned to 2 groups: the fasudil group (n = 15) in which fasudil solution 0.9 mg/dL was injected into the ITA, and the papaverine group (n = 15) in which papaverine solution (0.4 mg/mL) mixed with heparinized blood was used. Outcome measures were left ITA GFF, heart rate, and mean blood pressure during flow measurements, and histopathologic examination of the ITA. RESULTS: In the fasudil group, GFF increased significantly (p < 0.01) from 19.7 ± 15.2 mL/minute at baseline to 66.9 ± 31.7 mL/minute after fasudil injection. In the papaverine group, GFF increased significantly (p < 0.01) from 22.9 ± 17.3 mL/minute at baseline to 44.8 ± 26.7 mL/minute after papaverine injection. Blood pressure and heart rate did not change significantly after drug injection in both groups. The GFF was significantly higher (p = 0.038) in fasudil-treated ITA than in papaverine-treated ITA. Histopathologically, the diameter of the ITA was markedly increased after fasudil injection. Elastica van Gieson staining showed that the multiple elastic lamellae structure was intact. CONCLUSIONS: Fasudil exhibited very potent vasodilatory effect on the ITA compared with conventional papaverine resulting in increased GFF. This agent is a useful graft dilating agent.

A child with Epstein-Barr Virus-associated hemophagocytic lymphohistiocytosis complicated by coronary artery lesion mimicking Kawasaki disease.

There is considerable overlap between hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) in terms of aberrant immune response though the etiology of KD remains unknown. We present a case fulfilling the criteria of both HLH and KD complicated by coronary artery dilatation: HLH was confirmed to be triggered by Epstein-Barr virus. This case alarms us the possibility that even patients with HLH may be complicated by coronary artery lesion, which is one of the hallmarks of KD. We would like to draw attention that if features of KD become apparent in patients with HLH, echocardiographic examinations should be performed not to miss coronary artery lesion.