Transfer of Zolpidem to Cord Blood and Breast Milk: A Case Series Evaluating Zolpidem Serum Levels and Outcomes in Birth and Suckling Infants.

Background: Zolpidem is used for insomnia in pregnant and lactating women. Although zolpidem has been shown to cross the placenta and to be secreted into breast milk, it would not be expected to cause any adverse effects in newborn and breastfed infants. However, there is no relevant information on serum zolpidem levels in the newborn and breastfed infant from zolpidem-treated mother. This study aimed to present the outcomes of zolpidem exposure into infant who was delivered or breastfed by a zolpidem-treated mother. Methods: In this case series, zolpidem-treated pregnant women were recruited between September 2019 and April 2022, and maternal serum, cord blood, breast milk, and infants' serum were collected, and the zolpidem concentration in each sample was evaluated. Childbirth outcomes, including 1-month health care checkup, were also evaluated. Results: Three cases were recruited during investigation period. No spontaneous abortion or preterm live deliveries occurred. Oxygen intervention was required in one term infant, but the findings resolved on postpartum day 1. No medical intervention was required in other three infants. Zolpidem was not detected in infants' serum even after breastfeeding. There are no abnormal developmental findings in any of the infants in their 1-month health checkups. Conclusions: Zolpidem transferred into fetal circulation in utero and breast milk, however no harmful findings existed in infants during pregnancy and lactation. Exposure doses through breastfeeding is small, which may be a cause of rare detection from the infants' serum. Due to the limited number of cases, larger studies and integrated review are needed.

Trazodone Levels in Maternal Serum, Cord Blood, Breast Milk, and Neonatal Serum.

Background: Trazodone is used to treat anxiety disorder, insomnia, and sleep disorders, which occur in ∼15% of pregnant and lactating women. However, pharmacokinetic information on the transfer of trazodone and its active metabolite, 1-m-chlorophenylpiperazine (mCPP), across the placenta or into breast milk is limited. In this study, we describe the pharmacokinetic profile of trazodone and mCPP concentrations in maternal and neonatal blood and breast milk. Case Presentation: A 44-year-old female received oral trazodone 50 mg once daily during pregnancy (28-38 gestational weeks) and lactation, along with etizolam for anxiety disorder with depressive syndrome. A male infant weighing 2,918 g was born at 38 weeks of gestation. Because of persistent respiratory disturbance, oxygenation was initiated immediately after birth, and the infant was admitted in the neonatal intensive care unit for 5 days. No pulmonary dysfunction or birth defects were detected, and no medication and circulatory support were needed during admission. Trazodone and mCPP concentrations in cord blood at 7.4 hours after maternal dosing were 267.6 and 22.8 ng/mL, respectively, which were comparable with maternal serum levels. The trazodone and mCPP concentrations in breast milk collected 7.2 hours after maternal dosing were 50.2 and 3.2 ng/mL, respectively. The infant developed normally, with no drug-related adverse effects at the 1-, 3-, and 6-month postpartum checkups. Conclusion: Trazodone and its active metabolite were transferred into placenta and breast milk. However, their effects in utero could not be clarified. Further studies are warranted to assess the safety of trazodone in fetuses and breastfed infants.

Brotizolam During Pregnancy and Lactation: Brotizolam Levels in Maternal Serum, Cord Blood, Breast Milk, and Neonatal Serum.

Background: Brotizolam is a sedative-hypnotic thienotriazolodiazepine that is a benzodiazepine analog used for debilitating insomnia. Anxiety, depression, and sleep disorders occur in about 15% of pregnant and lactating women; however, no studies have examined brotizolam transfer across the placenta or its excretion into breast milk. In this case report, we assessed brotizolam concentrations in maternal and neonatal blood, cord blood, and breast milk. Materials and Methods: Brotizolam concentrations in maternal serum, breast milk, cord blood, and neonatal serum were measured while the mother was taking oral brotizolam 0.25 mg once daily. Case Report: A 28-year-old woman diagnosed with bipolar II disorder received brotizolam during pregnancy (28-40 weeks' gestational age) and lactation, along with sertraline, alprazolam, and trazodone. A male infant weighing 3,412 g was born at 40 weeks of gestation. Neonatal abstinence syndrome manifested as fever, limb tremor, and central cyanosis, requiring oxygenation and intravenous phenobarbital administration for 4 days. No pulmonary dysfunction or birth defects were detected. Brotizolam concentrations in maternal serum at 7.0 and 14.0 hours after maternal dosing were 0.51 and 0.22 ng/mL, respectively. Brotizolam was not detected in cord blood or infant serum 9.2 hours after maternal dosing. The brotizolam concentration in breast milk collected 7.1 hours after maternal dosing was 0.12 ng/mL. The infant developed normally, with no drug-related adverse effects at the 1-, 3-, or 6-month postpartum checkups. Conclusion: Brotizolam transfer into placenta and breast milk was negligible. Further studies should assess the safety of brotizolam in fetuses and breastfed infants.

Suppression of liver Apo E secretion leads to HDL/cholesterol immaturity in rats administered ethinylestradiol.

Ethinylestradiol (EE), a main component of the combined oral contraceptive pill, is associated with an increased risk of arterial diseases. However, the toxicity mechanism of EE is poorly understood. In this study, we found that the exposure to EE reduced the serum apolipoprotein E (Apo E) level and high-density lipoprotein (HDL)/cholesterol concentration in adult female rats. Diethylstilbestrol showed the same effects and both reductions were suppressed by coadministration of tamoxifen (TAM). Liver perfusion experiments revealed that the secretion rate of Apo E from the liver was significantly reduced. It is concluded that EE damages the maturation of HDL/cholesterol by delaying Apo E secretion from the liver, and this may lead to an increased risk of arterial diseases, such as atheromas.

Proposal of Comprehensive Model of Teaching Basic Nursing Skills Under Goal-Based Scenario Theory.

The purpose of this study is to design and develop a comprehensive model of teaching basic nursing skills on GBS theory and Four-Stage Performance Cycle. We designed a basic nursing skill program that consists of three courses: basic, application and multi-tasking. The program will be offered as blended study, utilizing e-learning.

[Severe Japanese Spotted Fever Complicated by Acute Respiratory Failure in Kobe City].

We report herein on a case of severe Japanese spotted fever complicated by acute respiratory failure in Kobe City. A 70-year-old female presenting with general malaise and systematic erythema was admitted to our hospital in June, 2013. From her history and physical examination, she was found to be suffering from scleroderma and mild interstitial pneumonia. From admission, the patient was noted to have a fever of 39 degrees C accompanied by relative bradycardia. Physical examination revealed a black eschar on her right leg, making us suspect rickettsial infection since Kobe City is not an area predisposed to Japanese spotted fever. Three days after admission, her condition worsened and treatment with minocycline and levofloxacin was initiated in accordance with the treatment protocol for Japanese spotted fever. The following day, the patient developed acute respiratory distress syndrome (ARDS) and was put on a respirator. She gradually recovered with the antibiotic treatment and was discharged from the hospital 23 days after admission. The diagnosis of Japanese spotted fever was confirmed by conducting a polymerase chain reaction test on the eschar. Japanese spotted fever is noted to occur in any place other than Kobe City. Late diagnoses may result in aggravated cases of Japanese spotted fever, with the possibility of developing ARDS as a complication.

Retrospective analysis of capecitabine and oxaliplatin (XELOX) plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer.

XELOX plus bevacizumab is an effective treatment strategy and has a manageable tolerability profile when administered to Japanese patients with metastatic colorectal cancer (mCRC). In this study, we retrospectively reviewed cases in which XELOX plus bevacizumab were administered in order to evaluate its efficacy and safety in clinical practice. In total, 40 patients with mCRC who presented at Fuchu Hospital received XELOX plus bevacizumab as a first-line treatment between September, 2009 and April, 2012. Eligible patients had histologically confirmed mCRC. XELOX consisted of a 2-h intravenous infusion of oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 1,000 mg/m2 twice daily for 2 weeks of a 3-week cycle. Overall survival (OS) and survival benefit were analyzed when patients continued with XELOX plus bevacizumab beyond disease progression. The median progression-free survival (PFS) was 290 days [95% confidence interval (CI): 222-409 days] and the median OS was 816 days (95% CI: 490 days-not calculated). The response rate (RR; complete plus partial response) was 67.5%, and the disease control rate (RR plus stable disease) was 90%. The most common adverse events observed following administration of XELOX plus bevacizumab were neurosensory toxicity (82.5%), anorexia (50%), hypertension (45%) and a decrease in the platelet count (40%). The most common grade 3/4 adverse events were neurosensory toxicity (15%) and fatigue (15%). In conclusion, XELOX plus bevacizumab may be considered a routine first-line treatment option for patients with mCRC. Notably, the combination of capecitabine and bevacizumab was safe with an acceptable toxicity profile and induced a significant rate of disease control.

Oligomannose-coated liposome as a novel adjuvant for the induction of cellular immune responses to control disease status.

Professional phagocytic cells, such as dendritic cells, are mainly responsible for phagocytosis, antigen presentation, and cytokine secretion, which induce subsequent activation of T cell-mediated immunity. Thus, strategies that deliver antigens and stimulatory signals to the cells have significant implications for vaccine design. In this paper, we summarize the potential for liposomes coated with the neoglycolipids containing oligomannose residues (OMLs) as a novel adjuvant for induction of Th1 immune responses and CTLs specific for the encased antigen. OMLs preferentially take up peripheral phagocytic cells. In response to OML uptake, the cells secrete IL-12 selectively, enhance the expression of costimulatory molecules, and migrate into lymphoid tissues from peripheral tissues. OMLs also have the ability to deliver encapsulated protein antigens to the MHC class I and class II pathways to generate antigen-specific CTLs and Th1 cells, respectively, and lipid antigen to CD1d to activate NKT cells. Since administration of OML-based vaccines can eliminate an established tumor, inhibit elevation of the serum IgE level, and prevent progression of protozoan infections in several murine, human, and bovine models, OML-based vaccines have revealed their potential for clinical use in vaccination for a variety of diseases in which CTLs and/or Th1 cells act as effector cells.

Effective stimulation of invariant natural killer T cells by oligomannose-coated liposomes.

vThe in vitro and in vivo response of invariant natural killer T (iNKT) cells to alpha-galactosylceramide (αGC)-containing oligomannose-coated liposomes (αGC-OMLs) was examined to determine whether selective delivery of αGC to dendritic cells (DCs) and subsequent activation of iNKT cells could be achieved. Splenocytes stimulated with αGC-OMLs produced higher levels of IFN-γ compared to those stimulated with bare liposomes without an oligomannose coating (αGC-BLs). The ratio of IFN-γ/IL-4 produced from αGC-OML-treated splenocytes was higher than those produced from αGC-BL- and soluble αGC-treated cells. Depletion of CD3(+)-, DX5(+)- or CD11c(+)-cells from splenocytes almost completely abolished the αGC-OML-stimulated cytokine production, suggesting that both NKT cells and DCs were involved in the response to αGC-OML stimulation. In addition, αGC-OMLs were incorporated into both splenic and bone marrow-derived DCs more effectively than αGC-BLs. iNKT cells stimulated with DCs with ingested αGC-OMLs produced much higher levels of IFN-γ than those stimulated with DCs containing αGC-BLs or soluble αGC. Systemic administration of αGC-OMLs led to modification of the kinetics of IFN-γ production in vivo and also resulted in predominant production of IFN-γ from splenocytes over IL-4. In addition, iNKT cells proliferated and expanded upon in vivo activation of the cells with αGC-OMLs much more extensively than with αGC-BLs or soluble αGC. Collectively, our results suggest that αGC-OMLs can be used as a preferential delivery system for lipid antigens to DCs to activate iNKT cells in vivo and ex vivo.

[Our experience of eribulin treatment in advanced breast cancer].

The clinical outcomes, including adverse events, in 40 advanced breast cancer patients treated with eribulin were analyzed to confirm the effectiveness and safety of this treatment. The objective response rate (ORR) in patients was 35.0%. The median overall survival and time to treatment failure (TTF) in these patients was 479 and 63 days, respectively. Cases wherein eribulin was used as early-line treatment experienced significantly longer TTF compared to the cases wherein eribulin was used as late-line treatment; however, there was no difference in this value according to the breast cancer subtype. Moreover, subtype analysis revealed no significant difference in adverse events. We observed no difference in the benefit or tolerability of eribulin treatment among different breast cancer subtypes. However, our results suggest that a significant therapeutic effect can be expected when using eribulin as early-line treatment.

[Effectiveness of eribulin chemotherapy for squamous cell carcinoma of the breast].

The patient was a 40-year-old woman who was aware of a tumor in her left breast that was gradually increasing in size. Ultrasonography revealed a hypoechoic mass with a skin cyst, approximately 3 cm in size, in the C area of the left breast. Core needle biopsy indicated estrogen receptor (ER) -negative, progesterone receptor (PR) -negative, and human epidermal growth factor receptor 2 (HER2) -negative squamous cell carcinoma. Overall examination did not indicate distant metastasis. A diagnosis of T4bN2aM0, stage IIIB triple-negative left breast cancer was made. Eribulin was administered at a dose of 1.4 mg/m2. The effect of eribulin was considered to be long-term stable disease( long-term SD). The patient did not experience severe adverse events during treatment. After 24 weeks of eribulin treatment, mastectomy of the left breast with axillary lymph node dissection was performed. At present, 1 year after surgery, the patient is alive with no recurrence. We conclude that eribulin chemotherapy is useful for the treatment of patients with squamous cell carcinoma of the breast.

[Case of a patient with inflammatory breast cancer who responded to preoperative chemotherapy with paclitaxel plus bevacizumab and could subsequently undergo surgery].

A 58-year-old woman observed swelling in her left breast a few weeks prior to presentation. Rigidity in the D area, breast warmth, swelling, and a peau d'orange appearance in the whole left breast was observed. She was diagnosed with inflammatory breast cancer (luminal A type) T4dN2M0, Stage IIIB. The patient underwent primary systemic therapy with 7 courses of FEC. Following FEC treatment, the disease was stable. We subsequently administered 4 courses of bevacizumab plus paclitaxel combination therapy. The patient exhibited a partial response to FEC chemotherapy. Thereafter, a left mastectomy with level II axillary lymph node dissection was performed. At present, 1 year after surgery, the patient is alive with no recurrence. We conclude that the combination therapy of bevacizumab plus paclitaxel is a useful treatment for inflammatory breast cancer.

Development of peritoneal macrophage along a dendritic cell lineage in response to uptake of oligomannose-coated liposomes.

In this study, we investigate the potential of peritoneal macrophages to differentiate into dendritic cell (DCs) in response to preferential uptake of oligomannose-coated liposomes (OMLs). About 30% of peritoneal cells (PECs) preferentially took up OMLs that were administered into the peritoneal cavity. The OML-ingesting cells expressed CD11b and F4/80, but lacked CD11c expression, indicating that the OML-ingesting PECs with a CD11b(high)CD11c(-) phenotype are resident peritoneal macrophages. During in vitro cultivation, CD11c(+) cells arose among the PECs with ingested OMLs. CD11c(+) cells also developed among enriched peritoneal CD11b(high)CD11(-) cells from OML-treated mice, and the resulting CD11c(+) cells expressed co-stimulatory molecules and MHC class II. In addition, OML-ingesting CD11b(high)CD11c(+) cells were found in spleen after the enriched peritoneal macrophages with ingested OMLs were transplanted in the peritoneal cavity of mice. These results show that a fraction of peritoneal macrophages can differentiate into mature DCs following uptake of OMLs.

Targeting with oligomannose-coated liposomes promotes maturation and splenic trafficking of dendritic cells in the peritoneal cavity.

In previous studies, we have shown that oligomannose-coated liposomes (OMLs) have a strong adjuvant effect in inducing T-helper 1 (Th1) immune responses and cytotoxic T cells specific for the encased antigen. In the present study, we demonstrate that preferential uptake of OMLs by DCs and subsequent DC maturation and splenic trafficking may be correlated with the adjuvant effect of OMLs. About 3% of resting murine peritoneal cells are CD11b(dull)CD11c(+) cells, which express MHC class II and CD86, and about 30% are CD11b(high)CD11c(-) cells, which express F4/80 and CD14. This indicates that these cells are resident peritoneal DCs and monocytes/macrophages, respectively. Both types of cells rapidly took up OMLs in the peritoneal cavity, but only CD11b(dull)CD11c(+) cells produced interleukin (IL)-12 in response to OML uptake. IL-6 was not produced by either type of cells. The expression levels of CD205 and CCR7, which are markers of cell maturity in murine DCs, were upregulated in CD11b(dull)CD11c(+) cells obtained from OML-treated mice. In addition, CD11b(dull)CD11c(+) cells with ingested OMLs were found in the spleen 18 h after intraperitoneal administration of OMLs. These results indicate that OMLs can be used as a vehicle for delivery of antigens to DCs and as an adjuvant to promote DC maturation, activation, and trafficking into lymphoid organs, thereby eliciting a Th1 immune response.

Anti-allergic potential of oligomannose-coated liposome-entrapped Cry j 1 as immunotherapy for Japanese cedar pollinosis in mice.

Administration of oligomannose-coated liposomes (OMLs) in mice can induce Th1 immune responses against antigens entrapped in the OMLs. In the present study, we investigated the anti-allergic effect of treatment with oligomannose-coated liposomes (OMLs) with entrapped Cry j 1, a major allergen of Japanese cedar pollen (Cry j 1/OMLs), in Balb/c mice sensitized with Cry j 1. Pretreatment of unsensitized mice with Cry j 1/OMLs repressed the elevation of total and allergen-specific IgE levels in sera elicited in response to subsequent sensitization with Cry j 1. Cry j 1-specific IgG1 in sera also decreased in Cry j 1/OML-treated mice, while the levels of Cry j 1-specific IgG2a in these mice significantly increased after sensitization with Cry j 1. In addition, Cry j 1/OML-treated mice showed high IFN-gamma production from spleen cells and low IL-4/IFN-gamma and IL-5/IFN-gamma ratios in response to in vitro stimulation with Cry j 1. These results indicate that allergen-specific Th1 immune responses predominate over Th2 responses and control IgE elevation in Cry j 1/OML-treated mice. The anti-allergic effect of Cry j 1/OML determined by suppression of serum IgE levels was also observed in Cry j 1-presensitized mice after challenge with antigen. Thus, Cry j 1/OMLs may be useful for immunotherapeutic control of allergic reactions to Japanese cedar pollinosis.

Mucosal adjuvant activity of oligomannose-coated liposomes for nasal immunization.

In the present study, we investigated the effectiveness of liposomes coated with a neoglycolipid consisting of mannotriose and dipalmitoylphosphatidylcholine (Man3-DPPE) as an adjuvant for induction of mucosal immunity. Immunization of BALB/c mice with ovalbumin (OVA)-encapsulated Man3-DPPE-coated liposomes (oligomannose-coated liposomes; OMLs) by a nasal route produced high levels of OVA-specific IgG and IgA antibodies in serum of immunized mice 1 week after the last nasal immunization, whereas no significant serum antibody responses were observed in mice that received OVA in uncoated liposomes or OVA alone. Seven weeks after the last nasal immunization, nasal challenge with an excess amount of OVA in mice that had received OVA/OMLs led to an anamnestic response to the antigen that resulted in 5- to 10-fold increases of antigen-specific serum IgG and IgA antibodies. Only mice immunized nasally with OML/OVA secreted antigen-specific secretory IgA in nasal washes and produced interferon-gamma secreting cells in nasopharyngeal-associated lymphoreticular tissue. Taken together, these results show that nasal administration of OMLs induces mucosal and systemic immunity that are specific for the entrapped antigen in the liposomes. Thus, liposomes coated with synthetic neoglycolipids might be useful as adjuvants for induction of mucosal immunity.

Cross-linking of SIGNR1 activates JNK and induces TNF-alpha production in RAW264.7 cells that express SIGNR1.

In this study, we evaluated the signaling ability of SIGNR1 in murine macrophage-like RAW264.7 cells that stably expressed FLAG-tagged SIGNR1 (SIGNR1-FLAG). Cross-linking of SIGNR1-FLAG expressed on the cells by an anti-FLAG antibody induced JNK phosphorylation without induction of phosphorylation of ERK1/2 and p38 MAP kinase, and led to phosphorylations of Src family kinases (SFKs) and Akt. The SIGNR1-FLAG molecules in the cells were found in lipid raft-enriched membrane fractions, and the tyrosine kinases Lyn, Hck, and Fgr co-precipitated with SIGNR1-FLAG in the lipid raft fractions. The antibody-induced JNK phosphorylation was inhibited by inhibitors of SFKs and tyrosine kinases. Furthermore, cross-linking of SIGNR1 led to production of TNF-alpha, and the JNK inhibitor inhibited the antibody-induced TNF-alpha production. These results show that cross-linking of SIGNR1 triggers phosphorylation of SFKs, which leads to activation of the JNK pathway and induction of TNF-alpha production in macrophage-like RAW264.7 cells.

Cooperation of specific ICAM-3 grabbing nonintegrin-related 1 (SIGNR1) and complement receptor type 3 (CR3) in the uptake of oligomannose-coated liposomes by macrophages.

Resident peritoneal macrophages (PEMs) express SIGNR1 on the cell surface as a major mannose receptor. These cells also ingest oligomannose-coated liposomes (OMLs) in an oligomannose-dependent manner following intraperitoneal administration. Therefore, the current study was conducted to investigate the possible role of SIGNR1 in capture of OMLs. Transient expression of several SIGN-related lectins potentially expressed on PEMs in CHO cells revealed that only SIGNR1 contributed to capture of OMLs. When SIGNR1 was introduced into mouse macrophage-like RAW264.7 cells, SIGNR1-expressing RAW (RAW-SIGNR1) cells recognized OMLs under serum-free conditions. OML recognition by RAW-SIGNR1 cells as well as that by PEMs was partially inhibited by an anti-SIGNR1 antibody (ER-TR9) and by mannan, and completely inhibited by EDTA. Interestingly, OML recognition by RAW-SIGNR1 cells was accelerated in the presence of serum, partially inhibited by an anti-complement receptor 3 (CR3) antibody (M1/70), and almost completely inhibited by a combination of ER-TR9 and M1/70. Complete inhibition of OML ingestion by the combination of ER-TR9 and M1/70 was also observed under serum-free conditions, suggesting that SIGNR1 and CR3 cooperate in an additive way in capture of OMLs by macrophage-like RAW cells. Administration of ER-TR9 or M1/70 into the peritoneal cavity led to a significant decrease of OML uptake by PEMs. Therefore, SIGNR1 expressed on macrophages acts as a receptor for recognition of OMLs under physiological conditions.