Analysis of contributory factors to incidents related to medication assistance for residents taking medicines in residential care homes for the elderly: a qualitative interview survey with care home staff.

BACKGROUND: In Japan, staff who are not doctors or nurses can assist the elderly in residential care facilities to take their pre-packaged medicines. Therefore, there is a potential risk of incidents specific to staffs. The aim of this study was to clarify the causes of incidents related to medication assistance by staff in residential care facilities. METHOD: Semi-structured interviews with staff involved in medication incidents in long-term care facilities, focusing on how and why each incident happened, were conducted. The interview covered basic information about the subject and resident, the circumstances under which the incident had occurred, contributing factors, and countermeasures put in place. Verbatim transcripts of the interviews were prepared. Based on thematic analysis, codes and themes were created. RESULTS: Twelve subjects participated in this study. All subjects were staffs (not doctors or nurses) in long-term care facilities. All incidents covered in this study were incidents in which the wrong resident was given the medication. The incidents arose because of "not following procedures", such as lack of "self-check of residents' faces/residents' names/residents' medicine envelopes" or "double-check with other staff" or "using a device for medication intake". Contributory factors were grouped into four categories: individual resident factor items such as "decreased ability to understand their medication" or "refusal to take medicines", individual staff factor items such as "lack of knowledge related to medication" or "mental burden" or "experience in medication assistance", team factor items such as "failure to communicate with other staff", work environment factor items such as "presence of other residents" or "other work besides medication assistance" or "not enough time" or "little understanding of fostering a safety culture at the facility". CONCLUSION: This study identified four categories of contributory factors that may lead to incidents during medication assistance by caregivers for residents of care homes. These findings should be helpful for risk management in residential care facilities where staff usually provide medication assistance. Separation of meal times and medication assistance, and professional review to stagger the timing of administration of residents' medication may be effective in reducing incidents.

Information provision and retrieval by registered salespersons from consumers during over-the-counter drug sales - a questionnaire survey.

BACKGROUND: In Japan, non-pharmacists who are accredited as registered salespersons can sell over-the-counter (OTC) drugs, and they play a very important role in supporting proper OTC drug use by consumers. The purpose of this study was to evaluate information provided to and information collected from consumers, and cooperation with pharmacists during OTC drug sales by registered salespersons, and to clarify their related concerns and behaviors. METHODS: A cross-sectional questionnaire-based survey of 385 registered salespersons working at 56 drugstores throughout Japan was conducted. Based on the questionnaire survey, the frequency of information provision/collection in various categories was determined for the registered salespersons. The relation between concerns of registered salespersons relating to OTC drug sales and the frequency of information provision/collection was examined. The frequency of consultation of registered salespersons with a pharmacist was calculated for registered salespersons with/without in-store pharmacists. The χ-square test or Fisher's exact test was performed to assess the significance of differences. RESULTS: Two hundred and seven registered salespersons (53.7%) responded completely. A greater number of OTC drug purchasers per day was associated with a greater frequency of information provision about "side effects" and information collection about "favorite items" (alcohol, tobacco, health foods, etc.) (p < 0.05). One hundred and thirty-nine (67.2%) participants had concerns about "interactions between OTC drugs and prescription drugs", and these concerns were related to the frequency of information provision/collection (p < 0.05). Regarding the frequency of consultation with a pharmacist, 35 of 46 participants (76.1%) working with pharmacists answered "always" or "usually", whereas only 19 of 161 participants (11.8%) working without full-time pharmacists answered "always" or "usually". More than half of the registered salespersons thought that cooperation with a pharmacist was necessary when they were "asked about concomitant use with prescription drugs" or "told that side effects happened." CONCLUSIONS: The results of this study show that experienced registered salespersons selling OTC drugs are more likely to collect information from consumers and to provide information to consumers. It appears to be important for registered salespersons to cooperate with pharmacists in order to provide and collect appropriate information about concomitant medications.

Questionnaire survey investigation of the present status of dietetic consultation at community pharmacies from the perspectives of registered dietitians and pharmacists.

BACKGROUND: Registered dietitians are rarely employed at community pharmacies in Japan, even though dietetic advice might benefit some patients. OBJECTIVE: To clarify the present status of dietetic consultation provided by registered dietitians and their collaboration with pharmacists in community pharmacies. METHODS: We conducted a cross-sectional questionnaire-based survey of pharmacists and registered dietitians who work in community pharmacies. The surveyed items were: frequency of dietetic consultation, awareness of one's knowledge and ability to conduct dietetic consultation, concerns, pharmacists' recognition of the need for nutritional support at community pharmacies, and cooperation between registered dietitians and pharmacists. RESULTS: Sixty-six registered dietitians, 53 pharmacists in pharmacies with registered dietitians/dietitians, and 110 pharmacists in pharmacies without registered dietitians/dietitians responded. The frequency of dietetic consultation regarding obesity and hypertension was significantly higher for registered dietitians than for pharmacists. The ability to conduct dietetic consultation regarding diseases/conditions such as kidney disease not requiring dialysis, hyperuricemia, gout, obesity and hypertension was also significantly higher for dietitians than pharmacists. More than 70% of pharmacists recognized the importance of nutritional support at community pharmacies, while 56.1% of registered dietitians noted that they were not able to fully utilize their occupational abilities. Registered dietitians were divided into two groups: registered dietitians who answered that they were able to utilize their occupational abilities and those that answered they were not. The former group was more likely to ask pharmacists about patients' medication for dietetic consultation and to be asked to provide dietetic consultation to patients. The latter group was more likely to find difficulty in scheduling dietetic consultation. CONCLUSION: Our results suggest that registered dietitians in community pharmacies have a greater explanatory ability than pharmacists concerning nutritional and dietary management for patients. It may be important for pharmacists to improve cooperation with registered dietitians by providing more opportunities for dietetic consultation.

Medications and fall risk: a case-control study in nursing home residents in Japan.

AIM: Falls are a significant problem for older people, but are few studies of the risk of falling in residents of nursing homes in Japan. We aimed to investigate the risk factors for falls and the association of medication use and falls in nursing home residents in Japan. METHODS: This case-control study reviewed the records of residents of who were ≥ 65 years of age and had fallen in 2012 and an age-, sex-, and facility-matched control group selected from 58 nursing homes in Japan. The odds ratios of potential risk factors and current medications were determined by conditional logistic regression. RESULTS: A total of 1832 residents (916 cases and 916 controls) were included. Falls were significantly associated with an inability to walk without assistance or stand up without assistance, need for toileting assistance, visual impairment, insomnia, and dementia. Current prescription of antithrombotic, nonsteroidal anti-inflammatory, or antiparkinson drugs, muscle relaxants, antiepileptics, antipsychotics, antidepressants, opioids, selective serotonin reuptake inhibitors, and memantine was also associated with increased risk of falling. CONCLUSIONS: Many medications were associated with falls in nursing homes residents in Japan. To prevent these falls, caregivers should provide adequate care, and healthcare professionals should consider switching or dose reduction for these medications.

Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data.

AIM: We encountered a case of fetal toxicity due to ductus arteriosus (DA) constriction in a 36-week pregnant woman who had applied multiple ketoprofen patches. The aim of the present study was to present the case and develop a model to predict quantitatively the fetal toxicity risk of transdermal administration of ketoprofen. METHODS: Human placenta perfusion studies were conducted to estimate transplacental pharmacokinetic (PK) parameters. Using a developed model and these parameters, human fetal plasma concentration profiles of ketoprofen administered to mothers were simulated. Using pregnant rats, DA constriction and fetal plasma drug concentration after ketoprofen administration were measured, fitted to an Emax model, and extrapolated to humans. RESULTS: Transplacental transfer value at the steady state of ketoprofen was 4.82%, which was approximately half that of antipyrine (passive marker). The model and PK parameters predicted almost equivalent mother and fetus drug concentrations at steady state after transdermal ketoprofen administration in humans. Maximum DA constriction and maximum plasma concentration of ketoprofen after administration to rat dams were observed at different times: 4 h and 1 h, respectively. The model accurately described the delay in DA constriction with respect to the fetal ketoprofen concentration profile. The model with effect compartment and the obtained parameters predicted that use of multiple ketoprofen patches could potentially cause severe DA constriction in the human fetus, and that fetal toxicity might persist after ketoprofen discontinuation by the mother, as observed in our case. CONCLUSION: The present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.

Prediction of fetal ductus arteriosus constriction by systemic and local dermatological formulations of NSAIDs based on PK/PD analysis.

AIM: Use of nonsteroidal antiinflammatory drugs (NSAIDs) during the final trimester of pregnancy can cause fetal toxicity, such as ductus arteriosus (DA) constriction. The aim of this study was to predict quantitatively the fetal DA-constrictive effects of NSAIDs after various routes of administration to the mother by means of harmacokinetic/pharmacodynamic (PK/PD) modeling. METHODS: We evaluated acetaminophen, which is a first-line analgesic/antipyretic for the third trimester of pregnancy, together with the following NSAIDs: indometacin, diclofenac, ibuprofen, flurbiprofen, ketoprofen, loxoprofen, felbinac, naproxen, and celecoxib. Drug concentration data obtained in rats and humans were collected from the literature to calculate PK parameters. Next, the PD parameters for DA constriction in rats were obtained by fitting an Emax model to the DA/pulmonary artery (PA) inner diameter ratio after oral administration of each drug to full-term pregnant rats (data taken from the literature) and the unbound plasma concentration in rat dams estimated from the obtained PK parameters. Finally, the inner DA diameter profile after administration of each drug to human mothers was predicted. RESULTS: This PK/PD model predicted continuous fetal DA constriction in third-trimester women after repeated systemic use of nearly all the NSAIDs evaluated. Local dermatological formulations of NSAIDs were also predicted to potentially cause DA constriction. CONCLUSION: These results suggest that risk to the fetus should be carefully considered before administration of NSAIDs (especially systemic formulations, but including dermatological formulations) to women in the third trimester of pregnancy.

Sisters who developed piloerection after administration of milnacipran.

OBJECTIVE: We previously reported the first case of piloerection in a patient receiving milnacipran hydrochloride (MLP). Here, we now present a second case of MLP-induced piloerection. We discuss this effect in terms of α1-adrenoceptor occupancy. CASE SUMMARY: After the first case of MLP-induced piloerection, we monitored occurrence of piloerection in our patients taking MLP. In response to our interview, a 43-year-old woman who had been prescribed MLP by a psychiatrist for depression mentioned that piloerection occurred frequently all over her body, starting soon after initiation of MLP administration (50 mg/day). Although she was concerned at the time, she assumed it might be related to her depression or to coldness in winter. She also mentioned that the incidence of piloerection increased with MLP dose escalation. The piloerection disappeared after several months. Interestingly, the previous patient and the current patient are biological sisters. DISCUSSION: Changes in α1-adrenoceptor occupancy by endogenous norepinephrine (as an index of the risk of piloerection) in the presence of MLP were estimated. The occupancy values increased with MLP dose escalation, in accordance with the patient's report of the phenomenon. other concomitant drugs, such as nortriptyline, had little effect. Since the two patients were sisters, genetic factors might influence the risk of piloerection. CONCLUSION: The incidence of piloerection appeared to increase with MLP dose escalation in this patient, who was the biological sister of the previously reported patient. Clinicians should recognize the possibility of MLP-induced piloerection in view of its potential impact on patients' quality of life and on drug compliance.

Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

OBJECTIVE: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. METHODS: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. RESULTS: The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. CONCLUSIONS: This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

Medications associated with falls in older people: systematic review of publications from a recent 5-year period.

PURPOSE: Falls are an important public health problem in older people. Medication use is considered a risk factor for falls. This study systematically reviewed recent studies to determine the medications that might be associated with the risk of falling in older people. METHODS: We conducted a systematic review of prospective and retrospective studies identified through the MEDLINE and CINAHL databases that quantitatively assessed the contribution of medications to falls risk in participants ≥60 years old published in English between May 2008 and April 2013. RESULTS: The search identified 1,895 articles; 36 articles met the inclusion criteria. Of the 19 studies that investigated the effect of polypharmacy on the risk of falling, six studies reported that the risk of falling increased with polypharmacy. Data on the use of antihypertensive medications including calcium channel blockers, beta-blockers, and angiotensin system blocking medications were collected in 14 studies, with mixed results. Twenty-nine studies reported an association between the risk of falls and psychotropic medications including sedatives and hypnotics, antidepressants, and benzodiazepines. CONCLUSIONS: The use of sedatives and hypnotics and antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors appears to be related with an increased risk of falls. It is not clear if the use of antihypertensive medications is associated with the risk of falls in older people.

First case report of suspected onset of convulsive seizures due to co-administration of valproic acid and tebipenem.

OBJECTIVE: A patient presented with convulsive seizures when sodium valproate (VPA) and tebipenem pivoxil (Orapenem) were co-administered accidentally. The seizures were suspected to be caused by a reduced concentration of VPA in the blood. CASE SUMMARY: A 6-year-old boy (weight: 16 kg, at the start of treatment) began sodium valproate (valproate syrup 5%) treatment for epilepsy in February 2012. At a dose of 350 mg/day, he experienced no convulsive seizures and maintained stable symptoms for the past 9 months. In December, he was prescribed 160 mg/day tebipenem pivoxil by an otolaryngologist for inflammation of the tympanic membrane. He experienced convulsive seizures the day after beginning co-administration. The concentration of VPA in his blood at this time was 30.0 µg/mL, which was lower than the optimal blood concentration. DISCUSSION: Marked reduction of VPA concentration in the blood due to co-administration of VPA and injectable carbapenem antibiotics has been well-documented; however, this is the first report of such an interaction with tebipenem, which is an orally-administered carbapenem antibiotic. Although the mechanism of drug interaction between VPA and carbapenem antibiotics is not fully understood, it is thought that VPA blood concentrations decrease due to production of valproic acid glucuronic acid conjugates (VPA-Gluc) being promoted directly or indirectly by carbapenem antibiotics. When we assessed the patient according to the DIPS system, we calculated a score of +4 (possibility of interaction). CONCLUSIONS: The results suggest that co-administration of oral carbapenem antibiotics and VPA should be avoided.

A Study on Drug Interaction between Warfarin and Capecitabine with Special Reference to the Co-Administered Term or the Discontinuation Term of Capecitabine.

We used the prothrombin time international normalized ratio(PT-INR)to investigate the change in degree and term of warfarin following co-administration and after discontinuation of capecitabine. In this study, approximately 3 years of medical records of 7 patients receiving co-administration therapy of warfarin and capecitabine were obtained from 4 hospitals. We observed daily increases in PT-INR values up to peak PT-INR levels following co-administration of warfarin and capecitabine. Interestingly, the peak PT-INR values of 4 of the patients remained remarkably high despite discontinuation of capecitabine. The peak PT-INR values for concomitant warfarin and capecitabine were attained after an average of 31.3 days of usage. When compared with the average PT-INR values attained before co-administration, the PT-INR values following co-administration significantly increased by 3 times (p<0.05). After discontinuation of capecitabine for an average of 15.1 days, i. e., for approximately 14 days, the PT-INR values returned to the PT-INR values attained prior to co-administration. These results suggest that capecitabine has influence on the anticoagulant effect of warfarin during not only the co-administered term but also the discontinuation term, and that this influence occasionally continues after discontinuation of capecitabine. These findings also suggest that a period of approximately 14 days after discontinuation is necessary for the interaction of capecitabine to dissipate and the PT-INR values to return the levels attained before receiving concomitant warfarin and capecitabine.

[Actual Access and Usage of Antipyretic Analgesics before and after COVID-19 Vaccination: Pharmacist's Roles in Promoting Proper Use of Medicines during the Infodemic].

An overwhelming surge of information regarding preparedness for postvaccination side effects had caused widespread confusion approximately since April 2021, when the coronavirus disease 2019 (COVID-19) vaccination had started for the general population in Japan. Notably, this resulted in a remarkably increased shortage of OTC acetaminophen formulations. The aim of this study was to elucidate the actual responses of the public in such an environment, how individuals acquired and understood information related to the management of postvaccination side effects, and how they obtained and used antipyretic analgesics before and after COVID-19 vaccination. We conducted a web-based survey in January 2022, targeting 400 individuals aged ≥20 years, who had received two COVID-19 vaccine doses, and excluded qualified professionals such as physicians and pharmacists. The results revealed that 67% of the respondents had obtained antipyretic analgesics in anticipation of adverse effects after vaccination, whereas 38% had taken these medicines before and/or after the second vaccination. Possible misappropriation of medicines from others, preventive administration, and lack of dosage and administration confirmation are the problems identified in medication acquisition and usage. Additionally, avoidance of antipyretic analgesics based on information without scientific evidence was observed. This study revealed no small amount of inappropriate use of medicines in situations, such as the COVID-19 pandemic, where there is an "infodemic" of mixed-quality information. Pharmacists, as experts in medication, should play a crucial role in promoting appropriate medication usage by consistently staying updated with the latest scientific evidence and proactively supporting OTC drug selection and counseling medication.

[Evaluation of Pharmacists' Active Intervention to Reduce Potentially Inappropriate Medications in Special Older Adult Nursing Home].

Currently, elderly care facilities that do not offer long-term care are not required to employ pharmacists, and duties such as the dispensing and distribution of medicines are entrusted to external pharmacies. Pharmacists seldom spend sufficient time at the facilities for elderly people requiring special care. Thus, in many cases, the pharmacists have insufficient knowledge of the residents' medication status, leading to their inability in determining whether the residents are receiving a suitable drug therapy. We previously documented various problems in the practices adopted by nursing staff (with negligible intervention by pharmacists) for assisting residents in taking their medications. In the present pilot study, we attempted to eliminate the use of potentially inappropriate medications by stationing a pharmacist at a nursing home for 24 h every week (3 d/week). We proactively collected information from nurses and other nursing staff and observed the residents' actual living conditions and medication use. As a result of this intervention, 56 prescriptions were changed. However, only two of these were changed exclusively based on the prescription information. Most prescriptions were able to change based on the information obtained by the pharmacist present at the facility. Therefore, pharmacists' presence at the facility (at least for a few hours) is necessary, as they can actively intervene and collaborate with other staff to prevent the use of potentially inappropriate medications.

Development of a quality of work life scale for Japanese community pharmacists: a questionnaire survey mostly in large companies.

BACKGROUND: Human resource management may become complex for community pharmacists owing to recent changes in work volume and content. Few studies have examined job satisfaction, well-being, and quality of work life (QWL) among community pharmacists in Japan. This study focused on QWL, a more comprehensive concept than job satisfaction, and aimed to develop the QWL questionnaire for Japanese community pharmacists (the QWLQ for JCP) and assess its reliability and validity. METHODS: A questionnaire survey was conducted among 2027 pharmacists who worked in pharmacies with the cooperation of 20 corporations running pharmacies. Collected data were subjected to principal component factor analysis with Promax rotation via SPSS Windows version 28. RESULTS: The factor analysis used data from 1966 pharmacists. In total, five significant components, which formed the basis of the QWLQ for JCP, were identified. These included "Influence of work on mind and body," "Relationships with colleagues," "Relationship with the boss," "Meaning of existence in the workplace," and "Pride in work." Cronbach's alpha, which expressed reliability, ranged from 0.585 to 0.854 for all the subscales. CONCLUSION: The QWLQ for the JCP significantly explained the concept of QWL, which indicated that its validity was sufficient.

Quality of work life (QWL) of community pharmacists and its association with subjective evaluations of pharmaceutical services.

Background: In Japan, pharmacists' role has drastically changed in recent years. However, previous studies have not performed internal marketing analysis for Japanese community pharmacists so that they improve the quality of work life (QWL) and be satisfied with it. Further, few studies are conducted on Japanese community pharmacists' QWL and its effect on the quality of pharmaceutical services. Objectives: This study aimed to reveal associations between community pharmacists' QWL and their subjective evaluations of pharmaceutical service. Methods: A questionnaire survey was conducted among 2027 pharmacists, with the cooperation of 20 corporations that run pharmacies. The collected data were subjected to multiple regression analysis, using SPSS 29. Results: Standard multiple regression shows that 27.4% of variance in pharmacists' subjective evaluations of their service was explained by QWL and other control variables, such as age, gender, and employee status (p < .001, R2 = 0.274). This analysis showed that factors behind pharmacists' QWL, "meaning of existence in the workplace" and "pride in work," explained pharmacists' subjective evaluations of pharmaceutical service (ß = 0.307, p < .001, ß = 0.277; p < .001, respectively). Conclusion: This study shows that improving QWL, especially "mental and physical effects on work" and "pride in work," might contribute to improving community pharmacists' services.

Medication incidents associated with the provision of medication assistance by non-medical care staff in residential care facilities.

The shift towards community-based care in Japan has led to increased medication assistance for older people by non-medical care staff. These staff members help take pre-packaged medications, apply patches, and administer eye drops. This study assessed the risks associated with such assistance by reviewing medication-related incidents across 106 residential care facilities between April 1, 2015, and March 31, 2016. An analysis of incident reports showed that all incidents were minor, with no serious outcomes. The incidents were categorized into four types: dropped drugs, misdelivery/misuse of medicines, forgetting to take medicines, and loss of medicines, with dropped drugs being the most frequent. Most incidents occurred in the morning and primarily involved residents with intermediate nursing care needs. These findings indicate a low risk of serious incidents because of medication assistance from non-medical staff. However, the frequency and nature of the incidents were influenced by the timing of medication administration and the care needs of the residents. These insights highlight the need for customized approaches to medication assistance, considering the residents' care levels and potentially optimizing medication administration times to improve safety in residential care settings.

Effects of Tongue Strength Training on Patients with Mild to Moderate Sleep-disordered Breathing: A Randomized Controlled Trial.

Objectives: : Several studies have reported that oropharyngeal myofunctional therapy (OMT) reduces the severity of obstructive sleep apnea (OSA). However, because OMT protocols are often complicated, they take time and effort to implement. The aim of this study was to determine the therapeutic effect of 8 weeks of simple tongue strength training with a training device. Methods: : Twenty patients with mild to moderate sleep-disordered breathing were randomized to the control group (n=10) or intervention group (n=10). The patients in the intervention group completed 8 weeks of daily tongue strength training using a training device. After 8 weeks, we evaluated each patient for sleep-disordered breathing by portable monitoring. We also evaluated each patient's body mass index (BMI), neck circumference, Epworth Sleepiness Scale (ESS) score, and tongue pressure. Results: No significant difference was found in the change in apnea hypopnea index (AHI) from baseline to 8 weeks between the control and intervention groups (P=0.44). However, the changes in neck circumference (P=0.02) and maximum tongue pressure (P=0.03) from baseline to 8 weeks were significantly different between the two groups. No significant difference was found for changes in BMI and ESS scores from baseline to 8 weeks between the two groups. Conclusions: : Tongue strength training in patients with sleep-disordered breathing did not significantly improve AHI as measured by portable monitoring, although significant changes were observed for increased tongue pressure and reduced neck circumference.

Mechanism of action of adapalene for treating EGFR-TKI-induced skin disorder.

BACKGROUND: Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder. METHODS: To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1ß. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR. RESULTS: Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene. CONCLUSION: We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.

Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.

Effect of the interaction between employment level and psychosocial work environment on insomnia in male Japanese public service workers.

BACKGROUND: Little is known about the combined risk of socioeconomic status and psychosocial environment for insomnia. PURPOSE: The purpose of this study was to investigate the combined risk of employment level and psychosocial work environment for insomnia in a large Japanese male working population. METHOD: We investigated 5,951 male employees aged 34-59 years from two local governments in Japan. Data were obtained from a questionnaire distributed in advance of their annual health check-up. Employment level was categorized as higher-level non-manual workers, lower-level non-manual workers, and manual workers. Psychosocial work environment was assessed using the Demand-Control Model and the Effort-Reward Imbalance Model (ERI). Insomnia was assessed using the Athens Insomnia Scale. RESULTS: The results showed that 1,382 (23.2 %) participants suffered from insomnia. Lower employment level was significantly associated with a higher risk of insomnia. Job strain (ratio of job demand to job control), E/R (ratio of job effort to job reward), and OC (over commitment) were also significantly associated with insomnia. The relative excess risk due to the interaction between employment level and psychosocial environment (job strain, E/R, and OC) was 0.09 (95 % CI -0.57 to 0.76), 2.61 (0.74 to 4.48), and 3.14 (0.82 to 5.45), respectively; synergy index = 1.07 (0.66 to 1.74), 1.99 (1.37 to 2.90), and 2.25 (1.46 to 3.46), respectively. CONCLUSION: We found supra-additive interactions between employment level and psychosocial environment, assessed by the ERI (E/R and OC). Our findings suggested that lower level workers are more vulnerable to an adverse psychosocial environment than those at a higher level.