Creating and evaluating the score to assess overdose: the OD score.

BACKGROUND: During disasters (including epidemics such as coronavirus disease 2019), the capacity of emergency departments is exceeded, thereby hindering the administration of appropriate lifesaving measures. Furthermore, the number of overdose patients increases because of the stress overload during emergency situation. The fact that overdose patients are forced to be transported to medical facilities that do not typically treat them is becoming worrisome. Moreover, there is no definitive score for overdose. This study aimed to create a patient-specific scoring system to assess overdose. METHODS: This was a retrospective single-center study. The evidence-based OD score was evaluated on a scale of 0-15. Further, logistic analysis and receiver operating characteristic (ROC) curve analysis were performed to evaluate the score. RESULTS: Overall, 262 patients (including 118 overdose patients) receiving care at the intensive care unit of Japan's Teikyo University Hospital in 2021 were targeted. Regarding the total OD score, ROC analysis revealed a cutoff of 8 (area under the curve [AUC]: 0.99, 95% confidence interval [CI]: 0.980-0.997, sensitivity: 0.95, specificity: 0.95, p < 0.05), which was considered to indicate an overdose. Of the items evaluated in the OD score, the scenario at the location of the patient's discovery (adjusted odds ratio [AOR]: 16.8, 95% CI: 5.0-255.9, p = 0.002) and recent experience of mental anxiety (AOR: 55.7, 95% CI: 2.8-5399.5, p = 0.03) significantly predicted an overdose in multivariable logistic regression analysis. External validation revealed that the OD score could also identify overdose in patients treated in a cohort from 2022 (average cutoff: 8.6, average AUC: 1.0, p < 0.0001). CONCLUSIONS: The OD score could accurately assess overdose patients. Medical facilities that do not frequently address overdose patients will benefit from the use of this score.

Identification of Factors Necessary for Gatekeeper of Overdose.

Overdose has become a global social problem. The Japanese government requires gatekeeper training to detect and prevent indicators of overdose and suicide. However, knowledge of necessary factors for the gatekeeper of overdose (patient intervention) is limited. This study aimed to investigate the characteristics of individuals who experienced intervening persons expected to overdose, and to identify the factors required of gatekeepers. A Google form was used to survey 298 pharmacists and registered sellers in Japan. We searched for factors by logistic analysis. Knowledge of prescription drugs used for overdose was higher among pharmacists than among registered sellers. Conversely, pharmacists and registered sellers had similar knowledge about OTC drugs. Overall multivariate logistic regression analysis revealed countermeasures against overdose at their workplace (odds ratio (OR): 4.01, 95% confidence interval (CI): 2.25-7.15, p < 0.01) and knowledge that overdose is on the rise (OR: 1.93, 95% CI: 1.04-3.69, p < 0.05) to be significantly associated with intervention experience as a gatekeeper. Countermeasures against overdose at their workplace (OR: 2.40, 95% CI: 1.10-5.25, p < 0.05) in pharmacists and years of work experience (OR: 1.13, 95% CI: 1.04-1.24, p < 0.05), countermeasure against overdose at their workplace (OR: 3.43, 95% CI: 1.18-10.0, p < 0.05), and willingness to participate in study sessions and workshops on overdose (OR: 3.50, 95% CI: 1.51-8.10, p < 0.05) in registered seller were significantly associated with intervention experience as a gatekeeper. These results are useful evidences for countermeasures and gatekeeper training for overdose at pharmacies and drugstores in the community.

Peptides Derived from Soybean ß-Conglycinin Induce the Migration of Human Peripheral Polymorphonuclear Leukocytes.

Food-derived peptides have various biological activities. When food proteins are ingested orally, they are digested into peptides by endogenous digestive enzymes and absorbed by the immune cell-rich intestinal tract. However, little is known about the effects of food-derived peptides on the motility of human immune cells. In this study, we aimed to understand the effects of peptides derived from a soybean protein ß-conglycinin on the motility of human peripheral polymorphonuclear leukocytes. We illustrated that MITL and MITLAIPVNKPGR, produced by digestion using in-vivo enzymes (trypsin and pancreatic elastase) of ß-conglycinin, induces the migration of dibutyryl cAMP (Bt2 cAMP)-differentiated human promyelocytic leukemia 60 (HL-60) cells and human polymorphonuclear leukocytes in a dose- and time-dependent manner. This migration was more pronounced in Bt2 cAMP-differentiated HL-60 cells; mRNA expression of formyl peptide receptor (FPR) 1 increased significantly than in all-trans-retinoic acid (ATRA)-differentiated HL-60 cells. This migration was inhibited by tert-butoxycarbonyl (Boc)-MLP, an inhibitor of FPR, and by pretreatment with pertussis toxin (PTX). However, the effect was weak when treated with WRW4, a selective inhibitor of the FPR2. We then demonstrated that MITLAIPVNKPGR induced intracellular calcium responses in human polymorphonuclear leukocytes and Bt2 cAMP-HL60 cells. Furthermore, pre-treatment by fMLP desensitized the calcium response of MITLAIPVNKPGR in these cells. From the above, MITLAIPVNKPGR and MITL derived from soybean ß-conglycinin induced polymorphonuclear leukocyte migration via the FPR1-dependent mechanism. We found chemotactic peptides to human polymorphonuclear leukocytes, which are the endogenous enzyme digests of soybean protein.

[An Attempt to Build the Practice Model of Pharmacist in Home Care Medicine for Children].

Although the need for homecare medicine for children is increasing in Japan, few studies have focused on the role of pharmacists in this area. The purpose of the present study was to clarify the practice process of pharmacists in pediatric homecare medicine and develop a practice model. Three pharmacists with experience in homecare medicine for children participated in semi-structured interviews. The data were analyzed using the modified-grounded theory approach (M-GTA). The analysis generated 8 categories and 21 concepts. The practice of pharmacists in homecare medicine for children is the pharmacotherapy management process, and it aims at "enabling the transition from hospital to home for children and continuity of their homelife with family" in collaboration with other professions. Above all, the two concepts of "optimization of prescription and device selection to enable the hospital-to-home transition" and "optimization of prescription and device selection for ensuring patient safety" form the core of clinical decision making in the pharmacotherapy management process. By integrating these two optimization concepts, the transfer of patients to home can be undertaken smoothly, leading to safer pharmacotherapy in the lives of patients and their families. Furthermore, pharmacists considered clinical decision making from two perspectives: "the child's growth-based approach" and "homelife-based approach." The foundation of these practice processes comprised "professional responsibilities" and "consideration of families' feelings."

[Survey on Visiting Nurses' Awareness of the Roles of Pharmacists in Pediatric in-Home Care].

In recent years, there has been an urgent need to build a pediatric in-home care system with multiple occupations. This study aims to clarify the role of pharmacists in this system by investigating what visiting nurses' expectation from them. A self-administered questionnaire survey was conducted, targeting nurses enrolled in 10 home-visit nursing facilities. Responses were received from 51 nurses at six facilities, and the questionnaire collection rate was 42.5%. The primary role of the pharmacists that nurses regarded was the management of prescribed oral medications such as "mixing powders, single-dose packages at each time" and "sorting and summarizing each time medicine packages are taken." Other roles included providing information based on the drug's physicochemical properties such as "the tube gets clogged easily when the medicine is administered" and "do not crush the medicine when administering it." The findings of this study are novel because they revealed that pharmacists need to perform pharmaceutical assessments on the influences of changes in children's physical condition and the presence or absence of effects of drugs, and share information in real time. They also need to participate in a conference at discharge. For the first time, this study revealed the roles of pharmacists expected by nurses in pediatric in-home care. However, further knowledge or training are required, especially in terms of the relationship between the symptoms in children and the medicine administered, for pharmacists to effectively practice their roles.

Prediction model for milk transfer of drugs by primarily evaluating the area under the curve using QSAR/QSPR.

PURPOSE: Information on milk transferability of drugs is important for patients who wish to breastfeed. The purpose of this study is to develop a prediction model for milk-to-plasma drug concentration ratio based on area under the curve (M/PAUC). The quantitative structure-activity/property relationship (QSAR/QSPR) approach was used to predict compounds involved in active transport during milk transfer. METHODS: We collected M/P ratio data from literature, which were curated and divided into M/PAUC ≥ 1 and M/PAUC < 1. Using the ADMET Predictor® and ADMET Modeler™, we constructed two types of binary classification models: an artificial neural network (ANN) and a support vector machine (SVM). RESULTS: M/P ratios of 403 compounds were collected, M/PAUC data were obtained for 173 compounds, while 230 compounds only had M/Pnon-AUC values reported. The models were constructed using 129 of the 173 compounds, excluding colostrum data. The sensitivity of the ANN model was 0.969 for the training set and 0.833 for the test set, while the sensitivity of the SVM model was 0.971 for the training set and 0.667 for the test set. The contribution of the charge-based descriptor was high in both models. CONCLUSIONS: We built a M/PAUC prediction model using QSAR/QSPR. These predictive models can play an auxiliary role in evaluating the milk transferability of drugs.

Relationship between tracheal intubation and the drugs used by patients with drug overdose due to self-harm.

BACKGROUND: Tracheal intubation may be performed in patients with drug overdose due to self-harm; however, the details of the causative drug are unknown. The purpose of this study was to clarify the relationship between drugs or its blood levels of patients with drug overdose and the need for tracheal intubation based on the actual measurement results. METHODS: From October 2018 to March 2020, 132 patients with drug overdose due to self-harm who were transported to the emergency department (ED) were studied. Patient drugs were measured using gas chromatography-mass spectrometry (GC-MS) and were analyzed on the basis of the GC/MS Forensic Toxicological Database. Logistic analysis was performed by combining patient information and GC-MS information. RESULTS: The Glasgow Coma Scale (GCS) and Japan Coma Scale (JCS) efficiently predicted tracheal intubation in patients with drug overdose during transport triage; GCS (cut-off value: 12, area under the curve (AUC): 0.81, 95% confidence interval (CI): 0.71-0.88, sensitivity: 0.85, specificity: 0.71, P < 0.05) and JCS (cut-off value: 3, AUC: 0.74, 95% CI: 0.60-0.84, sensitivity: 0.60, specificity: 0.84, P < 0.05). The drugs detected in all patients with drug overdose in order were benzodiazepine receptor agonists (BZs; 43.9%), anticonvulsants (38.6%), antipsychotics (25.0%), and antidepressants (9.8%). In univariate logistic analysis, antipsychotics (odds ratio (OR) 2.46, 95% CI 1.19-5.20, P < 0.05), anticonvulsants (OR 2.71, 95% CI 1.26-5.98, P < 0.05), and anticonvulsants above alert blood levels (OR 27.8, 95% CI 2.92-264.1, P < 0.05) were significantly associated with tracheal intubation in patients with drug overdose, but not BZs and antidepressants. Also, in multivariate logistic analysis, antipsychotics (OR 2.27, 95% CI 1.07-4.83, P < 0.05), anticonvulsants (OR 2.50, 95% CI 1.14-5.64, P < 0.05) and in multivariate logistic analysis of blood levels, anticonvulsants above the alert blood levels (OR 24.9, 95% CI 2.56-241.6, P < 0.05) were significantly associated with tracheal intubation in patients with drug overdose respectively. CONCLUSIONS: Logistic analysis revealed that the use of anticonvulsants and antipsychotics were significantly associated with an increased OR in the tracheal intubation of patients with drug overdose due to self-harm.

Evaluation of factors related to overdose in patients with impaired consciousness who are transported by emergency medical services: an age-specific research.

BACKGROUND: Drug overdose accounts for most of the admissions to the emergency department. Prescription drugs, most of which are psychotropic medications, are often misused for drug overdose. The purpose of this study was to investigate the association between overdose in patients transported with disorders of consciousness and psychotropic medications administered prior to transport, so as to enable quick differentiation of drug overdose patients from patients with disorders of consciousness. METHODS: We evaluated 222 patients transported to the Advanced Critical Care Center of Teikyo University Hospital due to disorders of consciousness. The patients were categorized into two groups: overdose group (n = 128) and control group with other disorders of consciousness (n = 94). Logistic regression models were used to assess the association between disorders of consciousness due to drug overdose and psychotropic drugs prescribed before emergency transportation based on sex and age. RESULTS: According to multivariate logistic regression analysis, only female sex (odds ratio [OR] 4.54, 95% confidence interval [CI] 2.43-8.05, P < 0.0001) was associated with overall overdose. Results from the univariate logistic regression analysis showed that in the group of patients aged 40-50 years, female sex (OR 4.36, 95% CI; 1.54-12.4, P = 0.006) and the use of psychotropic drugs (OR 5.05, 95% CI; 1.75-14.6, P = 0.003), benzodiazepines (OR 4.64, 95% CI; 1.61-13.4, P < 0.05), antidepressants (OR 11.4, 95% CI; 2.35-55.8, P = 0.003), and anticonvulsants (OR 4.46, 95% CI; 1.11-17.9, P = 0.035) were associated with overdose. According to multivariate logistic regression analysis, female sex (OR 4.44, 95% CI; 1.37-14.3, P = 0.013) and antidepressants (OR 7.95, 95% CI; 1.21-52.1, P = 0.031) were associated with overdose patients aged 40-50 years. CONCLUSIONS: As a reference in distinguishing overdose in women in their 40s and 50s who present with impaired consciousness, attention may need to be paid to the type of psychotropic drug used, especially antidepressants.

Effect of antipsychotics on breast tumors by analysis of the Japanese Adverse Drug Event Report database and cell-based experiments.

BACKGROUND: Since antipsychotics induce hyperprolactinemia via the dopamine D2 receptor, long-term administration may be a risk factor for developing breast tumors, including breast cancer. On the other hand, some antipsychotic drugs have been reported to suppress the growth of breast cancer cells in vitro. Thus, it is not clear whether the use of antipsychotics actually increases the risk of developing or exacerbating breast tumors. The purpose of this study was to clarify the effects of antipsychotic drugs on the onset and progression of breast tumors by analyzing an adverse event spontaneous reporting database and evaluating the proliferation ability of breast cancer cells. METHODS: Japanese Adverse Drug Event Report database (JADER) reports from April 2004 to April 2019 were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. Reports of females only were analyzed. Adverse events included in the analysis were hyperprolactinemia and 60 breast tumor-related preferred terms. The reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) were used to detect signals. Furthermore, MCF-7 cells were treated with haloperidol, risperidone, paliperidone, sulpiride, olanzapine and blonanserin, and cell proliferation was evaluated by WST-8 assay. RESULTS: In the JADER analysis, the IC signals of hyperprolactinemia were detected with sulpiride (IC, 3.73; 95% CI: 1.81-5.65), risperidone (IC, 3.69; 95% CI: 1.71-5.61), and paliperidone (IC, 4.54; 95% CI: 2.96-6.12). However, the IC signal of breast tumors was not observed with any antipsychotics. In cell-based experiments, MCF-7 cells were treated with six antipsychotics at concentrations of 2 and 32 µM, and none of the drugs showed any growth-promoting effects on MCF-7 cells. On the other hand, blonanserin markedly suppressed the growth of MCF-7 cells at a concentration of 32 µM, and the effect was concentration dependent. CONCLUSIONS: Analysis of the JADER using the IC did not show breast tumor signals due to antipsychotic drugs. In in vitro experiments, antipsychotics did not promote MCF-7 cell proliferation whereas blonanserin suppressed MCF-7 cell growth. Further research on the effects of blonanserin on the onset and progression of breast tumor is expected.

Relationship between the effects of food on the pharmacokinetics of oral antineoplastic drugs and their physicochemical properties.

BACKGROUND: Food is known to affect drug absorption by delaying gastric emptying time, altering gastrointestinal pH, stimulating bile flow, increasing splanchnic blood flow, or physically interacting with drugs. Although food is known to affect the pharmacokinetics of oral antineoplastic drugs, the relationship between the effects of food and the physicochemical properties of drugs remains unclear. METHODS: In this study, we surveyed the literature on three kinds of pharmacokinetic changes, AUC ratio, Cmax ratio and Tmax ratio, in the fasted and fed state for 72 oral antineoplastic drugs that were listed on the drug price standard in May 2018 in Japan. We further predicted the physicochemical properties from the 2D chemical structure of the antineoplastic drugs using in silico predictions. RESULTS: As a result of analyzing the relationship between the effects of food and physicochemical properties, we found that compounds that show increased absorption in the fed state had higher logP and lower solubility in fasted-state simulated intestinal fluid (FaSSIF). However, compounds with delayed absorption had higher solubility in FaSSIF. Furthermore, as a result of decision tree analysis, it was classified as AUC increase with logP ≥4.34. We found that an AUC increase in the fed state did not occur with compounds with low lipid solubilities (logP < 1.59). From these results, it is predicted that 7 compounds out of the 24 compounds for which the effects of food are unknown are at risk for increased absorption in the fed state and that no increase in absorption would occur in 13 compounds. CONCLUSION: In this study, we found that drugs that will show increased absorption in the fed state and drugs for which absorption is not dependent on food can generally be predicted by logP. These results suggest that logP can be a useful parameter for predicting the effects of food on drug absorption.

Utility and effectiveness of Symbicort® Turbuhaler® (oral inhalation containing budesonide and formoterol) in a patient with severe asthma after permanent tracheostomy.

BACKGROUND: The utility and effectiveness of inhalational asthma therapy in patients with a permanent tracheostomy has not been established. Previously, a few studies reported the use of nebulizer-type inhalers for treating these patients. Symbicort® Turbuhaler® (Symbicort) is an orally inhaled dry powder containing the corticosteroid budesonide and the bronchodilator formoterol. There are no reports describing the successful use of Symbicort in patients with a permanent tracheostomy. CASE PRESENTATION: We describe the case of a woman with poorly controlled severe asthma after a permanent tracheostomy. She had developed thyroid cancer with tracheal invasion for which right thyroid lobectomy and tracheal and esophageal resection were performed, with subsequent construction of a permanent tracheostomy. In our case, prior to surgery, asthma control had been improved by adding a bronchodilator-the long-acting muscarinic antagonist tiotropium-and the anti-IgE antibody agent omalizumab to single maintenance and reliever therapy (SMART) using Symbicort; surgery was then performed. After surgery, asthma control worsened as a result of a change from Symbicort to budesonide nebulizer and a tulobuterol patch. In order to resume SMART therapy, an In-Check® inspiratory flow meter was used to measure and assess whether the inspiratory flow rate was sufficient for a dry-powder inhaler. Inhalation guidance was provided. On inhalation with the tracheostomy closed at the same time, the inspiratory flow rate was 43 L/min at the maximum. This was judged to be sufficient for the effect of Symbicort, and thus the inhaler was changed to Symbicort. Asthma symptoms promptly improved, and the patient was subsequently discharged. CONCLUSIONS: The use of Symbicort resulted in improved asthma control in a patient with severe asthma following a permanent tracheostomy. Thus, it is suggested that inhalation powder could be an option for patients with permanent tracheostomy.

New low-dose liquid pilocarpine formulation for treating dry mouth in Sjögren's syndrome: clinical efficacy, symptom relief, and improvement in quality of life.

BACKGROUND: Patients with Sjögren's syndrome (SS) typically present clinically with xerostomia (dry mouth) because of progressive damage to the exocrine glands. We developed a new, low-dose pilocarpine/sodium alginate (LPA) solution with pilocarpine hydrochloride to inhibit systemic adverse effects by administering via the oral mucosa. The purpose of this study was to assess its stability, safety, and efficacy. METHODS: The pilocarpine concentration in an LPA liquid formulation was measured 3, 7, 14, and 28 days after preparation to assess its stability. A prospective clinical trial was undertaken to assess the efficacy and safety of the LPA solution as a symptomatic treatment for dry mouth in SS. Patients (n = 24) with clinically significant xerostomia were enrolled after providing written informed consent. Whole-mouth salivary flow rate was measured twice; immediately before and 60 min after LPA application. Symptoms were assessed by questionnaire with visual analog scales or checkboxes before the first application (baseline), and then once daily for 7 days. RESULTS: The pilocarpine content 3, 7, 14, and 28 days after preparation showed no marked change, confirming its stability. Salivary flow was significantly increased from 0.076 ± 0.092 g/30 s to 0.122 ± 0.140 g/30 s 60 min after LPA administration (P < 0.001). Dry mouth and thirstiness showed significant improvement compared with that of baseline (P ≤ 0.01). The only adverse effect was sweating, and no serious drug-related adverse events were reported. CONCLUSIONS: This new, low-dose pilocarpine formulation was well-tolerated and resulted in significant improvements in symptoms of dry mouth and other xerostomic conditions in patients with SS. TRIAL REGISTRATION: The study approval number in the institution; 08-068-2. Registered January 19, 2009. UMIN000029307. Registered 27 September 2017 (retrospectively registered).

The influence of dietary peptide inhibitors of angiotensin-converting enzyme on the hypotensive effects of enalapril.

BACKGROUND: Enalapril is an antihypertensive medicine that inhibits angiotensin I-converting enzyme (ACE). The present study investigated interactions between enalapril and a fermented milk product (FMP) containing the ACE-inhibitory peptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP). METHODS: Single-dose and long-term (6-week) in vivo studies were used to investigate the effects of enalapril and FMP on blood pressure in spontaneously hypertensive rats. RESULTS: Single-dose oral administration of concomitant enalapril and FMP (VPP, IPP: 3.5 mg/kg) produced a lower antihypertensive effect than enalapril monotherapy. However, this effect was not observed in animals administered a lower dose of FMP (VPP, IPP: 1.75 mg/kg) along with enalapril. In rats administered enalapril concomitantly with a fish protein product (FPP) containing a different ACE inhibitory peptide (Leu-Lys-Pro-Asn-Met), significant attenuation of the antihypertensive effect was also observed 1 and 2 h after administration, as compared to enalapril monotherapy. During a 6-week oral administration study, the enalapril monotherapy group showed significant antihypertensive effects compared to those observed in the controls on day 28. Oral administration of enalapril and FMP, with a 1-h interval between doses, resulted in significant antihypertensive effects on day 35, indicating a delayed onset in comparison to enalapril monotherapy. In rats receiving enalapril monotherapy for 28 days, followed by 14 days of concomitant FMP, significant antihypertensive effects were observed after day 35, and these did not differ significantly from the effects observed during enalapril monotherapy. CONCLUSIONS: The present findings suggested that long-term concomitant intake of FMP and enalapril could influence the antihypertensive effects of this drug.

[Efficacy of local steroid injection on rat skin lesions induced by extravasation of vesicant anticancer drugs].

The efficacy of local steroid injection on the extravasation of vesicant anticancer drugs is controversial. In this study, the efficacy of local steroid injection was evaluated macroscopically and histologically in the extravasation models of doxorubicin (DXR), vinorelbine (VNR), and paclitaxel (PTX)in rats. Macroscopically, gross skin lesions were reduced by local steroid injections in rats treated with DXR and VNR. PTX did not cause gross skin lesions in most rats regardless of local steroid injection. Histologically, however, DXR, VNR, and PTX all induced deep tissue lesions such as edema, inflammation, and necrosis. Therefore, the effect of local steroid injection seemed to be minimal. In particular, DXR induced extensive necrosis in the subcutaneous and muscle tissues. VNR-induced skin lesions were milder than those induced by DXR, but had full thickness. Lesions caused by PTX were the mildest. These findings suggest that although local steroid injections could serve a primary role in diluting anticancer drugs and reducing gross skin lesions by their anti-inflammatory effect, they have less ability for suppressing deep-tissue lesions developing over time.

[Establishment of a practical training program in smoking cessation for use by pharmacists using cognitive-behavioral therapy and the motivational interview method].

We established a practical training program to nurture pharmacists who can give smoking cessation instructions. The program was provided to 85 interns (45 males and 40 females) in Teikyo University Hospital. The one-day practical training was provided to groups comprised of five members each. The training consisted of studies on the adverse effects of smoking, general outlines of the outpatient smoking cessation service, experiencing Smokerlyzer, studies about smoking-cessation drugs, studies about a smoking cessation therapy using cognitive-behavioral therapy and motivational interviewing, and case studies applying role-playing. Before and after the practical training, we conducted a questionnaire survey consisting of The Kano Test for Social Nicotine Dependence (KTSND) and the assessment of the smoking status, changes in attitudes to smoking, and willingness and confidence to give smoking cessation instructions. The overall KTSND score significantly dropped from 14.1±4.8 before the training to 8.9±4.8 after the training. The confidence to give smoking cessation instructions significantly increased from 3.4±1.9 to 6.2±1.3. Regarding the correlation between the smoking status and willingness and confidence to give smoking cessation instructions, the willingness and confidence were lower among the group of interns who either smoked or had smoked previously, suggesting that smoking had an adverse effect. A total of 88.2% of the interns answered that their attitudes to smoking had "changed slightly" or "changed" as a result of the training, indicating changes in their attitudes to smoking. Given the above, we believe that our newly-established smoking cessation instruction training is a useful educational tool.

Enhancement or Suppression of ACE Inhibitory Activity by a Mixture of Tea and Foods for Specified Health Uses (FOSHU) That Are Marketed as "Support for Normal Blood Pressure".

The ACE inhibitory activities of mixtures of FOSHUs (Healthya, Goma-Mugicha, Lapis Support and Ameal) were examined in order to identify any antihypertensive interactions. Among combinations of Healthya with other samples that contain active peptides, only that with Ameal was found to have no inhibitory activity. Enhanced activity was observed in 2 other mixtures. The activity of a mixture of tea polyphenols and the whey component extracted from an Ameal solution was significantly decreased, thus demonstrating that whey protein lowered the ACE inhibitory activity of Healthya. Although oral administration of tea polyphenols alone significantly decreased SBP in SHR at 2 and 4 hr, combined administration with Ameal failed to decrease SBP at the same time points. In conclusion, the simultaneous intake of tea and FOSHUs that contain active peptides might affect daily self-antihypertensive management via enhancement or suppression of ACE inhibitory activity.

Expression of phosphatidylserine-specific phospholipase A(1) mRNA in human THP-1-derived macrophages.

The expression of phosphatidylserine-specific phospholipase A(1) (PS-PLA(1)) is most upregulated in the genes of peripheral blood cells from chronic rejection model rats bearing long-term surviving cardiac allografts. The expression profile of PS-PLA(1) in peripheral blood cells responsible for the immune response may indicate a possible biological marker for rejection episodes. In this study, PS-PLA(1) mRNA expression was examined in human THP-1-derived macrophages. The effects of several immunosuppressive agents on this expression were also examined in in vitro experiments. A real-time RT-PCR analysis revealed that PS-PLA(1) mRNA expression was found in human THP-1-derived macrophages. This expression was enhanced in the cells stimulated with lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. Other TLR ligands (TLR2, 3, 5, 7, and 9) did not show a significant induction of PS-PLA(1) mRNA. The time course of the mRNA expression profiles was different between PS-PLA(1) and tumor necrosis factor-α (TNF-α), which showed a maximal expression at 12 and 1 h after LPS stimulation, respectively. Among the observed immunosuppressive agents, corticosteroids, prednisolone, 6α-methylprednisolone, dexamethasone, and beclomethasone inhibited PS-PLA(1) expression with half-maximal inhibitory concentrations less than 3.0 nM, while methotrexate, cyclosporine A, tacrolimus, 6-mercaptopurine, and mycophenoic acid showed either a weak or moderate inhibition. These results suggest that the expression of PS-PLA(1) mRNA in THP-1-derived macrophages is activated via TLR4 and it is inhibited by corticosteroids, which are used at high dosages to suppress chronic allograft rejection.

Effects of oral supplementation of L-arginine in the treatment of pulmonary hypertension secondary to pulmonary embolism: a case report.

We tried L-arginine for the treatment of pulmonary hypertension secondary to pulmonary embolism. The plasma brain natriuretic peptide (BNP) level inversely correlated with the plasma concentration of L-arginine. After oral supplementation of L-arginine, patient's symptoms (shortness of breath and general malaise), state of congestive heart failure, and exercise capacity all improved. L-arginine may be effective in the treatment of pulmonary hypertension secondary to pulmonary embolism.

Quantification of the levels of CYP2D6 mRNA in peripheral blood leukocytes by reverse transcriptase polymerase chain reaction HPLC.

We developed a sensitive high performance liquid chromatography (HPLC) method for determining CYP2D6 mRNA in peripheral blood leukocytes (PBL) by using competitive reverse transcriptase polymerase chain reaction (RT-PCR). The method is specific, reproducible, and sensitive enough to quantify the absolute amount of low and high abundant CYP2D6 mRNA. The native CYP2D6 transcript and the internal standard, a CYP2D6 deletion RNA, were amplified with similar efficiency in RT-PCR. The PCR products were separated as the corresponding peaks in optimized HPLC. The coefficients of variation for competitive RT-PCR and HPLC determination were 1.5-6.5% and 0.6-2.4%, respectively, showing high reproducibility and reliability. This approach could also be applicable to the quantification of mRNA expressing on various tissues, including PBL, of which the expression levels were so low that they were hard to determine by existing agarose gel electrophoresis methods.

In-vitro and clinical evaluation of an oral mucosal adhesive film containing indomethacin.

To develop a new mucoadhesive film containing an analgesic combining clinical efficacy and patient comfort, we prepared and evaluated a two-layered film consisting of an adhesive layer containing indomethacin (IM) as the active ingredient and carboxyvinyl polymer (CP) as a bonding agent and a nonadhesive layer containing polyethylene glycol (PEG) to improve film texture. In in vitro and in vivo adhesive tests, the optimal concentration of CP that could be applied to the mucous membrane was 0.2% or 0.3%. Stability testing determined that the optimal storage conditions and expiration period were 4 degrees C without shade and 4 weeks, respectively. The film was clinically evaluated in patients with oral pain. IM at concentrations of 0.5% and 1% provided optimum analgesic effects, and the effects were the greatest in the 1% IM group. The addition of PEG to the nonadhesive layer reduced the number of patients experiencing discomfort at the site where the film was applied. Therefore this film formulation may be useful for local analgesic application due to its low dose requirement, moderate adhesion, and comfortable texture.