Association between the examination rate of treatment-resistant schizophrenia and the clozapine prescription rate in a nationwide dissemination and implementation study

Background: The decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment-resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine. Methods: After attending a 1-day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty-nine facilities in 2017 were included in the study. Results: There were dichotomous distributions in the examination rate of TRS and a non-normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (r s = 0.531, P = 1.032 × 10−4). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS. Conclusion: As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families

Field Effect of Alcohol, Cigarette Smoking, and Their Cessation on the Development of Multiple Dysplastic Lesions and Squamous Cell Carcinoma: A Long-term Multicenter Cohort Study

[Background and Aims] Multiple developments of squamous dysplasia and squamous cell carcinoma (SCC) in the upper aerodigestive tract have been explained by field cancerization phenomenon and were associated with alcohol and cigarette use. Second primary SCC development after curative treatment impairs patients’ quality of life and survival; however, how these consumption and cessation affect field cancerization is still unknown. [Methods] This is a multicenter cohort study including 331 patients with superficial esophageal SCC (ESCC) treated endoscopically and pooled data from 1022 healthy subjects for comparison. Physiological condition in the background esophageal mucosa was classified into 3 groups based on the number of Lugol-voiding lesions (LVLs) per endoscopic view: grade A, 0; grade B, 1–9; or grade C, ≥10 LVLs. Lifestyle surveys were conducted using a self-administered questionnaire. Patients were counseled on the need for alcohol and smoking cessation by physicians and were endoscopically surveyed every 6 months. [Results] LVL grades were positively associated with alcohol drinking intensity, flushing reactions, smoking, and high-temperature food and were negatively associated with eating green and yellow vegetables and fruit. Second primary ESCC and head/neck SCC were significantly more prevalent in the grade C LVL (cumulative 5-y incidences 47.1%, 95% confidence interval [CI] = 38.0–57.2 and 13.3%, 95% CI = 8.1–21.5, respectively). Alcohol and smoking cessation significantly reduced the development of second primary ESCC (adjusted hazard ratios 0.47, 95% = CI 0.26–0.85 and 0.49, 95% CI = 0.26–0.91, respectively). [Conclusion] Alcohol drinking, smoking, flushing reaction, and high-temperature food were closely associated with field cancerization, and cessation of alcohol and smoking significantly reduced the risk of development of second primary cancer. UMIN Clinical Trials Registry ID:UMIN000001676

Effects of Extracts from Thai Piperaceae Plants against Infection with <i>Toxoplasma gondii</i>

<div><p>Herbal medicines and natural herb extracts are widely used as alternative treatments for various parasitic diseases, and such extracts may also have potential to decrease the side effects of the standard regimen drugs used to treat toxoplasmosis (sulfadiazine-pyrimethamine combination). We evaluated how effective the Thai piperaceae plants <i>Piper betle</i>, <i>P</i>. <i>nigrum</i> and <i>P</i>. <i>sarmentosum</i> are against <i>Toxoplasma gondii</i> infection <i>in vitro</i> and <i>in vivo</i>. Individually, we extracted the piperaceae plants with ethanol, passed them through a rotary evaporator and then lyophilized them to obtain crude extracts for each one. The <i>in vitro</i> study indicated that the <i>P</i>. <i>betle</i> extract was the most effective extract at inhibiting parasite growth in HFF cells (IC₅₀ on RH-GFP: 23.2 μg/mL, IC₅₀ on PLK-GFP: 21.4 μg/mL). Furthermore, treatment of experimental mice with the <i>P</i>. <i>betle</i> extract for 7 days after infection with 1,000 tachyzoites of the <i>T</i>. <i>gondii</i> PLK strain increased their survival (survival rates: 100% in 400 mg/kg-treated, 83.3% in 100 mg/kg-treated, 33.3% in 25 mg/kg-treated, 33.3% in untreated mice). Furthermore, treatment with 400 mg/kg of the <i>P</i>. <i>betle</i> extract resulted in 100% mouse survival following infection with 100,000 tachyzoites. The present study shows that <i>P</i>. <i>betle</i> extract has the potential to act as a medical plant for the treatment of toxoplasmosis.</p></div

Effects of the three piperaceae extracts at 25 μg/mL and sulfadiazine at 1 mg/mL on extracellular <i>T</i>. <i>gondii</i>.

<p>The RH-GFP line, pre-treated with either of the extracts (<i>P</i>. <i>betle</i>, <i>P</i>. <i>nigrum</i> or <i>P</i>. <i>sarmentosum</i>) or sulfadiazine for 1 h, was then used to infect vero cells. After 24 h, the infected cells were analyzed by IFAT to measure the infection rates. (A) Representative images of <i>T</i>. <i>gondii</i> RH-GFP-infected vero cells. The cells were treated with either <i>P</i>. <i>betle</i> (25 μg/mL), <i>P</i>. <i>nigrum</i> (25 μg/mL), <i>P</i>. <i>sarmentosum</i> (25 μg/mL) extract or sulfadiazine (1 mg/mL). SAG1, red; GFP, green; nucleus, blue. (B) The % inhibition of infection for RH-GFP was measured by counting the number of SAG1-positive vero cells per 100 vero cells. Each bar represents the mean ± SD of three wells per group. The results represent two independent experiments. The different letters above the data bars in the graphs indicate statistically significant differences as determined by a one-way ANOVA plus Tukey–Kramer post-hoc analysis (<i>P</i> < 0.05).</p

Effects of the three piperaceae extracts at 25 μg/mL and sulfadiazine at 1 mg/mL on intracellular <i>T</i>. <i>gondii</i>.

<p>The RH-GFP-infected vero cells were treated with either of the three piperaceae extracts or sulfadiazine for 72 h, and were then analyzed by IFAT to measure the parasitophorous vacuole (PV) sizes. (A) Representative images of <i>T</i>. <i>gondii</i> RH-GFP-infected vero cells. The cells were treated with either <i>P</i>. <i>betle</i> (25 μg/mL), <i>P</i>. <i>nigrum</i> (25 μg/mL), <i>P</i>. <i>sarmentosum</i> (25 μg/mL) extract, or sulfadiazine (1 mg/mL). SAG1, red; GFP, green; nucleus, blue. (B) The number of parasites in PVs was measured by counting the number of SAG1-positive parasites per PV. Each bar represents the mean ± SD of three wells per group. Results represent two independent experiments. The different letters above the data bars in the graphs indicate statistically significant differences in the number of parasites in PVs as determined by two-way ANOVA plus Tukey–Kramer post-hoc analysis (<i>P</i> < 0.05).</p

Anti-<i>Toxoplasma</i> activity of <i>P</i>. <i>betle</i> extract on RH-GFP and PLK-GFP

<p>Anti-<i>Toxoplasma</i> activity of the <i>P</i>. <i>betle</i> extract on intracellular parasites RH-GFP (A) and PLK-GFP (B). The RH-GFP and PLK-GFP-infected HFF cells were treated with the <i>P</i>. <i>betle</i> extract for 72 h at different concentrations from 0 to 50 μg/mL. Data represent the mean values ± SD for three independent experiments. The IC₅₀ values of the <i>P</i>. <i>betle</i> extract on RH-GFP and PLK-GFP were 23.2 g/mL and 21.4 μg/mL, respectively. (C) Representative images of <i>T</i>. <i>gondii</i> RH-GFP-infected HFF cells treated with sulfadiazine (1 mg/mL), or either <i>P</i>. <i>betle</i> (50 μg/mL), <i>P</i>. <i>nigrum</i> (50 μg/mL) or <i>P</i>. <i>sarmentosum</i> (50 μg/mL) extract.</p

Clinical scores and survival of <i>T</i>. <i>gondii</i>-infected mice treated with <i>P</i>. <i>betle</i> extract.

<p>Mice were intraperitoneally administrated with <i>P</i>. <i>betle</i> extracts at 25, 100 and 400 mg/kg/day or PBS from 1 to 7 days post-infection with 10³ PLK tachyzoites per mouse. Clinical scores (A) and survival (B) were monitored for 30 days post-infection in the mice. The clinical scores represent the mean total values for all mice used in this study. Data represent the mean values of all the mice used in two independent experiments performed together (<i>P</i>. <i>betle</i> extract at 100 and 400 mg/kg/day, PBS, n = 6 + 6; <i>P</i>. <i>betle</i> extract at 25 mg/kg/day, n = 6). The clinical scores were analyzed by two-way ANOVA plus Tukey–Kramer post-hoc analysis at the time points indicated (*Difference between PBS and <i>P</i>. <i>betle</i> extract at 400 mg/kg/day, <i>P</i> < 0.05; # Difference between PBS and <i>P</i>. <i>betle</i> extract at 100 mg/kg/day, <i>P</i> < 0.05). Survival curves were generated with the Kaplan–Meier method. According to the log-rank test, the differences between the PBS and <i>P</i>. <i>betle</i> extracts were significant (*Difference between PBS and <i>P</i>. <i>betle</i> extract at 100 mg/kg/day, <i>P</i> < 0.05; *** Difference between PBS and <i>P</i>. <i>betle</i> extract at 400 mg/kg/day, <i>P</i> < 0.001).</p