Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia.

BACKGROUND: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. METHOD: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. RESULTS: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. CONCLUSION: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

Clostridium butyricum-induced ω-3 fatty acid 18-HEPE elicits anti-influenza virus pneumonia effects through interferon-λ upregulation.

The precise mechanism by which butyrate-producing bacteria in the gut contribute to resistance to respiratory viral infections remains to be elucidated. Here, we describe a gut-lung axis mechanism and report that orally administered Clostridium butyricum (CB) enhances influenza virus infection resistance through upregulation of interferon (IFN)-λ in lung epithelial cells. Gut microbiome-induced ω-3 fatty acid 18-hydroxy eicosapentaenoic acid (18-HEPE) promotes IFN-λ production through the G protein-coupled receptor (GPR)120 and IFN regulatory factor (IRF)-1/-7 activations. CB promotes 18-HEPE production in the gut and enhances ω-3 fatty acid sensitivity in the lungs by promoting GPR120 expression. This study finds a gut-lung axis mechanism and provides insights into the treatments and prophylaxis for viral respiratory infections.

Amikacin Therapy in Japanese Pediatric Patients: Narrative Review.

Children show a very wide range of physical development processes. These changes impact pharmacokinetic (PK) variability in pediatric patients. Most PK studies have been conducted on the Caucasian population. Therefore, whether current evidence of how developmental change affects PK and exposure-response relationships applies to Japanese pediatric patients remains unclear. This narrative review focuses on amikacin therapy in Japanese pediatric patients and shows the relationship between amikacin concentrations and efficacy/toxicity. Ten relevant articles were identified. Of these, nine articles were published in the 1980s. All studies reported a maximum concentration (Cmax) and minimum concentration (Cmin) of amikacin. Overall, articles reporting PK/pharmacodynamic (PD) indices and minimum inhibitory concentration (MIC) of isolated bacteria in Japanese pediatric patients is lacking, whereas all patients recovered from an infection state and showed negative cultures. Five of the included studies reported the association between Cmin and toxicity. The Cmin in three of four patients who developed toxicity was above 10 mg/L. This narrative review shows that further PK study of amikacin in Japanese pediatric patients is necessary. In particular, the pursuit of knowledge of Cmax/MIC ratio is vital. On the other hand, this review demonstrates that the optimal Cmin for Japanese pediatric patients is below 10 mg/L as a candidate concentration. However, it is noted that the number of patients who developed toxicity is very small.

In vivo study assessed meropenem and amikacin combination therapy against carbapenem-resistant and carbapenemase-producing Enterobacteriaceae strains.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE), especially for carbapenemase-producing Enterobacteriaceae (CPE), is an emerging cause that pose a significant threat to public health. However, efficient therapy has not been established. We assessed the antimicrobial efficacy of meropenem (MEPM) and amikacin (AMK) combination therapy. MATERIAL AND METHODS: Total eight isolates of Escherichia coli or Klebsiella pneumoniae, including CRE and/or CPE have carbapenemase genes were used. The relationship between phenotype and in vivo efficacy was assessed in neutropenic murine thigh infection model. Efficacy was determined using the change in bacterial density and survival rate. RESULTS: The combination therapy showed enhanced antimicrobial activities against CRE+/CPE+ and CRE+/CPE-K. pneumoniae isolates than MEPM monotherapy (0.63 ± 0.04 vs. 2.56 ± 0.24 ⊿log10 cfu/mL, p < 0.05; -1.05 ± 0.15 vs. -0.48 ± 0.30 ⊿log10 cfu/mL, p < 0.05). Likewise, the combination therapy showed enhanced antimicrobial activities against CRE+/CPE+ and CRE+/CPE-E. coli isolates than MEPM monotherapy (0.90 ± 0.68 vs. 1.86 ± 0.23 ⊿log10 cfu/mL, p < 0.05; -1.81 ± 0.06 vs. -0.88 ± 0.23 ⊿log10 cfu/mL, p < 0.05). Also, combination therapy group showed similar to higher survival rates in CRE + E. coli infection mice, compared to MEPM monotherapy group. CONCLUSION: Our results are the first supportive data to threat CRE infections with combination therapy of MEPM and AMK with in vivo model. The current results verify the promising utility of the combination therapy with MEPM and AMK against CRE isolates with a wide range of MEPM MICs.

Antimicrobial activity of solithromycin and levofloxacin against a murine pneumonia mixed-infection model caused by Streptococcus pneumoniae and anaerobic bacteria.

INTRODUCTION: Solithromycin is a novel fluoroketolide developed to treat pneumonia. But, few studies evaluating its antimicrobial activity against S. pneumoniae in a mixed-infection model with anaerobes are available, while community-acquired pneumonia can involve mixed-infection of Streptococcus pneumoniae and anaerobic bacteria. This study evaluated the antimicrobial activity of solithromycin against macrolide-resistant S. pneumoniae and anaerobic bacteria with a murine pneumonia mixed-infection model. MATERIAL AND METHODS: We evaluated antimicrobial activity of solithromycin (10 and 20 mg/kg) and levofloxacin (126 mg/kg) against S. pneumoniae with a three-point mutation in penicillin-binding protein and an ermB gene, and Parvimonas micra. Antimicrobial efficacy was calculated for each isolate as the change in bacterial count (Δlog10 CFU/mL) obtained in the treated mice after 24 h compared with the count in the starting control animals. RESULTS: The solithromycin and levofloxacin minimum inhibitory concentrations (MICs) for S. pneumoniae were 0.03 and 0.5 µg/mL, respectively. The solithromycin and levofloxacin MICs for P. micra were 0.015 and 0.12 µg/mL, respectively. In a mixed-infection model, solithromycin showed significantly higher antimicrobial activity against S. pneumoniae than levofloxacin (solithromycin 20 mg/kg; -2.87 ± 1.33 log10 CFU/mL vs. levofloxacin; -1.35 ± 0.37 log10 CFU/mL, p = 0.0397). Similarly, solithromycin showed significantly higher antimicrobial activity against P. micra than levofloxacin (solithromycin 20 mg/kg; -2.78 ± 0.98 log10 CFU/mL vs. levofloxacin; -1.57 ± 0.47 log10 CFU/mL, p = 0.0400). DISCUSSION: Solithromycin showed higher antimicrobial activities against macrolide-resistant S. pneumoniae and P. micra than levofloxacin, even though they were coexisted in murine lung tissue. Our results suggest that solithromycin could be effective for pneumonia patients due to S. pneumoniae to reduce bacterial density in lung tissue.

Considerations about the Use of a Loading Dose of Daptomycin in a Neutropenic Murine Thigh Infection Model with Methicillin-Resistant Staphylococcus aureus Infection.

Previous clinical studies have showed the clinical benefits of the initiation of treatment with a daptomycin (DAP) loading dose, but only a few studies have evaluated its antimicrobial benefits. We evaluated the efficacy of a DAP loading dose against methicillin-resistant Staphylococcus aureus (MRSA) infections in a neutropenic murine thigh infection model. Three MRSA isolates (DAP MIC: 0.5, 1, and 2 mg/L) were tested. Four DAP regimens simulating human concentration-time profiles, i.e., (i) day 1: 8 mg/kg and day 2: 6 mg/kg, (ii) days 1 and 2: 6 mg/kg/day, (iii) day 1: 8 mg/kg and day 2: 4 mg/kg, and (iv) days 1 and 2: 4 mg/kg/day, were administered to the mice. Efficacy was calculated as the change in bacterial density. DAP loading-dose regimen iii showed greater antimicrobial activity against MRSA with MIC 1 mg/L than nonloading regimen iv (-3.10 ± 0.63 vs. -0.71 ± 0.34 log10 CFU; p < 0.01). Loading-dose regimen iii achieved greater log10 CFU changes than nonloading regimen ii, while the total DAP dose for 2 days was the same (-3.10 ± 0.63 vs. -1.46 ± 0.48 log10 CFU; p < 0.05). DAP loading-dose regimen iii showed enhanced antimicrobial activity against MRSA with DAP MIC 0.5 mg/L when compared with nonloading regimen iv. However, loading-dose regimens i and iii did not reduce bacterial density for MRSA with DAP MIC 2 mg/L. Our data suggest that a DAP loading-dose regimen would be an advantageous procedure for patients infected with MRSA with DAP MIC ≤1 mg/L.

Efficacy of tedizolid against methicillin-resistant Staphylococcus aureus and Peptostreptococcus anaerobius in thigh mixed-infection mouse model.

OBJECTIVE: The purpose of this study is to compare the antimicrobial activity of human simulated exposures of tedizolid 200 mg daily, and linezolid 600 mg every 12 h for the treatment of complicated skin and skin structure infection (cSSSI) caused by MRSA and Peptostreptococcus anaerobius in both the neutropenic mice thigh mixed-infection models. MATERIAL AND METHOD: Tedizolid phosphate and linezolid were used for all in vivo testing. A total of one MRSA and two P. anaerobius isolates were utilized. Antimicrobial efficacy was calculated for each isolate as the change in bacterial numbers (Δlog10 CFU/ml) obtained in the treated mice after 24 h compared with the numbers in the starting control animals (0 h). RESULTS: The tedizolid and linezolid MICs for MRSA was 0.25 and 2 µg/ml. Tedizolid MIC for P. anaerobius was 0.12 µg/ml, and linezolid MICs for two P. anaerobius isolates were 0.5 and 1 µg/ml. In mixed infection model, tedizolid therapy showed similar antimicrobial activities for one MRSA and two P. anaerobius isolates evaluated, compared with linezolid therapy. Additionally, when comparing the activity of tedizolid and linezolid monotherapy between single infection and mixed infection model, antimicrobial activities of both antimicrobials were attenuated when mixed infection model was used. CONCLUSION: In the neutropenic murine thigh infection model, human simulated exposures of tedizolid and linezolid resulted in similar efficacies against MRSA, even though single and mixed infection models were used. These data support the clinical utility of tedizolid for use against MRSA and P. anaerobius in the treatment of cSSSI.

Colistin loading dose enhanced antimicrobial activity for in vivo mouse thigh infection model with Pseudomonas aeruginosa with highly antimicrobial resistant.

This is the first report to test the loading dosage of colistin against Pseudomonas aeruginosa, including MDRP. Using in vivo murine thigh infection model, in the loading dosage regimen (Day 1:50 mg/kg q12 h, Day 2-3: 25 mg/kg q12 h) group, 5 to 6 log10 CFU/ml reduction compared with control were observed for both strains of P. aeruginosa with colistin MIC 0.5 and 1 µg/mL at 72 h. But, similar reduction was observed for the strains with colistin MIC 0.5 µg/mL only in normal dosage regimen (Day 1-3: 25 mg/kg q12 h) group. For P. aeruginosa with colistin MIC 1 µg/mL, colistin loading dosage regimens showed greater antimicrobial activity than that of without loading dosage group (p < 0.05). These data suggest that the colistin loading regimen would be one of the useful options for P. aeruginosa with antimicrobial resistance infection treatment.

Histidine supplementation suppresses food intake and fat accumulation in rats.

OBJECTIVE: Histamine, a derivative of histidine, decreases food intake and body fat by activation of histamine neurons. Our objective was to clarify the effect of dietary histidine, in particular, on food intake and/or body fat accumulation in rats. METHODS: Male Wistar rats were assigned to one of four groups after acclimation and allowed free access to diets containing 20% casein (0% histidine), 20% casein plus 1.0% histidine, 20% casein plus 2.5% histidine, or 20% casein plus 5% histidine for 8 d. RESULTS: Food intake and body weight were recorded daily and compared between groups. During the experimental period, food intake decreased according to the increases in dietary histidine. There was a negative and significant (P < 0.01) correlation between dietary histidine (grams per 8 d) and retroperitoneal fat pad (grams per 100 g of body weight). Uncoupling protein-1 mRNA in brown adipose tissue increased with increases in dietary histidine. CONCLUSION: Our results indicate that dietary histidine suppresses food intake and fat accumulation in rats.

Evaluation of estrogenic activity in diets for experimental animals using in vitro assay.

We used a modified yeast-based human estrogen receptor alpha (ER alpha) bioassay to determine the estrogenic activity in 22 kinds of diets for experimental animals. The estrogenic activity of each diet was reevaluated by comparison with a calibration curve of 17 beta-estradiol. Almost all of the diets had estrogenic activity. The diets for rabbits and guinea pigs had the highest estrogenic activity compared to any other diets, including those for rats and mice. Estrogenic activity was found in dried skim milk, fishmeal, soybean meal, and alfalfa meal. In the NIH-07 diet opened for the ingredients, estrogenic activity was nearly all derived from the alfalfa meal. Multiple assays were performed to evaluate potential seasonal variations in the estrogenic potency in the raw materials of the rat and mouse diets. We found that the estrogenic activity in these raw materials changed throughout the year.

Laxative and anti-diarrheal activity of polycarbophil in mice and rats.

We investigated the laxative and anti-diarrheal activity of polycarbophil, an insoluble hydrophilic polymer, in comparison with other agents used for treating functional bowel disorder (FBD). In naive rats, polycarbophil (500 mg/kg) increased fecal weight and water contents without producing diarrhea. Carboxymethylcellulose (CMC) did not produce evident changes in bowel movement. Picosulfate markedly produced diarrhea. Loperamide, trimebutine and granisetron decreased stool output dose-dependently. Constipation, indicated by decrease in fecal weight, was produced by loperamide and clonidine in rats. Polycarbophil (500 mg/kg) and CMC increased fecal weight without diarrhea. Conversely trimebutine further decreased fecal weight in constipated rats. Polycarbophil (500 mg/kg) suppressed diarrhea induced by castor oil, and at 250-500 mg/kg, it produced shaped stools in animals with stools loosened by prostaglandin E2, serotonin or carbachol in mice. Polycarbophil (500 mg/kg) also reduced stools in rats with stool output increased by wrap restraint stress (WRS). CMC had no effect in the diarrhea models, except for carbachol-induced diarrhea, and WRS-induced evacuation. Loperamide, trimebutine and granisetron inhibited diarrhea production and WRS-induced evacuation, except for carbachol-induced diarrhea. The results show that polycarbophil prevents constipation and diarrhea without inducing diarrhea or constipation, which is different from the other agents. Hydrophilic polymers such as polycarbophil will be promising agents for the treatment of FBD.

Phytoestrogen-low diet for endocrine disruptor studies.

Hormonally active chemicals (HACs) that are capable of inducing adverse effects on wildlife as well as human beings are featured as "endocrine disruptors". Various animal studies conducted to clarify the characteristics of HACs, including the uterotrophic assay, are sufficiently sensitive to detect the effect of 17-beta-estradiol in micrograms per kilogram of body weight or lower. In such systems, a trace amount of HACs in the dietary pellets may interfere with the test results and thus can be a serious problem for the low-dose issue, which is now a major topic in the field of endocrine disruptor research. Here, the significance of the hormonal effects of phytoestrogen components in the NIH-07 diet is confirmed and a NIH-07-based open formula "phytoestrogen-low diet" (PLD) is proposed, which effectively reduces uterine weight as well as the uterine luminal epithelial labeling index in ovariectomized rats.

[Development of transdermal formulation of tulobuterol for the treatment of bronchial asthma].

beta 2-Adrenergic agonists have been widely used to treat patients with asthma. Usually, oral dosage forms of beta 2-agonists have been used, but side effects such as palpitation and tremor have been reported because of excessive serum levels around Tmax. It is said that circadian variations exist in the manifestation of asthma with maximum incidence of asthma attacks in early morning at around 4 a.m., the so-called morning dip. Chronotherapy for asthma based on circadian rhythm should be more efficient and have a lower frequency of side effects. Accordingly we developed a transdermal delivery system of the beta 2-agonist tulobuterol adapted to the circadian rhythm. The system is designed to administer the appropriate dose of the drug at an optimal time using the so-called Crystal Reservoir System. The superiority of the transdermal formulation of tulobuterol over the current therapy using oral formulations of beta 2-stimulants was indicated by its excellent pharmacokinetic profile, and confirmed by the results of clinical trials. This formulation is the first transdermal chrono-delivery system reported anywhere in the world, and is expected to provide more effective and safe treatment of asthma and related diseases not only in adults, but also especially in children.