Kampo medicines Rikkunshito and Hangeshashinto prevent cisplatin-induced intestinal mucosal injury in rats.

BACKGROUND/PURPOSE: We examined the effects and mechanisms of rikkunshito (RKT) and hangeshashinto (HST) on cisplatin-induced mucosal injuries in the rat small bowel. METHODS: Juvenile rats were divided into 6 groups: sham control, cisplatin injection without kampo medicines, and cisplatin injection with oral administration of low and high doses of RKT (1000 mg/kg and 2000 mg/kg) and HST (500 mg/kg and 1000 mg/kg). Fecal condition, intestinal morphological changes, enterocyte proliferation, and enterocyte apoptosis were assessed. RESULTS: Diarrhea and atrophy of ileal villi observed in the cisplatin group were significantly improved in all kampo groups. Injury scores of the jejunum were significantly lower with RKT (2000 mg/kg) and HST (500 and 1000 mg/kg) than with cisplatin, and those of the ileum were significantly lower with HST (500 and 1000 mg/kg) than with cisplatin. Enterocyte proliferation of the jejunum was significantly increased with RKT (2000 mg/kg) and HST (500 mg/kg) compared with cisplatin, and those of the ileum were significantly increased in all kampo groups compared with the cisplatin group. Jejunal and ileal apoptosis following cisplatin administration was significantly inhibited by HST. CONCLUSIONS: RKT and HST prevented cisplatin-induced intestinal mucosal injury with increasing proliferation of intestinal epithelial cells. HST also attenuated cisplatin-induced crypt cell apoptosis.

The Effect of Continuous Field Block through Intercostal Muscles after Atrial Septal Defect Closure via a Mini-Right Thoracotomy in Pediatric Patients.

BACKGROUND: Postoperative pain management in thoracotomy patients often is difficult. Furthermore, pediatric patients present more challenges because of their inability to effectively communicate their pain intensity. The purpose of this study was to evaluate the use of continuous field block through intercostal muscles as postoperative pain management in pediatric thoracotomy. METHODS: Between 2014 and 2018, 11 patients underwent an ASD closure using a cardiopulmonary bypass via a mini-right thoracotomy through the fourth intercostal space. At the time of chest closure, a single-shot field block via the fourth intercostal muscles was performed with levobupivacaine (0.6 mg/kg). The first five patients were only given the single-shot field block (Single group). The remaining six patients were given levobupivacaine continuously (0.1 mg/kg/hr) through an indwelling catheter until the chest tube removal (Continuous group). The groups' vital signs, total amounts of acetaminophen used, postoperative courses were compared. RESULTS: Although the heart rate did not differ between the groups, the respiratory rate was significantly higher in the Single group versus the Continuous group at 16 and 32 hr post-surgery (35.6 ± 9.7/min vs. 18.5 ± 4.7/min; p=0.007, 43.0 ± 10.4 vs. 25.3 ± 3.1; p=0.042, respectively). The accumulated dosage of acetaminophen given by postoperative day 2 was significantly higher in the Single group versus the Continuous group (55.3 ± 22.1 mg/kg vs. 7.8 ± 17.4 mg/kg; p=0.012). CONCLUSIONS: Continuous field block via intercostal muscles after ASD closure via a mini-right thoracotomy in children was effective to stabilize the vital signs and reduce the analgesic medication use.

Corynebacterium Species of the Conjunctiva and Nose: Dominant Species and Species-Related Differences of Antibiotic Susceptibility Profiles.

PURPOSE: Nondiphtherial Corynebacterium species are normal residents of human skin and mucosa, including the conjunctiva and nose, but can cause conjunctivitis and keratitis. Recently, resistance against various classes of antibiotics has been reported in Corynebacterium. The present study investigated the type of species and antibiotic susceptibilities of the conjunctival and nasal Corynebacterium species. METHODS: This study examined 183 strains of Corynebacterium species that were isolated from patients undergoing preoperative examinations for cataract surgery. Species were identified by RNA polymerase ß-subunit-encoding gene (rpoB) sequencing. Antibiotic susceptibility tests were performed by the microdilution method according to the Clinical and Laboratory Standards Institute standard method M45. RESULTS: Corynebacterium macginleyi was the most predominant species (84%; 46 of 55) in the conjunctiva. The 2 major species in the nasal cavity were Corynebacterium accolens and Corynebacterium propinquum (44% and 31%, respectively), followed by Corynebacterium pseudodiphtheriticum (8%), Corynebacterium jeikeium (7%), and C. macginleyi (3%). In contrast to other nasal Corynebacterium species, only C. macginleyi showed a high susceptibility to macrolides. However, among nonconjunctival Corynebacterium species, C. propinquum, was unique in having a high resistance rate to levofloxacin (29%), comparable with that observed in C. macginleyi (36%). Penicillin G and tobramycin showed good susceptibility in almost all strains. CONCLUSIONS: Drug resistance against fluoroquinolones and macrolides was observed in Corynebacterium species, with the antibiotic susceptibility profiles correlating with differences of the species and niche. Nasal and conjunctival Corynebacterium profiles of drug resistance suggest habitat segregation strictly at the species level.

A feasibility study of gemcitabine, S-1 and leucovorin combination therapy (GSL) for advanced biliary tract cancer.

Objective: Gemcitabine and cisplatin (GC) combination chemotherapy is the current standard of care for patients with advanced biliary tract cancer (BTC). Recently, a randomized controlled trial showed the non-inferiority in overall survival of gemcitabine and S-1 (GS) compared to GC. Because leucovorin is known to enhance the activity of S-1, we conducted this study to evaluate the feasibility of combination therapy of gemcitabine, S-1 and leucovorin (GSL). Methods: Advanced BTC patients without prior treatment other than surgery or adjuvant chemotherapy were eligible to this study. Gemcitabine was administered at a dose of 1000 mg/m2 on day 1, and oral S-1 at a dose of 40 mg/m2 and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. The primary endpoint was PFS and the secondary endpoints included OS, objective tumour response and the safety. Results: Between June 2013 and December 2015, 20 patients with advanced BTC (12 gallbladder, 4 extrahepatic, 2 intrahepatic, 2 ampulla) including 16 unresectable disease and 4 recurrent disease were enroled. The median PFS and OS were 5.5 (95% confidence interval [CI], 1.8 - not reached) and 16.0 (95% CI, 6.4-20.8) months, respectively. A partial response was achieved in 3 (15%) and stable disease in 8 (40%), giving a disease control rate of 55%. Major grade 3/4 toxicities included neutropenia (30%), anaemia (5%), stomatitis (15%), diarrhoea (15%) and anorexia (10%). There were no treatment-related deaths. Conclusions: This study showed the feasibility and potential efficacy of GSL as a first-line treatment in patients with advanced BTC.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

Potency of an inactivated avian influenza vaccine prepared from a non-pathogenic H5N1 reassortant virus generated between isolates from migratory ducks in Asia.

A reassortant influenza virus, A/duck/Hokkaido/Vac-1/2004 (H5N1) (Dk/Vac-1/04), was generated between non-pathogenic avian influenza viruses isolated from migratory ducks in Asia. Dk/Vac-1/04 (H5N1) virus particles propagated in embryonated chicken eggs were inactivated with formalin and adjuvanted with mineral oil to form a water-in-oil emulsion. The resulting vaccine was injected intramuscularly into chickens. The chickens were challenged with either of the highly pathogenic avian influenza virus strains A/chicken/Yamaguchi/7/2004 (H5N1) or A/swan/Mongolia/3/2005 (H5N1) at 21 days post-vaccination (p. v.), when the geometric mean serum HI titers of the birds was 64 with the challenge virus strains. The vaccinated chickens were protected from manifestation of disease signs upon challenge with either of the highly pathogenic avian influenza viruses. However, challenge virus was recovered at low titers from the birds at 2 and 4 days post-challenge (p.c.). All 3 chickens challenged at 6 days p.v. died, whereas 3 chickens challenged at 8 days p.v. survived. These results indicate that the present vaccine confers clinical protection and reduction of virus shedding against highly pathogenic avian influenza virus challenge and should be useful as an optional tool in emergency cases.