Drug repositioning of antipsychotic drugs for cisplatin-induced pica behavior in mice.

We aimed to clarify whether various antipsychotics ameliorate cisplatin-induced pica behavior in mice using a drug repositioning approach. Mice were administered cisplatin (12.5 mg/kg, i.p.) with or without olanzapine (1 mg/kg, i.p.), asenapine (4 mg/kg, i.p.), mirtazapine (5 mg/kg, i.p.) or standard three-drug antiemetics (granisetron [0.5 mg/kg, i.p.], fosaprepitant [25 mg/kg, i.p.], and dexamethasone [3 mg/kg, i.p.]). Kaolin, food, and water intake, and spontaneous motor activity on the day before and seven consecutive days after the cisplatin administration were measured using a telemetry system. At the primary endpoint, kaolin intake was significantly higher at day three in the cisplatin group than in the pre-treatment and saline groups ( p < 0.05). Additionally, kaolin intake was not significantly higher in cisplatin with olanzapine, asenapine, and mirtazapine groups for seven days than in the pre-treatment group. At the secondary endpoint, cisplatin decreased the food and water intake, and spontaneous motor activity in a time-dependent manner. Three antipsychotics failed to improve the cisplatin-induced decrease in food and water intake, and spontaneous motor activity. The findings suggest that prophylactic administration of antipsychotics besides olanzapine may improve cisplatin-induced nausea and vomiting in a delayed phase and de-escalate standard 3-drug antiemetics.

Preventive effects of self-administered cryotherapy on paclitaxel-induced peripheral neuropathy in patients with early-stage breast cancer: a propensity score analysis.

We hypothesized that suppression of peripheral circulation via cryotherapy may be effective in preventing paclitaxel-induced peripheral neuropathy (PIPN). Therefore, this study aimed to clarify whether self-administered cryotherapy could prevent PIPN in patients with early-stage breast cancer, using real-world data. A single-center, retrospective, observational study was conducted. Data from the electronic medical records of consecutive patients aged ≥ 20 years with early-stage breast cancer who received a regimen containing paclitaxel for 12 cycles with or without self-administered cryotherapy at the National Cancer Center Hospital from March 2018 to May 2019 were evaluated. The primary endpoint was the cumulative dose of paclitaxel until the onset of grade ≥ 2 PIPN. To compare the difference between the two groups, multivariable Cox proportional hazards models adjusted for prognostically important variables were used. Ninety Japanese patients were included in this study. The estimated incidence of grade ≥ 2 PIPN was 26.9% and 37.7% in the self-administered cryotherapy group and control group, respectively (P = 0.314). The multivariable Cox proportional hazards model showed that the self-administered cryotherapy group had a decreased risk of onset of grade ≥ 2 PIPN (hazard ratio: 0.63, 95% confidence interval: 0.25 to 1.39; P = 0.281). Sensitivity analyses using multivariable Cox proportional hazards models along with two propensity score-adjusted methods demonstrated consistent results. The findings suggest that the methods of self-administered cryotherapy may prevent PIPN and should be reinforced appropriately in clinical practice. A randomized controlled multicenter trial of self-administered cryotherapy is warranted.

Effect of renin-angiotensin system inhibitors on pemetrexed plus platinum-induced hematological toxicities: a multicenter retrospective study using three propensity score analyses.

Hematological toxicities induced by pemetrexed plus platinum therapy remain a critical issue in clinical practice. We hypothesized that inhibition of the renin-angiotensin system (RAS) can ameliorate pemetrexed-induced hematological toxicities through drug-drug interactions involving organic anion transporters. Thus, this study aimed to clarify whether RAS inhibitors (RASIs) could prevent pemetrexed plus platinum-induced hematological toxicities. We retrospectively analyzed data from 305 consecutive patients with non-small cell lung cancer or malignant pleural mesothelioma who received their first cycle of a pemetrexed plus platinum regimen and were treated with or without RASIs. The primary endpoint was the incidence of severe myelosuppression after the first cycle. Propensity score (PS)-matched, PS-adjusted, and inverse probability of treatment weighting (IPTW) analyses were used. The number of patients with grade ≥3 hematological toxicities was 27 (8.9%). PS-matched analyses revealed that the concomitant use of RASIs was slightly associated with a lower risk of grade ≥3 hematological toxicities (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.20-2.32; p = 0.536). Additionally, sensitivity analyses using PS-adjusted and IPTW methods demonstrated similar results (OR, 0.63; 95% CI, 0.19-2.15; p = 0.463 and OR, 0.37; 95% CI, 0.11-1.29; p = 0.117, respectively). These findings suggest that RASIs might prevent pemetrexed plus platinum-induced hematological toxicities.

Comparison of antiemetic efficacy between single and repeat treatment with dexamethasone in patients receiving carboplatin-based combination chemotherapy.

A retrospective study was carried out to compare the preventive effects of single and repeat treatment with dexamethasone (DEX) on delayed nausea and emesis in patients who had received carboplatin (CBDCA)-based combination chemotherapy. Sixty-four patients were evaluated. Efficacy was assessed using the nausea and emesis score, food intake score and the requirement for antiemetic medication. These forward scores were categorized as three-grade during the first 5 days after chemotherapy. Acute nausea and emesis were well controlled in both groups on day 1. Mean values of the nausea and emesis score on day 3 evening and the food intake score on day 4 morning in the repeat-treatment group was 1.31 ± 0.93 and 3.46 ± 1.03, respectively, which were significantly better when compared with the single-treatment group (2.00 ± 1.52; P = 0.028 and 2.79 ± 1.12; P = 0.018, respectively). Multivariate logistic regression analysis revealed that less frequent dispensing of antiemetic medication was significantly associated with the repeat-treatment group (adjusted odds ratio, 0.153; 95% confidence interval, 0.026-0.734; P = 0.018). These results suggest that repeat-dose DEX may be more effective than single-dose DEX for the prevention of delayed nausea and emesis after CBDCA-based combination chemotherapy.

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3beta positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-kappaB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3beta and to assess the anti-cancer effect of GSK-3beta inhibition in RCC. METHODS: Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3beta in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT-PCR, BrDU incorporation and MTS assays to study the effect of GSK-3beta inactivation on renal cancer cell proliferation and survival. RESULTS: We detected aberrant nuclear accumulation of GSK-3beta in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF-kappaB target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells. CONCLUSIONS: Our results show nuclear accumulation of GSK-3beta as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer.

Problems associated with prophylactic use of erythromycin in 1566 staff to prevent hospital infection during the outbreak of pertussis.

BACKGROUND AND OBJECTIVE: Pertussis developed in Kagawa University Medical School and University Hospital in May 2007. To control the outbreak and prevent the infection of hospital inpatients, the Infection Control Team (ICT) carried out the prophylactic administration of erythromycin (EM) to hospital staff (1566 staff) who might be exposed to Bordetella pertussis. METHODS: An oral dose of 1000 mg/day EM was given for 10 days. To assess compliance and estimate the frequency of adverse effect, the ICT conducted a questionnaire survey. RESULTS AND DISCUSSION: Of 942 respondents (response rate: 60.2%), 264 (28.0%) experienced some form of EM adverse effects, of which the most commonly reported involved digestive organ symptoms, e.g. diarrhoea (15.6%), stomachache (7.5%), nausea (3.6%), epigastric distress (2.1%) and abdominal distention (1.8%). More importantly, 246 participants (26.1%) stopped taking the EM before completing 10 days because of perceived adverse effects. CONCLUSION: These results indicate that EM appears to cause adverse effects more frequently than reported in the package insert in Japan. The prophylactic use of EM for pertussis infection is recognized in the guideline of the Centers for Disease Control and Prevention. However, this study suggests that attention should be paid to EM non-compliance during a pertussis outbreak, which could extend the duration of the outbreak and increase the number of affected patients.

Clinical application of visible light-cured fluoride-releasing sealant to non-etched enamel surface of partially erupted permanent molars.

A visible light-cured fluoride-releasing sealant was applied to non-etched enamel surfaces of partially erupted permanent molars. A scanning electron microscope was used to find an effective procedure to clean pits and fissures of the occlusal surfaces prior to application of the sealant. This procedure proved clinically acceptable and effective for prevention of dental caries immediately after eruption of permanent molars.

Preparation of Bragg gratings in sputter-deposited GeO(2)-SiO(2) glasses by excimer-laser irradiation.

GeO(2) - SiO(2) thin glass films were prepared by the rfsputtering deposition method. Changes in the refractive index of -3% and in the volume of +18% were induced in the film by irradiation with excimer-laser pulses. Bragg gratings a (periodic surface-relief pattern with a sinusoidal wave) have been written in the film by irradiation through a phase mask.

Ultraviolet-radiation-induced chemical reactions through one and two-photon absorption processes in GeO(2)-SiO(2) glasses.

Photochemical reactions in 10 GeO(2)-90 SiO(2) glass induced by irradiation with excimer lasers (KrF, 5.0 eV, XeCl, 4.0 eV) and a Hg lamp (4.9 eV) were examined. The irradiation with excimer lasers generated two types of paramagnetic defect, an electron-trapped center associated with fourfold coordinated Ge ions and a self-trapped hole center on bridging oxygen. Taking the optical band gap (~7.1 eV) of the glass obtained in this work and the power density of laser pulses [10-90 mJ/(cm(2) pulse), pulse duration 20 ns] into account, we concluded that these centers were formed by band-to-band excitation by two-photon absorption process. On the other hand, the lamp illumination ( 16 mW/cm(2)) caused the formation of Ge E' centers from preexisting oxygen-vacancy-type defects by the one-photon absorption process. These two kinds of reaction proceed independently, depending on the power densities of UV beams, at least in our experimental condition.

Dose-response studies on the induction of liver cytochromes P4501A1 and 1B1 by polycyclic aromatic hydrocarbons in arylhydrocarbon-responsive C57BL/6J mice.

1. To determine the biological effects of 23 polycyclic aromatic hydrocarbons (PAHs) and 3,4,3',4'-tetrachlorobiphenyl, the dose-response studies of the induction of CYP1-dependent xenobiotic oxidation activities by these chemicals in liver microsomes of C57BL/6J mice were studied. 2. In arylhydrocarbon-responsive C57BL/6J mice, the liver microsomal xenobiotic oxidation with substrates of 7-ethoxyresorufin, 7-ethoxycoumarin, (+/-)-benzo[a]pyrene-7,8-diol, dibenzo[a, pyrene-11,12-diol and 2-amino-3,5-dimethylimidazo[4,5-f]quinoline increased by increasing the doses of PAHs to mice, particularly when the PAHs that have been reported to be carcinogenic in experimental animals were used. In arylhydrocarbon receptor-knockout mice, there were no increases in liver microsomal 7-ethoxyresorufin O-deethylation activities nor in liver mRNA levels of CYP1A1, 1A2 and 1B1 by these chemicals. 3. Of the chemicals examined, benzo[k]fluoranthene, benzo[b]fluoranthene, benzo[j]-fluoranthene, 3-methylcholanthrene, dibenz[a,h]anthracene, dibenz[a,c]anthracene and 3,4,3',4'-tetrachlorobiphenyl were potent inducers of the induction of liver microsomal 7-ethoxyresorufin O-deethylation in mice. 4. Other PAHs such as 5-methylchrysene, benzo[a]pyrene, dibenzo[a,l]pyrene, dibenz[a,j]acridine, benzo[a]anthracene and 7,12-dimethylbenz[a]anthracene moderately induced 7-ethoxyresorufin O-deethylation activities in mice. PAHs reported to be weak or less carcinogenic in experimental animals did not induce the xenobiotic oxidation activities of CYP1A1 and 1B1 in the mice. 5. The results suggest that induction of liver microsomal CYP1-dependent xenobiotic oxidation activities is a good tool in determining the potencies of carcinogenic PAHs in arylhydrocarbon-responsive C57BL/6J mice.