Phase 2 study of bevacizumab plus carboplatin/nab-paclitaxel followed by bevacizumab plus nab-paclitaxel for non-squamous non-small cell lung cancer with malignant pleural effusion.

Objectives Vascular endothelial growth factor plays an important role in the pathogenesis of malignant pleural effusion (MPE). We previously showed the efficacy of bevacizumab (Bev) plus carboplatin (CBDCA)/paclitaxel (PTX) in the treatment of non-small lung cell cancer (NSCLC) with MPE. However, the toxicities were a little severe, and the efficacy was not satisfied sufficiently. Therefore, we conducted a phase II study for NSCLC with MPE to evaluate the efficacy and safety of Bev plus CBDCA/nab-PTX, which is a new combination therapy. Methods Chemotherapy-naive non-squamous (SQ) NSCLC patients with MPE participated in the study. A single aspiration (not allowing chest tube drainage) was allowed before chemotherapy. Patients received a maximum of six cycles of Bev (15 mg/kg, day1) plus CBDCA (AUC 6, day1)/nab-PTX (100 mg/m2, day1, 8) every 3 weeks followed by Bev (15 mg/kg, day1) plus nab-PTX (100 mg/m2, day1, 8) every 3 weeks without disease progression or unacceptable severe toxicities. The primary endpoint was objective response rate (ORR). Results The study enrollment was ceased because of suspension of the registration period (as scheduled) after 12 of 20 planned patients were treated successfully between March 2014 and February 2018. The ORR was 58.3 % (95 % CI, 27.7-84.8 %), and the disease control rate was 100 % (95 % CI, 73.5-100 %). Eight patients received maintenance therapy. Median progression-free and overall survival times were 14.4 and 26.9 months, respectively. Most patients experienced hematological toxicities, including ≥ grade 3 neutropenia and anemia; none experienced severe bleeding events and grade 5 toxicities. Conclusion The combination of Bev plus CBDCA/nab-PTX, a novel combination, might have efficacy with acceptable toxicities in chemotherapy-naïve non-SQ NSCLC patients with MPE.Trial Registration University Hospital Medical Information Network in Japan (UMIN) Clinical Trials Registry (No. UMIN000013329) registered on 4th March 2014.

Exacerbation of liver dysfunction in non-alcoholic steatohepatitis patients during the coronavirus disease 2019 (COVID-19) pandemic.

Many people were forced to stay at home, including non-alcoholic steatohepatitis (NASH) patients, however it is unclear how this home-life has affected the prognosis of NASH. In this study, we examined the influences of living at home during the coronavirus disease 2019 (COVID-19) pandemic NASH patients. In this study, we compared the clinical parameters of NASH patients without COVID-19 infection 3 months before with those 3 months after the declaration of a state of emergency. In the results, the changes of aspartate transaminase and alanine aminotransferase in the 3 months before (aspartate transaminase, -3.6 ± 13.8 U/L; alanine aminotransferase, -6.8 ± 19.5 U/L) was significantly exacerbated in the 3 months after (aspartate transaminase, 2.3 ± 7.5 U/L; alanine aminotransferase, 1.7 ± 10.4 U/L). Furthermore, the changes of the fibrosis-4 index in the 3 months before (-0.27 ± 0.84) was also significantly exacerbated in the 3 months after (0.38 ± 0.96). In conclusion, liver dysfunctions in NASH patients were exacerbated due to the emergency declaration and outing restriction which accompanied COVID-19.

Safety and efficacy of afatinib for the treatment of non-small-cell lung cancer following osimertinib-induced interstitial lung disease: A retrospective study.

Background Osimertinib is one of the first-line treatments for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the occurrence rate of osimertinib-induced interstitial lung disease (ILD) is particularly high in Japanese patients and little information on subsequent cancer treatment options after recovery from osimertinib-induced ILD is currently available. Thus, this study aims to determine the safety and efficacy of afatinib for the treatment of NSCLC following osimertinib-induced ILD. Methods We retrospectively investigated the clinical courses of all NSCLC patients with EGFR mutations at our facility between August 2018 and September 2019, who received osimertinib as first-line treatment and were subsequently treated with afatinib after developing osimertinib-induced ILD. Results Forty-two patients received osimertinib treatment at our facility during the study period, and four patients received afatinib after developing osimertinib-induced ILD. All events of ILD improved either spontaneously or with steroid therapy before the initiation of afatinib. For the four patients who were retrospectively reviewed, the overall response rate to afatinib therapy was 75%, and the disease control rate was 100%. During the study period, no ILD recurrence was observed in any of the four patients. Conclusions According to our study findings, afatinib treatment after osimertinib-induced ILD is considered safe and effective and it can be used as one of the treatment options for NSCLC following osimertinib-induced ILD.

In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals.

We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50-150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5-10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.

Paradoxical response in a patient with non-small cell lung cancer who received nivolumab followed by anti-Mycobacterium tuberculosis agents.

Anti-programmed cell death-1 (PD-1) agents enhance the antitumor immunoresponse. A number of reports have indicated that patients with malignancies who receive anti-PD-1 agents are at risk for tuberculosis (TB) infection. In this report, we present a patient with non-small cell lung cancer who developed pulmonary tuberculosis while receiving the anti-PD-1 agent nivolumab, and who subsequently demonstrated a paradoxical response (PR) 10 days after initiation of anti-MTB treatment. We suggest that anti-PD-1 agents not only induce the development of pulmonary TB, but also development of PR after anti-MTB treatment, through upregulation of the immune response. Furthermore, based on their radiological and immunological similarity, we speculate that the schema of development of PR closely resembles that of pseudoprogression in non-small cell lung cancer patients after anti-PD-1 treatment.

Clinical predictors of bevacizumab-associated intestinal perforation in non-small cell lung cancer.

Background Bevacizumab (Bev) is generally well-tolerated, and Bev-associated intestinal perforation (BAP) is a rare albeit serious side effect in cases of non-small cell lung cancer (NSCLC). Therefore, the present study aimed to identify clinical predictors of BAP to help predict and manage the development of life-threatening intestinal complications among patients receiving Bev. Methods This retrospective study evaluated demographic, clinical, and treatment factors for patients with NSCLC who were treated with Bev between February 2010 and August 2015 at our center. Results We identified 314 regimens (208 patients; median age: 65 years; 115 women) for analysis, which included 119 first-line regimens, 74 s-line regimens, and 121 third-line or later regimens. BAP occurred in 7 cases (2.23% among all regimens and 3.37% among all patients), which generally occurred during first- or second-line treatment and was caused by ulcerative colitis (1 case), colon diverticulitis (1 case), and idiopathic perforations (5 cases). Univariate analyses revealed that BAP was significantly associated with deteriorating PS during the first cycle of chemotherapy (odd ratio [OR]: 11.07, 95% confidence interval [CI]: 2.37-51.63, p = 0.0022), grade ≥ 3 diarrhea (OR: 11.37, 95% CI: 2.37-54.50, p = 0.0024), febrile neutropenia (OR: 9.16, 95% CI: 1.98-42.49, p = 0.0047), and stomatitis (OR: 4.60, 95% CI: 1.01-21.04, p = 0.0492). Conclusions Among patients with NSCLC, BAP was associated with deteriorating PS during the first cycle of chemotherapy, grade ≥ 3 diarrhea, febrile neutropenia, and stomatitis. Therefore, careful observation is needed for patients with NSCLC who receive Bev in any line of treatment, especially if they develop serious side effects that affect their PS or mucous membrane.

Phase1 study of cisplatin plus pemetrexed with erlotinib and bevacizumab for chemotherapy-naïve advanced non-squamous non-small cell lung cancer with EGFR mutations.

Background Cisplatin and pemetrexed are very effective against advanced non-squamous non-small cell lung cancer (NSCLC) without EGFR mutations. Erlotinib plus bevacizumab are highly effective against advanced NSCLCs with activating EGFR mutations. We performed this phase I 'Quartet Trial' to determine the safety and efficacy of all 4 agents as a first-line treatment for non-squamous NSCLC patients harboring activating EGFR mutations. Patients and Methods Patients received escalating quartet-agent doses every 3 weeks for 4 cycles. We examined the dose-limiting toxicity (DLT) to determine the maximum tolerated dose (MTD) and recommended dose (RD). Results Ten patients (3 men and 7 women) with a median age of 69 years were enrolled. Four and 6 patients had exon 19 and 21 mutations, respectively; 8 received maintenance therapy without unexpected or cumulative toxicities. One of 6 patients experienced grade 3 vagal reflex at 60 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab, which was designated the RD. Four patients experienced no DLT with 75 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab (designated the MTD); however, 3 underwent dose reduction due to severe toxicities (grade 3 gastrointestinal hemorrhage, skin rash, nausea, and febrile neutropenia) during induction chemotherapy. The most frequent DLT-phase adverse events were nausea, anorexia, and fatigue. The overall response rate was 100%. Furthermore, the progression-free and overall survival rates were 17.9 and 32.0 months, respectively. Conclusions This quartet chemotherapy regimen was tolerable and effective in our patient population (UMIN000012536).

Efficacy and safety of concurrent anti-Cancer and anti-tuberculosis chemotherapy in Cancer patients with active Mycobacterium tuberculosis: a retrospective study.

BACKGROUND: In our previous study, colorectal cancer (CRC) patients with active Mycobacterium tuberculosis (MTB) tolerated concurrent anti-cancer chemotherapy (anti-CCT) and anti-MTB chemotherapy. In this study, we retrospectively confirmed the efficacy and safety of concurrent chemotherapy in a greater number of patients with different types of malignancies. METHODS: We enrolled 30 patients who were treated concurrently with anti-CCT and anti-MTB regimens between January 2006 and February 2016. Cancer and MTB treatments were administered according to the approved guidelines. RESULTS: Patient demographics included: men/woman: 24/6; median age: 66.5 years; Eastern Cooperative Oncology Group performance status 0-1/2/3-4: 24/4/2; Stage IIB-IIIC/IV/recurrence: 6/22/2; lung cancer (LC)/CRC/other: 15/10/5; and MTB diagnosis (before or during anti-CCT): 20/10 (LC: 8/7; CRC: 8/2; other: 4/1). For anti-CCT, 23 patients received two cytotoxic agents with or without targeted agents and 7 patients received a single cytotoxic or targeted agent. The overall response rate was 36.7%. Regarding anti-MTB chemotherapy, 22 patients received a daily drug combination containing isoniazid, rifampicin, and ethambutol, plus pyrazinamide in 15 of the 22 patients, followed by daily isoniazid and rifampicin; the remaining 8 patients received other combinations. Hematological adverse events of Grade ≥ 3 were observed in 19 (67.9%) of 28 patients; laboratory data were lost for the remaining 2. Grade 3 lymphopenia and higher were significantly more frequent in LC compared to other malignancies (P < 0.005). Non-hematological adverse events of Grade ≥ 3 were observed in 5 (16.7%) of 30 patients. One CRC patient experienced Grade 3 hemoptysis and another 2 experienced Grade 3 anaphylaxis. One patient with cholangiocellular carcinoma and gastric cancer experienced Grade 3 pseudomembranous colitis as a result of a Clostridium difficile infection. One patient (3.3%) died of pemetrexed-induced pneumonitis. The success of the anti-MTB chemotherapy was 70.0%. There were no MTB-related treatment failures. The median overall survival (months, 95.0% confidence interval) was 10.5 (8.7-36.7), 8.7 (4.7-10.0), 36.7 (minimum 2.2), and 14.4 (minimum 9.6) for all patients combined, LC, CRC, and Other malignancies, respectively. LC patients experienced delayed MTB diagnosis and shorter overall survival. CONCLUSIONS: Concurrent chemotherapy is effective and safe for treating cancer patients with active MTB.

Enhancement in Corneal Permeability of Dissolved Carteolol by Its Combination with Magnesium Hydroxide Nanoparticles.

We prepared magnesium hydroxide (MH) nanoparticles, and investigated their effect when combined with dissolved carteolol on the bioavailability and intraocular pressure (IOP)-reducing effect of carteolol. The carteolol was solved in saline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; CRT-solution). MH nanoparticles were prepared by a bead mill method with additives. Then carteolol/MH microparticle and carteolol/MH nanoparticle fixed combinations (mCMFC and nCMFC) were prepared by mixing the CRT-solution and MH particles. The transcorneal penetration and IOP-reducing effect of carteolol was evaluated in rabbits. The mean particle size of mCMFC was 7.2 µm, and the particle size was reduced to 73.5-113.5 nm by the bead mill treatment. The MH particles in nCMFC remained in the nano size range for 8 days after preparation, and the amounts of lacrimal fluid and corneal damage were unchanged by repetitive instillation of nCMFC (twice a day for 4 weeks). The transcorneal penetration of carteolol was enhanced by the combination with MH nanoparticles, and the IOP-reducing effect of nCMFC was significantly higher than that of CRT-solution or mCMFC. In conclusion, we designed nCMFC, and showed that the high levels of dissolved carteolol can be delivered into the aqueous humor by the instillation of nCMFC. Combination with MH nanoparticles may achieve an enhancement of corneal penetration for water-soluble drugs. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.

Instillation of Sericin Enhances Corneal Wound Healing through the ERK Pathway in Rat Debrided Corneal Epithelium.

Sericin is a major constituent of silk produced by silkworms. We previously found that the instillation of sericin enhanced the proliferation of corneal epithelial cells, and acted to promote corneal wound healing in both normal and diabetic model rats. However, the mechanisms by which sericin promotes the proliferation of corneal cells have not been established. In this study, we investigated the effects of sericin on Akt and ERK activation in a human corneal epithelial cell line (HCE-T cells) and rat debrided corneal epithelium. Although Akt phosphorylation was not detected following the treatment of HCE-T cells with sericin, ERK1/2 phosphorylation was enhanced. The growth of HCE-T cells treated with sericin was significantly increased, with the cell growth of sericin-treated HCE-T cells being 1.7-fold higher in comparison with vehicle-treated HCE-T cells. On the other hand, both of an ERK inhibitor U0126 (non-specific specific inhibitor) and SCH772984 (specific inhibitor) attenuated the enhanced cell growth by sericin, and the growth level in the case of co-treatment with sericin and ERK1/2 inhibitor was similar to that of cells treated with ERK1/2 inhibitor alone. In an in vivo study using rat debrided corneal epithelium, the corneal wound healing rate was enhanced by the instillation of sericin, and this enhancement was also attenuated by the instillation of U0126. In addition, the corneal wound healing rate in rats co-instilled with sericin and U0126 was similar to that following the instillation of U0126 alone. In conclusion, we found that the instillation of sericin enhanced cell proliferation via the activation of the MAPK/ERK pathway, resulting in the promotion of corneal wound healing in rat eyes. These findings provide significant information for designing further studies to develop potent corneal wound-healing drugs.

Co-instillation of nano-solid magnesium hydroxide enhances corneal permeability of dissolved timolol.

We prepared magnesium hydroxide (MH) nanoparticles by a bead mill method, and investigated whether the co-instillation of MH nanoparticles improves the low transcorneal penetration of water-soluble drugs, such as the anti-glaucoma eye drug timolol maleate (TM). MH particle size was decreased by the bead mill treatment to a mean particle size of 71 nm. In addition, the MH nanoparticles were highly stable. Next, we demonstrated the effect of MH nanoparticles on the corneal surface. MH shows only slight solubility in lacrimal fluid, and the instillation of MH nanoparticles for 14 days did not affect the behavior (balance of secretion and excretion) of the lacrimal fluid in rabbit corneas. Moreover, there was no observable corneal toxicity of MH nanoparticles, and treatment with MH nanoparticles enhanced the intercellular space ratio in the eyes of rats. MH alone did not permeate into the cornea; however, the co-instillation of MH nanoparticles and dissolved TM (nMTFC) enhanced the corneal penetration of TM. In addition, the intraocular pressure (IOP)-reducing effect of nMTFC was significantly higher than those of the TM solution or the co-instillation of MH microparticles and TM. In conclusion, we found that MH nanoparticles enhance the corneal penetration of dissolved TM with no observable corneal stimulation or obstruction of the nasolacrimal duct by the MH nanoparticles. It is possible that the co-instillation of MH nanoparticles may provide a useful way to improve the bioavailability of water-soluble drugs in the ophthalmic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.

A Nanoparticle-Based Ophthalmic Formulation of Dexamethasone Enhances Corneal Permeability of the Drug and Prolongs Its Corneal Residence Time.

We designed ophthalmic formulations containing dexamethasone-loaded solid nanoparticles (DEXnano dispersion), and investigated corneal permeability and toxicity. 0.1% dexamethasone (DEX) powder (DEX microparticles), 0.026% methyl p-hydroxybenzoate (MP), 0.014% propyl p-hydroxybenzoate (PP), and 0.5% methylcellulose were used, and the DEXnano dispersion was prepared by the bead mill method. The mean particle size of DEXnano dispersion was 78 nm. Antimicrobial activity of the DEXnano dispersion were measured by using Escherichia coli, and the corneal epithelium-debrided rat model and HCE-T cells (immortalized human corneal epithelial cell line) were used to estimate the corneal toxicity. The transcorneal penetration of the DEXnano dispersion were evaluated in the corneas of rabbit. The DEXnano dispersion was found to be highly stable until 14 d after its preparation. Although DEX itself did not exhibit antimicrobial activity, the DEXnano dispersion containing parabens (MP and PP) showed high antimicrobial activity, approximately equal to that of the solution containing parabens without DEX. The corneal penetration rate (Jc) and mean residence time (MRT) of DEX from the DEXnano dispersion were approximately 5.1- and 1.3-fold higher, respectively, than those of a dispersion containing DEX microparticles (mean particle size, 11.3 µm). In addition, no significant difference was found in corneal stimulation between the vehicle and DEXnano dispersion. In conclusion, we successfully prepared high quality dispersion containing DEX solid nanoparticles, and the nanoparticle-based ophthalmic formulation of DEX enhanced the corneal permeability and residence time of the drug. It is possible that DEXnano dispersion will show increased effectiveness in treating ocular inflammation.

The preventive effect of the impaired liver function for antiemetic therapy against chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients.

Transarterial chemoembolization and hepatic arterial infusion chemotherapy are recommended for the treatment in patients with intermediate stage of hepatocellular carcinoma. Impaired liver function was sometime observed in patients with hepatocellular carcinoma after transarterial chemoembolization or hepatic arterial infusion chemotherapy. However, what kinds of factors deeply influence in impaired liver function are not clear. A retrospective study was performed to evaluate the risk factors of impaired liver function in cisplatin-naïve patients treated with these therapies using cisplatin. Prior to and 2 months after these therapies, we analyzed the liver function by Child-Pugh score in these patients. For assessing the severity of chemotherapy-induced nausea and vomiting, we utilized the Common Terminology Criteria for Adverse Events ver. 4.0. In hepatocellular carcinoma patients received these therapies using cisplatin, the cancer stage and treatment without neurokinin-1 (NK1) antagonist were found to be independent risk factors of the impaired liver function. The treatment with NK1 antagonist was effective in reducing chemotherapy-induced nausea and vomiting and patients treated with NK1 antagonist kept their liver functions after cisplatin-used these therapies. The treatment with NK1 antagonist was effective in chemotherapy-induced nausea and vomiting and prevented the impaired liver function associated with cisplatin-used these therapies in hepatocellular carcinoma patients.

Size effect of rebamipide ophthalmic nanodispersions on its therapeutic efficacy for corneal wound healing.

In a variety of tissues including gastrointestinal mucosa, rebamipide (REB) provides cytoprotection, prevents inflammation, and promotes wound healing. Clinically, REB ophthalmic dispersions are used to treat diabetic keratopathy. In this study, we investigated the optimal particle size of REB to promote corneal wound healing using a model of diabetic keratopathy, the debrided corneal epithelium from Otsuka Long-Evans Tokushima Fatty (OLETF) rats. First, we prepared three dispersions with different REB particle sizes (REB735, REB150, REB45) by treatment with zirconia beads and Bead Smash 12 (a bead mill). The mean particle sizes of the REB735, REB150, REB45 dispersions were approximately 735 nm, 150 nm and 45 nm, respectively. Next, we measured the amounts of REB in the corneal and conjunctival tissues of rats following the instillation of the REB dispersions. The amounts of REB in the corneal and conjunctival tissues following the instillation of REB dispersions was increased by using the mill method, and the amount of REB in rats instilled with the REB150 dispersion was significantly higher than in rats instilled with the REB45 dispersion. Moreover, the corneal wound healing rate for rats instilled with the REB150 dispersion was significantly higher than for rats instilled with the REB735 or REB45 dispersions. In addition, these REB dispersions enhanced corneal epithelial cell growth, resulting an enhancement of corneal wound healing rate. Thus, we found that the ocular drug accumulation and therapeutic effect on corneal wound healing of REB dispersions is enhanced by preparing particles with a size of ca. 150 nm. These findings provide significant information that can be used to design further studies aimed at developing ophthalmic dispersions.

Radial endobronchial ultrasound with a guide sheath for diagnosis of peripheral cavitary lung lesions: a retrospective study.

BACKGROUND: Radial endobronchial ultrasound with a guide sheath (EBUS-GS) has improved the diagnostic outcomes of peripheral lung lesions. However, to our knowledge, reports on the use of EBUS-GS for diagnosis of cavitary lesions are unavailable. Therefore, this study aimed to assess the effectiveness and safety of EBUS-GS for diagnosis of peripheral cavitary lung lesions (PCLLs). METHODS: This study was a single-institution retrospective review of PCLLs examined by using EBUS-GS between July 2013 and October 2015. The diagnostic results of different EBUS-GS samples, including cytologic, histopathologic, and microbiologic samples, were analysed separately. RESULTS: Of 696 radial EBUS procedures performed during the study period, 50 were performed for examination of PCLLs. The overall diagnostic yield for EBUS-GS was 80 % (40/50). Regarding 27 malignant lesions, the diagnostic yields for cytologic and histopathologic samples were 63.0 % (17/27) and 74.1 % (20/27), respectively. Regarding 23 benign lesions, the diagnostic yields for histopathologic and microbiologic samples were 69.6 % (16/23) and 47.8 % (11/23), respectively. Uni- and multivariate analyses indicated that the EBUS probe being within the lesion was the only factor significantly associated with increased diagnostic yield (odds ratio, 7.04; P = 0.03). Although pulmonary infection occurred after the procedure in 1 patient (2.0 %), no other complications, including pneumothorax or significant haemorrhage, were reported. CONCLUSION: EBUS-GS was found to be an effective and safe procedure for diagnosis of PCLLs.

Additional donepezil treatment for patients with geriatric depression who exhibit cognitive deficit during treatment for depression.

BACKGROUND: Depression is a frequent comorbid condition in patients with Alzheimer's disease (AD). In the present study, we reported the effect of additional donepezil treatment for patients with geriatric depression who exhibited cognitive deficit and were diagnosed with AD during treatment for depression. METHODS: The present retrospective study investigated 14 AD outpatients who were diagnosed with geriatric depression at first and received antidepressant treatment. When apparent cognitive decline was observed, all of them were diagnosed with AD and received donepezil (5 mg/day) for at least 1 year. All patients underwent periodic examination of cognitive function (Mini-Mental State Examination, Rorschach Cognitive Index) and clinical evaluation (Clinical Dementia Rating). The 14 patients were classified into three groups according to their treatment course: (i) 'A' group, patients who showed cognitive impairment during a long course of treatment for depression; (ii) 'B' group, patients who showed cognitive impairment at an early stage of treatment for depression and started to take additional donepezil at least 20 months after the first examination; and (iii) 'C' group, patients who showed cognitive impairment at an early stage of treatment for depression and began taking additional donepezil within 10 months of the first examination. The clinical feature and treatment effects were examined for each group. RESULTS: At 1 and 2 years after the start of treatment, the proportion of patients who had improved or maintained their Clinical Dementia Rating score was higher in 'A' and 'C' groups than in 'B' group. In 'B' group, additional donepezil treatment commenced later than in the other groups. Therefore, donepezil had an insufficient curative effect. CONCLUSION: The results of this study suggested that early induction of donepezil treatment was necessary when apparent cognitive decline was identified during the treatment of geriatric depression.

A nanoparticle formulation of disulfiram prolongs corneal residence time of the drug and reduces intraocular pressure.

The goal in the search for successful therapies for glaucoma is the reduction of intraocular pressure (IOP), and the search for effective eye drops that reduce IOP is a high priority. We previously reported the potential of a 2-hydroxypropyl-ß-cyclodextrin (HPßCD) solution containing 0.5% DSF (DSF solution) to provide effective anti-glaucoma treatment in eye drop form. In this study, we designed new ophthalmic formulations containing 0.5% DSF nanoparticles prepared by a bead mill method (DSFnano dispersion; particle size 183 ± 92 nm, mean ± S.D.), and compared the IOP-reducing effects of a DSFnano dispersion with those of a DSF solution. The high stability of the DSFnano dispersion was observed until 7 days after preparation, and the DSFnano dispersion showed high antimicrobial activity against Escherichia coli (ATCC 8739). In transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while no DSF was detected. The DDC penetration level (area under the curve, AUC) and corneal residence time (mean residence time, MRT) of the DSFnano dispersion were approximately 1.45- and 1.44-fold higher than those of the DSF, respectively. Moreover, the IOP-reducing effects of the DSFnano dispersion were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, DSFnano dispersion are tolerated better by a corneal epithelial cell than DSF solution and commercially available timolol maleate eye drops. It is possible that dispersions containing DSF nanoparticles will provide new possibilities for the effective treatment of glaucoma, and that an ocular drug delivery system using drug nanoparticles may expand their usage as therapy in the ophthalmologic field. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma drugs.

Hypercalcemia Leads to Delayed Corneal Wound Healing in Ovariectomized Rats.

Hypercalcemia is often observed in postmenopausal women as well as in patients with primary hyperparathyroidism or malignant tumors. In this study, we investigated the relationship between calcium ion (Ca(2+)) levels in lacrimal fluid and the rate of corneal wound healing in hypercalcemia using ovariectomized (OVX) rat debrided corneal epithelium. We also determined the effects of Ca(2+) levels on cell adhesion, proliferation and viability in a human cornea epithelial cell line (HCE-T). The calcium content in bones of OVX rats decreased after ovariectomy. Moreover, the Ca(2+) content in the blood of OVX rats was increased 1 month after ovariectomy, and decreased. The Ca(2+) content in the lacrimal fluid of OVX rats was also increased after ovariectomy, and then decreased similarly as in blood. Corneal wound healing in OVX rats was delayed in comparison with Sham rats (control rats), and a close relationship was observed between the Ca(2+) levels in lacrimal fluid and the rate of corneal wound healing in Sham and OVX rats (y=-0.7863x+8.785, R=0.78, n=25). In addition, an enhancement in Ca(2+) levels caused a decrease in the viability in HCE-T cells. It is possible that enhanced Ca(2+) levels in lacrimal fluid may cause a decrease in the viability of corneal epithelial cells, resulting in a delay in corneal wound healing. These findings provide significant information that can be used to design further studies aimed at reducing corneal damage of patients with hypercalcemia.

[Evaluation of the Safety of a Generic Formulation of Cisplatin in Patients with Thoracic Malignancies].

Cisplatin (CDDP) is a key drug in the systemic treatment of various solid tumors. Brand-name CDDP may differ across generic formulations considering various clinical parameters. Therefore, in this study, we aimed to assess the safety of a generic CDDP formulation. To compare brand-name CDDP with a generic formulation, the incidence of adverse events, especially renal toxicity, was investigated in 500 patients with thoracic malignancies who received chemotherapy with more than 60 mg/m2 of either brand-name or generic CDDP. We compared the maximum serum creatinine (Cr) level after chemotherapy in the 2 groups. The correlation coefficients between the pretreatment Cr and the maximum Cr after CDDP administration did not differ between brand-name CDDP and generic CDDP (0.610 and 0.644, respectively; p=0.528). Furthermore, the correlation coefficients did not differ in subgroup analysis according to sex or adjuvant therapy. The severity of adverse events was similar in the 2 groups. In conclusion, generic CDDP can safely be used as an alternative to brand-name CDDP in the clinical setting.

[Retrospective Analysis of the Afatinib Clinical Pathway during the 28-Day Introductory Period-The Japanese Style of Collaborative Drug Therapy Management(J-CDTM)].

Afatinib is a newly approved second-generation epidermal growth factor receptor-tyrosine kinase inhibito r(EGFR-TKI). Afatinib has been shown to prolongthe overall survival of patients with non-small cell lungcancer (NSCLC) with EGFR mutations compared with the standard chemotherapy. However, Grade 3 or 4 toxicities, includingdiarrhea, rash, paronychia, and stomatitis, have been observed more frequently in patients treated with afatinib than in those treated with first-generation EGFR-TKIs. Accordingly, our institution developed an afatinib clinical pathway (the afatinib pathway), which was designed by certified nurses, medical physicians, and certified pharmacists, with the goal of reducing the severity of diarrhea and rash that occur most frequently duringthe 28-day introductory period of afatinib treatment. Between May and October 2014, afatinib was administered accordingto the afatinib pathway to 14 patients with NSCLC and EGFR mutations. Of these patients, only one (7.1%) experienced Grade 3 diarrhea. No other patient experienced Grade 3 or 4 toxicity. The afatinib pathway was effective in reducingthe severities of the diarrhea and rash duringthe 28-day introductory period of the afatinib treatment. Our implementation of the afatinib pathway could be considered the Japanese style of collaborative drugtherapy management (J-CDTM).