The Distributions and Boundary of Two Distinct, Local Forms of Japanese Pond Frog, Pelophylax porosus brevipodus, Inferred From Sequences of Mitochondrial DNA.

The Nagoya Daruma pond frog Pelophylax porosus brevipodus is distributed in western Japan and is traditionally divided into two local forms: the Okayama form in the west and the Nagoya form in the east. These two forms are genetically differentiated, but have never been defined taxonomically because their distributions are unclear to date. To complete the distributions and identify the boundary of the two forms, we genetically investigated 16 populations including eight populations located within the unexamined area. We found that the distributional boundary is located within a small area of Hyogo Prefecture where haplotypes of mitochondrial cytochrome b (cytb) and D-loop region corresponding to the two forms co-existed. On the other hand, the polymorphic site of the nuclear gene SOX3 revealed introgression over the boundary into Okayama cytb clade. These results suggest that the two forms were geographically isolated from each other in the past, and secondarily contacted and then accepted one-way introgression. As a next step of the research, taxonomic approach is expected to define the two forms.

[Results of a Special Drug Use-Results Survey on Compliance to Tegafur/Uracil(UFT)Adjuvant Chemotherapy for Non-Small Cell Lung Cancer].

We report the results of a special drug use-results survey that used medication diaries about compliance to tegafur/uracil (UFT) adjuvant chemotherapy in patients who had undergone complete resection for non-small cell lung cancer. Between April1 , 2008, and March 31, 2010, 2,527 patients were enrolled. Of these patients, 2,411 and 1,811 were evaluated for treatment and compliance, respectively. The 2-year treatment completion rate was 59.1% in 2,093 of the 2,411 patients, excluding 318 patients with treatment failure owing to recurrence. The results were comparable with those from The Japan Lung Cancer Research Group on PostsurgicalAdjuvant Chemotherapy (JLCRG). The main reasons of the treatment failure were gastrointestinaland hepatic disorders. The proportion of patients with @75% compliance was 95.3% (1,726/1,811), and most of the patients who kept their medication diaries exhibited good compliance.

[Results of a drug use investigation of nanoparticle albumin-bound Paclitaxel for breast cancer].

A drug use investigation of nanoparticle albumin-bound paclitaxel was conducted based on conditions for approval. A total of 963 patients were enrolled in this study from September 24, 2010 to February 14, 2011. Twenty-nine patients were excluded, and a total of 934 patients were evaluated for determining the safety of nanoparticle albumin-bound paclitaxel. Adverse drug reactions were observed in 92.8%of the patients, and major adverse drug reactions included myelosuppression and peripheral sensory neuropathy, both of which are characteristic adverse reactions of paclitaxel treatment. Both adverse drug reactions were observed at a high frequency after the second course of treatment, resulting in these reactions being primary causes for discontinuation. Increase in the rates of continuous drug administration may be accomplished by carrying out laboratory tests and noting the medical history in order to prevent myelosuppression from becoming serious and to perform earlier countermeasures for peripheral sensory neuropathy, leading to improved therapeutic effects.

[Characteristics of and risk factors for interstitial pneumonia due to TS-1(R) capsule administration-case reviews from a drug use results survey on Non-Small Cell Lung cancer patients and spontaneous reports].

A drug use results survey for the TS-1(R)capsule was conducted on patients with non-small cell lung cancer. A total of 1,784 patients were registered for the survey, 1,669 of whomwere evaluated for safety. The incidence of adverse drug reactions was 67.9%(1,134/1,669). The overall incidence of interstitial pneumonia was 1.38%(23/1,669), while it was 1.34% in patients treated with TS-1(R) alone(14/1,046). The risk factors for interstitial pneumonia according to this survey included allergic predisposition, concomitant diseases(including interstitial pneumonia), past medical history(including interstitial pneumonia), and combination with anticancer drugs(excluding cisplatin). Among the spontaneous reports of interstitial pneumonia as an adverse drug reaction from physicians, test images were available in 39 cases. These images were analyzed by the Safety Review Committee for interstitial pneumonia, consisting of external medical experts. In addition, the imaging patterns, settings of occurrence, and patient's backgrounds were reviewed. Twenty-five of the 39 cases were assessed to be possible interstitial pneumonia, of which 10 were confirmed to have an imaging pattern of diffuse alveolar damage. Based on the above findings, it is essential to check the patient's medical history for conditions such as lung disorder through a medical interview and an imaging test, prior to starting treatment with TS-1(R).

Retrobulbar hemodynamic effects of nipradilol in normal and normal-tension glaucoma eyes.

Purpose. To investigate the effects of nipradilol on retrobulbar hemodynamics. Methods. We investigated normal and normal-tension glaucoma (NTG) eyes. Topical nipradilol (one eye) and placebo eye drops (fellow eye) were instilled for 1 week in volunteers. Nipradilol was also instilled in NTG patients. Ultrasound color Doppler imaging for the posterior vessels was performed before, 2 hr, 1 week (for normal), and at 4 weeks (for NTG). Results. In normal eyes, there were significant decreases in the resistance index (RI) for the temporal short posterior ciliary arteries (PCA) at 2 hr and for the ophthalmic arteries at 1 week. There were no significant changes in the placebo-treated eyes. In the NTG eyes, there was a significant decrease in the RI for the central retinal artery, nasal, and temporal PCA at 2 hr and 4 weeks. Conclusion. Short-term observations found that nipradilol increased the ocular blood flow in normal and NTG eyes.

Comparison of ocular hypotensive effect and safety of brinzolamide and timolol added to latanoprost.

PURPOSE: To compare the ocular hypotensive effect and safety of brinzolamide and timolol added to latanoprost monotherapy. METHODS: In prospective randomized fashion, we evaluated the ocular hypotensive effect and safety of brinzolamide or timolol in 1 eye of 32 patients with primary open-angle glaucoma, normal-tension glaucoma, or ocular hypertension who had been treated with latanoprost for more than 1 month. Intraocular pressure (IOP), blood pressure, and pulse were measured before and at 4, 8, and 12 weeks. Corneal endothelial cell density was measured at baseline and at 12 weeks. RESULTS: The IOP was 17.8+/-1.7 mm Hg (mean+/-SD) before the addition of brinzolamide (n=15) and 15.7+/-2.1 mm Hg at 12 weeks (P<0.01). In comparison, the IOP was 18.5+/-3.7 mm Hg before the addition of timolol (n=15) and 15.8+/-3.2 mm Hg at 12 weeks (P<0.01). Both brinzolamide and timolol significantly decreased IOP at 12 weeks, by a mean of 2.0 mm Hg and mean 2.7 mm Hg, respectively, and were more effective than latanoprost alone (P<0.01), but there were no significant differences between the drugs and no significant differences in corneal endothelial cell density and blood pressure before and after addition of either drug. At 12 weeks, pulse was decreased in patients receiving timolol (P<0.01). As systemic adverse events, there was one instance of malar flushing after brinzolamide addition and episodes of chest discomfort after timolol addition in 1 patient. Ocular adverse events were slight. CONCLUSIONS: Brinzolamide and timolol added to latanoprost have similar ocular hypotensive effects and safety in primary open-angle glaucoma, normal-tension glaucoma, or ocular hypertension.

Use of indocyanine green during excision of an overhanging filtering bleb.

BACKGROUND: We report the use of an indocyanine green (ICG) injection during the safe removal of an overhanging filtering bleb after trabeculectomy. CASE: A 63-year-old man with a history of trabeculectomy 5 years previously in his left eye complained of foreign body sensation in this eye and decreased vision from induced astigmatism. Slit-lamp examination revealed an expanding overhanging filtering bleb on the cornea. OBSERVATIONS: With a 30-G needle, 0.25% ICG was injected into the overhanging bleb. Use of ICG visualization of the inner space of the overhanging filtering bleb provided visualization of the border with the original bleb, allowing for safe excision of the overhanging filtering bleb without injury to the thin surface of the original bleb. CONCLUSION: Injection of ICG into an overhanging filtering bleb during excision can be useful in the prevention of damage to the original bleb.

[Example of safety measures for antineoplastic agents immediately after market launch--a case of TS-1 capsule all example use result investigation that executes safety monitoring--].

As a measure to ensure safe use of TS-1 during the early marketing period, a drug use investigation was conducted on an all-case basis. Extra safety monitoring,rarely included in the use investigation,was also planned for patients who began therapy with this agent. Of the 4,177 subjects registered during the year beginning in March 1999, 3,882 started TS-1 therapy. Aside from 74 dropouts, 3,808 cases were evaluable for safety. The overall incidence of adverse reactions, with high frequencies of myelosuppression and gastrointestinal disorders, was 74.3%: a result similar to an incidence of 77.5% (100/129) found in the early phase II trial with gastric cancer patients. Safety monitoring made it possible to check if a given patients was eligible for proper use before treatment is begun. During TS-1 administration,collaboration was formed between physicians and medical representatives to ensure regular laboratory testing and to check the test findings. Measures were considered necessary to secure the safe use of drugs with manifest risk of serious adverse reactions, such as antineoplastic agents, during the initial period of market introduction. Our present approach proved effective as one of such measures.

New gonioscopy system using only infrared light.

PURPOSE: To describe an infrared gonioscopy system designed to observe the anterior chamber angle under natural mydriasis in a completely darkened room. METHODS: An infrared light filter was used to modify the light source of the slit-lamp microscope. A television monitor connected to a CCD monochrome camera was used to indirectly observe the angle. RESULTS: Use of the infrared system enabled observation of the angle under natural mydriasis in a completely darkened room. CONCLUSION: Infrared gonioscopy is a useful procedure for the observation of the angle under natural mydriasis.

Japanese nationwide post-marketing survey of S-1 in patients with advanced gastric cancer.

BACKGROUND: It is likely that there are some discrepancies in the safety and efficacy results for anticancer agents between those shown in registration studies for approval and those shown in clinical practice after market release. The aim of this survey was to confirm the safety and efficacy of S-1 for advanced gastric cancer after market release. METHODS: After the approval of S-1 in 1999, all patients had to be registered with the manufacturer for a post-marketing survey, according to the government recommendation. All patients were monitored for safety and survival. The data for all registered patients were updated 1 year after each registration. RESULTS: During this survey, a total of 4177 patients with advanced gastric cancer were registered. The incidences of all adverse events and of grade 3 or worse adverse events in the 3808 patients evaluable for safety were 74.3% and 25.0%, respectively. In patients with lower creatinine clearance at baseline, the incidences of adverse reactions were higher for all grades combined, as well as for grades 3 or worse. There were 90 (2.4%) early deaths (within 30 days of the initiation of the treatment) and 5 (0.1%) deaths possibly related to the treatment. The median survival time and the 1-year survival rate for all patients evaluable for efficacy (n = 3801) were 8.3 months (95% confidence interval [CI], 8.0-8.6 months) and 33.3% (95% CI, 31.8-34.9%), respectively. CONCLUSION: This nationwide survey confirmed that the safety and efficacy profiles of S-1 were similar to those seen in the registration study. These results have proven the utility of this post-marketing survey in assessing the reproducibility of the safety and efficacy results obtained from prior clinical studies.

Evaluation and comparison of indentation ultrasound biomicroscopy gonioscopy in relative pupillary block, peripheral anterior synechia, and plateau iris configuration.

PURPOSE: To evaluate and compare the findings and changes of the anterior chamber angle configuration with indentation ultrasound biomicroscopy (UBM) gonioscopy in relative pupillary block (RPB), peripheral anterior synechia (PAS), and plateau iris configuration (PIC). METHODS: This study included 73 eyes of 52 patients with RPB (n = 26), PAS (n = 21), or PIC (n = 26). First, a conventional UBM scan was performed using a normal size standard eye cup before indentation. Then, for indentation UBM gonioscopy, scans were performed using a new eye cup that we designed. For evaluation of the angle, angle opening distance 500 and angle recess area were recorded and evaluated with regard to the effect of expansion on the anterior chamber angle. RESULTS: Indentation UBM gonioscopy showed the characteristic images in each of the eyes. The angle of all examined eyes was significantly widened with indentation (P < 0.01). The angle changes in eyes with RPB were significantly greater than in eyes with PAS or PIC (P < 0.01). CONCLUSION: Indentation UBM gonioscopy is a very useful method for observing the angle and diagnosis of RPB, PAS, and PIC.

Switch to latanoprost monotherapy from combined treatment with beta-antagonist and other antiglaucoma agents in patients with glaucoma or ocular hypertension.

PURPOSE: To investigate the effects on intraocular pressure (IOP) and the occurrence of adverse events upon switching directly to latanoprost monotherapy from multiple drug therapy, including a beta-antagonist, for glaucomatous eyes. METHODS: Patients with primary open-angle glaucoma or ocular hypertension and receiving long-term therapy with two or three topical ocular hypotensive drugs (including one topical beta-antagonist) were switched to latanoprost monotherapy for 12 weeks without any intervening washout period. Observations were performed before switching (baseline) and at weeks 4, 8, and 12 after switching to latanoprost monotherapy. RESULTS: Of the 29 enrolled patients, 26 (90%) completed this protocol. Three patients had excessive IOP elevation, and these patients were withdrawn. The switch to latanoprost monotherapy was followed by a significant ( P < 0.0001) mean reduction of 3.9 mmHg at week 12 in per-protocol cases ( n = 26) and a significant ( P = 0.0016) mean reduction of 2.8 mmHg at last postswitch visit in patients in the intent-to-treat analysis group ( n = 29). Adverse ocular events other than IOP elevation were mild. CONCLUSIONS: The switch to latanoprost monotherapy in glaucoma patients receiving multiple drug therapy resulted in an additional, significant IOP reduction.

Symmetry analysis for detecting early glaucomatous changes in ocular hypertension using optical coherence tomography.

PURPOSE: To compare symmetry analysis of the retinal nerve fiber layer (RNFL) in ocular-hypertensive, normal, and glaucomatous eyes using optical coherence tomography (OCT). METHODS: Thirty-three consecutive ocular-hypertensive patients (33 eyes), 25 normal volunteers (25 eyes), and 35 open-angle glaucoma patients (35 eyes) were enrolled in this study. Circular OCT scans were obtained using a diameter of 3.4 mm around the optic disc. RNFL thickness was measured, and a symmetry analysis was performed using symmetry ratios. To calculate the symmetry ratios, the circle was divided into the superior and inferior hemiretina. The superior hemiretina was further subdivided into three (area I, temporal 45 degrees; area II, superior 90 degrees; and area III, nasal 45 degrees ) or five (with areas 1-5, each spanning 36 degrees ) zones. The symmetry ratios were defined as the ratios comparing the RNFL thickness within each of the zones with that in the analogous zone in the inferior hemiretina. RESULTS: RNFL thickness measurements could distinguish glaucomatous eyes from other groups, but could not distinguish ocular-hypertensive from normal eyes. However, the symmetry analysis revealed differences between ocular-hypertensive and normal eyes in area II (mean +/- SD, 0.77 +/- 0.16 vs. 0.85 +/- 0.12, P = 0.0379). CONCLUSIONS: Early glaucomatous RNFL changes might exist in some areas of ocular-hypertensive eyes, and a symmetry analysis may be a useful method for detecting these changes.

Evaluation of eyes with relative pupillary block by indentation ultrasound biomicroscopy gonioscopy.

PURPOSE: To investigate changes in anterior chamber angle configuration with indentation ultrasound biomicroscopy gonioscopy of relative pupillary block (RPB). DESIGN: Cross-sectional study. METHODS: This study included 26 eyes of 26 patients with RPB. We determined angle opening distance 500 and angle recess area using indentation ultrasound biomicroscopy gonioscopy and compared a small-sized standard eye cup with a new eye cup with an area for inducing pressure. RESULTS: Indentation ultrasound biomicroscopy images documented concavity of the iris in eyes with RPB. Both the new and the small standard eye cups widened the anterior chamber angle significantly (P <.0001) without causing corneal damage. Angle changes were significantly greater for the new eye cup design. CONCLUSIONS: Indentation ultrasound biomicroscopy gonioscopy is a useful technique for observation and diagnosis of RPB. Using a small standard or the newly designed eye cup, the procedure can be performed easily and without causing corneal damage.

Supraciliochoroidal fluid in the eyes indicates good intraocular pressure control despite absence of obvious filtering bleb after trabeculectomy.

PURPOSE: To examine the presence of supraciliochoroidal fluid (SCF) by ultrasound biomicroscopy in posttrabeculectomy eyes that show good intraocular pressure (IOP) control despite the absence of an obvious filtering bleb. PATIENTS AND METHODS: Eyes were selected retrospectively according to the following criteria: IOP < 15 mm Hg, no antiglaucoma medication, no filtering bleb or a flattened bleb without microcystic spaces, and no ophthalmoscopic choroidal detachment after trabeculectomy with mitomycin C. The SCF was examined using 50-MHz ultrasound biomicroscopy (Zeiss-Humphrey). RESULTS: Ultrasound biomicroscopy detected SCF in five (63%) of eight eyes that met the study criteria. The extent of SCF in two of the eyes was four quadrants and one or two quadrants in three eyes. CONCLUSION: The presence of the SCF may explain increased uveoscleral outflow and may represent an IOP-lowering mechanism after trabeculectomy with mitomycin C, especially when IOP control is good and a filtering bleb is not obvious.

Supraciliochoroidal fluid at an early stage after trabeculectomy.

PURPOSE: To detect the presence of supraciliochoroidal fluid (SCF) by ultrasound biomicroscopy (UBM) at an early stage after trabeculectomy. METHODS: Trabeculectomy with mitomycin C was performed on 14 patients (15 eyes) with medically uncontrolled glaucoma. The ciliary bodies were observed using UBM testing, which was conducted preoperatively and within 2 weeks after the procedure. RESULTS: SCF was detected postoperatively in 6 eyes. One eye also had choroidal detachment (CD), as seen with an indirect ophthalmoscope; and 5 eyes (33%) had SCF without intraocular inflammatory clinical signs, postoperative changes of the anterior chamber depth, or obvious CD. The SCF in 4 eyes disappeared within 4 weeks after the trabeculectomy. The intraocular pressure (IOP) was 6.4 +/- 3.4 mm Hg (mean +/- SD) when SCF was detected and it rose to 13.2 +/- 7.2 mm Hg when the SCF disappeared. The IOP was 11.4 +/- 4.0 mm Hg in the eyes without SCF, which was significantly higher than that seen in the eyes with SCF. CONCLUSIONS: At an early stage after trabeculectomy, SCF without subclinical CD was detected in some cases by UBM. Compared with the reported frequency of SCF after 3 or 6 months, our study revealed that SCF was present more frequently at an early stage after trabeculectomy. Our results may indicate that the presence of SCF is related to the early low IOP after trabeculectomy and that the disappearance of SCF induces the elevation of IOP.

Effects of haloperidol on K(+) currents in acutely isolated rat retinal ganglion cells.

PURPOSE: Effects of haloperidol on K(+) currents (IKs) of rat retinal ganglion cells (RGCs) were examined, with the hypothesis that its alteration of IKs explains alterations in the pattern electroretinogram (PERG). METHODS: Fast blue was injected into superior colliculi of rats (3-8 days old) to identify RGCs under epifluorescence illumination after retrograde transport to retinas. Retinas were dissected, treated enzymatically, and dissociated with trituration. Effects of haloperidol on membrane currents at -70 mV, voltage-dependent IK, and Ca(2+)-dependent K(+) currents (K(Ca)) were examined by whole-cell patch voltage clamp. Na(+) currents were abolished by tetrodotoxin (1 microM; TTX). Voltage-gated IKs were isolated by Ca(2+)-free perfusate. Persistent and transient components of the voltage-sensitive IKs were isolated by prepulses, and sensitivity of each component to tetraethylammonium (TEA, 20 mM) and 4-aminopyridine (5 mM) was tested. K(Ca) was identified by its response to TEA, charybdotoxin (CTX), and apamin. Haloperidol (0.01-100 microM) was instilled into the perfusate dissolved in dimethyl sulfoxide (DMSO). RESULTS: Currents recorded at -70 mV were not affected by haloperidol, whereas the persistent component of the voltage-dependent IK was reversibly reduced by haloperidol, with a dose dependence fitted with the Hill equation (median inhibitory concentration [IC(50)] = 4.2 microM). The transient component of the voltage-gated IK was less sensitive to haloperidol. Haloperidol (10 nM) blocked the apamin-sensitive K(Ca) but not the CTX-sensitive K(Ca). CONCLUSIONS: Haloperidol reduced voltage-dependent IKs in RGCs, but at a higher concentration than that needed to antagonize dopamine receptors. Haloperidol (10 nM) blocked the apamin-sensitive K(Ca) which modulates the firing rate of RGCs and may contribute to the alteration of PERG.

Studies of rapidly disintegrating tablets in the oral cavity using co-ground mixtures of mannitol with crospovidone.

We attempted the development of rapid oral disintegration tablets by direct compression using co-ground mixture of D-mannitol and crospovidone. The co-ground mixture was prepared with a vibration rod mill. The tablets were formed by compression using a single punch-tableting machine after addition of the co-ground mixture to non-ground D-mannitol, crospovidone and magnesium stearate. Regarding the properties of tablets, hardness and the time of disintegration were measured. The particle diameter and specific surface area of the co-ground mixture were measured. The tablets manufactured from a physical mixture of 30% (w/w) co-ground mixture of D-mannitol and crospovidone (mixed ratio 9 :1) with 65.5% (w/w) of non-ground mannitol, 4% (w/w) of crospovidone, and 0.5% (w/w) of magnesium stearate had good properties for rapidly disintegrating tablets in the oral cavity. They showed the hardness of 4.9 kg and disintegration time of 33 s. We found that adding co-ground mixture of D-mannitol and crospovidone is useful in enhancing hardness of the tablets that could not be achieved by addition of their individually ground mixture. The improvement in the hardness of the tablets was also observed when other saccharides and disintegrants were used. This method was proved to be applicable in the manufacture of tables of ascorbic acid, a water-soluble drug and nifedipine, a slightly water soluble drug; and the dissolution rate of nifedipine from the tablets in water was remarkably improved. The particle sizes of D-mannitol in the co-ground mixture were smaller than that of the individually ground mixture, resulting in a larger specific surface area of the co-ground mixture than that of the individually ground mixture. Therefore, it was presumed that crospovidone acted as a grinding assistant for D-mannitol in the co-grinding process, enhancing the hardness of tablets by increasing the contact area among powder particles.