Burden of Menstrual Pain Measured by Heatmap Visualization of Daily Patient-Reported Data in Japanese Patients Treated with Ethinylestradiol/Drospirenone: A Randomized Controlled Study.

PURPOSE: Dysmenorrhea negatively affects women's quality of life and poses a considerable economic burden. A recent study in Japanese patients with dysmenorrhea (NCT01892904) reported a significant reduction in the number of days with menstrual pain after treatment with a flexible extended regimen of ethinylestradiol (EE)/drospirenone (DRSP) compared with a cyclic regimen. However, individual patients' menstrual pain patterns and intensities were not indicated. Heatmapping was used to visualize menstrual pain patterns and intensities by re-evaluating the previously published data from NCT01892904. PATIENTS AND METHODS: NCT01892904 was a Phase III, multicenter, randomized, open-label, active-control study of 212 women aged ≥20 years randomized 1:1 to receive flexible extended or 28-day cyclic EE/DRSP treatment. Daily pain levels were recorded in patient diaries, and menstrual pain patterns and intensities were visualized using heatmapping. Patients were stratified by baseline dysmenorrhea scores and primary or secondary dysmenorrhea. RESULTS: The heatmap data demonstrated that EE/DRSP reduced the degree of menstrual pain. Regular peaks of menstrual pain were alleviated in the extended regimen group but were still observed in the cyclic regimen group. While a decrease in the days with menstrual pain was observed in patients with higher baseline dysmenorrhea scores (5-6), those with lower baseline scores (3-4) were more likely to experience lower intensities of menstrual pain. Although pain relief was less likely in patients with secondary dysmenorrhea, those who had lower baseline dysmenorrhea scores (3-4) and received the flexible extended regimen experienced a greater reduction in the number of days with menstrual pain than those who received the cyclic regimen. CONCLUSION: Heatmapping effectively visualized the daily burden of menstrual pain in Japanese patients with dysmenorrhea. The analysis using heatmaps suggested that the flexible extended EE/DRSP treatment regimen was more likely to alleviate the regular occurrence of menstrual pain peaks compared with the cyclic regimen.

Impact of Q141K on the Transport of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by ABCG2.

The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 µM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.

Predictive Evaluation of Pharmaceutical Properties of Ulinastatin-Containing Vaginal Suppositories as a Hospital Preparation by Near-Infrared Spectroscopy.

A vaginal suppository containing ulinastatin (UTI) was developed as a hospital pharmacy product from UTI injection solution and Witepsol® S-55. After mixing at 50°C for 0-8 h, UTI suppositories were prepared, which had good UTI content uniformity. Because 2% surfactant was contained in S-55, the UTI injection solution formed a water-in-oil type emulsion as a suppository base. The measured residual moisture content (loss on drying (LOD)) in the prepared vaginal suppositories decreased as the mixing time increased, but their hardness (hardness test (HT)) increased. Near (N) IR spectra of UTI suppositories were measured after mixing for 0-8 h. The best calibration models to predict the HT and LOD of the suppositories were determined based on the NIR spectra by the leave-one-out method in a partial least-squares regression analysis (PLS). The validation result indicated that PLS models for HT and LOD were obtained based on the spectra treated by a combination of smoothing and normalized, respectively, and the model consisted of three latent variables. The plots between the predicted and measured pharmaceutical properties (HT and LOD) based on the calibration data were superimposed with those of the external validation data. The developed NIR spectroscopy method was applied to the preparation process monitoring for UTI vaginal suppositories. In the prepared vaginal suppositories, the predicted LOD decreased as the mixing time increased, and the measured LOD values superimposed well with the predicted values. In contrast, the predicted HT increased as the mixing time increased, and the measured values superimposed with the predicted values.

Endothelial cell loss and graft survival after penetrating keratoplasty for laser iridotomy-induced bullous keratopathy.

PURPOSE: To assess corneal endothelial cell loss after penetrating keratoplasty (PK) treatment for laser iridotomy (LI)-induced bullous keratopathy (BK). METHODS: A retrospective study conducted on consecutive patients who underwent PK between March 2000 and December 2011. Patients who had undergone more than 24 months of follow-up were included. Patients who underwent PK were subcategorized into two groups based on their diagnosis of BK prior to PK; PK was performed to treat either LI-BK or non LI-BK. The cell density of the central corneal endothelium and the graft survival were evaluated during follow-up. RESULTS: Corneal endothelial cell density decreased in a similar fashion in both the LI-BK and non LI-BK patients, though the cell density decreased significantly faster in the LI-BK group than in the non LI-BK group throughout the 108 months of the study (p = 0.026). The mean cell loss at 36 months for the LI-BK group was 57.7% vs. 63.2% for the non LI-BK, 76.9% vs. 70.1% at 72 months, and 85.6% vs. 72.0% at 108 months. No eye among 21 eyes in the LI-BK group (0%) had failed grafts, whereas 4 of 25 eyes in the non LI-BK group (16.0%) had failed grafts at 60 months (p = 0.114). CONCLUSIONS: The outcome of PK for BK secondary to LI was no worse than the outcome of PK for other types of BK. However, our long-term follow-up after PK showed that cell density decreased faster in the LI-BK group than in the non LI-BK, suggesting that cell loss might be involved in the existence of LI prior to PK.

Efficacy and safety of a flexible extended regimen of ethinylestradiol/drospirenone for the treatment of dysmenorrhea: a multicenter, randomized, open-label, active-controlled study.

BACKGROUND: Dysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen) is approved for this indication in Japan. AIM: The aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen) in Japanese women with dysmenorrhea. METHODS: This multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 µg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24-120 days followed by a 4-day tablet-free interval) or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles). The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed. RESULTS: A total of 216 women (mean age 29.7 years) were randomized to the flexible regimen (n=108) or 28d regimen (n=108) and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107). Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in disease severity reported in both treatment groups. According to the investigators, 64.8% and 59.4% of women in the flexible-regimen and 28d-regimen treatment groups had "very much improved" or "much improved" disease, while 54.3% and 50.9% of patients reported being "very much satisfied" or "much satisfied" with their treatment, respectively. CONCLUSION: In Japanese women with dysmenorrhea, a flexible extended regimen of ethinylestradiol/drospirenone decreased the number of days with dysmenorrheic pain versus the traditional 28d regimen.

Effect of Trabeculotomy on Corneal Endothelial Cell Loss in Cases of After Penetrating-Keratoplasty Glaucoma.

PURPOSE: The aim of this study was to evaluate the effect of trabeculotomy (TLO) on glaucoma and endothelial cell loss after penetrating keratoplasty (PK). METHODS: A retrospective study was conducted on consecutive patients who underwent PK and in whom more than 24 months of follow-up was available. Patients were categorized into the PK+TLO group [ie, TLO for post-PK glaucoma (n = 10)] and the PK group [PK alone (n = 73)]. Intraocular pressure (IOP) was evaluated during each follow-up examination. Central corneal endothelium images were obtained and analyzed to determine corneal endothelial cell (CEC) density. RESULTS: The mean duration period from original PK to TLO for secondary glaucoma was 25.5 ± 34.9 months in the PK+TLO group. Mean preoperative IOP in the PK+TLO group was 35.8 mm Hg, and decreased to 17.5 mm Hg at 24 months postoperative (P < 0.01). CEC density decreased in the same manner in both groups. In the PK+TLO group, mean CEC density was 1838 cells per square millimeter before TLO and decreased to 1195 cells per square millimeter at 24 months after TLO. In the PK group, mean CEC density decreased from 1870 to 1209 cells per square millimeter at each corresponding time point. CONCLUSIONS: TLO for post-PK glaucoma appeared to safely lower IOP, although repeated surgeries were required in some patients, and did not accelerate CEC loss.

Anti-neovascular therapy by liposomal drug targeted to membrane type-1 matrix metalloproteinase.

Because membrane type-1 matrix metalloproteinase (MT1-MMP) is expressed specifically on the angiogenic endothelium as well as tumor cells, an agent possessing the ability to bind to this molecule might be useful as a tool for active targeting of tumor angiogenic vessels. Based on the sequences of peptide substrates of MT1-MMP, which had been determined by using a phage-displayed peptide library, we examined the binding ability of peptide-modified liposomes for endothelial cells and targeting ability for tumor tissues by positron emission tomography (PET). Liposomes modified with stearoyl-Gly-Pro-Leu-Pro-Leu-Arg (GPLPLR-Lip) showed high binding ability to human umbilical vein endothelial cells and accumulated in the tumor about 4-fold more than did the unmodified liposomes. Because we reported previously that liposomalized 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (DPP-CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, strongly suppressed tumor growth when delivered in liposomes modified with another angiogenic homing peptide, we examined the antitumor activity of DPP-CNDAC entrapped in GPLPLR-Lip. DPP-CNDAC/GPLPLR-Lip showed significant tumor growth suppression compared to DPP-CNDAC/unmodified liposomes. These results suggest that DPP-CNDAC-liposomes modified with MT1-MMP-targeted peptide are useful for cancer anti-neovascular therapy (ANET), namely, tumor growth suppression by damage to angiogenic endothelial cells.

Polycation liposome-mediated gene transfer in vivo.

The polycation liposome (PCL), a recently developed gene transfer system, is simply prepared by a modification of liposomes with cetylated polyethylenimine (PEI), and shows remarkable transgene efficiency with low cytotoxicity. In the present study, we investigated the applicability of PCLs for in vivo gene transfer, since the PCL-mediated transgene efficiency was found to be maintained in the presence of serum. PCLs composed of dioleoylphosphatidylethanolamine (DOPE) with 5 mol% cetyl PEI (PEI average mr. wt. 1800), were superior for transfection to those of dipalmitoylphosphatidylcholine (DPPC) and cholesterol (2:1 as molar ratio) with 5 mol% cetyl PEI in vitro, although the latter PCLs were more efficient for gene transfer in vivo. PCL-DNA complexes were injected into mice via a tail or the portal vein, with the DNA being a plasmid encoding green fluorescent protein (GFP) or luciferase; and the expression was monitored qualitatively or quantitatively, respectively. Tail vein injection resulted in high expression of both GFP and luciferase genes in lung, and portal vein injection resulted in high expression of both genes in the liver. Concerning the gene delivery efficiency, the PCL was found to be superior to PEI or cetyl PEI alone. The optimal conditions for in vivo transfection with PCLs were also examined.

Anti-neovascular therapy by liposomal DPP-CNDAC targeted to angiogenic vessels.

We previously reported that liposomalized 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (DPP-CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, is quite useful for cancer therapy. On the other hand, for anti-neovascular therapy, we recently isolated peptides homing to angiogenic vessels from a phage-displayed random peptide library, and observed that peptide-modified liposomal adriamycin strongly suppressed tumor growth, perhaps through damaging angiogenic endothelial cells. In the present study, we modified DPP-CNDAC-liposomes with one of the angiogenic homing peptides, APRPG, and examined their antitumor activity. Three doses of APRPG-modified DPP-CNDAC-liposomes (15 mg/kg as CNDAC) strongly inhibited tumor growth compared with the same number of doses of unmodified DPP-CNDAC-liposomes. The life span was increased 31.8%, with one completely cured mouse out of the six mice treated. Since the accumulation of liposomes in the tumor tissue was not so much different between APRPG-liposomes and non-modified liposomes, the enhanced therapeutic efficacy may be explained as the alteration of targets, i.e. APRPG-modified DPP-CNDAC-liposomes caused tumor growth suppression through damage of angiogenic endothelial cells. Anti-neovascular therapy promises no drug resistance, and should be effective against essentially any kind of solid tumor; and thus the present results demonstrate another benefit of the therapy, namely, high efficacy of cancer treatment.