Randomized phase III and extension studies: efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer.

BACKGROUND: The efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies. PATIENTS AND METHODS: In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 97) or placebo (n = 96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires. RESULTS: Naldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ≤ 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) postinitial dose (all P < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL. CONCLUSIONS: Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. TRIAL REGISTRATION ID: www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

Patching retinal breaks with Seprafilm for treating retinal detachments in humans: 9 years of follow-up.

PurposeTo describe the long-term surgical outcomes of four patients treated for retinal detachment using Seprafilm as a novel technique.MethodsRetinal breaks in four eyes were covered with Seprafilm using a transvitreal approach after cataract surgery, pars plana vitrectomy, fluid-air exchange, and laser photocoagulation. Neither long-standing gas nor silicone oil was used. The patients were not instructed to maintain a specific head positioning postoperatively.ResultsSuccessful retinal reattachment was achieved with a single surgery in all four eyes, and none developed proliferative vitreoretinopathy. The mean best-corrected visual acuity preoperatively and 9 years postoperatively were 20/97 and 20/33, respectively. The intraocular pressure increased several days postoperatively that lasted no longer than 2 weeks. Visual field defects either in the inferonasal or inferotemporal quadrant were detected postoperatively. The mean electroretinogram a- and b-wave amplitude ratios of the operated eyes to the fellow eyes were 0.68 and 0.64 preoperatively and 0.87 and 0.92 postoperatively, respectively. The mean corneal endothelial cell density was 2365 cells/mm2 preoperatively and 2592 cells/mm2 postoperatively.ConclusionCovering retinal breaks with Seprafilm may promote retinal reattachment without gas tamponade and postoperative head positioning. The visual outcomes 9 years postoperatively showed no apparent adverse effects of intraocular application of Seprafilm.

Cancer emerging from the recurrence of sessile serrated adenoma/polyp resected endoscopically 5 years ago.

Since the serrated neoplastic pathway has been regarded as an important pathway of colorectal carcinogenesis, few reports have been published on clinical cases of cancer derived from sessile serrated adenoma/polyp, especially on recurrence after resected sessile serrated adenoma/polyp. An elderly woman underwent endoscopic mucosal resection of a flat elevated lesion, 30 mm in diameter, in the ascending colon; the histopathological diagnosis at that time was a hyperplastic polyp, now known as sessile serrated adenoma/polyp. Five years later, cancer due to the malignant transformation of the sessile serrated adenoma/polyp was detected at the same site. The endoscopic diagnosis was a deep invasive carcinoma with a remnant sessile serrated adenoma/polyp component. The carcinoma was surgically removed, and the pathological diagnosis was an adenocarcinoma with sessile serrated adenoma/polyp, which invaded the muscularis propria. The surgically removed lesion did not have a B-RAF mutation in either the sessile serrated adenoma/polyp or the carcinoma; moreover, the initial endoscopically resected lesion also did not have a B-RAF mutation. Immunohistochemistry confirmed negative MLH1 protein expression in only the cancer cells. Lynch syndrome was not detected on genomic examination. The lesion was considered to be a cancer derived from sessile serrated adenoma/polyp recurrence after endoscopic resection, because both the surgically and endoscopically resected lesions were detected at the same location and had similar pathological characteristics, with a serrated structure and low-grade atypia. Furthermore, both lesions had a rare diagnosis of a sessile serrated adenoma/polyp without B-RAF mutation. This report highlights the need for the follow-up colonoscopy after endoscopic resection and rethinking our resection procedures to improve treatment.

A randomized controlled trial comparing a prepackaged low-residue diet with a restricted diet for colonoscopy preparation: the impact on the results of colonoscopy in adenoma detection.

AIM: This study aimed to investigate the clinical utility of a prepackaged low-residue diet (PLD) compared with a restricted diet (RD) for colonoscopic bowel preparation. METHOD: A prospective randomized controlled trial was carried out with patients undergoing colonoscopy. One hundred patients were randomly assigned to PLD and RD groups. In the RD group, the patients received an information sheet containing acceptable low-residue options and instructions from the medical staff. All patients received 10 ml sodium picosulphate the day before colonoscopy and 1 l of polyethylene glycol with ascorbic acid (PEG-A) on the day of the colonoscopy. If the bowel preparation was not adequate, an additional PEG-A solution was given. The primary outcome was the efficacy of colonic cleansing as rated by the Boston Bowel Preparation Scale (BBPS). The additional amount of PEG-A solution, adenoma detection rate and patient tolerance were assessed as secondary outcomes. RESULTS: The BBPS score in the PLD group was 7.3 ± 1.7 compared with 6.5 ± 1.7 in the RD group. The quality of bowel preparation was significantly better in the PLD group (P < 0.05). The mean amount of additional PEG-A solution in the PLD group was smaller than in the RD group (293.8 ± 474.8 vs 444.1 ± 625.0 ml), but there was no statistical difference between the two groups. Adenoma detection rates and patient tolerance were similar in the two groups. CONCLUSION: Prepackaged low-residue diets PLD is superior to RD for bowel preparation for colonoscopy.

Clinical outcomes of endoscopic resection for nonampullary duodenal high-grade dysplasia and intramucosal carcinoma.

This study retrospectively analyzed the clinical outcomes of endoscopic resection of 26 sporadic (i. e., not associated with polyposis syndrome) nonampullary duodenal lesions representing high-grade dysplasia or intramucosal carcinoma (duodenal HGD/IMC) in 23 patients. No severe complications such as perforation were observed, but three cases of delayed bleeding were seen. The use of endoscopic clips significantly decreased the delayed bleeding rate (0/19, 0%) compared with cases in which clips were not used (3/7, 42.9%; P = 0.013, χ2 test). Eighteen lesions (69.2%) were removed by en bloc resection. The follow-up period after resection was 25.5 ± 23.3 months. Two lesions (7.7%) that recurred locally were detected at the first surveillance endoscopy 3 months after resection. These lesions were 22 and 15 mm in size respectively and were resected piecemeal. Endoscopic resection is an effective and safe procedure for treating duodenal HGD/IMC. En bloc resection and prophylactic clip usage are encouraged.

Concomitant use of enteral nutrition therapy is associated with sustained response to infliximab in patients with Crohn's disease.

BACKGROUND/OBJECTIVES: A significant proportion of Crohn's disease (CD) patients receiving infliximab (IFX) maintenance therapy show loss of responsiveness despite a good initial response. The factors other than immunomodulators that prevent IFX dose escalation have yet to be fully elucidated. This study was performed to identify clinical factors or concomitant therapies associated with sustained response to IFX. SUBJECTS/METHODS: Seventy-four consecutive CD patients who had successful IFX induction therapy between 2002 and 2010 underwent IFX maintenance therapy. Patients showing loss of response to IFX were treated with IFX intensification therapy. Factors involved in the sustained response to IFX were investigated retrospectively. RESULTS: After a median follow-up of 85 weeks, loss of response to IFX was observed in 30 (40.5%) cases. On logistic regression analysis, concomitant use of enteral nutrition (EN) therapy (elemental and/or polymeric formulas) was identified as an independent factor associated with sustained response to IFX. Receiver operating characteristic curve analysis indicated a cutoff value of 600 kcal/day. We divided the patients into the 'EN group' (≥ 600 kcal/day) and 'control group' (<600 kcal/day). The cumulative number of loss of response was significantly lower in the EN group (odds ratio: 0.23, P = 0.0043). Kaplan-Meier analysis confirmed the significantly lower rate of loss of response in the EN group (P = 0.013). Multivariate hazard ratio was 0.37 (P = 0.025). Type of EN formula did not affect the results. CONCLUSIONS: Concomitant use of EN ≥ 600 kcal/day is likely to yield a sustained response to IFX in CD patients.

Cochleovestibular nerve involvement in multifocal fibrosclerosis.

OBJECTIVES: To report a case of multifocal fibrosclerosis with a nine-year follow up, and to discuss this disease's radiological appearance and management. The disease is a rare systemic disorder of unknown cause characterised by fibrous proliferation involving multiple anatomical sites. CASE REPORT: A 50-year-old woman presented with histological findings characterised by similar inflammatory processes involving the meninges, pituitary gland, peritoneum, retroperitoneum and orbits, prompting a search for a common pathophysiology. A diagnosis of multifocal fibrosclerosis was postulated. Symptom improvement was noted after treatment with prednisone and azathioprine. CONCLUSION: This is the first documented case of involvement of the cochleovestibular nerve in a patient with multifocal fibrosclerosis. The rare association between fibrotic diseases and masses showing various clinical patterns should be kept in mind by otolaryngologists, and imaging performed to investigate for multifocal fibrosclerosis. However, diagnosis can only be confirmed with tissue biopsy and histopathological examination.

Longitudinal changes of the laboratory data of chronic hepatitis C patients with sustained virological response on long-term follow-up.

There is no study that follows up longitudinal changes in laboratory data of patients with C-viral chronic liver disease (C-CLD) who achieved sustained virological esponse (SVR) with interferon treatment in a long-term study. We investigated the laboratory data in a long-term retrospective cohort study of 581 patients with C-CLD who underwent liver biopsy between January 1986 and December 2005. 467 were treated with interferon and 207 of these patients achieved SVR with follow-up periods of 8.36 ± 5.13 years. Alanine aminotransferase (ALT) levels, albumin levels, platelet counts, and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values were serially examined during the follow-up period. None of the 207 patients with SVR exhibited hepatitis C virus (HCV) RNA positivity more than 6 months after the end of IFN treatment. Platelet counts and albumin levels increased only in those with eradication of HCV. APRI values decreased more in patients with SVR than in those with nonsustained virological responses (non-SVR). Patients who achieved SVR and had fibrosis stage 0-1 and 2-4 at enrolment had platelet counts that longitudinally increased by 2.81 ± 3.95 and 5.49 ± 4.53 × 10(3) /µL during the 10-year follow-up period, respectively. Albumin levels continuously increased during the first 2 years by 0.15 ± 0.31 and 0.33 ± 0.37 in fibrosis stage 0-1 and 2-4, respectively and then plateaued. ALT levels decreased rapidly one year after the start of treatment by 110.3 ± 140.0 and 100.5 ± 123.4 in fibrosis 0-1 and 2-4, respectively. HCV RNA negativity persisted in all patients with SVR, and laboratory data including APRI longitudinally improved during the long-term follow-up period.

Clinical importance of serum hepatitis B surface antigen levels in chronic hepatitis B.

Quantitative serology for hepatitis B surface antigen (HBsAg) is a new candidate marker for prediction of clinical outcome. The aim of this study was to investigate the clinical significance of quantifying HBsAg in patients with hepatitis B virus (HBV) infection. A total of 424 patients who tested positive for HBsAg and were referred to Chiba University Hospital between January 1985 and April 2008 were included in the study, and the following characteristics were analyzed: age, gender, status of hepatitis B e antigen (HBeAg), alanine aminotransferase level (ALT), HBV DNA level, number of platelets and development of hepatocellular carcinoma. Measurement of HBsAg was performed using the chemiluminescent enzyme immunoassay method. The study group consisted of 239 men and 185 women, and their average age was 40.6 ± 14.0 years. HBsAg showed a positive correlation with HBV DNA level (Pearson's product moment correlation, r = 0.586, P < 0.001) and a weak inverse correlation with age (r = 0.3325, P < 0.001). A control study, matched with age and sex, was performed between two groups with and without HBeAg seroconversion during follow-up period. Compared with the age and sex-matched controls, the change in HBsAg levels per year showed a significant decrease 2 years before seroconversion (paired t-test, P < 0.05). The serial measurement of quantitative HBsAg level has the possibility of predicting the occurrence of HBeAg seroconversion.

Concomitant expression of HER2 and HIF-1alpha is a predictor of poor prognosis in uterine cervical carcinoma treated with concurrent chemoradiotherapy: prospective analysis (KGROG0501).

BACKGROUND: In previously reported retrospective analyses of uterine cervical carcinoma cases, HER2 was correlated with poor radiation sensitivity and poor treatment outcomes and HIF-1alpha was found to be an indicator of poor prognosis. To date, no prospective studies have been performed to evaluate the radiation sensitivity and treatment outcomes of patients with uterine cervical carcinoma relative to HER2 and HIF-1alpha expressions. We conducted a prospective evaluation of HER2 and HIF-1alpha in cases of locally advanced uterine cervical carcinoma treated with concurrent chemoradiotherapy. METHODS: Between June 2005 and April 2008, 25 patients with locally advanced uterine cervical carcinoma were registered in this study, KGROG0501. Their clinical stages were Ib2/IIb/IIIb/IVa in 1/2/22/1 cases, respectively. Nineteen cases had squamous cell carcinoma and six had adenocarcinoma. HER2 expression and HIF-1alpha expression were analyzed using an immunohistochemical kit on pretreatment biopsied specimens. HIF-1alpha expression was studied using another commercial immunohistochemical kit on pretreatment biopsied specimens. The survival rates were compared between patients with and without positive HER2 and HIF-1alpha expressions. RESULTS: The 20-month survival of HER2(-) and HIF-1alpha(-) cases (n = 6) was 100% and that of HER2(+) and HIF-1alpha(+) cases (n = 4) was 37.5% (p = 0.0032). CONCLUSIONS: In this first prospective analysis of patients with uterine cervical carcinoma treated with concurrent chemoradiotherapy, concomitant expression of HER2 and HIF-1alpha was suggested to be a strong indicator of poor prognosis. A novel therapy including molecular targeted therapy such as anti-HER2 and anti-HIF-1alpha may be worth considering in patients with concomitant expression of HER2 and HIF-1alpha.

Xenografting of testicular tissue from an infant human donor results in accelerated testicular maturation.

BACKGROUND: Grafting of testicular tissue into immunodeficient mice has been used to differentiate the neonatal testes from different animal species up to the level of complete spermatogenesis; however, this approach has not been successful for human testicular tissue. The aim of this study was to evaluate the capacity for differentiation of infant human testicular tissue grafts. METHODS AND RESULTS: Testicular tissue from a 3-month-old patient with testicular cancer was grafted into immunodeficient nude mice. At the time of grafting, A spermatogonia were the only germ cells present in the testicular tissue. B spermatogonia and first spermatocytes were observed at 7 months and 1 year after grafting, respectively. Positive immunostaining with antibodies against BOULE and CDC25A suggested that spermatocytes in the graft were not arrested but in meiosis. Furthermore, ultrastructural and immunohistochemical analyses showed that the onset of both Sertoli cell maturation and partial differentiation of Leydig cells preceded the appearance of spermatocytes. Differentiation of testicular cells was accelerated compared with in vivo development. CONCLUSIONS: Spermatogenesis in the xenograft of infant human testicular tissues proceeded successfully from the stage of spermatogonial stem cells until pachytene spermatocyte formation. The differentiation of Sertoli cells and Leydig cells was reproduced in a manner similar to that in normal testicular development. Grafting of infant human testicular tissue may be a powerful tool to examine the early period of human spermatogenesis and may pave the way for fertility preservation among infant patients.

Functional and morphological changes of macula after subthreshold micropulse diode laser photocoagulation for diabetic macular oedema.

PURPOSE: To examine the early changes of retinal sensitivity by fundus-related microperimetry after subthreshold micropulse diode laser photocoagulation (SMDLP) for diabetic macular oedema (DMO). METHODS: Twenty-eight eyes of 28 patients with diffuse DMO were treated with SMDLP. The mean retinal sensitivity within the central 10 degrees measured with a fundus-related microperimeter, MP1, best corrected visual acuity (BCVA) in logarithm of minimum angle of resolution units, and optical coherence tomography-determined foveal thickness (FT) were examined before and 3 months after SMDLP. The pretreatment values of the retinal sensitivity, FT, BCVA, and funduscopic findings were compared with the corresponding values at 3 months after SMDLP. RESULTS: At 3 months, the BCVA was significantly improved (P=0.03), and the FT was significantly reduced (P=0.0043). The mean retinal sensitivity within the central 10 degree, however, did not change significantly (P=0.70). The correlation between the changes in the retinal sensitivities and the decrease in the FT was not significant. The correlation between the changes in the retinal sensitivities and the BCVA was also not significant. CONCLUSIONS: Significant improvements in retinal sensitivities within the central 10 degrees were not observed even though the decrease in FT and the improvement of BCVA were significant. On account of this difference of changes in retinal sensitivity and BCVA, the combination of retinal sensitivity by MP1 and BCVA may be beneficial in assessing the visual function from various angles after SMDLP for eyes with DMO.

Indications for the use of endoscopic mucosal resection for early gastric cancer in Japan: a comparative study with endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) has been reported to produce excellent treatment results for early gastric cancer. In terms of lesions that previously met the criteria for endoscopic mucosal resection (EMR), there is now controversy about which of the two methods is superior, and whether the two methods are comparable. PATIENTS AND METHODS: A total of 177 patients (202 lesions) with early gastric cancer who met the guidelines for EMR and who underwent either EMR or ESD were studied. The rates of en bloc resection, complete resection, local recurrence, and complications were compared between EMR and ESD. RESULTS: The overall en bloc and complete resection rates were lower in patients undergoing EMR than in those undergoing ESD (en bloc: 53.8 % vs. 94.3 %, P < 0.001; complete: 37.5 % vs. 92.6 %, P < 0.001). The overall 5-year recurrence-free rate was lower in the EMR group than in the ESD group (82.5 % vs. 100 %; P < 0.001). However, with regard to the tumor size, the two groups did not differ in en bloc ( P = 1.0) or complete resection rate ( P = 0.8) for tumors < or = 5 mm and in 5-year recurrence-free rate ( P = 0.19) for tumors < or = 10 mm. The mean time required for resection was longer for ESD than for EMR ( P < 0.001). Perforation and bleeding requiring blood transfusion occurred in a small percentage in the ESD group, but in none in the EMR group. CONCLUSION: In this study, EMR was comparable to ESD for the millimeter-sized lesions. We suggest that such small lesions might be well suited to treatment with EMR.

Patching retinal breaks with Seprafilm in experimental rhegmatogenous retinal detachment of rabbit eyes.

PURPOSE: To examine the short-term effect of Seprafilm for patching retinal breaks in experimental rhegmatogenous retinal detachment of rabbit eyes. METHODS: Experimental retinal detachment with a break was made and repaired by fluid-gas exchange during vitreous surgery in 10 rabbit eyes. In seven eyes, Seprafilm was applied to cover iatrogenic retinal breaks entirely (study group) and in other three eyes operations were finished without Seprafilm application (control group). Funduscopic examination was carried out in both groups and in study group optical coherence tomography (OCT) was performed to observe Seprafilm on the retinal break. Eyes of study group were enucleated on 7th and 14th postoperative day for histological evaluation. RESULTS: The funduscopic examination showed that the retina was reattached in all eyes of study group. Meanwhile all three eyes of control group resulted in proliferative vitreoretinopathy. OCT showed that Seprafilm adhered to the retina tightly. Funduscopic examination and OCT showed Seprafilm dissolved within 14 days. Histological examination revealed that Seprafilm adhered tightly to the retina and there was no inflammatory change at the Seprafilm application sites. CONCLUSIONS: In our small number of this study, Seprafilm was found to be beneficial to patch small and posteriorly located retinal breaks in vitreous surgery for rhegmatogenous retinal detachment.

Short-term changes in temporomandibular joint function in subjects with cleft lip and palate treated with maxillary distraction osteogenesis.

OBJECTIVES: To investigate the short-term effects of maxillary distraction osteogenesis (DO) on temporomandibular joint (TMJ) function in 21 subjects with cleft lip and palate (CLP). Design - Morphological changes in the maxillofacial region were measured using lateral cephalometric radiographs taken immediately before (pre-DO) and after DO (post-DO) and 1 year after DO (1-year follow-up). A questionnaire was evaluated using a visual analog scale. A chi-square test was used to compare the prevalence of TMJ symptoms between pre-DO and 1-year follow-up. The Spearman correlation coefficient was used to determine the correlation between changes in cephalometric variables and TMJ symptoms in association with maxillary DO. Statistical significance was set at p < 0.05. Results - The ANB (anteroposterior relationship of the maxilla with the mandible) angle and the mandibular plane angle at pre-DO, post-DO, and 1-year follow-up were -4.3 degrees , +5.8 degrees , +4.3 degrees and 32.1 degrees , 33.5 degrees , 33.6 degrees , respectively. The average amounts of anterior and downward movement of the maxilla at post-DO and 1-year follow-up were 8.3, -1.3 and 0.9, 1.1 mm, respectively. The prevalence of TMJ symptoms showed no significant increase in association with maxillary DO. Moreover, there was no significant correlation between changes in cephalometric variables and TMJ symptoms. Conclusion - These results suggest that there was no short-term (i.e., up to 1 year after DO) effect of maxillary DO on TMJ function in subjects with CLP.

Antithrombin inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by monocytes in vitro through inhibition of Egr-1 expression.

BACKGROUND: Antithrombin (AT) improves the outcome of septic patients with intravascular coagulation. However, the mechanisms underlying the therapeutic benefits of AT are not fully understood. Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the development of organ failure and intravascular coagulation in sepsis. AIM: This study aimed to elucidate a molecular mechanism by which AT inhibits TNF-alpha production. METHODS: Human peripheral monocyte was stimulated by lipopolysaccharide (LPS) and TNF-alpha concentration in media was measured. Levels of phosphorylation of extracellular signal-regulated protein kinases (ERK) 1/2 and early growth response factor-1 (Egr-1) were estimated by western blotting or by electrophoretic mobility shift assay. RESULTS: Antithrombin (3 U mL(-1)) inhibited TNF-alpha production by monocytes stimulated with LPS. Conversely, chemically modified AT that lacks affinity for heparin did not. AT inhibited the phosphorylation of ERK 1/2 and decreased the expression of Egr-1 in LPS-stimulated monocytes. However, it did not affect the activation of either nuclear factor-kappaB or activator protein-1. Pretreatment with KT5720, a protein kinase A inhibitor, reversed the inhibitory effect of AT on the LPS-induced phosphorylation of ERK1/2. Although 2 U mL(-1) AT slightly inhibited TNF-alpha production by LPS-stimulated monocytes, it significantly inhibited TNF-alpha production in the presence of a low concentration of beraprost, a stable derivative of prostacyclin. CONCLUSIONS: These observations suggest that AT might inhibit LPS-induced production of TNF-alpha by inhibiting the increase in Egr-1 expression in monocytes via interaction with heparin-like substances expressed on the cell surface.

Sum frequency generation spectroscopic studies on phase transitions of phospholipid monolayers containing poly(ethylene oxide) lipids at the air-water interface.

Vibrational sum frequency generation (SFG) spectroscopy was applied to study the phase transitions of the mixed monolayers of l-alpha-distearoyl phosphatidylethanolamine (DSPE) and DSPE covalently coupled with poly(ethylene oxide) at the amino head group (DSPE-EO(45), DSPE with 45 ethylene oxide monomers) at the air-water interface. The SFG spectra were measured for the mixed monolayers with the mole fractions of DSPE-EO(45) of 0, 1.3, 4.5, 9.0, 12.5, and 16.7% at the surface pressures of 5, 15, and 35 mN/m. The monolayer compression isotherms indicated that the mixed monolayers at 5, 15, are 35 mN/m are mainly in the so-called "pancake", "mushroom", and "brush" states, respectively. The SFG spectra in the OH stretching vibration region give rise to SFG bands near 3200 and 3400 cm(-1). The mean molecular amplitude of the former band due to the OH stretching of the "icelike" water molecules associated mainly with the hydrophilic poly(ethylene oxide) (PEO) chains, exhibits appreciable decrease on compression of the mixed monolayers from 5 to 15 mN/m. The result corroborates the model for the pancake-mushroom transition, which presumes the dissolution of the PEO chains from the air-water interface to the water subphase. Further compression of the mixed monolayers to 35 mN/m causes a slight decrease of the line amplitude, which can be explained by considering a squeezing out of water molecules from the hydrophilic groups of DSPE-EO(45) in the brush state, where the PEO chains strongly interact with each other to form a tight binding state of the hydrophilic groups. The relative intensities of the SFG bands due to the CH3 asymmetric and symmetric vibrations were used to estimate the tilt angles of the terminal methyl group of DSPE, indicating that the angle increases with increasing the mole fraction of DSPE-EO(45). The angles almost saturate at the mole fraction larger than 10%, the saturation angle being nearly 90 degrees at 5 mN/m, ca. 60 degrees at 15 mN/m, and ca. 47 degrees at 35 mN/ m. Then, the introduction of the hydrophilic PEO head group causes a large tilting of the alkyl groups of DEPE in the mixed monolayers.

Evaluation of C-2-substituted 19-nor-1alpha,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer.

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1alpha,25(OH)(2)D(3) can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized (3)H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1alpha,25(OH)(2)D(3) analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2alpha- or 2beta-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1alpha,25(OH)(2)D(3). The (3)H-thymidine incorporation data were supported by the cell counting data after cells were treated with 1alpha,25(OH)(2)D(3), 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) or 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) for 7 days. 19-Nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) and 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) were also shown to be about 10-fold more active than 1alpha,25(OH)(2)D(3) in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1alpha,25(OH)(2)D(3) molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer.