Photobiomodulation therapy at 632 nm wavelength ameliorates intrauterine adhesion via activation of cAMP/PKA/CREB pathway.

Intrauterine adhesion (IUA), a major cause of uterine infertility, is pathologically characterized by endometrial fibrosis. Current treatments for IUA have poor efficacy with high recurrence rate, and restoring uterine functions is difficult. We aimed to determine the therapeutic efficacy of photobiomodulation (PBM) therapy on IUA and elucidate its underlying mechanisms. A rat IUA model was established via mechanical injury, and PBM was applied intrauterinely. The uterine structure and function were evaluated using ultrasonography, histology, and fertility tests. PBM therapy induced a thicker, more intact, and less fibrotic endometrium. PBM also partly recovered endometrial receptivity and fertility in IUA rats. A cellular fibrosis model was then established with human endometrial stromal cells (ESCs) cultured in the presence of TGF-ß1. PBM alleviated TGF-ß1-induced fibrosis and triggered cAMP/PKA/CREB signaling in ESCs. Pretreatment with the inhibitors targeting this pathway weakened PBM's protective efficacy in the IUA rats and ESCs. Therefore, we conclude that PBM improved endometrial fibrosis and fertility via activating cAMP/PKA/CREB signaling in IUA uterus. This study sheds more lights on the efficacy of PBM as a potential treatment for IUA.

A predictive molecular signature consisting of lncRNAs associated with cellular senescence for the prognosis of lung adenocarcinoma.

The role of long noncoding RNAs (lncRNAs) has been verified by more and more researches in recent years. However, there are few reports on cellular senescence-associated lncRNAs in lung adenocarcinoma (LUAD). Therefore, to explore the prognostic effect of lncRNAs in LUAD, 279 cellular senescence-related genes, survival information and clinicopathologic parameters were derived from the CellAge database and The Cancer Genome Atlas (TCGA) database. Then, we constructed a novel cellular senescence-associated lncRNAs predictive signature (CS-ALPS) consisting of 6 lncRNAS (AC026355.1, AL365181.2, AF131215.5, C20orf197, GAS6-AS1, GSEC). According to the median of the risk score, 480 samples were divided into high-risk and low-risk groups. Furthermore, the clinicopathological and biological functions, immune characteristics and common drug sensitivity were analyzed between two risk groups. In conclusion, the CS-ALPS can independently forecast the prognosis of LUAD, which reveals the potential molecular mechanism of cellular senescence-associated lncRNAs, and provides appropriate strategies for the clinical treatment of patients with LUAD.

Predictors of treatment responses of superficial infantile hemangiomas to topical timolol.

Topical timolol is not effective in the treatment of some superficial infantile hemangiomas (IHs). This is a prospective study aiming to investigate the predictors of treatment response of superficial IHs to topical timolol. Patients with superficial IHs were prescribed timolol 0.5% cream four times daily and followed up every 2-3 months until 1 year of age. IH thickness was objectively measured by ultrasound, and the proportional change was calculated as a regression rate. In total, 193 patients (211 lesions) were enrolled. Topical timolol was initiated at an average age of 3.1 (0-6) months for 7.4 (2-11) months. The average regression rate of all lesions was 41.8% (-137.5%-100%). Lesion thickness (p = 0.000) and patient age at initial treatment (p = 0.001) were major variables that predicted the treatment response. On average, an increase in lesion thickness of 1 mm decreased the regression rate by 22.1%, and lesions thicker than 1.9 mm were unlikely to respond (average regression rate = -0.27%). Available results did not show a significant effect of sex (p = 0.659), lesion size (p = 0.311), or location (p > 0.05) on regression. Treatment for superficial IHs should be individualized according to lesion thickness and patient age.

Microstructure regulation of pitch-based soft carbon anodes by iodine treatment towards high-performance potassium-ion batteries.

Soft carbon has been regarded as one of the most promising anode materials for potassium-ion batteries. However, the rearrangement of planar aromatics at high carbonization temperature usually yields a highly graphitized structure, which generally leads to inferior rate and cycle performance. In addition, the role of intrinsic carbon defects on potassium storage has not been well reported yet. In this work, crosslinked pitch-based soft carbon nanosheets have been synthesized through the iodination/dehydroiodination process at low temperature and carbonization with NaCl template. The iodine-treatment efficiently crosslinks the planar aromatics to three-dimensional framework by alkyl-bridged linkages, and reduces the strong π-π interaction during carbonization. This unique microstructure yields an ordered-in-disordered carbon microstructure, enlarged interlayer spacing, and abundant intrinsic defect sites. Benefited from these merits, the optimal sample displays 140% increase of reversible capacity to the pristine pitch-based carbon at 5 A g-1. Particularly, it also presents 87.4% capacity retention after 1000 cycles at 1 A g-1. This facile but simple strategy is expected to expand to other high-performance carbon materials and further understand the effect of intrinsic defects for potassium storage and beyond.

Comparison of single-port vs. two-port VATS technique for primary spontaneous pneumothorax.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has been used for thoracic surgery for about two decades. As the trend in VATS is to use fewer ports to decrease postoperative complications, we compared the results of our experience with single-port and two-port VATS for primary spontaneous pneumothorax (PSP). MATERIAL AND METHODS: This is a non-randomized retrospective study. From January 2017 to December 2018, 104 patients with PSP underwent VATS. Fifty-six patients received single-port VATS and 48 patients received two-port VATS. Operation time, blood loss, number of staplers used, drainage time, postoperative hospital stay, complications, chest wall paresthesia, visual analog scale (VAS) pain scores, and patient satisfaction scale scores were compared between the two groups. RESULTS: There was no difference in age, gender, body mass index (BMI), smoking status, surgical indication, and involved side between the two groups. The procedures performed in the single-port group were similar to those performed in the two-port group. No significant difference was found in operation time, blood loss, number of staplers used, drainage time, and recurrence rate. The rate of chest wall paresthesia was lower in the single-port group than in the two-port group (28.6 vs. 52.1%, p = .014). The VAS scores in the single-port group were lower than those in the two-port group at 24 and 48 h (p = .032 and p = .004). CONCLUSIONS: Compared with two-port VATS, single-port VATS for PSP showed more favorable results in terms of postoperative paresthesia and pain. The single-port procedure may be considered a good alternative to the standard thoracoscopic treatment of PSP. Abbreviations: VATS: Video-assisted thoracic surgery; PSP: primary spontaneous pneumothorax.

Surgical outcomes of two different reconstruction routes for esophagectomy in esophageal cancer patients: a meta-analysis.

To evaluate the effects of two different reconstruction routes (the posterior mediastinal route (PR) and the retrosternal route (RR)) on the surgical outcomes of patients after esophagectomy for esophageal carcinoma. PubMed, Embase, Web of Science and Scopus were searched from database inception to March 2021. Randomized controlled trials (RCTs) and case-control trials on the surgical outcomes of patients undergoing esophagectomy via one of the two routes were included. RevMan 5.3 software was used for the meta-analysis. In total, 19 studies were included, 8 were RCTs and 11 were case-control studies. The meta-analysis showed that among the case-control trials, the PR had reduced rates of anastomotic leakage [odds ratio (OR) = 0.56, 95% confidence interval (CI) (0.43, 0.74), P < 0.01]. In addition, it had reduced rates of anastomotic stenosis [OR = 0.42, 95% CI (0.30, 0.59), P < 0.01] and pulmonary complications [OR = 0.63, 95% CI (0.47, 0.84), P < 0.01]. However, there was no significant difference in cardiac complications [RCTs, relative risk (RR) = 0.57, 95% CI (0.29, 1.11), P = 0.10; case-control trials, OR = 1.06, 95% CI (0.70, 1.62), P = 0.78] or postoperative mortality [RCTs, RR = 0.47, 95% CI (0.19, 1.16), P = 0.10; case-control trials, OR = 0.68, 95% CI (0.32, 1.44), P = 0.31]. Compared with the RR, the PR had reduced rates of anastomotic leakage, anastomotic stenosis and pulmonary complications.

Can anticoagulants improve the survival rate for patients with idiopathic pulmonary arterial hypertension? A systematic review and meta-analysis.

BACKGROUND: Anticoagulant therapy is believed to be an important component of treatment for idiopathic pulmonary arterial hypertension (IPAH). Recent data suggest that therapy that does not include anticoagulants results in no significant difference in patient survival. We sought to evaluate the effect of anticoagulants on survival in patients with IPAH. METHODS: A systematic review and a random-effects meta-analysis to estimate hazard ratio (HR) and 95% confidence intervals (CI) were performed. PubMed/MEDLINE, Web of Knowledge and other databases were searched for eligible literature. Review articles and references were also screened. RESULTS: 8 studies with a total of 1812 patients with IPAH were included in this analysis. No randomized controlled trials (RCT) were identified. All the 8 studies had a mean complete follow-up ranging from 3 to 14 years. In this analysis, use of anticoagulants did not significantly decrease mortality risk (P = 0.07, HR = 0.77, 95% CI [0.58, 1.02]). Sensitivity analysis showed similar results (P = 0.12, HR = 0.80, 95% CI [0.60, 1.06]). Subgroup analysis showed that anticoagulants performed no significant advantages with the use of PAH-specific therapies (P = 0.82, HR = 0.95, 95% CI [0.63, 1.44]). CONCLUSIONS: No randomized evidence to support the use of anticoagulants in IPAH. No significant benefit for patients' survival was found in our analysis. The potential biases of included observational studies made it hard to achieve a meaningful conclusion. The necessity of anticoagulants for IPAH patients remains to be evaluated.

Cell-Free Fat Extract Increases Dermal Thickness by Enhancing Angiogenesis and Extracellular Matrix Production in Nude Mice.

BACKGROUND: Although adipose-derived stem cells (ADSCs) and nanofat exert antiaging effects on skin, they contain cellular components that have certain limitations in clinical practice. Cell-free fat extract (Ceffe) is a fraction purified from nanofat through removal of cellular components and lipid remnants that contains various growth factors. OBJECTIVES: The purpose of this study was to evaluate the effects of Ceffe on cultured human dermal fibroblasts in vitro and on the dermis of nude mice in vivo. METHODS: In the in vitro study, human dermal fibroblasts were cultured with Ceffe for 72 hours, followed by flow cytometry measurement of cell proliferation and cell cycle. In the in vivo study, different concentrations of Ceffe were injected into the dorsal skin of nude mice for 4 weeks. The thickness of the dermis; proliferation of cells; density of the capillary; and expressions of type I and III collagen (Col-1 and Col-3), matrix metalloproteinase-1, matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-3 were measured through histologic and Western blot analyses. RESULTS: Ceffe significantly increased cell proliferation in cultured dermal fibroblasts. In the mouse skin, Ceffe significantly increased the thickness of the dermis, number of proliferating cells, density of the capillary, and expressions of Col-1 and Col-3. CONCLUSIONS: Ceffe increased the dermal thickness of nude mice, possibly by enhancing angiogenesis and extracellular matrix production, and can therefore be used for skin rejuvenation.

Protective Effect of Fat Extract on UVB-Induced Photoaging In Vitro and In Vivo.

BACKGROUND: Nanofat can protect against ultraviolet B- (UVB-) induced damage in nude mice. Fat extract (FE) is a cell-free fraction isolated from nanofat that is enriched with a variety of growth factors. OBJECTIVE: To determine whether FE can protect against UVB-induced photoaging in cultured dermal fibroblasts and in nude mice. METHOD: For the in vitro study, human dermal skin fibroblasts were pretreated with FE 24 h prior to UVB irradiation. Generation of reactive oxygen species (ROS) was analyzed immediately following irradiation, while cell cycle analysis was performed 24 h after UVB irradiation. Senescence-associated ß-galactosidase (SA-ß-gal) expression, cell proliferation, and expression of glutathione peroxidase 1 (GPX-1), catalase, superoxide dismutase-1 (SOD-1), SOD-2, and collagen type 1 (COL-1) were investigated 72 h after UVB irradiation. For the in vivo study, the dorsal skin of nude mice was irradiated with UVB and mice were then treated with FE for 8 weeks. The thickness of the dermis, capillary density, and apoptotic cells in skin tissue sections were investigated after treatment. The expression of GPX-1, catalase, SOD-2, SOD-1, and COL-1 in the tissue was also measured. RESULT: FE significantly increased cell proliferation and protected cells against UVB-induced cell death and cell cycle arrest. FE reduced ROS and the number of aged cells induced by UVB irradiation. FE promoted the expression of COL-1 and GPX-1 in cultured dermal fibroblasts. FE treatment of UVB-irradiated skin increased dermal thickness and capillary density, decreased the number of apoptotic cells, and promoted the expression of COL-1 and GPX-1. CONCLUSION: FE protects human dermal fibroblasts and the skin of nude mice from UVB-induced photoaging through its antioxidant, antiapoptotic, and proangiogenic activities.

Fat extract improves fat graft survival via proangiogenic, anti-apoptotic and pro-proliferative activities.

BACKGROUND: Our previous study proved that nanofat could enhance fat graft survival by promoting neovascularization. Fat extract (FE), a cell-free component derived from nanofat, also possesses proangiogenic activity. OBJECTIVES: The aim of this study was to investigate whether FE could improve fat graft survival and whether FE and nanofat could work synergistically to promote fat graft survival. The underlying mechanism was also investigated. METHODS: In the first animal study, human macrofat from lipoaspirate was co-transplanted into nude mice with FE or nanofat. The grafts were evaluated at 2, 4 and 12 weeks post-transplantation. In the second animal study, nude mice were transplanted with a mixture of macrofat and nanofat, followed by intra-graft injection of FE at days 1, 7, 14, 21 and 28 post-transplantation. The grafts were evaluated at 12 weeks post-transplantation. To detect the mechanism by which FE impacts graft survival, the proangiogenic, anti-apoptotic and pro-proliferative activities of FE were analysed in grafts in vivo and in cultured human vascular endothelial cells (HUVECs), adipose-derived stem cells (ADSCs) and fat tissue in vitro. RESULTS: In the first animal study, the weights of the fat grafts in the nanofat- and FE-treated groups were significantly higher than those of the fat grafts in the control group. In addition, higher fat integrity, more viable adipocytes, more CD31-positive blood vessels, fewer apoptotic cells and more Ki67-positive proliferating cells were observed in the nanofat- and FE-treated groups. In the second animal study, the weights of the fat grafts in the nanofat+FE group were significantly higher than those of the fat grafts in the control group. In vitro, FE showed proangiogenic effects on HUVECs, anti-apoptotic effects on fat tissue cultured under hypoxic conditions and an ability to promote ADSC proliferation and maintain their multiple differentiation capacity. CONCLUSIONS: FE could improve fat graft survival via proangiogenic, anti-apoptotic and pro-proliferative effects on ADSCs. FE plus nanofat-assisted fat grafting is a new strategy that could potentially be used in clinical applications.

Fat Extract Improves Random Pattern Skin Flap Survival in a Rat Model.

BACKGROUND: Adipose tissue and its derivatives, including adipose-derived stem cells, stromal vascular fraction (SVF), and SVF-gel, have been utilized in the treatment of many ischemic disorders. However, the utilization of these products is limited in clinical applications by concerns related to the presence of cells in these derivatives. OBJECTIVES: This study aimed to isolate a cell-free fat extract (FE) from fat tissue and to evaluate its proangiogenic ability in vitro as well as its protective effects on skin flap survival in vivo. METHODS: FE was isolated from human fat via a mechanical approach. The concentrations of several growth factors in the FE were determined by enzyme-linked immunosorbent assay. The proangiogenic ability of FE was evaluated utilizing assays of the proliferation, migration, and tube formation in human umbilical vein endothelial cells in vitro. The protective effects of FE on the survival of random pattern skin flaps were investigated by subcutaneous injection into rats. RESULTS: Enzyme-linked immunosorbent assay results revealed that FE contained proangiogenic growth factors that promoted proliferation, migration, and tube formation in human umbilical vein endothelial cells in vitro. In addition, FE reduced skin flap necrosis and increased survival, as demonstrated by macroscopic measurements and blood flow analysis. Histological analysis revealed that FE treatment increased the capillary density. CONCLUSIONS: FE is a cell-free, easy-to-prepare, and growth-factor-enriched liquid derived from human adipose tissue that possesses proangiogenic activity and improves skin flap survival by accelerating blood vessel formation. FE may be potentially used for treating ischemic disorders.

Factors Correlating to the Development of Hepatitis C Virus Infection in Hemodialysis Patients-Findings Mainly from Asiatic Populations: A Systematic Review and Meta-Analysis.

Hemodialysis is an effective replacement therapy for chronic renal failure patients. In recent decades, the number of hemodialysis patients has grown rapidly and some measures for preventing blood-borne diseases have been implemented, but hepatitis C virus (HCV) infection remains a significant problem. The meta-analysis published in 2009 on HCV infection-related factors was based on localized study objects, and some additional studies have been published since 2009; however, the contribution of these factors remains under dispute. Our study pooled the odds ratios (ORs) or mean standard deviations (MDs) with 95% confidence intervals (CIs) and analyzed sensitivity using Review Manager 5.1 software (5.1 version Copenhagen: The Nordic Cochrane Centre; 2011) by searching data in the PubMed, Elsevier, Springer, Wiley, and EBSCO databases. Spearman correlation analysis was performed using the SPSS package. In our meta-analysis, 1715 HCV-infected hemodialysis patients and 7093 non-HCV-infected hemodialysis patients from 44 studies were analyzed. The pooled ORs with 95% CIs were: histories of blood transfusion, 4.30 (3.11, 5.96); weekly hemodialysis times > 2, 6.00 (3.25, 11.06); kidney transplantation, 5.80 (3.95, 8.52); hemodialysis units > 2, 6.90 (2.42, 19.68); shared hemodialysis devices, 5.00 (2.35, 10.65); and drug addiction, 4.73 (1.54, 14.47). The pooled MDs with 95% CIs were duration of hemodialysis (months) 27.48 (21.67, 33.30). There was a positive correlation between duration of hemodialysis and the HCV infection rate (p < 0.01). Hemodialysis patients, especially from Asia, with shared hemodialysis devices, hemodialysis units > 2, blood transfusion, kidney transplantation, and drug addiction were at increased risk of HCV infection. The HCV infection rate increased with the duration of hemodialysis. High-risk hemodialysis patients should be monitored and receive timely screening.

MicroRNA-145 performs as a tumor suppressor in human esophageal squamous cell carcinoma by targeting phospholipase C epsilon 1.

Esophageal squamous cell carcinoma (ESCC) is the leading pathologic type in China. miR-145 has been reported to be downregulated in multiple tumors. This study was aimed to investigate the role of miR-145 in ESCC. miR-145 expression was investigated in 65 ESCC samples as well as four ESCC cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). Targetscan 6.2 website (http://www.targetscan.org/) was used to predict the targets of miR-145. Expression of phospholipase C epsilon 1 (PLCE1) messenger RNA and protein was detected by qRT-PCR or Western blot. MTT and wound healing assay were conducted to explore the effects of miR-145 on the proliferation and migration of ESCC cell lines, respectively. miR-145 was significantly decreased in ESCC tissues. An inverse correlation between miR-145 and invasion depth and TNM stage were observed. PLCE1 was a direct target of miR-145, and the expression of PLCE1 was inversely correlated with miR-145 expression in ESCC tissues. In addition, overexpression of miR-145 suppressed cell proliferation and migration in ESCC cells. The enforced expression of PLCE1 partially reversed the suppressive effect of miR-145. These results prove that miR-145 may perform as a tumor suppressor in ESCC by targeting PLCE1.

Using the synthesized peptide HAYED (5) to protect the brain against iron catalyzed radical attack in a naturally senescence Kunming mouse model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain. It cannot be cured currently, and those suffering from AD place a great burden on their caregivers and society. AD is characterized by high levels of iron ions in the brain, which catalyze radicals that damage the neurons. Knowing that the Aß42 peptide precipitates iron by binding iron ions at amino acid residues D1, E3, H11, H13, and H14, we synthesized a 5-repeat (HAYED) sequence peptide. By treating iron-stressed SH-SY5Y cells with it and injecting it into the cerebrospinal fluid (CSF) of naturally senescence Kunming mouse, which displaying AD-similar symptoms such as learning and memory dysfunction, neuron degeneration and high level of iron in brain, we found that HAYED (5) decreased the iron and radical levels in the cell culture medium and in the CSF. Specially, the synthesized peptide prevented cell and brain damage. Furthermore, functional magnetic resonance imaging (fMRI), Morris water maze and passive avoidance tests demonstrated that the peptide ameliorated brain blood-oxygen metabolism and slowed cognitive loss in the experimental senescence mice, and clinical and blood tests showed that HAYED (5) was innoxious to the kidney, the liver and blood and offset the AD-associated inflammation and anemia.

Fat extract promotes angiogenesis in a murine model of limb ischemia: a novel cell-free therapeutic strategy.

BACKGROUND: The proangiogenic capacity of adipose tissue and its derivatives has been demonstrated in a variety of studies. The paracrine mechanism of the cellular component is considered to play a critical role in the regenerative properties of these tissues. However, cell-based therapy for clinical application has been hindered by limitations such as safety, immunogenicity issues, and difficulties in cell preservation, transportation, and phenotype control. In the current study, we aimed to produce a cell-free extract directly from human fat tissue and evaluate its potential therapeutic efficacy. METHODS: We developed a novel physical approach to produce a cell-free aqueous extract from human fat tissue (fat extract (FE)). The therapeutic potential of FE was investigated in the ischemic hindlimb model of nude mice. After establishment of hindlimb ischemia with ligation of the left femoral artery and intramuscular injection of FE, blood perfusion was monitored at days 0, 7, 14, 21, and 28. Tissue necrosis and capillary density were evaluated. Enzyme-linked immunosorbent assay was used to analyze the growth factors contained in FE. Moreover, the proliferation, migration, and tube formation ability were tested on human umbilical vein endothelial cells (HUVECs) in vitro when treated with FE. The proangiogenic ability of FE was further assessed in an in-vivo Matrigel plug assay. RESULTS: FE was prepared and characterized. The intramuscular injection of FE into the ischemic hindlimb of mice attenuated severe limb loss and increased blood flow and capillary density of the ischemic tissue. Enzyme-linked immunosorbent assay showed that FE contained high levels of various growth factors. When added as a cell culture supplement, FE promoted HUVEC proliferation, migration, and tube formation ability in a dose-dependent manner. The subcutaneous injection of Matrigel infused with FE enhanced vascular formation. CONCLUSIONS: We developed a novel cell-free therapeutic agent, FE, produced from human adipose tissue. FE was able to attenuate ischemic injury and stimulate angiogenesis in ischemic tissues. This study indicates that FE may represent a novel cell-free therapeutic agent in the treatment of ischemic disorders.

Effects of milnacipran on cardiac repolarization in healthy participants.

Milnacipran is approved for management of fibromyalgia in the United States. In this double-blind, placebo- and active drug-controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest mean difference between milnacipran and placebo in time-matched baseline-adjusted QT interval corrected for heart rate using an individual correction formula (QTcNi). In addition, data were analyzed using the Fridericia formula (QTcF) and a post hoc piecewise QTcNi analysis based on a dichotomous cut of RR interval data at 800 ms. Moxifloxacin (400 mg single dose) was used to establish assay sensitivity. Using the QTcNi method, the largest difference in baseline-adjusted QTcNi between milnacipran 300 mg bid and placebo was -4.7 ms (90% confidence interval [CI]: -9.4 to -0.1), indicating no QT prolongation. Analysis using the Fridericia formula (QTcF) showed a maximum adjusted mean change of +7.7 ms, but QTcF versus RR interval plots indicated overcorrection with this method. The piecewise QTcNi correction method demonstrated a more accurate correction for drug-induced heart rate increase; mean baseline-adjusted between-group difference was +0.9 ms (90% CI: -6.6 to 8.3). The results suggest that milnacipran would not significantly affect cardiac repolarization at clinically relevant therapeutic and supratherapeutic concentrations.

Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study.

Escitalopram has been shown in clinical trials to improve anxiety symptoms associated with depression, panic disorder, and social anxiety disorder. This study was designed to evaluate the efficacy and tolerability of escitalopram in the treatment of generalized anxiety disorder (GAD). Outpatients (18 years or older) who met DSM-IV criteria for GAD, with baseline Hamilton Rating Scale for Anxiety (HAMA) scores > or = 18, were randomly assigned to double blind treatment with escitalopram (10 mg/day for the first 4 weeks and then flexibly dosed from 10-20 mg/day) or placebo for 8 weeks, following a 1-week, single-blind, placebo lead-in period. The primary efficacy variable was the mean change from baseline in total HAMA score at Week 8. The escitalopram group (N = 158) showed a statistically significant, and clinically relevant, greater improvement at endpoint compared with placebo (N = 157) in all prospectively defined efficacy parameters. Significant improvement in HAMA total score and HAMA psychic anxiety subscale score for the escitalopram-treated group vs. the placebo-treated group was observed beginning at Week 1 and at each study visit thereafter. Mean changes from baseline to Week 8 on the HAMA total score using a last-observation-carried-forward (LOCF) approach were -11.3 for escitalopram and -7.4 for placebo (P<.001). Response rates at Week 8 were 68% for escitalopram and 41% for placebo (P<.01) for completers, and 58% for escitalopram and 38% for placebo LOCF values (P<.01). Treatment with escitalopram was well tolerated, with low rates of reported adverse events and an incidence of discontinuation due to adverse events not statistically different from placebo (8.9% vs. 5.1%; P=.27). Escitalopram 10-20 mg/day is effective, safe, and well tolerated in the treatment of patients with GAD.

Escitalopram continuation treatment prevents relapse of depressive episodes.

BACKGROUND: Current guidelines for antidepressant use recommend 4 to 6 months of continuation treatment to prevent relapse of depression following symptom resolution. This study evaluates the efficacy and safety of continuation escitalopram treatment. METHOD: Outpatients diagnosed with DSM-IV major depressive disorder (male or female, aged 18 to 81 years) who had completed 8 weeks of randomized double-blind treatment with escitalopram, citalopram, or placebo entered an 8-week flexible-dose, open-label phase in which all patients received escitalopram (10-20 mg/day). This study was initiated November 3, 1999, and completed April 5, 2001. Patients who met responder criteria (score of < or = 12 on the Montgomery-Asberg Depression Rating Scale [MADRS]) were randomly assigned in a 2:1 ratio to escitalopram (at the dose each patient was receiving at the end of the open-label phase) or placebo for 36 weeks of double-blind treatment. The primary efficacy variable was time to depression relapse (defined as MADRS score > or = 22 or discontinuation due to an insufficient therapeutic response) from the start of the double-blind treatment phase. RESULTS: A total of 502 patients received open-label escitalopram treatment and had at least 1 MADRS assessment. A total of 274 evaluable subjects entered the double-blind treatment phase; 93 received placebo and 181 received escitalopram. Time to depression relapse was significantly longer (p =.013) and the cumulative rate of relapse was significantly lower in patients who received escitalopram (26% escitalopram vs. 40% placebo; hazard ratio = 0.56; p =.01). Escitalopram-treated subjects had significantly lower depression ratings than those of placebo-treated patients. Escitalopram continuation treatment was safe and well tolerated. Discontinuation rates due to adverse events were 7% for the placebo group and 4% for the escitalopram-treated group. CONCLUSION: Continuation treatment with escitalopram is effective in preventing relapse into an episode of major depressive disorder.

Combination oxycodone 5 mg/ibuprofen 400 mg for the treatment of postoperative pain: a double-blind, placebo- and active-controlled parallel-group study.

OBJECTIVE: This study compared the efficacy and safety of a single dose of oxycodone 5 mg/ibuprofen 400 mg versus its individual components and placebo in a third-molar extraction model. METHODS: In this multicenter, double-blind, double-dummy, parallel-group investigation, subjects with moderate to severe pain within 5 hours after extraction of > or =2 ipsilateral bony impacted third molars were randomized to single doses of oxycodone 5 mg/ibuprofen 400 mg, ibuprofen 400 mg, oxycodone 5 mg, or placebo. Primary efficacy variables were the sum of pain intensity difference over 6 hours (SP1D6) and total pain relief through 6 hours (TOTPAR6). The pharmacokinetics of oxycodone and ibuprofen, alone and in combination, were also determined in a subset of patients. RESULTS: A total of 498 subjects were randomized to treatment (187 to oxycodone 5 mg/ibuprofen 400 mg, 186 to ibuprofen 400 mg, 63 to oxycodone 5 mg, and 62 to placebo). Baseline demographics were generally similar among treatment groups, despite differences in sex (P = 0.041) and race (P = 0.023). Combination therapy was associated with greater analgesia than ibuprofen alone, oxycodone alone, or placebo (mean [SE] TOTPAR6: 13.3 [0.52], 12.2 [0.52], 4.3 [0.82], and 4.2 [0.83], respectively [P < 0.001 vs oxycodone or placebo, P = 0.012 vs ibuprofen]; mean [SE] SP1D6: 6.54 [0.42], 5.41 [0.44], 0.14 [0.60], and 0.32 [0.59], respectively [P < 0.001 vs oxycodone or placebo, P = 0.002 vs ibuprofen]). Combination therapy was well tolerated. Pharmacokinetic results implied no interaction between oxycodone and ibuprofen. CONCLUSIONS: In this study, a single dose of oxycodone 5 mg/ibuprofen 400 mg was fast-acting, effective, and well tolerated in subjects with moderate to severe pain after dental surgery. Oxycodone 5 mg alone did not provide an efficacy benefit over placebo in this study.