不同腹腔镜术式治疗近端胃癌的效果比较

目的 探讨不同腹腔镜术式治疗近端胃癌（PGC）临床效果的差异。方法 回顾性分析2009年5月至2012年10月安徽医科大学第一附属医院胃肠腔镜外科行手术治疗的70例PGC患者的临床资料,其中23例行腹腔镜辅助下近端胃切除术（LAPG）为LAPG组,34例行腹腔镜辅助下全胃切除加食道空肠Roux-en-Y吻合术（LATG-RY）为LATG-RY组,13例行腹腔镜辅助下全胃切除加食道空肠OrVil^TM吻合术（LATG-OrVil^TM）为LATG-OrVil^TM组,比较3组患者手术安全性、肿瘤根治情况、术后恢复情况及术后并发症发生情况。结果 LAPG组、LATG-RY组及LATG-OrVil^TM组患者手术时间、术中出血量、TNM分期、远期并发症发生率及住院总费用的差异均有统计学意义（P<0.05）。LAPG组患者手术时间、术中出血量低于其他两组,Ⅰ期患者比例高于其他两组,远期并发症发生率高于其他两组,差异均有统计学意义（P<0.05）。LATG-OrVil^TM组住院总费用高于其他两组,差异有统计学意义（P<0.05）。结论 LAPG、LATG-RY与LATG-OrVil^TM治疗PGC均安全、有效。LAPG适用于早期PGC的治疗,LATG-RY治疗进展期PGC具有减少反流的优势,LATG-OrVil^TM是治疗累及食管下段及食管胃结合部PGC的最佳选择。     

Real-time imaging as an emerging process analytical technology tool for monitoring of fluid bed coating process

Abstract

A direct imaging system (Eyecon^TM) was used as a Process Analytical Technology (PAT) tool to monitor fluid bed coating process. Eyecon^TM generated real-time onscreen images, particle size and shape information of two identically manufactured laboratory-scale batches. Eyecon^TM has accuracy of measuring the particle size increase of ±1?μm on particles in the size range of 50–3000?μm.

Eyecon^TM captured data every 2?s during the entire process. The moving average of D90 particle size values recorded by Eyecon^TM were calculated for every 30?min to calculate the radial coating thickness of coated particles. After the completion of coating process, the radial coating thickness was found to be 11.3 and 9.11?μm, with a standard deviation of?±0.68 and 1.8?μm for Batch 1 and Batch 2, respectively. The coating thickness was also correlated with percent weight build-up by gel permeation chromatography (GPC) and dissolution. GPC indicated weight build-up of 10.6% and 9.27% for Batch 1 and Batch 2, respectively.

In conclusion, weight build-up of 10% can also be correlated with 10?±?2?μm increase in the coating thickness of pellets, indicating the potential applicability of real-time imaging as an endpoint determination tool for fluid bed coating process.     

Eluvia™ peripheral stent system for the treatment of peripheral lesions above the knee

ABSTRACT

Introduction: Drug-eluting stents promise to reduce restenosis following endovascular treatment of diseased arteries, but technologies used in peripheral arteries of the leg have not yet achieved desired success rates.

Areas covered: The rationale behind the development of the Eluvia^TM Drug-Eluting Vascular Stent (Boston Scientific, Marlborough, MA) is described and current preclinical and clinical evidence related to use of the stent is reviewed.

Expert opinion: Stents remain an important endovascular treatment option for femoropopliteal lesions, especially those that are long, occluded, and calcified. Drug-eluting stent technologies show promise to improve patency rates, potentially shifting the primary treatment preference away from balloon-based treatment. The available preclinical and clinical data on treatment with Eluvia^TM suggest that prolonged paclitaxel elution in the femoropopliteal arteries prevents restenosis and may reduce the need for reintervention.     

A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine

Introduction: AVP-825, formerly ‘OptiNose Sumatriptan,’ is an investigational Breath-Powered^TM Bi-Directional^TM intranasal delivery system containing low-dose sumatriptan (22 mg intranasal powder) that avoids limitations of other types of intranasal administration by taking advantage of unique features of nasal anatomy and physiology.

Areas covered: This review summarizes intranasal drug delivery for migraine, how the breath-powered technology works, and AVP-825 pharmacokinetic, efficacy and safety/tolerability findings. To identify AVP-825 clinical studies, a PubMed/MEDLINE database search was conducted with the terms AVP-825, OptiNose, OptiNose Sumatriptan, Breath-Powered Nasal Delivery or sumatriptan powder. Of 20 articles, 5 clinical studies were identified, including the head-to-head comparative COMPASS trial (AVP-825 vs oral sumatriptan) and two placebo-controlled studies.

Expert opinion: AVP-825 has faster sumatriptan absorption versus oral tablets or traditional liquid nasal spray. In Phase II/III randomized, double-blind, placebo-controlled trials, AVP-825 produced early and sustained efficacy with minimal triptan-related adverse effects. In COMPASS, AVP-825 produced earlier reduction of migraine pain intensity and migraine-associated symptoms than 100 mg oral sumatriptan, and higher early rates of pain relief and pain freedom, similar sustained efficacy, and fewer atypical sensations. AVP-825 has the potential to provide migraine patients with improved intranasal administration of sumatriptan that may enhance efficacy and tolerability.     

A strategy for early-risk predictions of clinical drug–drug interactions involving the GastroPlusTM DDI module for time-dependent CYP inhibitors

1.?A set of reference compounds for time-dependent inhibition (TDI) of cytochrome P450 with available literature data for k_inact and K_I was used to predict clinical implications using the GastroPlus^TM software. Comparisons were made to in vivo literature interaction data.

2.?The predicted AUC ratios (AUC_+inhibitor/AUC_control) could be compared with the observed ratios from literature for all compounds with detailed information about in vivo administration, pharmacokinetics and in vivo interactions (N?=?21). For this dataset, the difference between predicted and observed AUC ratios for interactions with midazolam was within twofold for all compounds except one (telaprevir, for which non-CYP-mediated metabolism likely plays a role after multiple dosing).

3.?The sensitivity, specificity and accuracy of the GastroPlus^TM predictions using a binary classification as no-to-weak interaction versus moderate-to-strong interaction for all compounds with available in vivo interaction data, were 80%, 82% and 81%, respectively (N?=?31).

4.?As a result of our evaluations of the DDI module in GastroPlus^TM, we have implemented an early TDI risk assessment decision tree for our drug discovery projects involving in vitro screening and early GastroPlus^TM predictions. Shifted IC₅₀ values are determined and k_inact/K_I estimated (by using a regression line established with in house-shifted IC₅₀ values and literature k_inact/K_I ratios), followed by GastroPlus^TM predictions.     

Etanercept-induced injection site reactions: potential pathomechanisms and clinical assessment

Introduction: Etanercept (ETN) is a tumor necrosis factor alpha (TNF-α) antagonist used for the treatment of chronic inflammatory disorders. Injection site reactions (ISRs) are reported to be the most common adverse event of ETN therapy. While their mechanisms are not completely understood, the occurrence of ETN-ISRs could indicate a risk of systemic immune-mediated severe adverse drug reactions.

Areas covered: Based on two cases and a review of the literature, the characteristics and frequency of ETN-ISRs were assessed. This article discusses their potential mechanisms and clinical relevance, and provides recommendations for the management of patients presenting with ETN-ISRs.

Expert opinion: Basically, irritative and immune-mediated ISRs may be distinguished. The formation of anti-drug antibodies (ADAs) may promote immune-mediated ISRs that likely represent either anaphylactic type I reactions, or cutaneous Arthus-like type III reactions according to the Coombs and Gell classification. A differentiation between these reactions by clinical course and etanercept-skin testing may help to decide if ETN treatment should be stopped to avoid the development of more severe adverse drug reactions if ISRs occur.     

Binding site comparisons for target-centered drug discovery

Introduction: The success of binding site comparisons in drug discovery is based on the recognized fact that many different proteins have similar binding sites. Indeed, binding site comparisons have found many uses in drug development and have the potential to dramatically cut the cost and shorten the time necessary for the development of new drugs.

Areas covered: The authors review recent methods for comparing protein binding sites and their use in drug repurposing and polypharmacology. They examine emerging fields including the use of binding site comparisons in precision medicine, the prediction of structured water molecules, the search for targets of natural compounds, and their application in the development of protein-based drugs by loop modeling and for comparison of RNA binding sites.

Expert opinion: Binding site comparisons have produced many interesting results in drug development, but relatively little work has been done on protein–protein interaction sites, which are particularly relevant in view of the success of biological drugs. Growth of protein loop modeling for modulating biological drugs is anticipated. The fusion of currently distinct methods for the comparison of RNA and protein binding sites into a single comprehensive approach could allow the search for new selective ribosomal antibiotics and initiate pharmaceutical research into other nucleoproteins.     

An overview on the methods of determining the activity of Indoleamine 2, 3-Dioxygenase 1

Abstract

Immune escape plays an important hallmark of cancer. The tryptophan-catabolizing enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) is involved in the immune escape mechanism of human tumours, the expression of which is associated with a poor prognosis in cancer and correlated with tumour progression clinically. Therefore, finding the inhibitors targeting IDO1 may be an impellent approach that can reverse the complicated processes in tumour immune escape and induce an antitumor response as well. Here, we summarised and compared some methods of determining the activity of IDO1 and they can be used to screen IDO1 inhibitors as well, including HPLC, fluorescence detection, cell-based assay, NFK GreenScreen^TM and absorbance assay. Each determining method possesses special advantages and disadvantages, so we need to have a comprehensive view of these methods and select the most suitable one for further research.     

Primer for Evaluating Ecological risk at Petroleum Release Sites

ABSTRACT

Increasingly, risk-based approaches are being used to guide decision making at sites such as service stations and petroleum product terminals, where petroleum products have been inadvertently released to the soil. For example, the API Decision Support System software, DSS, evaluates site human health risk along six different routes of exposure. The American Society for Testing and Materials' Risk-Based Corrective Action (RBCA) standard, ASTM 1739, establishes a tiered framework for evaluating petroleum release sites on the basis of human health risk. Though much of the risk assessment focus has been on human health risk, regulatory agencies recognize that protection of human health may not fully protect the environment; and EPA has developed guidance on identifying ecological resources to be protected through risk-based decision making.

Not every service station or petroleum product terminal site warrants a detailed ecological risk assessment. In some cases, a simple preliminary assessment will provide sufficient information for decision making. Accordingly, the American Petroleum Institute (API) is developing a primer for site managers, to assist them in conducting this preliminary assessment, and in deciding whether more detailed ecological risk assessments are warranted. The primer assists the site manager in identifying relevant ecological receptors and habitats, in identifying chemicals and exposure pathways of concern, in developing a conceptual model of the site to guide subsequent actions, and in identifying conditions that may warrant immediate response.     

Selective TNF-α inhibitor-induced injection site reactions

Introduction: During the last decade, many new biological immune modulators entered the market as new therapeutic principles. TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune-mediated or inflammatory diseases. TNF-α blockers have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs.

Areas covered: Although generally well tolerated and safe, potential adverse events may be associated with TNF-α inhibitor treatment. The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions (ISRs) in patients treated with etanercept and adalimumab.

Expert opinion: Patients treated with TNF-α inhibitors can develop ISR around the sites of injections. ‘Type IV delayed type reaction' or ‘recall ISRs'. Eosinophilic cellulitis or ‘Wells syndrome', ‘Type III' and ‘Type I' reactions are reported. Long-term studies are necessary to determine the durability of response and the real risk of ISRs with golimumab and certolizumab pegol. Further studies are also necessary to evaluate the immunogenicity of these drugs.     

Assessment of biological responses of EpiAirway 3-D cell constructs versus A549 cells for determining toxicity of ambient air pollution

Context: EpiAirway^TM 3-D constructs are human-derived cell cultures of differentiated airway epithelial cells that may represent a more biologically relevant model of the human lung. However, limited information is available on their utility for exposures to air pollutants at the air-liquid interface (ALI).

Objective: To assess the biological responses of EpiAirway^TM cells in comparison to the responses of A549 human alveolar epithelial cells after exposure to air pollutants at ALI.

Methods: Cells were exposed to filtered air, 400?ppb of ozone (O₃) or a photochemically aged Synthetic Urban Mixture (SynUrb54) consisting of hydrocarbons, nitrogen oxides, O₃ and other secondary oxidation products for 4?h. Basolateral supernatants and apical washes were collected at 9 and 24?h post-exposure. We assessed cytotoxicity by measuring lactate dehydrogenase (LDH) release into the culture medium and apical surface. Interleukin 6 (IL-6) and interleukin 8 (IL-8) proteins were measured in the culture medium and in the apical washes to determine the inflammatory response after exposure.

Results: Both O₃ and SynUrb54 significantly increased basolateral levels of LDH and IL-8 in A549 cells. No significant changes in LDH and IL-8 levels were observed in the EpiAirway^TM cells, however, IL-6 in the apical surface was significantly elevated at 24?h after O₃ exposure.

Conclusion: LDH and IL-8 are robust endpoints for assessing toxicity in A549 cells. The EpiAirway^TM cells show minimal adverse effects after exposure suggesting that they are more toxicologically resistant compared to A549 cells. Higher concentrations or longer exposure times are needed to induce effects on EpiAirway^TM cells.     

Influence of intraoperative remifentanil and sufentanil on sensory perception: a randomized trial

Objective: The clinical relevance of pro- and hyperalgesic effects of opioids is still a matter of debate. Particularly for remifentanil, an increased postoperative need for analgesics has been demonstrated suggesting opioid-induced hyperalgesia as a possible cause. The aim of the study was therefore to investigate the effect of intraoperatively applied remifentanil compared to sufentanil on somatosensory thresholds investigated with the quantitative sensory testing (QST) battery of the German Research Network on Neuropathic Pain (DFNS).

Research design and methods: Twenty-three patients undergoing surgery of the female breast were randomly assigned to intraoperative remifentanil (0.4?μg?×?kg^?1?×?min^?1) or sufentanil (0.25?μg?×?kg^?1 bolus, 0.15?μg?×?kg^?1, repetition after 60?min) application. Anesthesia was maintained BIS-guided (Bispectral index^TM) with propofol and postoperative analgesia was ensured with paracetamol (max. 3?g/24?h). Quantitative sensory testing was performed in the region of dermatome Th 5 in the mid-axillary line preoperatively and 20?h postoperatively.

Clinical Trial registration: The study was registered at the German registry for clinical studies (DRKS00009002).

Main outcome measures: Comparison of somatosensory thresholds before versus after surgery and application of intraoperative remifentanil or sufentanil.

Results: Sixteen patients could be finally included in the analysis. No differences of mechanical or thermal detection or pain thresholds were observed between pre- and postoperative testing or between remifentanil and sufentanil.

Conclusion: A change of somatosensory thresholds or a clinically relevant opioid-induced hyperalgesia in the selected small patient sample (segmental resections or mastectomy with or without sentinel lymph node biopsy, surgery length <90?minutes, sufficient postoperative pain medication with paracetamol due to rather low postoperative pain intensities) with remifentanil or sufentanil was not detected 20?h after surgery.     

QuilliChew extended-release chewable tablets for the treatment of ADHD in patients ages 6 years old and above

ABSTRACT

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder affecting as many as 6.4 million children and adolescents in the United States. Since amphetamine (AMPH) and methylphenidate (MPH) were found to be effective more than 60 years ago, numerous formulations of these compounds have been developed. New preparations have focused on convenience, with extended-release (ER) drugs allowing once-daily dosing. Multiple ER formulations do not require patients to swallow a tablet or capsule. Recent ER preparations include liquids, oral disintegrating tablets, and chewable tablets. Several new formulations use ion exchange technology containing both immediate-release and ER components.

Areas covered: Quillichew ER^TM (MPH-ERCT) is an ER methylphenidate designed to be chewed before swallowing. The technology and pharmacokinetics, along with efficacy and safety data, are presented.

Expert opinion: Extensive safety and efficacy data exist for MPH. ER formulations can be distinguished by preparation (tablet, capsule, liquid) and onset and duration of effect, but efficacy is similar for all ER MPH products. Each formulation has attributes, such as ease of titration, portability, and taste, that make it more acceptable for certain patients. Because AMPH and MPH are so effective, current technology research is focused on improving safety, convenience, and onset and duration of effect.     

Ertugliflozin as a monotherapy for the treatment of type 2 diabetes

ABSTRACT

Introduction: Sodium-dependent glucose transporter 2 (SGLT2) inhibitors are novel, potent oral anti-diabetic agents in a β-cell function-independent manner, inhibiting SGLT2-mediated renal glucose reabsorption and thus increasing urinary glucose excretion. Ertugliflozin (Steglatro^TM) is a new oral SGLT2 inhibitor for the treatment of patients with type 2 diabetes mellitus (T2DM) as a monotherapy or in combination with other anti-diabetic agents.

Areas covered: This review summarizes the collected data concerning the pharmacokinetics, clinical efficacy, as well as safety and tolerability profiles of ertugliflozin given as a monotherapy for the management of T2DM.

Expert opinion: Good glycemic control is crucial to the management of T2DM, and accordingly, anti-diabetic agents with various anti-hyperglycemic mechanisms are developed one after another. Based on the available clinical trials of ertugliflozin as a monotherapy for T2DM, it could be found that ertugliflozin effectively improves the glycemic control, body weight and blood pressure of patients with a low risk of hypoglycemia. It is also found that ertugliflozin moderately reduces their blood pressure, which is beneficial for decreasing the risk of cardiovascular disease. These attributes show the good potential of ertugliflozin as an adjunct treatment to diet and exercise for improving glycemic control in patients with T2DM.     

A single nucleotide polymorphism in the human serotonin transporter introduces a new site for N-linked glycosylation

The human serotonin transporter (hSERT) is responsible for reuptake of serotonin (5-HT) from the synaptic cleft and is target for antidepressant medicine. Differential hSERT activity caused by genetic polymorphisms is believed to affect the risk of developing depression and, moreover, to affect the response to antidepressant therapy. The hSERT contains in the second extracellular loop (EL2) two sites for N-linked glycosylation that are critical for functional transporter expression. Here we examine a non-synonymous single nucleotide polymorphism (SNP) in EL2 that gives rise to a potential third glycosylation site due to substitution of a lysine at position 201 with an asparagine (K201N). In agreement with introduction of an additional glycosylation site, western blot analysis showed migration of hSERT K201N corresponding to a higher molecular weight than wild type hSERT upon expression in both HEK293 cells and primary cultures of cortical neurons. An increase in molecular weight was not observed after removal of glycans with peptide N-glycosidase F (PNGase F). Quantitative analysis of western blots indicated significantly increased total transporter expression (∼30%) for hSERT K201N as compared to hSERT in both cell systems. The increase in expression was accompanied by corresponding significant increases in the number of [³H]citalopram binding sites and in the V_max for [³H]5-HT uptake. Characterization of mutants carrying all possible combinations of glycosylation sites demonstrated clear correlation between the number of glycosylation sites and the level of transporter activity, and showed that K201N could substitute for either one of the two original glycosylation sites.     

The VA Ostomy Health-Related Quality of Life Study: objectives,methods, and patient sample

ABSTRACT

Objective: To present the design and methods of a multisite study of health-related quality of life (HR-QOL) in veterans living with ostomies.

Research design and methods: Veterans from Tucson, Indianapolis, and Los Angeles VA Medical Centers were surveyed using the validated City of Hope ostomy-specific tool (mCOH-QOL-Ostomy) and the SF‐36V. Cases (ostomates) had a major gastrointestinal procedure that required an intestinal stoma, while controls had similar procedures for which an ostomy was not required. Ostomy subjects were recruited for four focus groups in each of two sites divided by ostomy type (colostomy versus ileostomy) and overall mCOH-QOL-Ostomy HR-QOL score (highest versus lowest quartile). The focus groups further evaluated barriers, concerns, and adaptation methods and skills.

Main outcome measures: This report presents recruitment results, reliability of survey instruments, and demographic characteristics of the sample.

Results: The overall response (i.e., recruitment) rate across all sites was 48% and by site was 53%, 57%, and 37%, respectively (?p < 0.001). Internal consistency reliability estimates indicated that both instruments remain reliable in this population (Cronbach's alpha for HR‐QOL domains/scales: 0.71–0.96). Cases and controls were similar in demographic characteristics. Proportions of minority subjects matched projections from the site patient populations. Subjects with ostomies had significantly longer time since surgery than controls (?p < 0.001). Focus groups were comprised of two to six subjects per group and demonstrated racial diversity at the Los Angeles site.

Conclusions: The unique design of our study of VA patients with ostomies is an illustration of a successful mixed methods approach to HR‐QOL research. We collected meaningful quantitative and qualitative data that will be used in the development of new approaches to care that will lead to improved functioning and well-being in persons living with ostomies. Subsequent reports will provide the results of this research project.     

The Utilization of a Fax Program to Computer Process Case Report Forms Resulted in a Speedier NDA in a 13 Site Clinical Trial

Abstract

Galderma Labs recently completed a multi-center trial that compared the time to final NDA for lotion, gel and cream forms of an acne-related retinoid product (Adapalene^TM). the lotion and gel versions of Adapalene were tested with Galderma's traditional methodologies. the differentiating factor for the cream was the use of remote case report form collection fax technology. the cream study, using computer and fax technology, resulted in a quicker time to NDA for the cream than for the lotion and gel. This was the largest faxed CRF study ever done.     

Evogliptin: a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon^TM) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise.

Areas covered: This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed.

Expert opinion: Evogliptin is effective in improving glycosylated hemoglobin (HbA_1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and β-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.     

Effect of application site,clothing barrier,and application site washing on testosterone transfer with a 1.62% testosterone gel

Abstract

Objectives:

To evaluate the effect of application site location, clothing barrier, and application site washing on testosterone transfer from males dosed with 1.62% testosterone gel to female partners.