达格列净联合利拉鲁肽治疗2型糖尿病的临床研究

目的 探究达格列净联合利拉鲁肽治疗2型糖尿病患者的临床效果。方法 收集2017年1月—2019年4月在郑州人民医院治疗的2型糖尿病患者126例,随机分为对照组（63例）和治疗组（63例）。对照组口服盐酸二甲双胍片,0.5 g/次,3次/d,同时于睡前皮下注射利拉鲁肽注射液0.6 mg,1周后根据患者肠道反应增加至1.2 mg,1次/d。治疗组早餐前口服达格列净片,10 mg/次,1次/d;利拉鲁肽注射液的用法同对照组。两组患者治疗时间均为3个月。观察两组患者临床疗效,同时比较治疗前后两组患者糖化血红蛋白（HbA1c）、空腹血糖（FPG）、餐后2 h血糖（2 h PG）、体质量指数（BMI）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、对纤溶酶原激活物抑制物-1（PAI-1）和胱抑素C（CysC）水平。结果 治疗后,对照组和治疗组临床有效率分别为79.37%和93.65%,两组比较差异有统计学意义（P<0.05）。治疗后,两组患者HbA1c、FPG、2 h PG、BMI、IL-6、TNF-α、PAI-1、CysC均显著降低（P<0.05）,且治疗组上述指标比对照组更低（P<0.05）。结论 达格列净联合利拉鲁肽治疗2型糖尿病患者效果显著,且不增加不良反应,降低发生糖尿病血管并发症的风险。     

Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE₂) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE₂ receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (Aβ) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-Aβ effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2 −/−), were hemizygous for DOCK2 (DOCK2 +/−), or that expressed two DOCK2 genes (DOCK2 +/+) with APPswe-PS1Δe9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1Δe9 mice, cerebral cortical and hippocampal Aβ plaque area and size were significantly reduced in 10-month-old APPswe-PS1Δe9/DOCK2 −/− mice compared with APPswe-PS1Δe9/DOCK2 +/+ controls. DOCK2 hemizygous APPswe-PS1Δe9 mice had intermediate Aβ plaque levels. Interestingly, soluble Aβ₄₂ was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar Aβ. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to Aβ plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD.     

维生素D3联合格列美脲治疗2型糖尿病的疗效观察

目的探讨维生素D_3片联合格列美脲片治疗2型糖尿病的临床疗效。方法选取2016年2月—2017年1月在襄阳市中心医院接受治疗的2型糖尿病患者86例,依据治疗方法差别分为对照组与治疗组,每组各43例。对照组初始口服格列美脲片,1 mg/次,1次/d,根据血糖调整用药,最大维持剂量不超过6 mg/d。治疗组在对照组的基础上口服维生素D_3片,1片/次,2次/d。两组患者均治疗4周。比较两组治疗前后临床疗效、血糖指标变化以及内环境稳态模型评估-β(HOMA-β)、HOMA-IR和25(OH)D_3水平。结果治疗后,对照组和治疗组的总有效率分别为81.40%和95.35%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者空腹血糖(FPG)、餐后2 h血糖(2 hPG)、糖化血红蛋白(Hb Alc)及空腹胰岛素(FINS)水平均显著下降(P0.05);且治疗组血糖指标变化水平显著好于对照组(P0.05)。治疗后,两组HOMA-β及25(OH)D_3水平显著升高,并且HOMA-IR水平明显降低,同组比较差异具有统计学意义(P0.05);且治疗组上述指标改善情况显著优于对照组,两组比较差异具有统计学意义(P0.05)。结论维生素D_3片联合格列美脲片治疗2型糖尿病具有较好的临床效果,可有效改善胰岛素抵抗和提高敏感性,具有一定的临床推广应用价值。     

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.     

Investigating phase separation in amorphous solid dispersions via Raman mapping

The bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs) can be significantly improved by so-called amorphous solid dispersions (ASDs). However, the long-term stability of ASDs might be impaired by API recrystallization and/or amorphous phase separation (APS). So far, no methods have been reported to quantify APS in ASDs. In this work, phase-separation kinetics as well as the compositions of the two amorphous phases evolving due to APS were quantitatively determined for the first time using confocal Raman spectroscopy. Raman spectra were evaluated via non-linear multivariate Indirect Hard Modeling and verified by differential scanning calorimetry and hot-stage microscopy. APS in water-free ASDs of ibuprofen and poly (DL-lactic-co-glycolic acid) was investigated considering the influence of temperature and polymer architecture (linear vs. star-shaped). Water absorbed at 40?°C and 75% relative humidity (RH) promotes APS which was quantified for formulations of felodipine/poly(vinyl pyrrolidone) and ibuprofen/poly(vinyl pyrrolidone).     

The safety of treatments used in pyoderma gangrenosum

Introduction: Pyoderma gangrenosum (PG) is a severe ulcerating orphan dermatosis characterized by painful and rapidly progressive skin ulcers often associated with underlying inflammatory disease.

Areas covered: In this article, we review and analyze the literature regarding treatment options for patients with PG, with particular attention to the efficacy and safety of therapies. Despite the significance of this problem, there are few studies devoted to the efficacy or safety of therapeutics in PG. We aim to present and evaluate existing studies and reports, and to make treatment recommendations based on the efficacy and safety data reviewed.

Expert opinion: All patients with PG should be counseled on avoiding trauma, optimizing glycemic control, and smoking cessation. Proper local wound care and surveillance of superimposed infection is essential to healing. Control of underlying inflammatory conditions should be co-managed with appropriate specialists. Patients with limited disease should consider high potency topical steroid or topical calcineurin inhibitors. For systemic therapy, the best evidence supports the use of systemic steroids or cyclosporine. Biologic therapy should be reserved in patients as a third line therapy or in patients with underlying systemic inflammatory disease. There is an existing need for well-designed studies to evaluate the efficacy and safety of therapeutics in PG.     

Lipid based nanocarriers: a translational perspective

Over the recent couple of decades, pharmaceutical field has embarked most phenomenal noteworthy achievements in the field of medications as well as drug delivery. The rise of Nanotechnology in this field has reformed the existing drug delivery for targeting, diagnostic, remedial applications and patient monitoring. The convincing usage of nanotechnology in the conveyance of medications that prompts an extension of novel lipid-based nanocarriers and non-liposomal systems has been discussed. Present review deals with the late advances and updates in lipidic nanocarriers, their formulation strategies, challenging aspects, stability profile, clinical applications alongside commercially available products and products under clinical trials. This exploration may give a complete idea viewing the lipid based nanocarriers as a promising choice for the formulation of pharmaceutical products, the challenges looked by the translational process of lipid-based nanocarriers and the combating methodologies to guarantee the headway of these nanocarriers from bench to bedside.     

Canagliflozin,a sodium glucose co-transporter 2 inhibitor,reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial

Objective

Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin.

Materials/Methods

Patients (N = 37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300 mg/placebo, (C) canagliflozin 300 mg/canagliflozin 300 mg, or (D) canagliflozin 300 mg/canagliflozin 150 mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B–D). A mixed-meal tolerance test (MMTT) was given 20 minutes post-dose on Day 3 of each period.

Results

A single dose of canagliflozin 300 mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B–D. An additional dose of canagliflozin 300 mg (Treatment C), but not 150 mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC_0–2h, − 7.5% for B vs A; − 18.5% for C vs A; − 12.0% [P = 0.012] for C vs B), leading to modestly greater reductions in total glucose AUC_0–2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated.

Conclusions

These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.     

应用前列腺素E1治疗慢性肾功不全的临床观察

目的探讨前列腺素E1治疗慢性肾功能不全的疗效。方法将CRF患者随机分为治疗组和对照组,治疗组静点前列腺素E1(凯时)15d,其余治疗方法与对照组相同,测治疗前后血肌酐值及24h尿量进行统计学分析。结果治疗组患者经静脉滴注前列腺素E1(凯时)15d后,血肌酐水平下降,24h尿量增多。结论前列腺素E1能改善CRF患者的肾功能,保护残余肾功能。