Reduction In Capillary Permeability Research Articles

Diabetic Nephropathy: Pathogenesis and Drug Delivery System

Diabetic nephropathy is the leading cause of chronic kidney disease. The pathogenesis of diabetic nephropathy consists of four main pathways that indicate intracellular metabolic abnormalities identified in diabetic nephropathy, namely the activation of polyol and protein kinase C pathways, formation of advanced glycation end products, increased oxidative stress, and intraglomerular hypertension. Conventional treatment approaches for diabetic nephropathy that have been through clinical trials are, among others, the use of glucose-lowering agents, reduction of blood pressure, reduction of capillary permeability, and antioxidants. Although such treatments have been proven to slow the severity of diabetic nephropathy which leads to chronic kidney failure, their effectiveness does not cure diabetic nephropathy in patients. Thus, the modification of drug delivery systems and the widely-performed gene therapy need to be reviewed for their effectiveness with the previous treatments of diabetic nephropathy. This review article discusses the perspective of implementing the most effective diabetic nephropathy treatment system in order to achieve the therapeutic goals of diabetic nephropathy. The modification of drug delivery system and the gene therapies are expected to be able to increase the effectiveness of the drugs and guarantee their safety. The characteristics of the therapeutic targets in each kidney cell need to be understood more deeply so that the therapeutic goals can be achieved. It is hoped that the testing in the clinical phase of diabetic nephropathy by modifications of the drug delivery system and gene-based therapies will be widely carried out in the future.

Qualitative and quantitative analyses of chemical constituents in vitro and in vivo and systematic evaluation of the pharmacological effects of Tibetan medicine Zhixue Zhentong capsules.

Introduction: Zhixue Zhentong capsules (ZXZTCs) are a Tibetan medicine preparation solely composed of Lamiophlomis rotata (Benth.) Kudo. L. rotata is the only species of the genus Laniophlomis (family Lamiaceae) that has medicinal constituents derived from the grass or root and rhizome. L. rotata is one of the most extensively used folk medicines by Tibetan, Mongolian, Naxi, and other ethnic groups in China and has been listed as a first-class endangered Tibetan medicine. The biological effects of the plant include hemostasis, analgesia, and the removal of blood stasis and swelling. Purpose: This study aimed to profile the overall metabolites of ZXZTCs and those entering the blood. Moreover, the contents of six metabolites were measured and the hemostatic, analgesic, and anti-inflammatory effects of ZXZTCs were explored. Methods: Ultra-performance liquid chromatography-tandem quadrupole time-of-flight high-resolution mass spectrometry (UPLC-Q-TOF-MS) was employed for qualitative analysis of the metabolites of ZXZTCs and those entering the blood. Six metabolites of ZXZTCs were quantitatively determined via high-performance liquid chromatography The hemostatic, analgesic, and anti-inflammatory effects of ZXZTCs were evaluated in various animal models. Results: A total of 36 metabolites of ZXZTCs were identified, including 13 iridoid glycosides, 9 flavonoids, 9 phenylethanol glycosides, 4 phenylpropanoids, and 1 other metabolite. Overall, 11 metabolites of ZXZTCs entered the blood of normal rats. Quantitative analysis of the six main metabolites, shanzhiside methyl ester, chlorogenic acid, 8-O-acetyl shanzhiside methyl ester, forsythin B, luteoloside, and verbascoside, was extensively performed. ZXZTCs exerted hemostatic effects by reducing platelet aggregation and thrombosis and shortening bleeding time. Additionally, ZXZTCs clearly had an analgesic effect, as observed through the prolongation of the latency of writhing, reduction in writhing, and increase in the pain threshold of experimental rats. Furthermore, significant anti-inflammatory effects of ZXZTCs were observed, including a reduction in capillary permeability, the inhibition of foot swelling, and a reduction in the proliferation of granulation tissue. Conclusion: Speculative identification of the overall metabolites of ZXZTCs and those entering the blood can provide a foundation for determining its biologically active constituents. The established method is simple and reproducible and can help improve the quality control level of ZXZTCs as a medicinal product. Evaluating the hemostatic, analgesic, and anti-inflammatory activities of ZXZTCs can help reveal its mechanism.

Effect of TiO2, Al2O3 and CaCO3 nano-additives in singular, binary and ternary forms on the mechanical, thermal and microstructural propertites of fly ash supplemented cement matrix

In this paper, we focus on how nanoadditives such as nano-Al2O3, nano-TiO2 and nano-CaCO3 modify the mechanical and capillary permeability of fly ash cement mortars (5:1). When nanoadditives are added in proportions of 2%, 4% and 6% of the binder volume, hydration products are generated, and thermal conductivity and microstructure of cement mortars undergo a change. Mechanical property measured at 7, 28 and 90 days are measured to understand the underlying pozzolanic reaction and filling effect. The experimental findings reveal that the form and quantity of refractory chemicals in mortar production had an impact hardened matrix at the early age between 7 and 28 days, but thereafter, there is only a marginal strength gain. Nano-Al2O3 and nano-CaCO3 (at 2% of binder volume) additives were able to increase the mortar strength to the extent of 27% of the 28-day compressive strength at 7 days. The addition of 2% nano-TiO2 did not produce this effect. The addition of 6% nano-Al2O3 + nano-CaCO3 in binary and 6% nano-TiO2 + nano-Al2O3 + nano-CaCO3 blend in ternary combinations produced a phenomenally positive effect on the compressive strength with the reduction of capillary permeability at 90 days of setting. The X-ray diffraction patterns of these matrices compared with control showed a clear evidence of reduction of CH growth. Formation of a compact binding gel can be observed in scanning electron microscopic (SEM) pictures. A dense microstructure of binary and ternary nano additive mixes is establish to be favourable in decreasing the thermal conductivity of fly ash blend cement mortar measured at 30 °C. The combination of non-siliceous nano-size materials such as nano-Al2O3, nano-TiO2 and nano-CaCO3 in small quantities have an impact on the pozzolanic reaction with continual strength gain and are effective in counteracting the shortcomings of fly ash blended with cement mortars.

Dynamic contrast-enhanced MRI to predict response to vinorelbine–cisplatin alone or with rh-endostatin in patients with non-small cell lung cancer and bone metastases: a randomised, double-blind, placebo-controlled trial

BackgroundMetastatic bone disease is a frequent complication of advanced non-small-cell lung cancer and causes skeletal-related events which result in a poor prognosis. A standard method to assess the therapeutic response of bone metastases does not currently exist. We used dynamic contrast-enhanced MRI to obtain quantitative measures to assess the suitability of this technique to gauge therapeutic response to vinorelbine–cisplatin plus rh-endostatinfor previously untreated non-small cell lung cancer with bone metastases. MethodsWe did a phase 4, randomised, prospective, double-blind, placebo-controlled clinical trial in Shanghai Sixth People's Hospital, Shanghai, China. Inclusion criteria were non-small-cell lung cancer patients with bone metastases confirmed by pathology or cytology; available imaging data of pelvic metastatic lesions; aged 18 to 75 years old; expected survival at least 3 months; not receiving taxane, bevacizumab, thalidomide, rh-endostatin, or bisphosphonate; not having radiation therapy within 3 months of enrollment into study; normal results of routine blood tests, liver and kidney function, and electrocardiogram; absence of cardiovascular disease, autoimmune disease, vasculitis, severe infection, diabetes, and other concomitant disease; and signed informed consent. Exclusion criteria were receiving granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor during chemotherapy, intolerance to adverse reaction, and allergy to contrast agents. Patients were randomly assigned to treatment group and control group at a ratio of 2:1 by random code generation by an independent biostatistician in a double-blind fashion. Participants received either vinorelbine–cisplatin plus rh-endostatin or vinorelbine–cisplatin plus placebo. Vinorelbine (25 mg/m2) and cisplatin (75 mg/m2) were administered intravenously on the first day of a 21 day cycle. Patients received rh-endostatin (7·5 mg/m2) or placebo on days 1–14 of a cycle. The primary end points were objective response rate (complete remission+partial remission)/total × 100) and disease control rate (complete remission+partial remission+stable disease)/total × 100). Measurements including Ktrans, Kep, and Ve were evaluated by dynamic contrast-enhanced MRI before treatment and after completion of 2 treatment cycles. Blood concentrations of bone metabolites, tumour markers, and tumour vascular growth related factors were measured before and after treatment. Comparisons were made using paired t-test. Kaplan-Meier survival analysis was used to indicate the correlation between some measurements and progression-free survival or overall survival. The difference in Ktrans between patients who had partial remission or stable disease group and those who had disease progression was tested using the Chi-square test. All statistical analyses were performed with SPSS version 21.0. This trial was approved by the State Food and Drug Administration (No: S20050088) and China State Food and Drug Administration. The trial is registered with China Clinical Trials Registry, number chictr-ctr-09000569. Written informed consent and ethical approval was obtained. FindingsWe enrolled 33 patients (aged 52–70, 15 men and 18 women) of whom 28 were evaluable (20 in treatment group and 8 in control group). Five patients were excluded: 2 patients in treatment group and 1 patient in control group used granulocyte-macrophage colony stimulating factor, and 2 patients in the control group refused treatment. Objective response rate was higher (30% vs 0%; p<0·00001), mean overall survival was longer (21·44 [SD 17·28] vs 7·71 [4·68] months, p=0·008), and reduction in capillary permeability (measured by Ktrans) was greater (60·0% vs 4·4%; p=0·026) in the group given rh-endostatin than in the control group. Disease control rate was 80% in the treatment group and 75% in the control group (p=0·07). Overall survival was longer in patients with a greater than 50% reduction in Ktrans than in patients with a decrease of up to 50% (13·2 [1·8] vs 9·8 [0·2] months, p=0·026). InterpretationAddition of rh-endostatin to treatment with vinorelbine–cisplatin increased the treatment response in patients with non-small cell lung cancer and bone metastases. Quantitative analysis using dynamic contrast-enhanced MRI can be used to evaluate therapeutic response and to predict survival of bone metastases after anti-angiogenesis therapy. Limitations of this study include the small number of patients and the single-centre design. FundingNational Natural Science Foundation of China [grant number 81201628].

Synthesis, antispasmodic and antidiarrheal activities of some 1-substituted imidazole derivatives

A series of 1-substituted imidazoles 1a-d and 2a-d were synthesized and screened for antispasmodic and antidiarrheal activities. Antispasmodic activity was tested at various concentrations on isolated tissue preparations; concentration-response curves were plotted and compared with atropine. All compounds were found to inhibit contraction of the guinea pig ileum. Castor oil-induced diarrhea model in rats was used for evaluation of antidiarrheal activity. Parameters such as intestinal transit and volume of intestinal fluid were measured for antidiarrheal activity at 40 mg kg-1 dose and compared with the standard drug loperamide at 6 mg kg-1 dose. Defecation frequency in the test group was found to be significantly lower (p < 0.01) compared to the control group and comparable with that of the standard. The present study reveals that the compounds exert antidiarrheal activity through possible inhibition of intestinal movement and reduction of capillary permeability in the abdominal cavity.

Juvenile bone-marrow oedema of the acetabulum treated by iloprost

The bone-marrow oedema syndrome is associated with local vascular disturbances and may be treated either conservatively or by core decompression after which recovery may take several weeks. We describe a 15-year-old girl with bone-marrow oedema of the left acetabulum which was confirmed by MRI. She presented with a four-week history of severe constant pain. Routine blood tests and plain radiographs were normal. She was treated with intravenous infusions of iloprost on five consecutive days (20 μg administered in 500 ml of sodium chloride). Iloprost causes vasodilatation with reduction of capillary permeability and it inhibits platelet aggregation. She had relief from pain at rest after three days of treatment and was completely free from symptoms after two weeks. MRI after six weeks showed almost complete resolution of the marrow oedema and was normal after four months. This is the first report of the pharmacological treatment of the bone-marrow oedema syndrome in children.

Reduction of Capillary Permeability in the Fructose-Induced Hypertensive Rat

Impaired insulin transcapillary transport and the subsequent decrease in insulin delivery to target organs have been suggested to play a role in insulin resistance. These defects were studied in fructose-fed rats, an animal model with insulin resistance. For this study, male Sprague-Dawley rats were fed with either a 60% fructose enriched (F) or a standard chow diet (N) for a total of 2, 4, or 8 weeks. Capillary permeability to albumin was assessed at the end of each dietary period by quantifying the extravasation of albumin-bound Evans blue (EB) dye in different organs. Unanesthetized animals were injected with Evans blue dye (20 mg/kg) in the caudal vein 10 min before being killed and EB dye was extracted by formamide from selected organs collected after exsanguination. As expected, rats had an increase in blood pressure upon feeding with fructose at 4 and 8 weeks (F, 149 ± 3 mm Hg; N, 139 ± 3 mm Hg; P < .05). Using this technique, we showed a 56% and a 51% reduction in capillary permeability in skeletal muscles at 4 and 8 weeks of fructose feeding, respectively (4 weeks: N, 44.5 ± 5.0 μg/g of dry tissue; F, 19.8 ± 4.2 μg/g of dry tissue; P < .01 and 8 weeks: N, 23.3 ± 3.7 μg/g of dry tissue; F, 11.3 ± 4.0 μg/g of dry tissue; P < .05). Similar changes were observed at 4 weeks in the thoracic aorta (N, 82.8 ± 8.8 μg/g of dry tissue; F, 53.0 ± 5.1 μg/g of dry tissue; P < .02) and skin (N, 36.0 ± 5.3 μg of dry tissue; F, 15.0 ± 2.3 μg/g of dry tissue; P < .02) and at 8 weeks in the liver (N, 107.5 ± 4.3 μg/g of dry tissue; F, 80.9 ± 3.2 μg/g of dry tissue; P < .01). In conclusion, fructose feeding is accompanied by a significant and selective reduction of Evans blue leakage primarily in skeletal muscle and liver, and transiently in the skin and aorta, consistent with a role for decreased tissue insulin delivery in insulin resistance.

Permeability characteristics of brain adjacent to tumors in rats.

The brain immediately surrounding 9L sarcoma and Walker 256 carcinosarcoma was evaluated, using radioactive water, albumin, red blood cells, urea, and sodium to quantitate isotopic exchange and permeability in the brain adjacent to tumor (BAT), normal brain, and, to a lesser extent, tumor. Exchange between blood and BAT for 14C-urea and 22Na averaged 53% of that for comparable regions of normal brain. This reduction in exchange is not explainable by differences in capillary surface area for transcapillary exchange in the BAT. This reduction in capillary permeability in the BAT could be detrimental to the delivery of watersoluble and rapidly binding drugs.