Structure and viscoelastic behavior of pharmaceutical biocompatible anionic microemulsions containing the antitumoral drug compound doxorubicin

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effects of antithyroid drug on the rectal temperature and metabolic parameters of ducks (Cairina moschata).

The effect of propylthiouracil oral treatment (400 mg/day per bird for 20 days) on body and thyroid weight, rectal temperature and plasma metabolic parameters of ducks (Cairina moschata) was determined. Propylthiouracil treatment produced a reduction (P less than .01) in body weight and an increase (P less than .01) in thyroid weight. The antithyroid drug also produced a decrease in rectal temperature starting from the 15th day of treatment, but did not significantly change blood glucose. Plasma free fatty acids and cholesterol concentrations progressively increased from the 5th and 10th day, respectively, in treated animals.

Effects of simvastatin on bone regeneration in the mandibles of ovariectomized rats and on blood cholesterol levels.

The purpose of this study was to evaluate the effects of simvastatin on guided bone regeneration in the mandibles of ovariectomized rats, and to observe their blood cholesterol levels. Seventy female rats were divided into two groups: control and treated, both groups containing normal and ovariectomized rats. A month after ovariectomy a bone defect was created in the mandible, and was covered by a polytetrafluoroethylene membrane. The treated groups received simvastatin orally for 15 or 30 days. The rats were sacrificed 15, 30 or 60 days after surgery, at which time a blood sample was extracted for blood cholesterol level analysis and the mandible was extracted for densitometric, histological and morphometric analysis. All specimens underwent analysis of variance. The ovariectomized animals had higher cholesterol levels than the treated normal animals, and no significant difference was found between the different treatment periods and the sacrifice times. The densitometric, histological and morphometric analysis showed that the treated ovariectomized animals developed more new bone than the control ovariectomized rats, but no significant difference was observed between the treatment periods. It can be concluded that the deficiency of estrogen increased the level of blood cholesterol and that the simvastatin aided new bone formation in the ovariectomized animals.

Influence of simvastatin on bone regeneration of tibial defects and blood cholesterol level in rats

The purpose of this study was to evaluate the effects of simvastatin, by oral or subcutaneous administration, on tibial defects regeneration and blood cholesterol level in rats. A surgical defect was made on the right tibia of 40 male animals assigned to 4 groups (n=10), based on two routes of administration and on the use or not of simvastatin: subcutaneous injection of simvastatin (7 mg/kg) (group AT) or only the vehicle of drug suspension (group AC), above the defect area, for 5 days; and 20 mg/kg of simvastatin macerated on water (group BT) or only water (group BC), orally, daily, during the whole observation period. The animals were sacrificed after 15 or 30 days, when blood samples were analyzed to check plasma cholesterol levels. Tibiae were removed and, after decalcification and routine laboratorial processing, histological and histomorphometrical analyses were carried out. ANOVA was used for statistical analysis at 5% signficance level. The histological and histomorphometrical analyses showed significant differences only between the experimental periods (p<0.05). Animals sacrificed after 30 days showed better bone repair (p<0.05). There was no statistically significant difference (p>0.05) for blood cholesterol levels between the groups. In conclusion, simvastatin administration either orally or subcutaneously did not improve bone repair of experimental tibial defects and did not alter blood cholesterol levels in rats.

Soybean glycinin (11S) increases HDL-cholesterol in hypercholesterolemic rats

Purpose: The purpose of this paper is to determine the effects of isolated soy glycinin (11S) on lipid metabolism in animals subjected to a hypercholesterolemic diet. Design/methodology/approach: Male Wistar rats were kept in individual cages under appropriate conditions. The animals were divided into three groups (n=9): normal diet (STD) given a diet containing casein as protein source, recommended in AIN-93M; hypercholesterolemic (HC) fed a normal diet with 1 per cent cholesterol and 0.5 per cent cholic acid; and hypercholesterolemic+glycinin (HC+11S), fed a hypercholesterolemic diet, plus 11S soy protein (300 mg/kg/day), dissolved in saline and administered by gavage. After 28 days, the animals were sacrificed and blood and liver removed for biochemical analysis of total cholesterol (TC), HDL-cholesterol (HDL-C) and triglycerides (TG) in the plasma, hepatic TC and TG. Findings: A single daily dose of glycinin given to the hypercholesterolemic group demonstrated its functional role, particularly in raising HDL-C and reducing triglycerides in the liver. Originality/value: This study demonstrates the action of the 11S globulin in soybean as a serum lipid lowering agent, in addition to its nutritional properties, especially in raising the HDL-C. © Emerald Group Publishing Limited.

Study of quercetin-loaded liposomes as potential drug carriers: in vitro evaluation of human complement activation

Liposomes have been employed as potential drug carriers. However, after their in vivo administration, they can be destabilized by proteins of complement system, contributing to the clearance of vesicles from blood circulation. Antioxidant flavonoids such as quercetin have been reported to be beneficial to human health, but their low water solubility and bioavailability limit their enteric administration. Therefore, the development of appropriate flavonoid-carriers could be of great importance to drug therapy. The aim of the present study was to evaluate the activation of human complement system proteins by liposomes composed of soya phosphatidylcholine (SPC) and cholesterol (CHOL) or cholesteryl ethyl ether (CHOL-OET) loaded with quercetin or not. The consumption of complement, via classical (CP) and alternative (AP) pathways, by different vesicles was evaluated using a hemolytic assay and quantitative determination of iC3b and natural antibodies deposited on empty liposomal surfaces by ELISA. The main results showed that empty liposomes composed of large amounts of CHOL consumed more complement components than the others for both CP and AP. Furthermore, replacement of CHOL with CHOL-OET reduced complement consumption via both CP and AP. Incorporation of quercetin did not change CP and AP consumption. Deposition of iC3b, IgG and IgM in vesicles composed of SPC: CHOL-OET at a molar ratio of 1.5:1 was lower compared to the others. Taken together, these observations suggest that liposomes composed of SPC: CHOL-OET at a molar ratio of 1.5:1 are the most appropriate among the vesicles studied herein to be used as a drug carrier system in further investigations.

Treatment With Methotrexate Inhibits Atherogenesis in Cholesterol-Fed Rabbits

A decrease in the number of cardiovascular events in patients with rheumatoid arthritis or psoriasis treated with methotrexate (MTX) has been observed in the literature. The aim of this study was to test whether MTX could promote anti-inflammatory effects and reduce the atherosclerotic lesions in rabbits with atherosclerosis induced by cholesterol feeding. Twenty male New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30 of cholesterol feeding, 10 animals were treated with 4 weekly intravenous injections of MTX (4 mg/kg) and 10 with 4 weekly saline solution injections for 30 days. MTX reduced the size of the lesion areas of cholesterol-fed animals by 75% and intima-media ratio 2- fold. The drug inhibited macrophage migration into the intima by 50% and the presence of apoptotic cells by 84% but did not inhibit the intimal proliferation of smooth muscle cells. MTX treatment also diminished the positive staining area of metalloproteinase 9 in the intima, which is probably beneficial. In the tumor necrosis factor-alpha-treated human umbilical vein endothelial cell line, incubation with MTX led to downregulation of 5 pro-inflammatory genes, TNF-alpha, VAP-1, IL-1 beta, CXCL2, and TLR2, and upregulation of the antiinflammatory TGF-beta 1 gene, thus showing endothelium-protective properties. In conclusion, MTX showed direct in vivo anti-atherosclerotic action and may have potential in the treatment of this disorder.

A comparison of non-HDL and LDL cholesterol goal attainment in a large, multinational patient population: The Lipid Treatment Assessment Project 2

Objective: This study evaluated the success in attaining non-HDL-cholesterol (non-HDL-C) goals in the multinational L-TAP 2 study. Methods: 9955 patients >= 20 years of age with dyslipidemia on stable lipid-lowering therapy were enrolled from nine countries. Results: Success rates for non-HDL-C goals were 86% in low, 70% in moderate, and 52% in high-risk patients (63% overall). In patients with triglycerides of >200 mg/dL success rates for non-HDL-C goals were 35% vs. 69% in those with <= 200 mg/dL (p < 0.0001). Among patients attaining their LDL-C goal, 18% did not attain their non-HDL-C goal. In those with coronary disease and at least two risk factors, only 34% and 30% attained respectively their non-HDL-C and LDL-C goals. Rates of failure in attaining both LDL-C and non-HDL-C goals were highest in Latin America. Conclusions: Non-HDL-C goal attainment lagged behind LDL-C goal attainment; this gap was greatest in higher-risk patients. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

Multifunctional nanocarriers encapsulating anti-Alzheimer drug for nasal delivery to central nervous system

Alzheimer's disease (AD) is a fatal neurodegenerative condition characterized clinically by progressive memory loss and irreversible cognitive deterioration. It has been shown that there is a progressive degeneration of the brain cholinergic neurons which leads to the appearance of cognitive symptoms of the disease. The aim of this work was the formulation of multifunctional nanocarriers for nasal administration of tacrine-HCl (THA). This route has many advantages; in particular is possible to convey the drug directly to the Central Nervous System, through the olfactory bulb. In particular, were prepared Albumin nanoparticles carrying beta cyclodextrin and two different beta cyclodextrin derivatives (hydroxypropyl beta cyclodextrin and sulphobutylether beta cyclodextrin), and Multifunctional liposomes, prepared using traditional excipients (cholesterol and phosphatidylcholine), partly enriched with α-tocopherol (Toc) and/or polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) (Ω3). Both nanosystems were characterized in terms of size, Zeta potential and encapsulation efficiency. Were also evaluated their functional properties such as mucoadhesion and permeability, using an ex-vivo assay based on nasal sheep mucosa. On Liposomes were also assessed drug neuronal uptake, cell toxicity, antioxidant and, cytoprotective activity in the human neuronal cell line SH-SY5Y and finally tocopherol trans-membrane diffusion. Both the nanocarriers produced presented excellent properties and a high potential as new systems for CNS-delivery of anti-Alzheimer drugs via the nasal route.

Effect of drug physicochemical properties on the release from liposomal systems in vitro and in vivo

Liposomes were discovered about 40 years ago by A. Bangham and since then they became very versatile tools in biology, biochemistry and medicine. Liposomes are the smallest artificial vesicles of spherical shape that can be produced from natural untoxic phospholipids and cholesterol. Liposome vesicles can be used as drug carriers and become loaded with a great variety of molecules, such as small drug molecules, proteins, nucleotides and even plasmids. Due to the variability of liposomal compositions they can be used for a large number of applications. In this thesis the β-adrenoceptor antagonists propranolol, metoprolol, atenolol and pindolol, glucose, 18F-Fluorodeoxyglucose (FDG) and Er-DTPA were used for encapsulation in liposomes, characterization and in vitro release studies. Multilamellar vesicles (MLV), large unilamellar vesicles (LUV) and smaller unilamellar vesicles (SUV) were prepared using one of the following lipids: 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC), 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC), Phospholipone 90H (Ph90H) or a mixture of DSPC and DMPC (1:1). The freeze thawing method was used for preparation of liposomes because it has three advantages (1) avoiding the use of chloroform, which is used in other methods and causes toxicity (2) it is a simple method and (3) it gives high entrapping efficiency. The percentage of entrapping efficiencies (EE) was different depending on the type and phase transition temperature (Tc) of the lipid used. The average particle size and particle size distribution of the prepared liposomes were determined using both dynamic light scattering (DLS) and laser diffraction analyzer (LDA). The average particle size of the prepared liposomes differs according to both liposomal type and lipid type. Dispersion and dialysis techniques were used for the study of the in vitro release of β-adrenoceptor antagonists. The in vitro release rate of β-adrenoceptor antagonists was increased from MLV to LUV to SUV. Regarding the lipid type, β-adrenoceptor antagonists exhibited different in vitro release pattern from one lipid to another. Two different concentrations (50 and 100mg/ml) of Ph90H were used for studying the effect of lipid concentration on the in vitro release of β-adrenoceptor antagonists. It was found that liposomes made from 50 mg/ml Ph90H exhibited higher release rates than liposomes made at 100 mg/ml Ph90H. Also glucose was encapsulated in MLV, LUV and SUV using 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC), 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC), Phospholipone 90H (Ph90H), soybean lipid (Syb) or a mixture of DSPC and DMPC (1:1). The average particle size and size distribution were determined using laser diffraction analysis. It was found that both EE and average particle size differ depending on both lipid and liposomal types. The in vitro release of glucose from different types of liposomes was performed using a dispersion method. It was found that the in vitro release of glucose from different liposomes is dependent on the lipid type. 18F-FDG was encapsulated in MLV 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC), 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC), Phospholipone 90H (Ph90H), soybean lipid (Syb) or a mixture of DSPC and DMPC (1:1). FDG-containing LUV and SUV were prepared using Ph90H lipid. The in vitro release of FDG from the different types of lipids was accomplished using a dispersion method. Results similar to that of glucose release were obtained. In vivo imaging of FDG in both uncapsulated FDG and FDG-containing MLV was performed in the brain and the whole body of rats using PET scanner. It was found that the release of FDG from FDG-containing MLV was sustained. In vitro-In vivo correlation was studied using the in vitro release data of FDG from liposomes and in vivo absorption data of FDG from injected liposomes using microPET. Erbium, which is a lanthanide metal, was used as a chelate with DTPA for encapsulation in SUV liposomes for the indirect radiation therapy of cancer. The liposomes were prepared using three different concentrations of soybean lipid (30, 50 and 70 mg/ml). The stability of Er-DTPA SUV liposomes was carried out by storage of the prepared liposomes at three different temperatures (4, 25 and 37 °C). It was found that the release of Er-DTPA complex is temperature dependent, the higher the temperature, the higher the release. There was an inverse relationship between the release of the Er-DTPA complex and the concentration of lipid.

Current cardiovascular risk management patterns with special focus on lipid lowering in daily practice in Switzerland

There may be a considerable gap between LDL cholesterol (LDL-C) and blood pressure (BP) goal values recommended by the guidelines and results achieved in daily practice.

[Drug-independent blood pressure control through the autonomous nervous system]

Arterial hypertension is a chronic disease with a therapeutical challenge for the patient and the physician involved. Patient-independent techniques with good efficacy and tolerability are wanted. The autonomous nervous system insufficiently therapeutically exploited to date, is now approachable by two types of intervention: renal nerve ablation, an endovascular approach without remaining foreign body, and BAT, baroreflex activating therapy using an implantable device stimulating the carotid sinus. The blood pressure lowering potency of BAT appears more than with renal nerve ablation and also clinical study data are more prevalent. With both treatment options the patients having the most profit are insufficiently defined. Given this knowledge, any form of secondary hypertension needs to be excluded beforehand.

Unhealthy alcohol use, HIV infection and risk of liver fibrosis in drug users with hepatitis C

Aim To analyze alcohol use, clinical data and laboratory parameters that may affect FIB-4, an index for measuring liver fibrosis, in HCV-monoinfected and HCV/HIV-coinfected drug users. Patients and Methods Patients admitted for substance abuse treatment between 1994 and 2006 were studied. Socio-demographic data, alcohol and drug use characteristics and clinical variables were obtained through hospital records. Blood samples for biochemistry, liver function tests, CD4 cell count, and serology of HIV and HCV infection were collected at admission. Multivariate linear regression was used to analyze the predictors of FIB-4 increase. Results A total of 472 (83% M, 17% F) patients were eligible. The median age at admission was 31 years (Interquartile range (IQR) 27–35 years), and the median duration of drug use was 10 years (IQR 5.5–15 years). Unhealthy drinking (>50 grams/day) was reported in 32% of the patients. The FIB-4 scores were significantly greater in the HCV/HIV-coinfected patients (1.14, IQR 0.76–1.87) than in the HCV-monoinfected patients (0.75, IQR 0.56–1.11) (p<0.001). In the multivariate analysis, unhealthy drinking (p = 0.034), lower total cholesterol (p = 0.042), serum albumin (p<0.001), higher GGT (p<0.001) and a longer duration of addiction (p = 0.005) were independently associated with higher FIB-4 scores in the HCV-monoinfected drug users. The effect of unhealthy drinking on FIB-4 scores disappeared in the HCV/HIV-coinfected patients, whereas lower serum albumin (p<0.001), a lower CD4 cell count (p = 0.006), higher total bilirubin (p<0.001) and a longer drug addiction duration (p<0.001) were significantly associated with higher FIB-4 values. Conclusions Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are important risk factors associated with liver fibrosis in the respective populations.

[Drug therapy of type-II diabetes: tablets, insulin or a combination of these]

Optimal therapy of diabetes has to be based on the known pathophysiology of metabolic disturbances and should eventually alleviate reduced secretion of insulin as well as reduce the usually present resistance to insulin in order to normalize the average blood glucose levels. In less than 30% of patients with type-II diabetes, dietetic measures combined with increased physical activity alone, are sufficient for metabolic control, thus increasing the importance of pharmacologic treatment immensely. Biguanides are the therapeutic choice in patients with massive overweight, because they usually do not induce weight gain; however, specific contraindications (renal failure in particular) have to be taken into consideration. The effect of blood glucose lowering by biguanides is not due to increased secretion of insulin, thus neither hypoglycemias nor hyperinsulinism are induced or increased, respectively. Patients with normal or slightly increased body weight should profit best from sulfonylureas that stimulate insulin production. Combinations of sulfonylurea and biguanides or of insulin and oral antidiabetics or insulin alone have to be taken into account when monotherapy with oral antidiabetics is too inefficient; however, clear and generally accepted guidelines for correct indications of these therapeutic modalities are lacking. Particularly in long-lasting diabetes and for patients with distinct overweight an adequate therapeutic success is often not obtained with the currently available therapeutic means. Possibly, future developments will provide new therapeutic ways with drugs that increase insulin sensitivity or reduce gluconeogenesis.

Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study

BACKGROUND AND OBJECTIVES: Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. DESIGN, SETTING, PARTICIPANTS, ; MEASUREMENTS: A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of <130 mg/dl were randomly assigned to double-blind therapy with 10 or 80 mg/d atorvastatin. Estimated GFR using the Modification of Diet in Renal Disease equation was compared at baseline and at the end of follow-up in 9656 participants with complete renal data. RESULTS: Mean estimated GFR at baseline was 65.6 +/- 11.4 ml/min per 1.73 m2 in the 10-mg group and 65.0 +/- 11.2 ml/min per 1.73 m2 in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of 3.5 +/- 0.14 ml/min per 1.73 m2 with 10 mg and 5.2 +/- 0.14 ml/min per 1.73 m2 with 80 mg (P < 0.0001 for treatment difference). In the 80-mg arm, estimated GFR improved to > or = 60 ml/min per 1.73 m2 in significantly more patients and declined to < 60 ml/min per 1.73 m2 in significantly fewer patients than in the 10-mg arm. CONCLUSIONS: The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related.