Selma B. Souto

Design of cationic lipid nanoparticles for ocular delivery: development, characterization and cytotoxicity.

In the present study we have developed lipid nanoparticle (LN) dispersions based on a multiple emulsion technique for encapsulation of hydrophilic drugs or/and proteins by a full factorial design. In order to increase ocular retention time and mucoadhesion by electrostatic attraction, a cationic lipid, namely cetyltrimethylammonium bromide (CTAB), was added in the lipid matrix of the optimal LN dispersion obtained from the factorial design. There are a limited number of studies reporting the ideal concentration of cationic agents in LN for drug delivery. This paper suggests that the choice of the concentration of a cationic agent is critical when formulating a safe and stable LN. CTAB was included in the lipid matrix of LN, testing four different concentrations (0.25%, 0.5%, 0.75%, or 1.0%wt) and how composition affects LN behavior regarding physical and chemical parameters, lipid crystallization and polymorphism, and stability of dispersion during storage. In order to develop a safe and compatible system for ocular delivery, CTAB-LN dispersions were exposed to Human retinoblastoma cell line Y-79. The toxicity testing of the CTAB-LN dispersions was a fundamental tool to find the best CTAB concentration for development of these cationic LN, which was found to be 0.5 wt% of CTAB.

Impact of Lipodystrophy on the prevalence and components of metabolic syndrome in HIV-infected patients.

BackgroundIn HIV-infected patients, combination antiretroviral therapy (cART) is associated with clinical lipodystrophy (CL) and metabolic abnormalities (MA). This study aimed to evaluate the prevalence of the metabolic syndrome (MS) and its components, and to determine whether patients with or without CL had a different prevalence of MA.MethodsWe evaluated 345 HIV-infected patients on cART using two different MS definitions (NCEP-ATPIII-2005 and IDF-2005) and the Framingham risk score.ResultsCL was present in 58.7% of the patients. The prevalence of the MS was 52.2% (ATPIII) and 43.2% (IDF), and it was not significantly different between patients with (W) or without (WT) CL, regardless of the definition used (ATPIII WCL 52.9% vs WT CL 51.1%; p = 0.738; IDF WCL 41.3% vs WTCL 46.0%; p = 0.379). Moderate concordance was observed between the 2 definitions (kappa = 0.484; p < 0.001) and after gender stratification there was good concordance in women (kappa = 0.759; p < 0.001). Patients with CL had lower waist circumference and HDL-C and higher triglycerides levels. In women, CL was significantly associated with MS, hypertriglyceridemia and low HDL cholesterol independently of age, cART and BMI. Patients with CL had a significantly higher risk of coronary heart disease at 10 years, measured by the Framingham risk score, than patients without CL. Those with CL and with MS had higher frequencies of moderate and high risk categories than those without MS.ConclusionsThe prevalence of the MS was high in these HIV-infected patients with an age average of 40 years and this finding could explain why HIV patients have an increased risk for cardiovascular disease (CVD).

A novel lipid nanocarrier for insulin delivery: production, characterization and toxicity testing.

A novel nanocarrier based on solid lipid nanoparticles (SLNs) was developed for insulin delivery using a novel double emulsion method. Physical stability of particles was assessed by size analysis using dynamic light scattering (DLS), matrix crystallinity by differential scanning calorimetry (DSC) and toxicity analysis by Drosophila melanogaster testing. Insulin-SLNs were composed of Softisan®100 1.25% wt, Lutrol®F68 1% wt, soybean lecithin 0.125% wt, and loaded with 0.73–0.58 mg/mL peptide. Placebo-SLNs (insulin-free) also contained 0.025% wt Tween®80. Mean particle sizes of placebo-SLN and insulin-SLN were 958 ± 9.5 and 978 ± 8.3 nm, respectively. The polydispersity index (PI) was 0.28 ± 0.018 and 0.29 ± 0.013, respectively. Polarized light microscopy analysis depicted no aggregation of developed particles. DSC analysis allowed characterizing SLN with 43–51% matrix crystallinity. Using Drosophila melanogaster test, no toxicity was reported for SLN and for the bulk lipid. This study shows that SLNs are promising and helpful to overcome conventional insulin therapy, in particular for their lack of toxicity for oral delivery.

Prevention and current onset delay approaches of type 2 diabetes mellitus (T2DM)

The urgent need to treat type 2 diabetes mellitus (T2DM), which is currently reaching epidemic proportions, has been a major focus of healthcare systems and policy makers worldwide. Pharmacological treatment and lifestyle interventions together with the control of cardiovascular risk factors are the main strategies to prevent or delay the onset of T2DM. The present review discusses the state of the art knowledge of effective therapeutic approaches (metformin, thiazolidinediones, nateglinides, α-glucosidase inhibitors, incretin-based and angiotensin-based therapies, weight reducers, statins, fibric acid derivatives), including surgery, and identifies the major lifestyle changes for specific target groups.

Oral glucose lowering drugs in type 2 diabetic patients with chronic kidney disease

Chronic kidney disease (CKD) represents a challenge in the treatment of type 2 diabetic patients. Renal impairment may affect drug clearance and other pharmacokinetic processes which can increase toxicity and drug to drug interactions or cause ineffective therapy. There are many oral glucose lowering drugs available for the treatment of type 2 diabetes mellitus (T2DM) with different mechanisms of action and different pharmacokinetic profiles. While all classes may be used in patients with mild renal impairment, therapeutic options for patients with moderate to severe CKD are still limited. This review focuses on the pharmacokinetics, metabolism, and safety of oral glucose lowering drugs in patients with T2DM and CKD.

Ovarian Leydig cell tumor in a post-menopausal patient with severe hyperandrogenism

Leydig cell tumors are rare ovarian steroid cell neoplasms. More than 75% of patients show signs of virilization due to overproduction of testosterone. We report a case of an 81-year-old woman with progressive signs of virilization, and presenting vaginal bleeding. Clinical analyses revealed high levels of serum testosterone, delta 4-androstenedione and estradiol, and also inappropriate low levels of gonadotrophins for a post-menopausal woman. Transvaginal ultrasound showed no evidence of ovarian tumor, but pelvic and abdominal computerized axial tomography imaging revealed a left ovarian solid nodule, and no evidence of alteration in the adrenal glands. Total hysterectomy and bilateral salpingoophorectomy were performed. Histopathology and immunohistochemistry confirmed the diagnosis of Leydig cell tumor. After surgery, androgen levels returned to normal, and there was regression of the signs of virilization.

Ovarian intratumoral 21-hydroxylase deficiency in a postmenopausal hirsute woman

Virilising ovarian tumours are a rare cause of hyperandrogenism in women, accounting for less than 5% of all ovarian neoplasms. It occurs most often in - and postmenopausal women. We report a case of a 64 year-old woman with signs of virilisation that had started 3 years before. Blood hormone analysis revealed increased levels of testosterone, and 17-hydroxyprogesterone. The tetracosactin test revealed 21-hydroxylase deficiency. Radiological imaging demonstrated a nodule in her left ovary. The patient was submitted to bilateral laparoscopic oophorectomy, and histopathological examination revealed a luteoma of the left ovary. Postoperative serum testosterone level and 17-hydroxyprogesterone returned to normal levels in one month. Virilism regressed within six months. Our patient also showed an elevation in 17-OHP serum levels. Normalization of 17-OHP after oophorectomy suggests a case of intratumoral 21-hydroxylase deficiency. To our knowledge, this is the first description of ovarian intratumoral 21-hydroxylase deficiency in a postmenopausal woman.

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

Human lipodystrophies are a heterogeneous group of diseases characterized by generalized or partial fat loss. If localized, they are often associated with fat hypertrophy in other depots, varying according to the type of lipodystrophy. Lipodystrophies can be genetic, which is usually uncommon, or acquired. Genetic lipodystrophy is generally related to severe meta‐ bolic alterations including insulin resistance (IR) and its associated complications, such as glucose intolerance and diabetes, dyslipidemia, hepatic steatosis, polycystic ovaries, acan‐ thosis nigricans and early cardiovascular (CV) complications [1, 2]. The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familiar partial lipo‐ dystrophy (FPL) are the two most common types of genetic lipodystrophy [2]. Lipodystro‐ phies have been reported in the medical literature for more than 100 years [2, 3]. However, only 13 years ago, new lipodystrophy syndromes were recognized, being associated with vi‐ ral infection, specifically with the human immunodeficiency virus, in patients treated with combined antiretroviral therapy (cART) [4]. This has become the most frequent form of lipo‐ dystrophy [2]. Some first-generation antiretroviral drugs used in HIV patients are strongly related with peripheral lipoatrophy and metabolic alterations [1].

Phase Behavior of Polymorphic Fats in Drug Delivery Systems - A Review of the State of Art

Fats are essential nutrients that have a significant role in the human diet and are essential to provide energy. Fatty acids are present in several types of lipids, such as triglycerides and phospholipids. Fatty acids differ among them, depending on the number of double bonds and on the length of the hydrocarbon chains. If there are no double bonds, the fatty acids are considered saturated and show a linear structure. Compounds with double bonds are unsaturated and have bent structure. The saturated fatty acids are usually solid at room temperature and the unsaturated fatty acids are liquid at that very same temperature. These compounds are of recognized value as raw materials for drug delivery systems, such as lipid nanoparticles. The behaviour of the macroscopic aspects of fat polymorphisms is directly influenced by the melting point, the crystallization and their polymorphic transformations. In this work, we revise the most critical factors contributing for the long-term stability of lipid nanoparticles, as well as the influence of the polymorphism on the loading capacity for drug molecules.

Cancer therapies: applications, nanomedicines and nanotoxicology

Abstract Nanotechnology is one of the most innovative scientific research fields, especially with regard to medical applications. The use of nanotechnology in medical applications is called nanomedicine and is based on the application of nanoparticles for diagnosis and treatment of several clinical conditions. In particular, many physicochemically distinct nanomaterials have been tested in the form of nanoparticles for cancer diagnosis and therapy. This new branch of science, in which nanotechnology is used against cancer, has been named nanooncology. Nanooncology uses materials in nanoscale to delineate the tumor margins, to separate cancer cells from healthy cells, to identify micrometastasis, and to determine if the tumor has been completely removed or not. This approach means fewer side effects and less drug use. Nanoparticles also have the potential of site-specific targeting and controlled drug release; thus, a strong dose of drug could be concentrated within a specific area, but with a planned and scheduled release, to ensure maximum effectiveness and patient safety. Although being designed to target specific organs/tissues/cells, nanoparticles may interfere with other organs/tissues, such as liver and blood. Nanoparticles can be engineered to avoid the immune system recognition or to specifically inhibit or enhance the immune responses; they are strange bodies for the immune system and may induce undesirable immunotoxicity. This chapter highlights the benefits of nanotechnology and of nanomedicines for cancer diagnosis and therapy, focusing on the relevant aspects of nanotoxicology.