Phytochemical Characterization and Biological Evaluation of Origanum vulgare L. Essential Oil Formulated as Polymeric Micelles Drug Delivery Systems.

This study presents phytochemical characterization and biological evaluation of Origanum vulgare L. essential oil (OEO) formulated as polymeric micelles drug delivery systems as a possible non-invasive approach for the management of skin tags. GC-MS analysis of Romanian OEO revealed the identification and quantification of 43 volatile compounds (thymol and carvacrol being the main ones). The antioxidant activity was shown by four consecrated methods: CUPRAC, ABTS, ORAC and DPPH. OEO was incorporated by micellar solubilization into a binary hydrogel based on a Pluronic F 127/L 31 block-copolymers mixture. The pH, consistency, spreadability, particle size, polydispersity index and zeta potential of the OEO-loaded poloxamer-based binary hydrogel (OEO-PbH) were investigated. OEO-PbH was skin compatible in terms of pH and exhibited adequate spreadability and consistency. The minimal inhibitory concentrations of the tested OEO were similar to those obtained for the formulation, lower (2.5 µg/mL) for yeast and higher (40-80 µg/mL) for Gram-negative bacilli. As keratinocytes are among main components of skin tags, an in vitro evaluation was conducted in order to see the effect of the formulation against HaCaT human keratinocytes. OEO-PbH decreased HaCaT cells migration and proliferation and elicited a cytotoxic and pro-apoptotic effect in a dose- and time-dependent manner. No harmful effect on the viability of dendritic cells (DCs) was detected following the incubation with different concentrations (0-200 µg/mL) of the 5% formulation. Treatment in inflammatory DCs (+LPS) indicated a decrease in cytokine production of IL-6, TNF-α and IL-23 but no significant effect on IL-10 in any of the tested concentrations.

In Vitro Assessment of the Cytotoxic and Antiproliferative Profile of Natural Preparations Containing Bergamot, Orange and Clove Essential Oils.

Medicinal plants and essential oils (EOs), in particular, were intensively studied in recent years as viable alternatives for antiproliferative chemical synthetic agents. In the same lines, the present study focuses on investigating the effects of natural preparations (emulsions) based on EOs obtained from Citrus bergamia Risso (bergamot-BEO), Citrus sinensis Osbeck (orange-OEO), and Syzygium aromaticum Merill et L. M. Perry (clove-CEO) on different healthy (human immortalized keratinocytes-HaCaT and primary human gingival fibroblasts-HGF) and human tumor cell lines (human melanoma-A375 and oral squamous carcinoma-SCC-4) in terms of the cells' viability and cellular morphology. The obtained results indicate that the CEO emulsion (ECEO) induced a dose-dependent cytotoxic in both healthy (HaCaT and HGF) and tumor (A375 and SCC-4) cells. OEO emulsion (EOEO) increased cell viability percentage both for HaCaT and A375 cells and had an antiproliferative effect at the highest concentration in HGF and SCC-4 cells. BEO emulsion (EBEO) decreased the viability percentage of SCC-4 tumor cells. By associating OEO with CEO as a binary mixture in an emulsified formulation, the inhibition of tumor cell viability increases. The E(BEO/OEO) binary emulsion induced an antiproliferative effect on oral health and tumor cells, with a minimal effect on skin cells. The non-invasive tests performed to verify the safety of the test compound's emulsions at skin level indicated that these compounds do not significantly modify the physiological skin parameters and can be considered safe for human skin.

Oleogel Formulations for the Topical Delivery of Betulin and Lupeol in Skin Injuries-Preparation, Physicochemical Characterization, and Pharmaco-Toxicological Evaluation.

The skin integrity is essential due to its pivotal role as a biological barrier against external noxious factors. Pentacyclic triterpenes stand as valuable plant-derived natural compounds in the treatment of skin injuries due to their anti-inflammatory, antioxidant, antimicrobial, and healing properties. Consequently, the primary aim of the current investigation was the development as well as the physicochemical and pharmaco-toxicological characterization of betulin- and lupeol-based oleogels (Bet OG and Lup OG) for topical application in skin injuries. The results revealed suitable pH as well as organoleptic, rheological, and textural properties. The penetration and permeation of Bet and Lup oleogels through porcine ear skin as well as the retention of both oleogels in the skin were demonstrated through ex vivo studies. In vitro, Bet OG and Lup OG showed good biocompatibility on HaCaT human immortalized cells. Moreover, Bet OG exerted a potent wound-healing property by stimulating the migration of the HaCaT cells. The in ovo results demonstrated the non-irritative potential of the developed formulations. Additionally, the undertaken in vivo investigation indicated a positive effect of oleogels treatment on skin parameters by increasing skin hydration and decreasing erythema. In conclusion, oleogel formulations are ideal for the local delivery of betulin and lupeol in skin disorders.

Melissa officinalis L. Aqueous Extract Exerts Antioxidant and Antiangiogenic Effects and Improves Physiological Skin Parameters.

Melissa officinalis (MO) is a medicinal plant well-known for its multiple pharmacological effects, including anti-inflammatory, anticancer and beneficial effects on skin recovery. In this context, the present study was aimed to investigate the in vitro and in vivo safety profile of an MO aqueous extract by assessing cell viability on normal (HaCaT-human keratinocytes) and tumor (A375-human melanoma) cells and its impact on physiological skin parameters by a non-invasive method. In addition, the antioxidant activity and the antiangiogenic potential of the extract were verified. A selective cytotoxic effect was noted in A375 cells, while no toxicity was noticed in healthy cells. The MO aqueous extract safety profile after topical application was investigated on SKH-1 mice, and an enhanced skin hydration and decreased erythema and transepidermal water loss levels were observed. The in ovo CAM assay, performed to investigate the potential modulating effect on the angiogenesis process and the blood vessels impact, indicated that at concentrations of 100 and 500 µg/mL, MO aqueous extract induced a reduction of thin capillaries. No signs of vascular toxicity were recorded at concentrations as high as 1000 µg/mL. The aqueous extract of MO leaves can be considered a promising candidate for skin disorders with impaired physiological skin parameters.

Solid Polymeric Nanoparticles of Albendazole: Synthesis, Physico-Chemical Characterization and Biological Activity.

Albendazole is a benzimidazole derivative with documented antitumor activity and low toxicity to healthy cells. The major disadvantage in terms of clinical use is its low aqueous solubility which limits its bioavailability. Albendazole was incorporated into stable and homogeneous polyurethane structures with the aim of obtaining an improved drug delivery system model. Spectral and thermal analysis was used to investigate the encapsulation process and confirmed the presence of albendazole inside the nanoparticles. The in vitro anticancer properties of albendazole encapsulated in polyurethane structures versus the un-encapsulated compound were tested on two breast cancer cell lines, MCF-7 and MDA-MB-231, in terms of cellular viability and apoptosis induction. The study showed that the encapsulation process enhanced the antitumor activity of albendazole on the MCF-7 and MDA-MB-23 breast cancer lines. The cytotoxic activity manifested in a concentration-dependent manner and was accompanied by changes in cell morphology and nuclear fragmentation.

Correlations on Phenolic Screening Related to In Vitro and In Ovo Assessment of Ocimum basilicum L. Hydro-Alcoholic Extracts Used as Skin Active Ingredient.

The current study was aimed to evaluate the phenolic composition parameters of two hydro-alcoholic extracts of Ocimum basilicum L. (OB) obtained from the aerial part (without leaves) and leaves, in order to determine their contribution to the antioxidant activity (AOA). Both hydro-alcoholic extracts have proven to be rich in polyphenolic compounds, flavonoids, flavonols and tannins. Therefore, the leaves' extracts reveal an inhibition percentage of 89%, almost comparable with the standard reference (95%). To complete the toxicological profile, the study also assessed the potential cytotoxicity of basil hydro-alcoholic extracts on immortalized human keratinocytes (HaCaT), skin human fibroblasts (1BR3), mice epidermis (JB6Cl41-5a) and primary human melanocytes (HEMa) cells, correlated to A375 antitumor in vitro activity. The extracts did not induce significant cytotoxic effect on any of the selected normal cell lines but showed relevant activity on A375 cells. Considering the low values obtained regarding the irritative effects in the chorionallantoic membrane of the egg on blood vessels, we can emphasize that both extracts can be considered as biocompatible ingredients. Regarding the potential activity of hydro-alcoholic extracts on human skin, the decrease of erythema values after the application of extracts was a relevant observation which indicates the anti-inflammatory potential of Ocimum basilicum L.

Thyroid Pathology in End-Stage Renal Disease Patients on Hemodialysis.

OBJECTIVES: Chronic kidney disease is a rising cause of morbidity and mortality in developed countries, including end-stage renal disease (ESRD). The prevalence of thyroid comorbidities in persons with chronic kidney disease is documented higher than in normal population. The study aims to investigate the prevalence of morphological and functional thyroid disorders in patients with chronic kidney disease, with renal replacement therapy (hemodialysis). METHODS: A cross-sectional study was performed on 123 consecutive patients with chronic kidney disease stage 5, on hemodialysis during a period of one month (May 2019-June 2020). All patients were enrolled for maintenance hemodialysis in B Braun Hemodialysis Center Timisoara and were examined on conventional 2B ultrasound. Thyroid blood tests were done, including serum free thyroxin (FT4), free triiodothyronine (FT3) and thyroid-stimulating hormone (TSH) at the time of starting hemodialysis. RESULTS: We evaluated 123 patients (male to female ratio 70/53) mean age 62.2 ± 11.01, mostly above 65 years old, enrolled in the end-stage renal disease program, on renal replacement therapy. From the cohort, 76/123 presented thyroid disease, including autoimmune hypothyroidism, nodular goiter or thyroid cancer. Among them, 63 patients presented nodular goiter, including 3 thyroid cancers, confirmed by surgery and histopathological result, 22 patients had thyroid autoimmune disease. The serum thyroid-stimulating hormone levels found in the cohort was 3.36 ± 2.313 mUI/mL, which was in the normal laboratory reference range. The thyroid volume was 13 ± 7.18 mL. A single patient in the cohort presented Graves Basedow disease, under treatment and three patients present subclinical hyperthyroidism. We have found that thyroid disease risk is increased by 3.4-fold for the female gender and also the increase of body mass index (BMI) with one unit raises the risk of developing thyroid disease with 1.083 times (p = 0.018). CONCLUSION: To conclude, this study aimed to quantify the prevalence of thyroid disease in end-stage kidney disease population, especially nodular goiter, important for differential diagnosis in cases with secondary hyperparathyroidism. Thyroid autoimmune disease can be prevalent among these patients, as symptoms can overlap those of chronic disease and decrease the quality of life. We have found that thyroid disease has a high prevalence among patients with end-stage renal disease on hemodialysis. Thyroid goiter and nodules in ESRD patients were more prevalent than in the general population. Clinical surveillance and routine screening for thyroid disorders can improve the quality of life in these patients.

TI-RADS Diagnostic Performance: Which Algorithm is Superior and How Elastography and 4D Vascularity Improve the Malignancy Risk Assessment.

Given the increased prevalence of thyroid nodules in the general population (~50%), the real challenge resides in correctly recognizing the suspicious ones. This study proposes to compare four important Thyroid Imaging and Reporting Data Systems (TI-RADS) and evaluate the contribution of elastography and 4D Color Doppler assessment of vascularity in estimating the risk of malignancy. In the study, 133 nodules with histopathological examination were included. Of these, 35 (26.31%) proved to be malignant. All nodules were classified using the four selected systems and our proposed improved score. The American College of Radiology (ACR) and EU TI-RADS had good sensitivity (94.28%, 97.14%) and NPV (93.33%, 95.83%), but fairly poor specificity (31.81%, 23.46%) and PPV (35.48%, 31.19%), with an accuracy of 42.8% and 45.8%, respectively. Horvath TI-RADS had better accuracy of 66.9% and somewhat improved specificity (62.24%), but poorer sensitivity (80%). Russ' French TI-RADS includes elastography in the risk assessment strategy. This classification proved superior in all aspects (Se: 91.42%, Sp:82.65%, NPV:96.42%, PPV:65.30%, and Acc of 84.96%). The mean strain ratio (SR) value for malignant lesions was 5.56, while the mean SR value for benign ones was significantly lower, 2.54 (p < 0.05). It also correlated well with the response variable: histopathological result (p < 0.001). Although, adding 4D vascularity to the French score generated a similar calculated accuracy and from a statistical point of view, the parameter itself proved beneficial for predicting the malignancy risk (p < 0.001) and may add important knowledge in uncertain situations. Advanced ultrasound techniques definitely improved the risk estimation and should be used more extensively.

The Predictive Value of Endothelial Inflammatory Markers in the Onset of Schizophrenia.

PURPOSE: This study aimed to assess the serum levels of intracellular adhesion molecule (sICAM-1), and vascular cell adhesion molecule (sVCAM-1), in the first psychotic episode schizophrenia (SZ) patients, before and after six months of antipsychotic treatment. PATIENTS AND METHODS: The study included 50 patients with a first hospitalization for SZ and 50 healthy control subjects that were patient-matched regarding age, gender, body mass index and smoking status. The evaluation included the presence of cardiovascular risk factors, measurements of systolic and diastolic blood pressure, body mass index, smoking status, ankle-brachial index, carotid intima-media thickness, and echocardiography. The Brief Psychiatric Rating Scale (BPRS) score was calculated for the patients. The plasma levels of fasting glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, sICAM-1 and sVCAM-1 were determined at baseline in all subjects and after six months of antipsychotic treatment. Thirty patients (60%) were treated with olanzapine and 20 (40%) with risperidone. RESULTS: The average age of patients experiencing their first episode of SZ was 29.7±6.6 years, and 23 (46%) were men. The initial sICAM-1 levels of the patients were lower than those of the control group (P<0.0001), and increased after treatment (P=0.02), but remained lower than in the healthy controls (P=0.026). The initial levels of sVCAM-1 levels were higher in the patients (P<0.0001) and decreased after treatment (P<0.0001) to values that were similar to those of the control group (P=0.39). The only independent predictor of a baseline BPRS over 120 was the baseline sVCAM-1 level (P<0.0001). Antipsychotic treatment induced significant decreases in BPRS score (P<0.0001), in systolic (P=0.005) and diastolic (P<0.0001) blood pressure, in HDL-c (P=0.02), as well as significant increases in blood glucose (P<0.01) and LDL-c (P<0.001), with no differences between olanzapine and risperidone. CONCLUSION: In the patients experiencing an FEP of SZ, the levels of sICAM-1 were lower, while the levels of sVCAM-1 were higher than in the healthy control subjects. The antipsychotics used in the treatment of schizophrenia increased sICAM-1 and decreased sVCAM. The baseline level of sVCAM-1 was an independent predictor of a BPRS score >120 at baseline.

Shear Wave Elastography in Diagnosing Secondary Hyperparathyroidism.

This study evaluates the diagnostic value of two-dimensional shear wave elastography (2 D-SWE) technique in the evaluation of hyperplastic parathyroid glands in cases with secondary and tertiary hyperparathyroidism. A total of 59 patients (end-stage renal disease, under supplemental dialysis program) with visible parathyroid hyperplastic glands on ultrasound, confirmed by biochemical assay and scintigraphy, were enrolled; they were examined on grayscale ultrasound and 2 D shear wave elastography. We determined the elasticity index (EI) in the parathyroid gland, thyroid parenchyma and surrounding muscles, and the elasticity ratio of hyperplastic parathyroid glands compared to muscle, specifically sternocleidomastoid muscle. Patients presented fibrocystic bone disease with secondary hyperparathyroidism induced by end-stage chronic kidney disease; being on prolonged chronic dialysis therapy, they had positive sestamibi scintigraphy and high values of serum parathormone (1141.04 pg/mL). Nodules placed posterior to the thyroid capsule that were cystic, had a hypoechoic aspect, and were homogenous with an independent afferent artery were found. Mean EI in the parathyroid gland was 7.83 kPa, the median value in thyroid parenchyma was 13.76 kPa, and mean muscle EI value was 15.78 kPa. The observed mean parathyroid/muscle SWE ratio was 0.5356 and the value for parathyroid/normal thyroid parenchyma was 0.5995. Using receiver operating characteristic (ROC) analysis, we found that EI below 9.74 kPa correctly identifies parathyroid tissue, with a sensitivity of 94.8%, specificity of 90.7%, and accuracy of 92.26% when compared to normal thyroid tissue. Compared with the muscle tissue, we identified that EI below 9.98 kPa has a sensitivity, specificity, and accuracy of 93.8%, 90.7%, and 91.75%, respectively. Ultrasound elastography is a helpful tool in identifying parathyroid hyperplasia in patients with chronic kidney disease. A cutoff value of 9.98 kPa can be used in 2 D-SWE for accurate diagnosis of parathyroid disease.

Strain Elastography as a Valuable Diagnosis Tool in Intermediate Cytology (Bethesda III) Thyroid Nodules.

Fine needle aspiration (FNA) is considered the gold standard in the diagnostic of thyroid nodules. Using the recommended BETHESDA reporting system, up to 20% of results are classified as intermediate cytology. As there is no consensus whether ultrasound evaluation, lobectomy or surgery is the best treatment option, intermediate cytology results are considered a grey zone of the FNA. The main aim of our study was to evaluate the performance of combined advanced ultrasound techniques in the process of diagnosis and evaluation of the intermediate cytology cases after FNA. We evaluated 54 consecutive cases with intermediate cytology on FNA, using conventional B-mode ultrasound (2B), and strain elastography, using a linear multifrequency 6-13 MHz linear probe (Hitachi Prerius Machine, Hitachi Inc, Japan). All nodules were classified with our Thyroid Imaging Report and Data System (TI-RADS) proposed model, considering: vertical appearance, with antero-posterior diameter bigger than the transvers diameter, the so called taller than wide shape, irregular borders, intranodular inhomogeneity, marked hypoecogenicity, micro calcifications, the presence of suspect lymph nodes, and increased stiffness as suspicious for malignancy. The classification outcomes were compared with the pathology results, considered the gold standard diagnosis. The prevalence of cancer was 28.8%, with 13/45 cases having a clear diagnostic of cancer. Six cases were diagnosed with borderline follicular neoplasia, a category with unclear evolution, also considered as malignant in the analysis of the imaging results. In total, 16/19 cancer cases had increased stiffness on elastography. The cancer prevalence increased with TI-RADS category, being 25% in TI-RADS 4b category and 92.8% in TI-RADS 5 category. The AUROC (Area Under Receiver Operating Curve) of elastography alone, in differentiation of malignant thyroid nodules was 74.9%; the combination of elastographic and conventional ultrasound characteristics generated an even better AUROC, of 84.5%. The combined conventional ultrasound and elastography identified thyroid cancer in cases with intermediate cytology with a sensitivity of 89.5% with a specificity of 50%. High risk thyroid nodules, identified by combined high risk conventional ultrasound characteristics and increased stiffness, on strain elastography, are highly predictive for malignancy, in the intermediate cytology cases.

Mistletoe and Garlic Extracts as Polyurethane Carriers - A Possible Remedy for Choroidal Melanoma.

BACKGROUND: Melanoma is known as the most dangerous form of skin cancer; whereas the malignant choroidal melanoma is an orphan disease known as the most common primary intraocular malignancy in adults. Literature suggests that the consumption of garlic and mistletoe leads to a reduced risk of developing cancer. OBJECTIVE: The aim of this study was the obtaining and the characterization of polymer structures containing mistletoe or garlic extract. METHODS: The structures were obtained in a polyaddition process combined with a spontaneous emulsification; they were characterized by pH, size, Zeta potential and DSC measurements, evaluation of encapsulation efficacy, penetrability through membranes and in vitro cytotoxicity tests. RESULTS: The microstructures present sizes between 1.05 and 2.60 µm and Zeta potentials between -7 and +36 mV. A good encapsulation was observed on different evaluations (88-92%). It was determined that approx. 30% of polymer microstructures containing vegetal extracts pass through an artificial membrane in 4 days. An in vitro cytotoxicity test revealed that these products are safe for administration. The analysis of antitumor efficacy indicates that garlic extracts have important effects after 48 and 72 hours on A375 cells; however, polymer microstructures with herbal extracts did not reveal antiproliferative activities on A375 cells because these polymer structures present a slow degradation. CONCLUSION: Sterile eye drops solutions based on polymer microstructures containing garlic or mistletoe extracts were obtained; the sample based on garlic extracts may be used in the pharmaceutical field as drug carrier with an antiproliferative effect which occurs after a prolong period.

In Vivo Biological Evaluation of Polyurethane Nanostructures with Ursolic and Oleanolic Acids on Chemically-induced Skin Carcinogenesis.

BACKGROUND/AIM: Oleanolic and ursolic acids (OA and UA) are two pentacyclic triterpenes, ubiquitously spread in plants, previously known for their chemopreventive capacity on different types of cancer. The major pharmacological disadvantage of these phytocompounds is their poor water solubility, which often limits their applicability. MATERIALS AND METHODS: Using the interfacial polycondensation combined with spontaneous emulsification technique, polyurethane nanostructures (PU) were synthetized in order to improve this problem. In order to test the in vivo chemopreventive potential of the two pure compounds, as well as the encapsulated compounds in PU used as drug carriers, a chemically-induced skin carcinogenesis model was constructed. RESULTS: UA and OA have a moderate chemopreventive activity against tumors induced by 7,12-dimethylbenzantracene (DMBA) and 12-O-tetradecanoilphorbol-13-acetate (TPA) application. Incorporation of active agents in PU did not lead to increased chemopreventive effect. CONCLUSION: PU is not a suitable formulation of UA and OA.

Sex differences and pathology status correlated to the toxicity of some common carcinogens in experimental skin carcinoma.

The increased susceptibility of men as compared to women to develop different types of cancer, including skin cancer, is well known; however, the mechanisms involved in this process are still a matter of debate. This study aimed to obtain animal models of photo-chemically-induced skin carcinogenesis by exposure to ultraviolet radiation B (UVB) coupled with topical applications of a tumor initiator (7,12-dimethylbenz(a)anthracene, DMBA) and a tumor promoter (12-O-tetradecanoylphorbol-13-acetate, TPA) in order to characterize the gender disparities regarding the skin lesions developed by the female and male SKH-1 hairless mice included in this study. Histopathological analysis confirmed the presence of malignant lesions in both cases, in female and male mice, following chronic exposure (24 weeks) to the noxious effects of the carcinogens applied, whereas the tumors in male mice had a more severe histological grade. In addition, tumor incidence, size and multiplicity were higher in male mice than in female mice.

Anti-proliferative and antibacterial in vitro evaluation of the polyurethane nanostructures incorporating pentacyclic triterpenes.

CONTEXT: Oleanolic and ursolic acids are antitumor and antibacterial agents which are extensively studied. Their major disadvantage is the poor water solubility which limits their applications. OBJECTIVES: Oleanolic and ursolic acid were encapsulated into polyurethane nanostructures that act as drug carriers. In order to evaluate the effectiveness of the particles, anti-microbial and anti-proliferative activity compared to un-encapsulated active compounds was tested. MATERIALS AND METHODS: Using an interfacial polycondensation technique, combined with spontaneous emulsification, structures with nanoscale dimensions were obtained. Scanning electron microscopy, differential scanning calorimetry and X-ray assays confirmed the encapsulation process. Concentrations of 10 and 30 µM particles and un-encapsulated compounds were tested by MTT viability assay for several breast cancer lines, with an exposure time of 72 h. For the antibacterial studies, the dilution method with MIC determination was used. RESULTS: Ursolic acid had an excellent inhibitory effect with IC50 value of 2.47, 1.20, 1.26 and 1.34 µM on MCF7, T47D, MDA-MB-231 and MDA-MB-361, respectively. Oleanolic acid did not show anti-proliferative activity. The pure compounds showed their antibacterial activity only against Bacillus species and Candida albicans, but MIC values were too high to be considered efficient antimicrobial agents (2280 and 4570 µg mL - 1, respectively). Polyurethane nanoparticles which incorporated the agents did not show any biological activity. DISCUSSION AND CONCLUSION: Although the active compounds did not fully exert their anti-proliferative activity following encapsulation inside polymeric nanoparticles, in vivo evaluation is needed in order to obtain an exhaustive conclusion, as the active compounds could be released as a result of metabolic activity.

Individualized Follow-up of Pregnant Women with Asymptomatic Autoimmune Thyroid Disease.

Maternal hormones are essential for the normal fetal development during pregnancy. Autoimmune thyroid disease is a frequent pathology in our iodine replete region. The aim of this study is to evaluate the occurrence of subclinical hypothyroidism (SCH) in cases with known autoimmune thyroid disease, which were in a euthyroid state prior to pregnancy, and to assess the association between supplemental treatments administered and the outcome of the pregnancy. The study is a prospective interventional controlled study. The two cohorts comprise the interventional group, consisting of 109 pregnant women with known autoimmune asymptomatic thyroid disease, without any levothyroxine (LT4) treatment and an aged-matched control group, with an unknown thyroid disease. After the pregnancy, a monthly evaluation of TSH, FT3, and FT4 was performed. Offspring evaluation was made at birth time. 88.8% of the women developed SCH in the first four weeks of pregnancy. Average LT4 doses increased as the pregnancy progressed. The monthly adjustment was 12.5 or 25 µg. All SCH cases developed in the first trimester of pregnancy. There was no significant difference regarding the gestational week, weight, or length at birth between the interventional group and controls, when TSH values were in the optimal range, during the whole pregnancy. Premature birth was described in one case in the interventional group.

Evaluation of the Therapeutic Properties of Mastoparan- and Sifuvirtide- Derivative Antimicrobial Peptides Using Chemical Structure-Function Relationship - in vivo and in silico Approaches.

Antimicrobial peptides, also called body defense peptides, are chemical structures widely distributed across the animal and vegetal kingdoms that have a fundamental role as part of the immune system. These peptides are used against a wide range of pathogens, such as Gram-negative and - positive bacteria, fungi and viruses, etc. Their action spectrum makes them important for the pharmaceutical industry, as they could represent templates for the design of new and more potent structures by using drug design and drug delivery systems. Here we present the antimicrobial activity against Bacillus subtilis (expressed as minimal inhibitory concentration values) for 33 mastoparan analogs and their new derivatives by quantitative structure-activity relationship method (2D, aligned and also non-aligned 3D-QSAR). We establish the contribution to antimicrobial activity of molecular descriptors like hydrophobicity, hydrogen bond donor and steric hindrance, correlated with contributions from the membrane environment (sodium, potassium, chloride ions). Also the studies of HIV-1 fusion inhibitor sifuvirtide and its analogs are presented in context of interaction with lipid structures during fusion and delivery of these drugs.

Polyurethane Microstructures--a Good or Bad in vitro Partner for the Isoflavone Genistein?

In recent years polyurethane microstructures (PM) have gained increasing attention in the pharmaceutical field due to the importance of their practical application. Since finding that such a formulation with genistein could improve its applications, we have conducted a preliminary study regarding the in vitro antiproliferative (MCF7, MDA-MB-231 and T47D) and antimicrobial (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis (D), Bacillus subtilis, B. cereus, and Candida albicans) activity in order to test whether polyurethane micro structuresre present a good option for further modulation of genistein's bioavailability. It was concluded that the polyurethane micro structures are a bad in vitro partner for the isoflavone genistein.

Betulinic acid in complex with a gamma-cyclodextrin derivative decreases proliferation and in vivo tumor development of non-metastatic and metastatic B164A5 cells.

Betulinic acid, a very promising anti-melanoma agent, has very low water solubility that causes low bioavailability. To overcome this inconvenience, a highly water-soluble cyclodextrin was used (octakis-[6-deoxy-6-(2-sulfanyl ethanesulfonic acid)]-γ-cyclodextrin). The complex was physico-chemically analyzed using differential scanning calorimetry (DSC), X-ray and scanning electron microscopy (SEM) methods and then in vitro tested for its antiproliferative activity by the MTT assay and by cell cycle analysis. Finally, the complex was tested in vivo using an animal model of murine melanoma developed in C57BL/6J mice, where it caused a reduction in tumor volume and weight. The study revealed the beneficial influence of betulinic acid inclusion into the cyclodextrin in terms of antiproliferative activity and in vivo tumor development.

The synergistic biologic activity of oleanolic and ursolic acids in complex with hydroxypropyl-γ-cyclodextrin.

Oleanolic and ursolic acids are natural triterpenic compounds with pentacyclic cholesterol-like structures which gives them very low water solubility, a significant disadvantage in terms of bioavailability. We previously reported the synthesis of inclusion complexes between these acids and cyclodextrins, as well as their in vivo evaluation on chemically induced skin cancer experimental models. In this study the synergistic activity of the acid mixture included inside hydroxypropyl-gamma-cyclodextrin (HPGCD) was monitored using in vitro tests and in vivo skin cancer models. The coefficient of drug interaction (CDI) was used to characterize the interactions as synergism, additivity or antagonism. Our results revealed an increased antitumor activity for the mixture of the two triterpenic acids, both single and in complex with cyclodextrin, thus proving their complementary biologic activities.