Journals
2015 EN
Suênia de Paiva Lacerda · Fabienne Espitalier · Valérie Hoffart
+1 more
This study concerns a new compound named CRS 74 which has the property of inhibiting Human Immunodeficiency Virus (HIV) protease, an essential enzyme involved in HIV replication process. It is proved in this study that the original CRS 74 exhibits poor aqueous solubility and a very low dissolution rate, which can influence its bioavailability and clinical response. In an attempt to improve the dissolution rate, CRS 74 was recrystallized by liquid anti-solvent (LAS) crystallization. Ethanol was chosen as solvent and water as the anti-solvent. Recrystallized solids were compared with the original drug crystals in terms of physical and dissolution properties. Recrystallization without additives did not modify the CRS 74 dissolution profile compared to the original drug. CRS 74 was then recrystallized using different additives to optimize the process and formulate physicochemical properties. Steric stabilizer in organic phase ensured size-controlling effect, whereas electrostatic stabilizer in aqueous phase decreased particle agglomeration. Cationic additives avoided drug adsorption onto stainless steel T-mixer. In general, additive improved drug dissolution rate due to improvement of wetting properties by specific interactions between the drug and the additives, and ensured continuous production of CRS 74 by electrostatic repulsion.
Journals
2015 EN
Sarah Regina Pereira Camelo · Sophie FranceschiMessant · Émile Perez
+2 more
This article proposes solid-like systems from sunflower oil structured with a fibrillar network built by the assembly of 12-hydroxystearic acid (12-HSA), a gelator molecule for an oil phase. The resulting organogels were studied as oral controlled release formulations for a lipophilic drug, Efavirenz (EFV), dissolved in the oil. The effects of the gelator concentration on the thermal properties of the organogels were studied by Differential Scanning Calorimetry (DSC) and showed that drug incorporation did not change the sol-gel-sol transitions. The erosion and drug release kinetics from organogels under conventional (filling gelatin capsules) or multiparticulate (beads obtained by prilling) dosage forms were measured in simulated gastric and intestinal fluids. EFV release profiles were analyzed using model-dependent (curve-fitting) and independent approaches (Dissolution Efficiency DE). Korsmeyer-Peppas was the best fitting release kinetic model based on the goodness of fit, revealing a release mechanism from organogels loaded with EFV different from the simple drug diffusion release mechanism obtained from oily formulations. From organogels, EFV probably diffuses through an outer gel layer that erodes releasing oil droplets containing dissolved EFV into the aqueous medium.
Journals
2015 EN
Guimes Rodrigues Filho · Flávia Souza Almeida · Sabrina Dias Ribeiro
+4 more
In this paper, cellulose triacetate (CTA) was produced from sugarcane bagasse and used as matrices for controlled release of paracetamol. Symmetric and asymmetric membranes were obtained by formulations of CTA/dichloromethane/drug and CTA/dichloromethane/water/drug, respectively, and they were characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Different morphologies of membranes were observed by SEM, and the incorporation of paracetamol was confirmed by lowering of the glass transition temperature (Tg) in the DSC curves. This indicates the existence of interactions between the matrix and the drug. The evaluation of drug release was based on the electrochemical monitoring of paracetamol through its oxidation at a glassy carbon electrode surface using square-wave voltammetry (SWV), which provides fast, precise and accurate in situ measurements. The studies showed a content release of 27% and 45% by the symmetric and asymmetric membranes, respectively, during 8 h.
Journals
2015 EN
Mehran Afshar · Patrick Hamilton · Jenny F. Seligmann
+5 more
Imatinib therapy has improved outcomes in advanced GISTs. Current guidelines suggest monitoring with CT scanning every 12 weeks. There are no validated biomarkers to assist disease evaluation. We identified 50 patients treated with imatinib for GIST in a single tertiary center. We assessed the prognostic value of D-dimers by Cox regression, and the utility as a biomarker for radiological progression (rPD) using receiver-operator curve (ROC) analysis. In asymptomatic patients with D-dimer levels <1,000 and falling levels, the negative predictive value for rPD was 92%. D-dimers may reduce the burden of CT scanning in a proportion of patients in this setting.
Journals
2015 EN
André Moreni Lopes · Laura de Oliveira Nascimento · Artur Ribeiro
+13 more
l-asparaginase (l-asparagine amino hydrolase, E.C.3.5.1.1) is an enzyme clinically accepted as an antitumor agent to treat acute lymphoblastic leukemia and lymphosarcoma. It catalyzes l-asparagine (Asn) hydrolysis to l-aspartate and ammonia, and Asn effective depletion results in cytotoxicity to leukemic cells. Microbial l-asparaginase (ASNase) production has attracted considerable attention owing to its cost effectiveness and eco-friendliness. The focus of this review is to provide a thorough review on microbial ASNase production, with special emphasis to microbial producers, conditions of enzyme production, protein engineering, downstream processes, biochemical characteristics, enzyme stability, bioavailability, toxicity and allergy potential. Some issues are also highlighted that will have to be addressed to achieve better therapeutic results and less side effects of ASNase use in cancer treatment: (a) search for new sources of this enzyme to increase its availability as a drug; (b) production of new ASNases with improved pharmacodynamics, pharmacokinetics and toxicological profiles, and (c) improvement of ASNase production by recombinant microorganisms. In this regard, rational protein engineering, directed mutagenesis, metabolic flux analysis and optimization of purification protocols are expected to play a paramount role in the near future.
Journals
2015 EN
Maria Küüsmaa · Milan Sedliak · Keijo Häkkinen
It has been clearly established that maximal force varies during the day in human muscles but the exact mechanisms behind the diurnal rhythms are still not fully clarified. Therefore, the aim of this study was to examine the diurnal rhythms in maximal isometric force production in a large group of participants and also by separating the high morning performance types (n = 8) and the high evening performance types (n = 19) from the neutral types (n = 45) based on their actual maximal isometric force levels. Measurements were performed in the morning (7:26 h ± 63 min) and in the evening (17:57 h ± 74 min) for maximal bilateral isometric leg press force (MVCLP) together with myoelectric activity (EMGLP), maximal unilateral isometric knee extension force (MVCKE) and maximal voluntary activation level (VA%) during maximal unilateral isometric knee extension force (MVCVA) together with myoelectric activity (EMGVA). In addition, venous blood samples were drawn four times a day and serum testosterone and cortisol concentrations were analyzed. None of the participants belonged to the extreme morning or evening chronotype according to the Munich Chronotype Questionnaire. In the total group of participants, MVCLP and MVCKE were 4.4 ± 12.9% (p < 0.01) and 4.3 ± 10.6% (p < 0.01) higher in the evening compared to the morning. MVCVA and VA% did not show significant diurnal variation. The high morning performance types showed lower force values in the evening compared to the morning for MVCLP (10.8 ± 9.1%; p < 0.05) and MVCKE (5.7 ± 4.9%; p < 0.05). No significant diurnal variation was observed for MVCVA and VA%. The high evening performance types showed higher force values in the evening for MVCLP (16.1 ± 15.9%; p < 0.001), MVCKE (13.5 ± 11.3%; p < 0.001) and MVCVA (6.2 ± 9.9%; p < 0.05) with a concomitant higher VA% in the evening (p < 0.05). The neutral types showed significantly higher evening force values for the MVCLP (2.1 ± 6.7%; p < 0.05). All the other neuromuscular variables did not show significant diurnal variations. EMGLP and EMGVA did not show significant diurnal fluctuations in any group. Serum testosterone and cortisol concentrations showed normal daily rhythms with higher values observed in the morning in all of the groups (p < 0.001). Between-group differences were observed for MVCLP (p < 0.001) and MVCKE (p < 0.001) between all of the three groups. Diurnal changes in VA% differed between the high evening performance types and the neutral types (p < 0.05) and the testosterone/cortisol ratio (p < 0.05) as well as vastus lateralis EMGVA (p < 0.05) differed between the high morning and high evening performance types. In conclusion, we were able to identify the high morning performance types, the high evening performance types and the neutral types who showed significantly different diurnal rhythms in force production, irrespective of their actual chronotype. Therefore, the questionnaires designed to determine the chronotype may not always be sensitive enough to determine the "morningness" or "eveningness" in maximal neuromuscular performance. In general, central factors could partially explain the diurnal fluctuations in maximal strength performance, but peripheral mechanisms were also possibly involved.
Journals
2015 EN
Marco Tampellini · R. S. Polverari · Azzurra Ottone
+13 more
Seasonal variation of baseline diagnosis (or clinical suspect) of stage I-III colorectal cancer patients has been repeatedly reported as an independent variable influencing overall survival. However, data are conflicting and no information is available about such a rhythm in advanced stage patients. To test whether a circannual rhythm of efficacy outcomes can be detected in this setting, we collected data about response rate (RR), progression-free survival (PFS), and overall survival (OS) to first-line chemotherapy of 1610 newly diagnosed metastatic patients treated at four independent centers. Responses to first-line chemotherapy were available for 1495 patients. A strong circannual rhythm in RR was evident, with the higher proportion of responding patients in the subgroup diagnosed in January (acrophase). At the time of data cutoff, 1322 patients progressed and 986 died, with median PFS and OS of 11 and 25.6 months, respectively. A circannual rhythmicity of the proportion of patients progressing at 6 months and surviving at 1 year was demonstrated, with acrophases located both in winter (February and January, respectively), similar to what reported for RR. Several interpretations about the genesis of this cyclic variation could be claimed: the rhythm in sunlight exposure and, as a consequence, of vitamin D serum levels and folate degradation, the variability in toxic effect intensity of chemotherapy, and the rhythm in the biological behavior of tumor cells. This observation is worth of further investigation both in preclinical and in clinical settings in order to better elucidate the underlying mechanisms.
Journals
2015 EN
Martino F. Pengo · Giacomo Rossitto · Valeria Bisogni
+7 more
Absolute blood pressure (BP) values are not the only causes of adverse cardiovascular consequences. BP variability (BPV) has also been demonstrated to be a predictor of mortality for cardiovascular events; however, its determinants are still unknown. This study considers 426 subjects with ambulatory BP monitoring (ABPM) measuring 24-h, diurnal and nocturnal absolute BP values and their standard deviations of the mean, along with nocturnal fall, age, sex and current treatment. Patients were divided in two subgroups, controlled and uncontrolled BP, and BPV of patients with "true" and "false" resistant hypertension was also analyzed. Nocturnal and 24-h BPV were higher in the group with uncontrolled hypertension. Multiple regression analysis showed that absolute BP, age, nocturnal fall, but not sex predicted BPV. Patients with "true" resistant hypertension had greater BPV than "false" resistant hypertension patients. Absolute BP resulted as the main determinant of 24-h and nocturnal BPV but not daytime BPV. Also nocturnal BP fall and age resulted as predictors of BPV in treated and untreated patients. Patients with "true" resistant hypertension have a higher BPV, suggesting a higher sympathetic activation. Evidence is still limited regarding the importance of short-term BPV as a prognostic factor and assessment of BPV cannot yet represent a parameter for routine use in clinical practice. Future prospective trials are necessary to define which targets of BPV can be achieved with antihypertensive drugs and whether treatment-induced reduction in BPV is accompanied by a corresponding reduction in cardiovascular events.
Journals
2015 EN
Ana Lygia R. de Carvalho · Roberto Vital · Cláudio Mueller Kakuda
+7 more
Ischemic acute kidney injury is a common occurrence in the perioperative period and in critical patients admitted to intensive care units. The reestablishment of blood supply may worsen injury through the ischemia-reperfusion (I/R) mechanism. We investigated the effect of dexmedetomidine on the kidneys of rats subjected to an experimental I/R model.
Journals
2015 EN
Valeria Cernaro · Maria Antonietta Medici · Giuseppa Leonello
+5 more
Indole-3-acetic acid is the main auxin produced by plants and plays a key role in the plant growth and development. This hormone is also present in humans where it is considered as a uremic toxin deriving from tryptophan metabolism. However, beyond this peculiar aspect, the involvement of auxin in human pathophysiology has not been further investigated. Since it is a growth hormone, we evaluated its proliferative properties in an in vitro model of mammalian renal tubular epithelial cells. We employed an experimental model of renal tubular epithelial cells belonging to the LLC-PK1 cell line that is derived from the kidney of healthy male pig. Growth effects of auxin against LLC-PK1 cell lines were determined by a rapid colorimetric assay. Increasing concentrations of auxin (to give a final concentration from 1 to 1000 ng/mL) were added and microplates were incubated for 72 h. Each auxin concentration was assayed in four wells and repeated four times. Cell proliferation significantly increased, compared to control cells, 72 h after addition of auxin to cultured LLC-PK1 cells. Statistically significant values were observed when 100 ng/mL (p < 0.01) and 1000 ng/mL (p < 0.05) were used. In conclusion, auxin influences cell growth not only in plants, where its role is well documented, but also in mammalian cell lines. This observation opens new scenarios in the field of tissue regeneration and may stimulate a novel line of research aiming at investigating whether this hormone really influences human physiology and pathophysiology and in particular, kidney regeneration.