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INTRODUCTION: The history of levothyroxine has been linked to advances in the treatment of thyroid disease and to date it is the standard therapy for the treatment of hypothyroidism. Bioequivalence studies are the most widely used method to demonstrate interchangeability, although controversy persists regarding the best design for this molecule declared as a narrow therapeutic index product in many countries. This study aimed to evaluate the pharmacokinetic profile of two formulations of levothyroxine to determine bioequivalence between them. METHODS: This two-period, randomized, crossover, blind study was conducted in 80 healthy volunteers, of both sexes, using a single levothyroxine dose of 600 µg with a washout period of 42 days. Blood sampling was performed at - 30 min, - 15 min, and 0 h pre-dose and 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, and 48 h post-dose. RESULTS: A total of 78 subjects successfully completed both periods. There were no serious adverse events during the study and both formulations were well tolerated. Baseline correction of serum levothyroxine concentrations was performed before statistical analysis. The mean maximum plasma concentration of the test product (Levotiroxina MK®) was 57.49 ng/mL while for the reference product it reached 59.32 ng/mL. Importantly, both test and reference formulations reached maximum concentrations in plasma at about the same time. The areas under the pharmacokinetic curves with the test product showed AUC0-t of 1407.1 ng h/mL and the reference product 1394.3 ng h/mL. The bioequivalence statistical analysis showed that the 90% confidence interval (CI90%) of the ratio of test over reference formulation was within the bioequivalence margins of 90-111%. For Cmax, the test/reference ratio was 96.2% with CI90% of 91.6-100.9%, and for AUC0-t the test/reference ratio was 99.9 with CI90% of 93.3-107.0%. CONCLUSIONS: Both formulations have the same pharmacokinetic profile and are bioequivalent in the narrow therapeutic index required by some health authorities.

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Introduction: The use of chitosan in pharmaceutical formulations is an advantageous approach due to this compound intrinsic biodegradability and biocompatibility, as well as ready availability and low polymer cost. Methods: Herein, the naphthoquinones 3- chloromethylene-menadione (NQ1) and 2,3-dichloro-1,4-naphthoquinone (NQ2) were nanoencapsulated into chitosan (CNP) by the ionotropic gelatinization technique and characterized by DLS, FTIR, SEM, TGA and DSC, and their release profiles evaluated. The antimicrobial and wound healing activities were investigated. Results and Discussion: Homogeneous chitosan nanocapsulses of about 193 nm and Z potential ranging from +30.6 to +33.1 mV loaded with NQ1 (CNP-NQ1) or NQ2 (CNPQNQ2). With nanoencapsulation efficiencies of ≥ 96%, the solubility of naphthoquinones in aqueous environments was improved, making them suitable for biological system applications. The encapsulated naphthoquinones displayed a controlled release of approximately 80% for CNP-NQ1 and 90% for CNP-NQ2 over an 8 h period at 36°C. Both CNP-NQ1 and CNP-NQ2 retained the already established free naphthoquinone antimicrobial activity against two Staphylococcus aureus strains, Staphylococcus epidermidis, Streptococcus pyogenes and Pseudomonas aeruginosa. Although presenting low toxicity to healthy human cells, only CNP-NQ1 displayed therapeutic indices above 100 for S. aureus and S. epidermidis and above 27 for S. pyogenes and P. aeruginosa, allowing for safe use in human tissues. Furthermore, CNP-NQ1 did not impair the migration of human fibroblast cells in scratch assays, adding promising wound healing properties to this formulation. These findings emphasize that CNP-NQ1 may be useful in protecting injured skin tissue from bacterial contamination, avoiding skin infections not only by reducing bacterial loads but also by accelerating the healing process until complete dermal tissue recovery.

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Resumen Objetivo Identificar la proporción de hipertensos no controlados y sus factores asociados, en pacientes del programa de hipertensión arterial de Pueblorrico, Antioquia, 2018. Método: Estudio transversal de asociación, en el que se obtuvieron datos sociodemográficos, clínicos y antropométricos. Se aplicaron encuestas y la revisión de historias clínicas en una muestra de 272 pacientes. Se realizó la caracterización de los pacientes. Por regresión logística multivariada se obtuvieron las razones de disparidad y los intervalos de confianza del 95% (IC95%). Resultados El no control de la presión arterial se evidenció en el 35.3% (IC 95%: 29.41-41.20). Las variables obesidad (odds ratio [OR]: 2.1; IC95%: 1.05-4.31), utilizar más de tres medicamentos al día (OR: 2.0; IC95%: 1.19-3.44) y asistir a menos de cuatro controles de seguimiento al año (OR: 2.2; IC95%: 1.03-4.74) se asociaron de manera significativa como factores de riesgo para el no control de la presión arterial. Tener excelente percepción de la calidad del programa fue un factor protector (OR: 0.5; IC95%: 0.28-0.87). Conclusiones La proporción de pacientes hipertensos que no logran la meta terapéutica (presión arterial ≤ 140/90 mm Hg) continúa siendo un desafío para la práctica clínica y la salud pública. La adherencia a los controles y el control de factores de riesgo, como la obesidad, son intervenciones importantes en este contexto.

Abstract Objective To identify the proportion of uncontrolled hypertensive patients and their associated factors in a population attending an HBP program. Method Cross-sectional association study. Sociodemographic, clinical and anthropometric data were obtained. Surveys and review of medical records were applied in a sample of 272 participants. The characterization of the patients was performed. By multivariate logistic regression the odds ratios (OR) and confidence intervals (95% CI) were obtained. Results The non-control of blood pressure was evidenced in 35.3% (95% CI: 29.41-41.20). The variables obesity (OR: 2.1; 95% CI: 1.05-4.31), use more than three medications per day (OR: 2.0; 95% CI: 1.19-3.44), and attending less than four follow-up controls per year (OR: 2.2; 95% CI: 1.03-4.74), were significantly associated as a risk factor for non-BP control. Having an excellent perception of the quality program was a protective factor (OR: 0.5; 95% CI: 0.28-0.87). Conclusions The proportion of hypertensive patients who do not achieve the therapeutic goal (PA ≤ 140/90 mm Hg), remains a challenge for clinical practice and public health. The adherence and control of risk factors such as obesity are important interventions in this context.

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Silver nanoparticles (AgNPs) not only have shown remarkable results as antimicrobial and antiviral agents but also as antitumor agents. This work reports the complete characterization of five polyvinylpyrrolidone-coated AgNP (PVP-AgNP) formulations, their cytotoxic activity against human colon tumor cells (HCT-15), their cytotoxic effect on primary mouse cultures, and their lethal dose on BALB/c mice. The evaluated AgNP formulations have a composition within the ranges Ag: 1.14-1.32% w/w, PVP: 19.6-24.5% and H2O: 74.2-79.2% with predominant spherical shape within an average size range of 16-30 nm according to transmission electron microscopy (TEM). All formulations assessed increase mitochondrial ROS concentration and induce apoptosis as the leading death pathway on HCT-15 cells. Except for AgNP1, the growth inhibition potency of AgNP formulations of human colon tumor cancer cells (HCT-15) is 34.5 times higher than carboplatin, one of the first-line chemotherapy agents. Nevertheless, 5-10% of necrotic events, even at the lower concentration evaluated, were observed. The cytotoxic selectivity was confirmed by evaluating the cytotoxic effect on aorta, spleen, heart, liver, and kidney primary cultures from BALB/c mice. Despite the cytotoxic effects observed in vitro, the lethal dose and histopathological analysis showed the low toxicity of these formulations (all of them on Category 4 of the Globally Harmonized System of Classification and Labelling of Chemicals) and minor damage observed on analyzed organs. The results provide an additional example of the rational design of safety nanomaterials with antitumor potency and urge further experiments to complete the preclinical studies for these AgNP formulations.

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Antimicrobial peptides (AMPs) have been recognised as a significant therapeutic option for mitigating resistant microbial infections. It has been found recently that Plasmodium falciparum-derived, 20 residue long, peptide 35409 had antibacterial and haemolytic activity, making it an AMP having reduced selectivity, and suggesting that it should be studied more extensively for obtaining new AMPs having activity solely targeting the bacterial membrane. Peptide 35409 was thus used as template for producing short synthetic peptides (<20 residues long) and evaluating their biological activity and relevant physicochemical characteristics for therapeutic use. Four of the sixteen short peptides evaluated here had activity against E. coli without any associated haemolytic effects. The 35409-1 derivative (17 residues long) had the best therapeutic characteristics as it had high selectivity for bacterial cells, stability in the presence of human sera, activity against E. coli multiresistant clinical isolates and was shorter than the original sequence. It had a powerful membranolytic effect and low potential for inducing resistance in bacteria. This peptide's characteristics highlighted its potential as an alternative for combating infection caused by E. coli multiresistant bacteria and/or for designing new AMPs.

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AIM: To evaluate the potential drug-drug interactions (PDDI) between drugs used by older adults, any associated factors and recommended clinical management. METHODS: A cross-sectional, population-based study was carried out through a home survey of 934 older adults (from December 2009 to April 2010). A questionnaire was applied, and the participants were asked to show all the drugs used and their respective prescriptions, thus providing data to identify polypharmacy, self-medication and PDDI. PDDI, their consequences, severity and clinical management were identified using Micromedex. RESULTS: Overall, 2846 drugs and 665 PDDI were identified, 71.0% of which were moderate and 22.4% serious. The prevalence of PDDI was 36.9%. Drugs with a narrow therapeutic index were involved in 17.0% of the PDDI. The variables female sex (PR = 1.11, 95% CI 1.02-1.20), age ≥80 years (PR = 1.15, 95% CI 1.03-1.28), no polypharmacy (PR = 0.72, 95% CI 0.67-0.78) and no hospitalization in the past year (PR = 0.90, 95% CI 0.82-0.97) remained associated with the presence of three or more PDDI in the final multivariate analysis model. CONCLUSIONS: Most PDDI were related to routinely used drugs (enalapril, hydrochlorothiazide, calcium, captopril, levothyroxine and simvastatin), and more than one-third of the older adults were exposed to PDDI with the possible risk of serious health consequences. Drugs with a narrow therapeutic index were involved in several PDDI, with increased risk of toxicity. The clinical management procedures most recommended are dose adjustment and dosing changes, control of the drugs' serum levels, and monitoring of the clinical conditions. Geriatr Gerontol Int 2017; 17: 2336-2346.

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The antimicrobial potential of two new non-disulfide bound peptides, named VpAmp1.0 (LPFFLLSLIPSAISAIKKI, amidated) and VpAmp2.0 (FWGFLGKLAMKAVPSLIGGNKSSSK) is here reported. These are 19- and 25-aminoacid-long peptides with +2 and +4 net charges, respectively. Their sequences correspond to the predicted mature regions from longer precursors, putatively encoded by cDNAs derived from the venom glands of the Mexican scorpion Vaejovis punctatus. Both peptides were chemically synthesized and assayed against a variety of microorganisms, including pathogenic strains from clinical isolates and strains resistant to conventional antibiotics. Two shorter variants, named VpAmp1.1 (FFLLSLIPSAISAIKKI, amidated) and VpAmp2.1 (FWGFLGKLAMKAVPSLIGGNKK), were also synthesized and tested. The antimicrobial assays revealed that the four synthetic peptides effectively inhibit the growth of both Gram-positive (Staphylococcus aureus and Streptococcus agalactiaea) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria, with MICs in the range of 2.5-24.0 µM; yeasts (Candida albicans and Candida glabrata) with MICs of 3.1-50.0 µM; and two clinically isolated strains of Mycobacterium tuberculosis-including a multi-drug resistant one- with MICs in the range of 4.8-30.5 µM. A comparison between the activities of the original peptides and their derivatives gives insight into the structural/functional role of their distinctive residues.

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Tem se tornado prática comum em nosso país a troca de medicamentos prescritos por outros similares, por produtos genéricos e até mesmo por produtos manipulados, muitas vezes ignorando-se preceitos básicos de bioequivalência, permutabilidade, estabilidade e características específicas do composto farmacêutico. No caso de drogas de índice terapêutico estreito, como a levotiroxina, esses problemas se agravam colocando em sério risco a eficácia do tratamento e a saúde do paciente. Revemos a legislação pertinente ressaltando as características da levotiroxina e os efeitos adversos que limitam a permutabilidade do composto.

The exchange of a prescribed drug by other similar, by generic products and even by custom products has become common practice in our country, often ignoring basic tenets of bioequivalence, interchangeability, stability and characteristics of the pharmaceutical compounds. In the case of drugs of narrow therapeutic index, such as levothyroxine, these problems are intensified, putting the effectiveness of treatment and patient health at serious risk. We review the pertinent legislation, emphasizing the characteristics of levothyroxine and adverse effects that limit the interchangeability of the compound.

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