Predictive Modelling in pharmacokinetics: from in-silico simulations to personalized medicine.

INTRODUCTION: Pharmacokinetic parameters assessment is a critical aspect of drug discovery and development, yet challenges persist due to limited training data. Despite advancements in machine learning and in-silico predictions, scarcity of data hampers accurate prediction of drug candidates' pharmacokinetic properties. AREAS COVERED: The study highlights current developments in human pharmacokinetic prediction, talks about attempts to apply synthetic approaches for molecular design, and searches several databases, including Scopus, PubMed, Web of Science, and Google Scholar. The article stresses importance of rigorous analysis of machine learning model performance in assessing progress and explores molecular modeling (MM) techniques, descriptors, and mathematical approaches. Transitioning to clinical drug development, article highlights AI (Artificial Intelligence) based computer models optimizing trial design, patient selection, dosing strategies, and biomarker identification. In-silico models, including molecular interactomes and virtual patients, predict drug performance across diverse profiles, underlining the need to align model results with clinical studies for reliability. Specialized training for human specialists in navigating predictive models is deemed critical. Pharmacogenomics, integral to personalized medicine, utilizes predictive modeling to anticipate patient responses, contributing to more efficient healthcare system. Challenges in realizing potential of predictive modeling, including ethical considerations and data privacy concerns, are acknowledged. EXPERT OPINION: AI models are crucial in drug development, optimizing trials, patient selection, dosing, and biomarker identification and hold promise for streamlining clinical investigations.

[Adequate medication doses for pregnant women and their unborn children]. / Gepaste medicatiedoseringen voor zwangere en foetus.

Most women use medication during pregnancy. The disposition of drugs may be altered due to changes in pregnant women's bodies. This may call for pregnancy-adjusted doses for certain medications. However, in the face of scarce evidence, such doses are generally lacking, potentially contributing to an increased risk of treatment failure or toxicity in pregnant women and their unborn children. By integrating physiological and/or population data, pharmacokinetic models can be used to determine appropriate medication dosages among pregnant women and their unborn children, as well as other patient groups for which evidence-based doses may be lacking such as children, elderly or obese patients. In order to translate model predictions into clinically usable doses, a number of conditions must be met, including careful model validation, an assessment of evidence from pharmacokinetic modelling alongside available clinical studies by multidisciplinary experts, as well as transparent communication towards end-users on the considerations for determining appropriate medication doses.

Hospital Prices for Physician-Administered Drugs for Patients with Private Insurance.

BACKGROUND: Hospitals can leverage their position between the ultimate buyers and sellers of drugs to retain a substantial share of insurer pharmaceutical expenditures. METHODS: In this study, we used 2020-2021 national Blue Cross Blue Shield claims data regarding patients in the United States who had drug-infusion visits for oncologic conditions, inflammatory conditions, or blood-cell deficiency disorders. Markups of the reimbursement prices were measured in terms of amounts paid by Blue Cross Blue Shield plans to hospitals and physician practices relative to the amounts paid by these providers to drug manufacturers. Acquisition-price reductions in hospital payments to drug manufacturers were measured in terms of discounts under the federal 340B Drug Pricing Program. We estimated the percentage of Blue Cross Blue Shield drug spending that was received by drug manufacturers and the percentage retained by provider organizations. RESULTS: The study included 404,443 patients in the United States who had 4,727,189 drug-infusion visits. The median price markup (defined as the ratio of the reimbursement price to the acquisition price) for hospitals eligible for 340B discounts was 3.08 (interquartile range, 1.87 to 6.38). After adjustment for drug, patient, and geographic factors, price markups at hospitals eligible for 340B discounts were 6.59 times (95% confidence interval [CI], 6.02 to 7.16) as high as those in independent physician practices, and price markups at noneligible hospitals were 4.34 times (95% CI, 3.77 to 4.90) as high as those in physician practices. Hospitals eligible for 340B discounts retained 64.3% of insurer drug expenditures, whereas hospitals not eligible for 340B discounts retained 44.8% and independent physician practices retained 19.1%. CONCLUSIONS: This study showed that hospitals imposed large price markups and retained a substantial share of total insurer spending on physician-administered drugs for patients with private insurance. The effects were especially large for hospitals eligible for discounts under the federal 340B Drug Pricing Program on acquisition costs paid to manufacturers. (Funded by Arnold Ventures and the National Institute for Health Care Management.).

Deglufarm: aplicación móvil con recomendaciones para la administración segura de medicamentos en pacientes con disfagia o problemas de deglución / Deglufarm: Mobile application with recommendations for safety drug administration in patients with dysphagia or deglution disorders

Objetivo desarrollar una app para su uso en la práctica asistencial, con información actualizada y veraz sobre la manipulación de medicamentos en los pacientes con disfagia y otros problemas de deglución, así como su compatibilidad con alimentos y espesantes. Método el desarrollo de la app Deglufarm® se hizo con un proyecto de los grupos de trabajo CRONOS, Nutrición y Tecno de la Sociedad Española de Farmacia Hospitalaria. Se constituyó un grupo de farmacéuticos especialistas, de diferentes ámbitos de la atención al paciente con disfagia. La creación de Deglufarm® constó de varias etapas: selección de principios activos, revisión bibliográfica, elaboración de contenidos, diseño (se contactó con una empresa experta en diseño de apps), testing, lanzamiento, actualización de contenidos y seguimiento. Resultados Deglufarm® está disponible para Android e IOS gratuitamente desde julio de 2022. Ha sido testada entre los miembros del grupo investigador y colaboradores. En la actualidad se han revisado y registrado en Deglufarm® 540 monografías de principios activos. La primera versión está dirigida a profesionales sanitarios. Conclusiones Deglufarm® es una herramienta fácil y sencilla de consultar, con la evidencia más actual sobre la manipulación de los medicamentos que contiene. (AU)

Objective Develop an App to use in healthcare practice, with updated and accurate information on the handling of medications in patients with dysphagia or deglution disorders, as well as their compatibility with food and thickeners. Methods The development of the Deglufarm® App was based on the CRONOS, Nutrition and Techno working groups of the Sociedad Española de Farmacia Hospitalaria. A group of specialist pharmacists was created from different care areas for patients with dysphagia. The creation of Deglufarm® consisted of several stages: Selection of active drugs, literature review, content development, design (an expert company in App design was contacted), testing, launch, content update and follow-up. Results Deglufarm® is available for Android and IOS free of charge from July 2022. It has been tested among the members of the research group and collaborators, currently, 540 monographs of active drugs have been reviewed and registered in Deglufarm. The first version is aimed at healthcare professionals. Conclusions Deglufarm® is an easy tool to consult, with the most current evidence on handling the medicines it contains. (AU)

Consumo de fármacos anticolinérgicos en ancianos de entre sesenta y cinco y ochenta años consultantes de un servicio de Urgencias / Consumption of anticholinergic drugs in elderly people between 65 and 80 years of age consultants in an emergency service

Fundamentos: Con la edad aumenta el consumo de fármacos, entre ellos los anticolinérgicos. La carga anticolinérgica es predictora decaídas, deterioro cognitivo y mortalidad, y su cálculo resulta de utilidad. El objetivo de este trabajo fue conocer la prevalencia del consumode anticolinérgicos y la carga anticolinérgica según diferentes escalas, así como las variables que influyen en la prevalencia y en la carga.Métodos: Se llevó a cabo un estudio analítico y transversal. La muestra fue obtenida por muestreo por conglomerados (nivel de confianza del95%, precisión del 3%) de pacientes de sesenta y cinco-ochenta años consultantes de un servicio de Urgencias. Las variables dependientes fueronlos fármacos anticolinérgicos consumidos y la carga anticolinérgica calculada mediante diez escalas:Anticholinergic Activity Scale (AAS);Anticholinergic Burden Classification (ABC);Anticholinergic Cognitive Burden Scale (ACB);Anticholinergic Drug Scale (ADS);Anticholinergic Load Scale (ALS);Anticholinergic Risk Scale (ARS);Clinician-Rated Anticholinergic Scale (CrAS);Chew’s scale (Chew);Drug Burden Index (DBI); yDuran’s scale (Duran).Las variables independientes fueron demográficas, patologías crónicas y fármacos consumidos. Como análisis estadístico se realizó la descripciónde variables y el estudio analítico a través de un análisis multivariante (análisis de regresión) para evitar factores de confusión.Resultados: Participaron 456 pacientes, y el consumo medio fue de siete fármacos (IC 95% 6,81-7,59). El 75,2% (IC 95%; 71%-79%) tomaban al-gún anticolinérgico; la media de anticolinérgicos fue de 1,91 (IC 95%; 1,75%-2,08%). Utilizando las escalas simultáneamente, el 58,1%, (IC 95%; 53,4%-62,5%) tenían alta carga anticolinérgica. Las escalas que más riesgo anticolinérgico detectaron fueron DBI (50,7%) y ALS (45,8%) y las que másalta carga, ABC (19,1%) y DBI (17,3%)...

Background: With age increases the consumption of drugs, including anticholinergics. The anticholinergic load is a predictor of falls, cognitiveimpairment and mortality, and its calculation is useful. The objectives of this paper was to know the prevalence of anticholinergic consumption andanticholinergic load according to different scales, and the variables that influence the prevalence and load.Methods: An analytical and cross-sectional study was carried out. The sample was obtained by cluster sampling (95% confidence level, 3%precision) of patients aged sixty-five/eighty consulting an emergency department. Dependent variables were Anticholinergic drugs consumed andanticholinergic load calculated using 10 scales:Anticholinergic Activity Scale (AAS);Anticholinergic Burden Classification (ABC);AnticholinergicCognitive Burden Scale (ACB);Anticholinergic Drug Scale (ADS);Anticholinergic Load Scale (ALS);Anticholinergic Risk Scale (ARS);Clinician-RatedAnticholinergic Scale (CrAS);Chew’s scale (Chew);Drug Burden Index (DBI); andDuran’s scale (Duran). Independent variables were demographics,chronic pathologies and drugs consumed. Statistical analysis: description of variables and analytical study through a multivariate analysis (regres-sion analysis) to avoid confounding factors.Results: 456 patients participated, mean consumption was seven drugs (95% CI 6.81-7.59). 75.2% (95% CI 71%-79%) were taking someanticholinergic; mean of anticholinergics of 1.91 (95% CI 1.75%-2.08%). Using the scales simultaneously, 58.1% (95% CI 53.4%-62.5%) had a highanticholinergic load. The scales that detected the highest anticholinergic risk were DBI (50.7%) and ALS (45.8%), and those with the highest, ABCload (19.1%) and DBI (17.3%)...(AU)

[Does recommending the dosing frequency in the electronic prescription improve its adequacy? Before and after study]. / ¿Recomendar la frecuencia de administración de medicamentos en la prescripción electrónica mejora su adecuación? Estudio antes-después.

OBJECTIVE: To assess whether reporting the dosing frequency into the prescription module of the Institut Català de la Salut (ICS) primary care electronic clinical workstation improves the dosing frequency's adequacy of the prescriptions. DESIGN: Before and after study with non-equivalent control of prescriptions without any change in the dosing frequency. The study periods includes from September 1st, 2019 to February 29th, 2020. LOCATION: Primary care setting. PARTICIPANTS: Prescriptions issued by ICS General Practitioner, during the study period of those medicines which indications have a single appropriate dosing frequency or mostly appropriate, are included. INTERVENTION: Recommendation of the appropriate dosing frequency in the prescription module. MAIN MEASUREMENTS: Adequacy defined as the coincidence between the prescribed dosing frequency and the appropriate dosing frequency. RESULTS: After the intervention there was a 22.75% increase in prescriptions with adequate dosing frequency. The largest increase occurred in the medicines for the genitourinary system and sex hormones. In absolute terms, the group of anti infective for systemic use is the one that obtained more prescriptions with an adequate dosing frequency between the two periods. CONCLUSIONS: The intervention increased the dosing frequency's adequacy leading to improvements in the safety and effectiveness of the treatments. It is evident that the design and implementation of improvements in electronic prescription systems contributes to increasing the quality of the prescription.

Uso de misoprostol em obstetrícia / Misoprostol use in obstetrics

PONTOS-CHAVE O misoprostol é um análogo da prostaglandina E1 (PGE1) que consta na Lista de Medicamentos Essenciais da Organização Mundial da Saúde (OMS) desde 2005 O Brasil possui uma das regulações mais restritivas do mundo relacionadas ao uso do misoprostol, estabelecendo que o misoprostol tem uso hospitalar exclusivo, com controle especial, e venda, compra e propaganda proibidas por lei Atualmente, o misoprostol é a droga de referência para tratamento medicamentoso nos casos de aborto induzido, tanto no primeiro trimestre gestacional quanto em idades gestacionais mais avançadas O misoprostol é uma medicação efetiva para o preparo cervical e indução do parto O misoprostol é um medicamento essencial para o manejo da hemorragia pós-parto

Parameters to consider for successful medication use in older adults - An AGePOP review.

Older adults are the main users of medicine and due to common multimorbidity they are often confronted with a complex medication management. This review article provides a brief overview on aspects of medication management, i.e., maintaining a stock of the required medicine, understanding and following the instructions for use, coping with the primary and secondary packaging, as well as the preparation prior to use. However, the main focus is on the drug intake itself and the review provides an overview of the current understanding of real life dosing conditions in older adults and geriatric patients. It elaborates the acceptability of dosage forms, in particular solid oral dosage forms as they represent the majority of dosage forms taken by this patient population. An improved understanding of the needs of older adults and geriatric patients, their acceptability of various dosage forms, and the circumstances under which they manage their medications will allow for the design of more patient-centric drug products.

Hard to Swallow: A Review of Interventions to Improve Swallowing Solid Medication.

Solid oral medications are preferred over intravenous or liquid formulations; however, difficulty swallowing solid medication remains a common barrier to adherence. Previous reviews have demonstrated limited evidence on interventions to improve solid medication swallowing abilities. PubMed, Medline (OVID), CINAHL, Scopus, and Web of Science databases were searched for interventions to improve the pediatric population's ability to swallow solid medications. We included studies in English published after the latest review, from January 2014 through April 2022, with pediatric patients not having comorbid conditions affecting swallowing ability. The authors independently reviewed each study's sampling strategy, study design, and the strength of outcome measures and assigned a numerical rating representing "poor," "fair," or "good" for each category. Individual ratings were averaged per category and a final quality rating score given based on the average of all 3 categories. Our search identified 581 unique records; 10 were included in the final review. Interventions varied and included behavioral therapies and novel products or medication formulations. Three received a "good" quality rating, 5 were "fair," and 2 were "poor." All studies showed their intervention(s) to be successful in improving a child's ability to swallow solid oral medications. Despite the availability of several different effective interventions, pediatric providers do not routinely address patients' difficulty with swallowing solid oral medications. Patients would benefit from implementation of a universal screening process followed by a guideline for appropriate patient-centered interventions; the opportunity exists to use this process as a national quality benchmark reflecting institutional commitment to high-value care.

Development of Best Evidence Dosing Recommendations for Term and Preterm Neonates (NeoDose Project).

Many drugs are used off-label in neonates which leads to large variation in prescribed drugs and dosages in neonatal intensive care units (NICUs). The NeoDose project aimed to develop best evidence dosing recommendations (DRs) for term and preterm neonates using a three-step approach: 1) drug selection, 2) establishing consensus-based DRs, and 3) establishing best evidence DRs. METHODS: The selection of drugs was based on frequency of prescribing, availability of a neonatal DR in the Dutch Pediatric Formulary, and the labeling status. Clinical need, pharmacological diversity, and Working Group Neonatal Pharmacology (WGNP) preferences were also taken into account, using a consensus-based approach. For the second step, we requested local dosing protocols from all ten Dutch NICUs and established consensus-based DRs within the WGNP, consisting of neonatologists, clinical pharmacologists, hospital pharmacists, and researchers. In the third step, the consensus-based DRs were compared with the available literature, using standardized PubMed searches. RESULTS: Fourteen drugs were selected for which the local dosing protocols were collected. These protocols differed mostly in total daily dose, dosing frequency, and/or route of administration. Strikingly, almost none of the dosing protocols of these 14 drugs distinguished between preterm and term neonates. The working group established consensus-based DRs, which after literature review needed modification in 56%, mainly in terms of a dose increase. Finally, we established 37 best evidence DRs, 22 for preterm and 15 for term neonates, representing 19 indications. CONCLUSION: This project showed the successful three-step approach for the development of DRs for term and preterm neonates.

Mapping the methodological diversity of published drug discontinuation studies-a scoping review of study topics, objectives, and designs.

BACKGROUND: Trials evaluating drug discontinuation (drug discontinuation trials, DDTs) show a broad methodological spectrum. There are several specific methodological aspects in drug discontinuation trials (e.g., determination of research question; configuration of intervention; definition of outcomes). To verify this specifies, we did a scoping review about the study designs of drug discontinuation trials. METHODS: A systematic literature search in Medline (PubMed), The Cochrane Library, EMBASE, CINAHL, Web of Science, and PsycINFO was performed. In a two-step selection process, we identified DDTs, which evaluate the discontinuation of one or more long-term medication as the investigated intervention, by two independent reviewers. Besides bibliographic data, we extracted several parameters to describe the used study design of the included DDTs: motivation for DDT, initially treatment aim of the discontinued medication, study design, methods of discontinuation, follow-up times, number of study participants, and outcome parameter. RESULTS: Out of 12,132 records, we included 581 DDTs. The most common motivation for doing a DDT were expected side effects (48.8%), the motivation of proving the efficacy of medication (21.6%), or doubts on the expected benefit of the used medication (13.8%). The majority of the discontinued medication was initially prescribed to improve the prognosis of a chronic disease (60.4%) or to relieve symptoms (31%). The study designs of the trials showed a broad methodological spectrum. The minority of the drug discontinuation trials were randomized controlled trials (34%). CONCLUSION: The results of this scoping review illustrates the need for an evidence-based methodological standard for planning and conducting drug discontinuation trials.

O efeito do tratamento com rapamicina em órgãos linfoides de camundongos propensos à senescência acelerada / The effect of rapamycin treatment on lymphoid organs of senescence accelerated mice prone

Envelhecer compreende um fenômeno complexo, natural e irreversível, que submete o organismo a inúmeras alterações nos processos biológicos, fisiológicos, ambientais, psicológicos, comportamentais e sociais. Esse processo é caracterizado por um declínio gradual dos mecanismos homeostáticos do organismo, intimamente relacionados com o estado senescente. A senescência, quando diz respeito ao sistema imunológico, é denominada de imunossenescência, que pode ser definida como uma parada estável do ciclo celular associada a mudanças, com uma resposta que limita a proliferação de células envelhecidas ou danificadas. A autofagia está diretamente relacionada com a manutenção do fenótipo senescente, em que a atividade autofágica exerce um papel essencial e ativo na influência da biossíntese de proteínas e organelas. Essa via é regulada naturalmente pela proteína mTOR e quimicamente pelo fármaco rapamicina. Assim, pretendemos investigar: (1) as alterações no perfil corporal e hematimêtrico dos animais ao longo do tratamento com rapamicina; (2) avaliar o perfil de citocinas; (3) observar as modificações histológicas em órgãos linfoides primários e secundário; (4) analisar as populações de células linfoides e mieloides; e (5) avaliar a capacidade proliferativa de linfócitos in vitro. Camundongos SAMP-8 e SAMR-1 foram tratados com rapamicina durante dois meses. A mensuração da massa corporal e análises hematológicas foram realizadas antes e durante o tratamento. Amostras de soro, medula óssea, timo e baço foram analisados em ensaios de ELISA, histologia, população e subpopulações de células. Alterações na massa corporal, parâmetros hematológicos e celularidade de células foram nítidas entre os dois modelos utilizados. Diferenças também foram percebidas na detecção de citocinas IL-1ß. IL-6 e TNF-α, com resultados significantes nas amostras de baço, timo e medula óssea. As citocinas IL-7 e IL-15 apresentaram diferenças de secreção entre os grupos, sendo a primeira maior detectada em camundongos com senescência acelerada tratados com rapamicina. Em nossa análise histológica observamos que os camundongos SAM-P8 apresentaram involução tímica. E nas subpopulações de linfócitos T do baço, células TCD4+ e TCD8+ estavam, respectivamente, em maior e menor quantidade nos camundongos SAM-P8 tratados com rapamicina. Dessa forma, o camundongo da linhagem SAM-P8 é um excelente modelo para se estudar as alterações da senescência, em que o mesmo apresenta características fisiológicas distintas dos camundongos utilizados como controle (SAM-R1). Além disso, verificamos que a dose de rapamicina empregada não desencadeou alterações que pudessem comprometer a resposta imunológica desses camundongos, bem como na possibilidade de atuar na resposta contra os efeitos complexos do envelhecimento

Aging comprises a complex, natural, and irreversible phenomenon, which subjects the organism to countless alterations in biological, physiological, environmental, psychological, behavioral, and social processes. This process is characterized by a gradual decline in the organism's homeostatic mechanisms, closely related to senescence effects. Senescence, when it concerns the immune system, is called immunosenescence, which can be defined as a stable cell cycle arrest associated with changes and is a response that limits the proliferation of aged or damaged cells. Autophagy is a genetically regulated, conserved cellular process and a metabolic pathway essential for maintaining cellular homeostasis, which plays a constitutive and active role in controlling the biosynthesis of proteins and organelles. This pathway is regulated naturally by mTOR or chemically by the drug rapamycin, having a direct relationship with cellular homeostasis and maintenance of the senescent phenotype. Thus, we intend to investigate: (1) the changes in the body and hematimetic profile of the animals throughout the rapamycin treatment; (2) evaluate the cytokine profile; (3) observe histological changes in primary and secondary lymphoid organs; (4) analyze lymphoid and myeloid cell populations; and (5) evaluate the proliferative capacity of lymphocytes in vitro. SAMP-8 and SAMR-1 mice were treated with rapamycin for two months. Body mass measurement and hematological analyses were performed before and during treatment. Serum, bone marrow, thymus and spleen samples were analyzed in ELISA assays, histology, cell population and subpopulations. Changes in body mass, hematological parameters, and cellularity were clear between the two models used. Differences were also noticed in the detection of cytokines IL-1ß. IL-6 and TNF-α, with significant results in the spleen, thymus and bone marrow samples. The cytokines IL-7 and IL-15 showed differences in secretion between groups, the former being higher detected in mice with accelerated senescence treated with rapamycin. In our histological analysis we observed that SAM-P8 mice showed thymic involution. And in the spleen T-lymphocyte subpopulations, TCD4+ and TCD8+ cells were, respectively, in higher and lower quantities in SAM-P8 mice treated with rapamycin. Thus, the SAM-P8 mouse is an excellent model to study the changes of senescence, since it presents physiological characteristics different from the control mice (SAM-R1). Furthermore, we verified that the dose of rapamycin used did not trigger changes that could compromise the immune response of these mice, as well as the possibility of acting in the modulatory response against the complex effects of aging

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Antiproliferative effects of 13α/ß-steroids on triple-negative MDA-MB-231 breast cancer cells: unraveling intracellular signaling without ERα

Abstract This study aimed to investigate the activities of novel 20(R)-3,20-dihydroxy-19-norpregn-1,3,5(10)-trienes (kuz7 and kuz8b) of natural 13ß- and epimeric 13α-series against triple-negative MDA-MB-231 breast cancer cells. High antiproliferative activity of synthesized compounds kuz8b and kuz7 against MDA-MB-231 triple-negative cancer cells was revealed. The steroid kuz7 of natural 13ß-configuration was more active against MDA-MB-231 cells than the 13α-steroid kuz8b. Cell cycle analysis revealed common patterns for the action of both tested compounds. The number of cells in the subG1 phase increased in a dose-dependent manner, indicating induction of apoptosis, which was also verified by PARP cleavage. In contrast, the number of cells in the G0/G1 phase decreases with increasing compound concentration. Steroid kuz7 at micromolar concentrations reduced the expression of GLUT1, a glucose transporter. High efficacy of the combination of kuz7 with biguanide metformin was shown, and synergistic effects on MDA-MB-231 cell growth and expression of the anti-apoptotic protein Bcl-2 were revealed. According to the obtained results, including the high activity of kuz7 against triple-negative cancer cells, the detected induction of apoptosis, and the decrease in GLUT1 expression, 13ß-steroid kuz7 is of interest for further preclinical studies both alone and in combination with the metabolic drug metformin

Microemulsions Improve Topical Protoporphyrin IX (PpIX) Delivery for Photodynamic Therapy of Skin Cancer

Abstract We report here microemulsions (MEs) for topical delivery of protoporphyrin IX (PpIX) for Photodynamic Therapy (PDT) of skin cancers. Selected MEs consisting of Oil/Water (O/W) bicontinuous (BC) and Water/Oil (W/O) preparations were characterized as to pH, nanometric size, zeta potential, drug content, and viscosity. Sustained in vitro PpIX release was achieved from MEs 2A (O/W), 10B (BC) and 16B (W/O) through an artificial membrane for up to 24 h, characterizing MEs as drug delivery systems. None of these MEs showed permeation through the skin, demonstrating the required topical effect. After 4 h, in vitro retention of PpIX in the stratum corneum (SC) was higher from both ME 10B and control (PpIX at 60 µg/mL in PEG 300). However, in the Epidermis + Dermis ([Ep + D]), retention from ME 10B and ME 16B was ~40 times higher compared to control. Confocal Laser Scanning Microscopy (CLSM) showed higher fluorescence intensity in the SC for both control and ME 10B, whereas ME 10B fluorescence was higher in [Ep+D]. The results indicate that ME 10B is suitable for PpIX encapsulation, showing good characteristics and a localized effect for a potential delivery system for PDT-associated treatments of skin cancers.

Applicability of an HPLC method for analysis of alcoholic and glycolic Brazilian green-propolis extracts

Abstract Brazilian green propolis has been widely used in food and pharmaceutical products due to its valuable source of phenolic compounds and versatile biological activities. The development and validation of analytical methods are extremely useful for the characterization and quality control of products containing propolis. Therefore, the aim of this study was to optimize, validate and investigate the applicability of a reversed-phase HPLC method for analysis of different types of Brazilian green propolis extracts (glycolic and ethanolic). The method showed to be selective for the propolis phenolic markers. The analysis of variance and residues demonstrated that the method had significant linear regression, without lack of fit. It was also a precise, accurate and robust method, which was of utmost importance to analyze both glycolic and ethanolic extracts and at different concentrations. Moreover, as these products can display most complex matrices to analyze, a valid HPLC method can also prove to be specific and versatile.

Organic osmolyte betaine mitigates the deleterious effects of Diclofenac in vivo in wistar albino rats

Abstract Diclofenac sodium (DF) is a non-steroidal anti-inflammatory drug (NSAID) that possesses antipyretic, analgesic, antinociceptive and anti-inflammatory activities. Like other NSAIDs, DF is known to be associated with renal, cardiovascular, and gastrointestinal complications. The present study was carried out to evaluate the adverse effects of DF in vivo in wistar albino rats and to assess if oral administration of the organic osmolyte betaine mitigates the adverse effect of DF. Eighteen male Wistar rats were divided into three groups, one group of animals was fed orally with 20 mg/kg of DF once/day, and the other group received a combination of 20 mg/kg of DF and 30 mg/kg of betaine, once/day. Apart from the hematological and biochemical parameters, histopathological changes in the liver, lungs, brain, heart and kidney were also investigated. Histopathological alterations that were found in the liver, kidney, and lungs of DF-treated animals were found to be minimal or absent in DF + betaine-treated animals, as compared to untreated control. The results showed that betaine mitigates the adverse effects associated with DF treatment.