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Microphysiological systems (MPS) are designed to recapitulate aspects of tissue/organ physiology in vivo, thereby providing potential value in safety and efficacy assessments of FDA-regulated products and regulatory decision-making. While there have been significant advances in the development, use, and proposals of qualification criteria for human organ MPS, there remains a gap in the development using animal tissues. Animal MPS may be of value in many areas including the study of zoonotic diseases, assessment of the safety and efficacy of animal therapeutics, and possibly reduction of the use of animals in regulatory submissions for animal therapeutics. In addition, the development of MPS from various animal species enables comparison to animal in vivo data. This comparison, while not always critical for all contexts of use, could help gain confidence in the use and application of human MPS data for regulatory decision-making and for the potential identification of species-specific effects. The use of animal MPS is consistent with the replacement, reduction, and refinement (3Rs) principles of animal use by identifying toxic compounds before conducting in vivo studies and identifying the appropriate species for testing.

Microphysiological systems (MPS) mimic aspects of organs in humans or animals. These systems may provide information useful for FDA-regulated products. While there have been significant advances in the development of MPS made from human cells, there remains a gap in the development of MPS using animal cells. FDA believes animal MPS may be of value in many areas including the study of diseases transmitted from animals to humans, assessment of the safety and efficacy of animal drugs, and reduction of the use of animals in regulatory submissions. The development of animal MPS enables comparison to data from studies conducted in animals. This comparison provides confidence in the use of human MPS data for regulatory decision-making. The use of animal MPS is consistent with the 3Rs principles of animal use by allowing identification of toxic compounds before conducting animal studies and by helping select the appropriate species for further testing.

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INTRODUCTION: Seizures are known potential side effects of nicotine toxicity and have been reported in electronic nicotine delivery systems (ENDS, e-cigarettes) users, with the majority involving youth or young adults. AREAS COVERED: Using chemoinformatic computational models, chemicals (including flavors) documented to be present in ENDS were compared to known neuroactive compounds to predict the blood-brain barrier (BBB) penetration potential, central nervous system (CNS) activity, and their structural similarities. The literature search used PubMed/Google Scholar, through September 2023, to identify individual chemicals in ENDS and neuroactive compounds.The results show that ENDS chemicals in this study contain >60% structural similarity to neuroactive compounds based on chemical fingerprint similarity analyses. The majority of ENDS chemicals we studied were predicted to cross the BBB, with approximately 60% confidence, and were also predicted to have CNS activity; those not predicted to passively diffuse through the BBB may be actively transported through the BBB to elicit CNS impacts, although it is currently unknown. EXPERT OPINION: In lieu of in vitro and in vivo testing, this study screens ENDS chemicals for potential CNS activity and predicts BBB penetration potential using computer-based models, allowing for prioritization for further study and potential early identification of CNS toxicity.

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INTRODUCTION: Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (i.e., vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as "GRAS". This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes. IMPLICATIONS: The rise in prevalence of e-cigarette use and emerging evidence of adverse effects, particularly on lung health, warrant assessing all aspects of e-cigarette toxicity. One development is manufacturers' stated or implied claims of the safety of using e-cigarette products containing ingredients determined to be "Generally Recognized As Safe" (GRAS) for use in food. Such claims, typically placed on e-cigarette product labels and used in marketing, are unfounded, as pointed out by the United States Food and Drug Administration (FDA)1 and the Flavor and Extract Manufacturers Association (FEMA)2. Assessment of inhalation health risks of all ingredients used in e-liquids, including those claimed to be GRAS, is warranted.

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Alzheimer's Disease (AD) is characterized by synapse and neuronal loss and the accumulation of neurofibrillary tangles and Amyloid ß plaques. Despite significant research efforts to understand the late stages of the disease, its etiology remains largely unknown. This is in part because of the imprecise AD models in current use. In addition, little attention has been paid to neural stem cells (NSC), which are the cells responsible for the development and maintenance of brain tissue during an individual's lifespan. Thus, an in vitro 3D human brain tissue model using induced pluripotent stem (iPS) cell-derived neural cells in human physiological conditions may be an excellent alternative to standard models to investigate AD pathology. Following the differentiation process mimicking development, iPS cells can be turned into NSCs and, ultimately, neural cells. During differentiation, the traditionally used xenogeneic products may alter the cells' physiology and prevent accurate disease pathology modeling. Hence, establishing a xenogeneic material-free cell culture and differentiation protocol is essential. This study investigated the differentiation of iPS cells to neural cells using a novel extracellular matrix derived from human platelet lysates (PL Matrix). We compared the stemness properties and differentiation efficacies of iPS cells in a PL matrix against those in a conventional 3D scaffold made of an oncogenic murine-matrix. Using well-defined conditions without xenogeneic material, we successfully expanded and differentiated iPS cells into NSCs via dual-SMAD inhibition, which regulates the BMP and TGF signaling cascades in a manner closer to human conditions. This in vitro, 3D, xenogeneic-free scaffold will enhance the quality of disease modeling for neurodegenerative disease research, and the knowledge produced could be used in developing more effective translational medicine.

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Flavor chemicals contribute to the appeal and toxicity of tobacco products, including electronic nicotine delivery systems (ENDS). The assortment of flavor chemicals available for use in tobacco products is extensive. In this study, a chemistry-driven computational approach was used to evaluate flavor chemicals based on intrinsic hazardous structures and reactivity of chemicals. A large library of 3012 unique flavor chemicals was compiled from publicly available information. Next, information was computed and collated based on their (1) physicochemical properties, (2) global harmonization system (GHS) health hazard classification, (3) structural alerts linked to the chemical's reactivity, instability, or toxicity, and (4) common substructure shared with FDA's harmful and potentially harmful constituents (HPHCs) flavor chemicals that are respiratory toxicants. Computational analysis of the constructed flavor library flagged 638 chemicals with GHS classified respiratory health hazards, 1079 chemicals with at least one structural alert, and 2297 chemicals with substructural similarity to FDA's established and proposed list of HPHCs. A subsequent analysis was performed on a subset of 173 chemicals in the flavor library that are respiratory health hazards, contain structural alerts as well as flavor HPHC substructures. Four general toxicophore structures with an increased potential for respiratory toxicity were then identified. In summary, computational methods are efficient tools for hazard identification and understanding structure-toxicity relationship. With appropriate context of use and interpretation, in silico methods may provide scientific evidence to support toxicological evaluations of chemicals in or emitted from tobacco products.

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Serious adverse health effects have been reported with the use of vaping products, including neurologic disorders and e-cigarette or vaping product use-associated lung injury (EVALI). Vitamin E acetate, likely added as a diluent to cannabis-containing products, was linked to EVALI. Literature searches were performed on vitamin E and vitamin E acetate-associated neurotoxicity. Blood brain barrier (BBB) penetration potential of vitamin E and vitamin E acetate were evaluated using cheminformatic techniques. Review of the literature showed that the neurotoxic potential of inhalation exposures to these compounds in humans is unknown. Physico-chemical properties demonstrate these compounds are lipophilic, and molecular weights indicate vitamin E and vitamin E acetate have the potential for BBB permeability. Computational models also predict both compounds may cross the BBB via passive diffusion. Based on literature search, no experimental nonclinical studies and clinical information on the neurotoxic potential of vitamin E via inhalation. Neurotoxic effects from pyrolysis by-product, phenyl acetate, structurally analogous to vitamin E acetate, suggests vitamin E acetate has potential for central nervous system (CNS) impairment. Cheminformatic model predictions provide a theoretical basis for potential CNS permeability of these inhaled dietary ingredients suggesting prioritization to evaluate for potential hazard to the CNS.

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Vitamin E acetate (VEA) has been strongly linked to outbreak of electronic cigarette (EC) or vaping product use-associated lung injury. How VEA leads to such an unexpected morbidity and mortality is currently unknown. To understand whether VEA impacts the disposition profile of inhaled particles, we created a biologically inspired robotic system that quantitatively analyzes submicron and microparticles generated from ECs in real-time while mimicking clinically relevant breathing and vaping topography exactly as happens in humans. We observed addition of even small quantities of VEA was sufficient to alter size distribution and significantly enhance total particles inhaled from ECs. Moreover, we demonstrated utility of our biomimetic robot for studying influence of nicotine and breathing profiles from obstructive and restrictive lung disorders. We anticipate our system will serve as a novel preclinical scientific research, decision-support tool when insight into toxicological impact of modifications in electronic nicotine delivery systems is desired.

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INTRODUCTION: Wounds are associated with ranges of simple to complex disruption or damage to anatomical structure and function. They are also associated with enormous economic and social costs, increasing yearly, resulting in a severe impact on the wellbeing of individuals and society. Technology that might accelerate wound healing is associated with many benefits to injured people. METHODS: BALBc mice underwent symmetrical excisional wounds through the panniculus carnosus. They were divided into a treatment group placed on an autonomous ceramic far-field infrared blanket (cIFRB) and a control group maintained under standard conditions. We also expanded and cultured adipose tissue-derived mesenchymal stem cells (MSCs) on cIFRB and compared them to standard conditions subjected to a scratch injury to compare survival, proliferation, and wound healing. RESULTS: The wound healing of the cIRFB treatment group was significantly faster than the control group of mice. The wound-healing effect of mesenchymal stem cells on cIRFB was also increased and associated with significant migration to the wound area. CONCLUSIONS: Wound healing is improved in a mouse model exposed to cFIRB. The ceramic blanket also promotes survival, proliferation, increased migration, and wound healing of MSCs without affecting their survival and proliferation. The utilization of cFIRB in cellular biology and medical applications may be promising in many situations currently explored in animal and human models. This technology needs no direct or battery power source and is entirely autonomous and noninvasive, making its application possible in any environment.

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There has been limited toxicity testing of cigarillos, including comparison to cigarettes. This study compared the smoke chemistry and the cytotoxic and genotoxic potential of 10 conventional cigarettes and 10 cigarillos based on the greatest market share. Whole smoke and total particulate matter (TPM) were generated using the Canadian Intense and International Organization for Standardization puffing protocols. Tobacco-specific nitrosamines, carbonyls, and polycyclic aromatic hydrocarbons were measured using gas chromatography-mass spectrometry. TPM smoke extracts were used for the in vitro assays. Cytotoxicity was assessed in human bronchial epithelial continuously cultured cell line cells using the neutral red uptake assay. Genotoxic potential was assessed using the micronucleus (human lung adenocarcinoma continuously cultured cell line cells), Ames, and thymidine kinase assays. TPM from all cigarillos tested was more cytotoxic than cigarettes. Micronucleus formation was significantly greater for cigarillos compared with cigarettes at the highest dose of TPM, with or without rat liver S9 fraction. In the Ames test +S9, both tobacco products exhibited significant dose-dependent increases in mutation frequency, indicating metabolic activation is required for genotoxicity. In the thymidine kinase assay +S9, cigarillos showed a significantly enhanced mutation frequency although both tobacco products were positive. The levels of all measured polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, and carbonyls (except acrolein) were significantly greater in cigarillos than cigarettes. The Canadian Intense puffing protocol demonstrated increased smoke constituent levels compared with International Organization for Standardization. Even though the gas vapor phase was not tested, the results of this study showed that under the tested conditions the investigated cigarillos showed greater toxicity than comparator cigarettes. This study found that there is significantly greater toxicity in the tested U.S. marketed cigarillos than cigarettes for tobacco constituent levels, cytotoxicity, and genotoxicity. These findings are important for understanding the human health toxicity from the use of cigarillos relative to cigarettes and for building upon knowledge regarding harm from cigarillos to inform risk mitigation strategies.

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Military personnel use dietary supplements (DS) for performance enhancement, bodybuilding, weight loss, and to maintain health. Adverse events, including cardiovascular (CV) effects, have been reported in military personnel taking supplements. Previous research determined that ingestion of multi-ingredient dietary supplements (MIDS), can lead to signals of safety concerns. Therefore, to assess the safety of MIDS, the Department of Defense via a contractor explored the development of a model-based risk assessment tool. We present a strategy and preliminary novel multi-criteria decision analysis (MCDA)-based tool for assessing the risk of adverse CV effects from MIDS. The tool integrates toxicology and other relevant data available on MIDS; likelihood of exposure, and biologic plausibility that could contribute to specific aspects of risk.Inputs for the model are values of four measures assigned based on the available evidence supplemented with the opinion of experts in toxicology, modeling, risk assessment etc. Measures were weighted based on the experts' assessment of measures' relative importance. Finally, all data for the four measures were integrated to provide a risk potential of 0 (low risk) to 100 (high risk) that defines the relative risk of a MIDS to cause adverse reactions.We conclude that the best available evidence must be supplemented with the opinion of experts in medicine, toxicology and pharmacology. Model-based approaches are useful to inform risk assessment in the absence of data. This MCDA model provides a foundation for refinement and validation of accuracy of the model predictions as new evidence becomes available.

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Neural stem cells (NSCs), capable of self-renew and differentiate into neural cells, hold promise for use in studies and treatments for neurological diseases. However, current approaches to obtain NSCs from a live brain are risky and invasive, since NSCs reside in the subventricular zone and the in the hippocampus dentate gyrus. Alternatively, mesenchymal stem cells (MSCs) could be a more available cell source due to their abundance in tissues and easier to access. However, MSCs are committed to producing mesenchymal tissue and are not capable of spontaneously differentiating into neural cells. Thus, the process of reprogramming of MSCs into neural cells to use in clinical and scientific settings has significantly impacted the advancement of regenerative medicine. Previously, our laboratory reported trans-differentiation of MSCs to neural cells through the induced pluripotent stem (iPS) cells state, which was produced by overexpression of the embryonic stem cell gene NANOG. In the current study, we demonstrate that treatment with exosomes derived from NSCs makes MSCs capable of expressing neural cell markers bypassing the generation of iPS cells. An epigenetic modifier, decitabine (5-aza-2'-deoxycytidine), enhanced the process. This novel Xeno and transgene-free trans-differentiation technology eliminates the issues associated with iPS cells, such as tumorigenesis. Thus, it may accelerate the development of neurodegenerative therapies and in vitro neurological disorder models for personalized medicine.

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Tobacco products contain thousands of chemicals, including addictive and toxic chemicals. We utilized in silico toxicology tools to predict in a validation test and in a separate screening test, the mutagenic potential of chemicals reported in tobacco products and tobacco smoke. Different publicly available (quantitative) structure-activity relationship (Q)SAR software platforms were used in this study. The models were validated against 900 chemicals relevant to tobacco for which experimental Ames mutagenicity data are available from public sources. The predictive performance of the individual and combined (Q)SAR models was evaluated using various performance metrics. All the (Q)SAR models represented >95% of the tobacco chemical space indicating a high potential for screening tobacco products. All the models performed well and predicted mutagens and nonmutagens with 75-95% accuracy, 66-94% sensitivity and 73-97% specificity. Subsequently, in a screening test, a combination of complementary SAR-based and QSAR-based models was used to predict the mutagenicity of 6820 chemicals catalogued in tobacco products and/or tobacco smoke. More than 1200 chemicals identified in tobacco products are predicted to have mutagenic potential, with 900 potential mutagens in tobacco smoke. This research demonstrates the validity of in silico (Q)SAR tools to make mutagenicity predictions for chemicals in tobacco products and/or tobacco smoke, and suggest they hold utility as screening tools for hazard identification to inform tobacco regulatory science.

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Electronic nicotine delivery systems (ENDS) are regulated tobacco products and often contain flavor compounds. Given the concern of increased use and the appeal of ENDS by young people, evaluating the potential of flavors to induce DNA damage is important for health hazard identification. In this study, alternative methods were used as prioritization tools to study the genotoxic mode of action (MoA) of 150 flavor compounds. In particular, clastogen-sensitive (γH2AX and p53) and aneugen-sensitive (p-H3 and polyploidy) biomarkers of DNA damage in human TK6 cells were aggregated through a supervised three-pronged ensemble machine learning prediction model to prioritize chemicals based on genotoxicity. In addition, in silico quantitative structure-activity relationship (QSAR) models were used to predict genotoxicity and carcinogenic potential. The in vitro assay identified 25 flavors as positive for genotoxicity: 15 clastogenic, eight aneugenic and two with a mixed MoA (clastogenic and aneugenic). Twenty-three of these 25 flavors predicted to induce DNA damage in vitro are documented in public literature to be in e-liquid or in the aerosols produced by ENDS products with youth-appealing flavors and names. QSAR models predicted 46 (31%) of 150 compounds having at least one positive call for mutagenicity, clastogenicity or rodent carcinogenicity, 49 (33%) compounds were predicted negative for all three endpoints, and remaining compounds had no prediction call. The parallel use of these predictive technologies to elucidate MoAs for potential genetic damage, hold utility as a screening strategy. This study is the first high-content and high-throughput genotoxicity screening study with an emphasis on flavors in ENDS products.

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The presence of flavors is one of the commonly cited reasons for use of e-cigarettes by youth; however, the potential harms from inhaling these chemicals and byproducts have not been extensively studied. One mechanism of interest is DNA adduct formation, which may lead to carcinogenesis. We identified two chemical classes of flavors found in tobacco products and byproducts, alkenylbenzenes and aldehydes, documented to form DNA adducts. Using in silico toxicology approaches, we identified structural analogs to these chemicals without DNA adduct information. We conducted a structural similarity analysis and also generated in silico model predictions of these chemicals for genotoxicity, mutagenicity, carcinogenicity, and skin sensitization. The empirical and in silico data were compared, and we identified strengths and limitations of these models. Good concordance (80-100%) was observed between DNA adduct formation and models predicting mammalian mutagenicity (mouse lymphoma sassy L5178Y) and skin sensitization for both chemical classes. On the other hand, different prediction profiles were observed for the two chemical classes for the modeled endpoints, unscheduled DNA synthesis and bacterial mutagenicity. These results are likely due to the different mode of action between the two chemical classes, as aldehydes are direct acting agents, while alkenylbenzenes require bioactivation to form electrophilic intermediates, which form DNA adducts. The results of this study suggest that an in silico prediction for the mouse lymphoma assay L5178Y, may serve as a surrogate endpoint to help predict DNA adduct formation for chemicals found in tobacco products such as flavors and byproducts.

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Despite the well-known adverse health effects associated with tobacco use, addiction to nicotine found in tobacco products causes difficulty in quitting among users. Nicotinic acetylcholine receptors (nAChRs) are the physiological targets of nicotine and facilitate addiction to tobacco products. The nAChR-α7 subtype plays an important role in addiction; therefore, predicting the binding activity of tobacco constituents to nAChR-α7 is an important component for assessing addictive potential of tobacco constituents. We developed an α7 binding activity prediction model based on a large training data set of 843 chemicals with human α7 binding activity data extracted from PubChem and ChEMBL. The model was tested using 1215 chemicals with rat α7 binding activity data from the same databases. Based on the competitive docking results, the docking scores were partitioned to the key residues that play important roles in the receptor-ligand binding. A decision forest was used to train the human α7 binding activity prediction model based on the partition of docking scores. Five-fold cross validations were conducted to estimate the performance of the decision forest models. The developed model was used to predict the potential human α7 binding activity for 5275 tobacco constituents. The human α7 binding activity data for 84 of the 5275 tobacco constituents were experimentally measured to confirm and empirically validate the prediction results. The prediction accuracy, sensitivity, and specificity were 64.3, 40.0, and 81.6%, respectively. The developed prediction model of human α7 may be a useful tool for high-throughput screening of potential addictive tobacco constituents.

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OBJECTIVE: Vitamin D receptor (VDR) activities have been noted for a number of B cell malignancies which showed varying sensitivities to vitamin D3 (1,25-dihydroxyvitamin D3, VD3, calcitriol) and its synthetic analogs. The objective of this study was to address the potential effects of VD3 and vitamin D3 analogs (VDAs) on the growth of Hodgkin's lymphoma (HL), a malignant pathology of B cell origin, in vitro. RESULTS: Immunofluorescence staining showed the expression of VDR by primary Hodgkin's (H) and Reed-Sternberg (RS)-HRS-tumor cells in HL histological sections. Western blot analyses revealed expression of VDR in the HL cell lines Hs445, HDLM2, KMH2, and L428. One-way analysis of variance (ANOVA) on data obtained from water-soluble tetrazolium 1 (WST-1) cell proliferation assay showed decreased cell growth in HDLM2 and L428, 72 h after treatment with 10 µM of either VD3 of VDAs. Western blot analyses showed that treatment of L428 cells with the VDAs (calcipotriol and EB1089) resulted in modest increases in nuclear accumulation of VDR (nuVDR) compared to either dimethyl sulfoxide (DMSO) or VD3 treatments. nuVDR for DMSO control and VD3 was comparable. These results suggest that VD3 or VDAs may affect growth of HL.

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This publication is the second in a series by the Expert Panel of the Flavor and Extract Manufacturers Association summarizing the conclusions of its third systematic re-evaluation of the safety of flavorings previously considered to be generally recognized as safe (GRAS) under conditions of intended use. Re-evaluation of GRAS status for flavorings is based on updated considerations of exposure, structural analogy, metabolism, pharmacokinetics and toxicology and includes a comprehensive review of the scientific information on the flavorings and structurally related substances. Of the 12 substituted thiophenes reviewed here, 11 were reaffirmed as GRAS based on their rapid absorption, metabolism and excretion in humans and animals; the low estimated dietary exposure from flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels; and the lack of significant genotoxic and mutagenic potential. For one of the substituted thiophenes, 3-acetyl-2,5-dimethylthiophene, it was concluded that more detailed exposure information, comparative metabolism studies and comprehensive toxicity data, including an in-depth evaluation of the mechanism of action for any adverse effects observed, are required for continuation of its FEMA GRAS™ status. In the absence of these data, the compound was removed from the FEMA GRAS list.

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CONTEXT: Dietary supplements are widely used by military personnel and civilians for promotion of health. OBJECTIVE: The objective of this evidence-based review was to examine whether supplementation with l-arginine, in combination with caffeine and/or creatine, is safe and whether it enhances athletic performance or improves recovery from exhaustion for military personnel. DATA SOURCES: Information from clinical trials and adverse event reports were collected from 17 databases and 5 adverse event report portals. STUDY SELECTION: Studies and reports were included if they evaluated the safety and the putative outcomes of enhanced performance or improved recovery from exhaustion associated with the intake of arginine alone or in combination with caffeine and/or creatine in healthy adults aged 19 to 50 years. DATA EXTRACTION: Information related to population, intervention, comparator, and outcomes was abstracted. Of the 2687 articles screened, 62 articles meeting the inclusion criteria were analyzed. Strength of evidence was assessed in terms of risk of bias, consistency, directness, and precision. RESULTS: Most studies had few participants and suggested risk of bias that could negatively affect the results. l-Arginine supplementation provided little enhancement of athletic performance or improvements in recovery. Short-term supplementation with arginine may result in adverse gastrointestinal and cardiovascular effects. No information about the effects of arginine on the performance of military personnel was available. CONCLUSIONS: The available information does not support the use of l-arginine, either alone or in combination with caffeine, creatine, or both, to enhance athletic performance or improve recovery from exhaustion. Given the information gaps, an evidence-based review to assess the safety or effectiveness of multi-ingredient dietary supplements was not feasible, and therefore the development of a computational model-based approach to predict the safety of multi-ingredient dietary supplements is recommended.

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Between the end of 2013 and the beginning of 2014 the most internationally influential hypertension guidelines were published. Although there are no major differences between them, there are discrepancies that can have an impact on treatment and prognosis for individuals with hypertension. This article analyzes the main controversial elements in the guides and presents the recommendations of the Sociedad Centroamericana y del Caribe de Hipertensión y Prevención Cardiovascular (Caribbean Society for Hypertension and Cardiovascular Prevention). The main differences are found a) in the categorization of prehypertension, b) in the use of global cardiovascular risk in the decision to begin antihypertensive treatment, c) in the validity of beta-blockers as first-line drugs in treating uncomplicated hypertension, and d) the increase in the therapeutic goal of maintaining values between < 140/90 and < 150/90 mmHg in patients over 60 years of age with no history of diabetes or chronic kidney disease. All the factors in favor of and against accepting each of these four controversial criteria are analyzed critically and the observations made by the Society are included. The conclusion is that there are pros and cons for all controversial elements in the hypertension guides. However, the weight of the evidence and clinical judgment favor subdividing prehypertension into stages I and II, seeking a therapeutic goal of maintaining systolic blood pressure below 140 mmHg in all the hypertensive patients under 80 years of age, retaining beta-blockers as first-line drugs in uncomplicated hypertension, and not delaying the start of drug treatment for hypertension stage I with low global cardiovascular risk. Finally, seven recommendations by the Society based on the analysis are included.

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Entre finales de 2013 y principios de 2014 se publicaron las guías de hipertensión arterial (HTA) más influyentes a nivel internacional. Aunque no existen grandes diferencias entre ellas, hay discrepancias que pueden repercutir en el tratamiento y el pronóstico de las personas con hipertensión. En este artículo se analizan los principales elementos polémicos de estas guías y se emiten las recomendaciones de la Sociedad Centroamericana y del Caribe de Hipertensión y Prevención Cardiovascular sobre el tema. Las principales divergencias se centran en la categoría de prehipertensión arterial, el uso del riesgo cardiovascular global en la decisión de iniciar el tratamiento antihipertensivo, la vigencia de los betabloqueantes como medicamentos de primera línea en el tratamiento de la HTA no complicada, y el aumento del objetivo terapéutico de mantener las cifras de tensión arterial entre < 140/90 mmHg y < 150/90 mmHg en pacientes mayores de 60 años de edad, sin antecedentes personales de diabetes ni de enfermedad renal crónica. Se analizan críticamente todos los factores a favor y en contra de aceptar cada uno de estos cuatro elementos controvertidos y se incluyen los comentarios que sobre ellos ha realizado la Sociedad. Se concluye que todos los elementos polémicos de las guías de la HTA tienen elementos a favor y en contra. Sin embargo, el peso de la evidencia o el juicio clínico están a favor de subdividir la prehipertensión (Grado I y II), buscar la meta terapéutica de mantener la tensión sistólica de < 140 mmHg en todos los hipertensos de menos de 80 años de edad, mantener a los betabloqueantes como medicamentos de primera línea en la HTA no complicada, y no demorar el inicio del tratamiento farmacológico de la HTA Grado I de bajo riesgo cardiovascular global. Finalmente, se incluyen siete recomendaciones de la Sociedad basadas en los análisis realizados.

Between the end of 2013 and the beginning of 2014 the most internationally influential hypertension guidelines were published. Although there are no major differences between them, there are discrepancies that can have an impact on treatment and prognosis for individuals with hypertension. This article analyzes the main controversial elements in the guides and presents the recommendations of the Sociedad Centroamericana y del Caribe de Hipertensión y Prevención Cardiovascular (Caribbean Society for Hypertension and Cardiovascular Prevention). The main differences are found a) in the categorization of prehypertension, b) in the use of global cardiovascular risk in the decision to begin antihypertensive treatment, c) in the validity of beta-blockers as first-line drugs in treating uncomplicated hypertension, and d) the increase in the therapeutic goal of maintaining values between < 140/90 and < 150/90 mmHg in patients over 60 years of age with no history of diabetes or chronic kidney disease. All the factors in favor of and against accepting each of these four controversial criteria are analyzed critically and the observations made by the Society are included. The conclusion is that there are pros and cons for all controversial elements in the hypertension guides. However, the weight of the evidence and clinical judgment favor subdividing prehypertension into stages I and II, seeking a therapeutic goal of maintaining systolic blood pressure below 140 mmHg in all the hypertensive patients under 80 years of age, retaining beta-blockers as first-line drugs in uncomplicated hypertension, and not delaying the start of drug treatment for hypertension stage I with low global cardiovascular risk. Finally, seven recommendations by the Society based on the analysis are included.

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