Targeted In Vivo Loading of Red Blood Cells Markedly Prolongs Nanocarrier Circulation.

Engineering drug delivery systems for prolonged pharmacokinetics (PK) has been an ongoing pursuit for nearly 50 years. The gold standard for PK enhancement is the coating of nanoparticles with polymers, namely polyethylene glycol (PEGylation), which has been applied in several clinically used products. In the present work, we utilize the longest circulating and most abundant component of blood─the erythrocyte─to improve the PK behavior of liposomes. Antibody-mediated coupling of liposomes to erythrocytes was tested in vitro to identify a loading dose that did not adversely impact the carrier cells. Injection of erythrocyte targeting liposomes into mice resulted in a ∼2-fold improvement in the area under the blood concentration versus time profile versus PEGylated liposomes and a redistribution from the plasma into the cellular fraction of blood. These results suggest that in vivo targeting of erythrocytes is a viable strategy to improve liposome PK relative to current, clinically viable strategies.

PARkinson's: From cellular mechanisms to potential therapeutics.

Our understanding of the progression and mechanisms underlying the onset of Parkinson's disease (PD) has grown enormously in the past few decades. There is growing evidence suggesting that poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation is involved in various neurodegenerative disorders, including PD, and that poly (ADP-ribose) (PAR)-dependent cell death is responsible for neuronal loss. In this review, we discuss the contribution of PARP-1 and PAR in the pathological process of PD. We describe the potential pathways regulated by the enzyme, review clinically relevant PARP-1 inhibitors as potential disease-modifying therapeutics for PD, and outline important factors that need to be considered for repurposing PARP-1 inhibitors for use in PD.

Manejo integral de la disfunción neurogénica del tracto urinario inferior en lesión medular: actualización / Comprehensive management of neurogenic dysfunction of the lower urinary tract in spinal cord injury: update

La disfunción neurogénica del tracto urinario inferior es una consecuencia frecuente en pacientes con lesión de la médula espinal y es secundaria a la hiperactividad del músculo detrusor, que compromete dos funciones principales: el almacenamiento y el vaciamiento de la orina por daño en los centros de control neurológico de la micción. Se asocia con una morbimortalidad significativa, altos costos en la atención médica y disminución en la calidad de vida. Por ello se debe detectar y tratar de manera temprana, al igual que realizar un seguimiento estrecho que reduzca el riesgo de deterioro de las vías urinarias superiores. El presente artículo tiene como finalidad revisar algunos conceptos básicos en relación con la definición, epidemiología, fisiopatología, presentación clínica, complicaciones y, en especial, el tratamiento de esta condición, siendo este último el objetivo de esta revisión.

Neurogenic lower urinary tract dysfunction is a frequent consequence in patients with spinal cord injury and is secondary to detrusor muscle hyperactivity, which compromises two main functions: storage and emptying of urine due to damage to the neurological control centers of micturition. It is associated with significant morbidity and mortality, high health care costs and decreased quality of life. Therefore, it should be detected and treated early, as well as closely monitored to reduce the risk of upper urinary tract impairment. The purpose of this article is to review some basic concepts in relation to the definition, epidemiology, pathophysiology, clinical presentation, complications and, especially, the treatment of this condition, the latter being the objective of this review.

Poly (ADP-ribose) Interacts With Phosphorylated α-Synuclein in Post Mortem PD Samples.

Poly (ADP-ribose) (PAR) is a negatively charged polymer that is biosynthesized by Poly (ADP-ribose) Polymerase-1 (PARP-1) and regulates various cellular processes. Alpha-synuclein (αSyn) is an intrinsically disordered protein (IDP) that has been directly implicated with driving the onset and progression of Parkinson's disease (PD). The mechanisms by which α-synuclein (αSyn) elicits its neurotoxic effects remain unclear, though it is well established that the main components of Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients are aggregated hyperphosphorylated (S129) forms of αSyn (pαSyn). In the present study, we used immunofluorescence-based assays to explore if PARP-1 enzymatic product (PAR) promotes the aberrant cytoplasmic accumulation of pαSyn. We also performed quantitative measurements using in situ proximity ligation assays (PLA) on a transgenic murine model of α-synucleinopathy (M83-SNCA∗A53T) and post mortem PD/PDD patient samples to characterize PAR-pαSyn interactions. Additionally, we used bioinformatic approaches and site-directed mutagenesis to identify PAR-binding regions on αSyn. In summary, our studies show that PAR-pαSyn interactions are predominantly observed in PD-relevant transgenic murine models of αSyn pathology and post mortem PD/PDD patient samples. Moreover, we confirm that the interactions between PAR and αSyn involve electrostatic forces between negatively charged PAR and lysine residues on the N-terminal region of αSyn.

Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson's Disease.

Repurposing PARP-1 inhibitors (PARPi) for non-oncological applications offers an attractive therapeutic strategy for pathological conditions characterized by PARP-1 hyperactivity. In the context of Parkinson's disease (PD), PARP-1 hyperactivity has been linked to neuronal death and disease progression. From a therapy perspective, the evaluation of PARPi as neuroprotective agents may offer a new therapeutic alternative for neurodegenerative disorders. An ideal PARPi needs to inhibit PARP-1 hyperactivity while also limiting downstream DNA damage and cellular toxicity-an effect that is attractive in cancer but far from ideal in neurological disease applications. Consequently, in this study, we set out to evaluate the neuroprotective properties of a previously reported low-toxicity PARPi (10e) using in vitro neuronal models of PD. 10e is a structural analogue of FDA-approved PARPi olaparib, with high PARP-1 affinity and selectivity. Our studies revealed that 10e protects neuronal cells from oxidative stress and DNA damage. In addition, 10e exhibits neuroprotective properties against α-synuclein pre-formed fibrils (αSyn PFF) mediated effects, including reduction in the levels of phosphorylated αSyn and protection against abnormal changes in NAD+ levels. Our in vitro studies with 10e provide support for repurposing high-affinity and low-toxicity PARPi for neurological applications and lay the groundwork for long-term therapeutic studies in animal models of PD.

Molecular Imaging: PARP-1 and Beyond.

The genetic code to life is balanced on a string of DNA that is under constant metabolic and physical stress from environmental forces. Nearly all diseases have a genetic component caused by or resulting in DNA damage that alters biology to drive pathogenesis. Recent advancements in DNA repair biology have led to the development of imaging tools that target DNA damage response and repair proteins. PET has been used for early detection of oncogenic processes and monitoring of tumor response to chemotherapeutics that target the DNA repair machinery. In the field of precision medicine, imaging tools provide a unique opportunity for patient stratification by directly measuring drug target expression or monitoring therapy to identify early responders. This overview discusses the state of the art on molecular imaging of DNA damage and repair from the past 5 years, with an emphasis on poly[adenosine diphosphate ribose]polymerase-1 as an imaging target and predictive biomarker of response to therapy.

ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells.

The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.

Manifestaciones neurológicas periféricas en la infección por Sars-CoV-2: enfoque desde la Medicina Física y la Rehabilitación / Peripheral neurological manifestations in Sars-CoV-2 infection Approach from Physical Medicine and Rehabilitation

Desde su notificación a finales del 2019, la infección secundaria a coronavirus se ha difundido a nivel global hasta ser calificada como una pandemia. La respuesta inflamatoria generalizada que produce la infección por Sars-CoV-2, compromete múltiples órganos y sistemas, siendo el sistema respiratorio uno de los más afectados y con desenlace fatal, sin embargo, la afectación del sistema nervioso periférico puede implicar el desarrollo de déficits permanentes, con limitaciones en las actividades de la vida diaria y restricción en la participación, llevando a la pérdida de independencia y reducción de la calidad de vida. El médico rehabilitador debe estar enfocado al reconocimiento y detección temprana de la patología nerviosa periférica, así como a determinar la intervención de la cual se beneficia más el paciente, liderar el equipo interdisciplinario de salud y mantener un trabajo fluido con otras especialidades médicas.

Since its notification at the end of 2019, the infection secondary to coronavirus has spread globally to the point of being qualified as a pandemic. The generalized inflammatory response produced by Sars-CoV-2 infection involves multiple organs and systems, being the respiratory system one of the most affected and with fatal outcome, however, the involvement of the peripheral nervous system may involve the development of permanent deficits, with limitations in activities of daily living and restriction in participation, leading to loss of independence and reduced quality of life. The rehabilitation physician should be focused on the early recognition and detection of peripheral nerve pathology, as well as to determine the intervention from which the patient will benefit the most, lead the interdisciplinary health team and maintain a fluid work with other medical specialties.

Compromiso, secuelas y rehabilitación del Sistema Nervioso Central debido a infección por Coronavirus, Sars-CoV-2 (Covid-19 / Compromise, sequelae and rehabilitation of the Central Nervous System due to infectionby Coronavirus, Sars - Co V - 2 (Covid-19)

La infección por coronavirus Sars-CoV-2 desde su aparición en 2019, se ha manifestado con el compromiso multiorgánico y con la consecuente necesidad de un abordaje multidisciplinario que incluye a varios profesionales de la salud para la intervención aguda, la estabilización del paciente, la exploración neurológica y el proceso de rehabilitación. En conjunto las manifestaciones neurológicas, respiratorias y cardiovasculares son causa de discapacidad, alteración en la funcionalidad, de la participación y del entorno social en los pacientes con infección por Sars-CoV-2, por lo que requieren de una rehabilitación temprana como también de programas diseñados en torno a la pandemia y al compromiso neurológico, con el fin de prevenir complicaciones tempranas. Estas son razones por las que la presente revisión narrativa tiene como fin describir los principales compromisos del sistema nervioso central así como las secuelas neurológicas, basados en la búsqueda y referencia de diferentes tipos de artículos publicados hasta la fecha.

Sars-CoV-2 coronavirus infection since its emergence in 2019, has manifested with multiorgan involvement and the consequent need for a multidisciplinary approach that includes several health professionals for acute intervention, patient stabilization, neurological examination and rehabilitation process. As a whole, neurological, respiratory and cardiovascular manifestations are the cause of disability, alteration in functionality, participation and social environment in patients with Sars-CoV-2 infection, thus requiring early rehabilitation as well as programs designed around the pandemic and neurological involvement, in order to prevent early complications. These are the reasons why the present narrative review aims to describe the main central nervous system compromises as well as neurological sequelae, based on the search and reference of different types of articles published to date.

Targeting PARP-1 with Alpha-Particles Is Potently Cytotoxic to Human Neuroblastoma in Preclinical Models.

Alpha-emitters can be pharmacologically delivered for irradiation of single cancer cells, but cellular lethality could be further enhanced by targeting alpha-emitters directly to the nucleus. PARP-1 is a druggable protein in the nucleus that is overexpressed in neuroblastoma compared with normal tissues and is associated with decreased survival in high-risk patients. To exploit this, we have functionalized a PARP inhibitor (PARPi) with an alpha-emitter astatine-211. This approach offers enhanced cytotoxicity from conventional PARPis by not requiring enzymatic inhibition of PARP-1 to elicit DNA damage; instead, the alpha-particle directly induces multiple double-strand DNA breaks across the particle track. Here, we explored the efficacy of [211At]MM4 in multiple cancers and found neuroblastoma to be highly sensitive in vitro and in vivo Furthermore, alpha-particles delivered to neuroblastoma show antitumor effects and durable responses in a neuroblastoma xenograft model, especially when administered in a fractionated regimen. This work provides the preclinical proof of concept for an alpha-emitting drug conjugate that directly targets cancer chromatin as a therapeutic approach for neuroblastoma and perhaps other cancers.

TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death.

Sigma-2 receptors have been implicated in both tumor proliferation and neurodegenerative diseases. Recently the sigma-2 receptor was identified as transmembrane protein 97 (TMEM97). Progesterone receptor membrane component 1 (PGRMC1) was also recently reported to form a complex with TMEM97 and the low density lipoprotein (LDL) receptor, and this trimeric complex is responsible for the rapid internalization of LDL. Sigma-2 receptor ligands with various structures have been shown to induce cell death in cancer cells. In the current study, we examined the role of TMEM97 and PGRMC1 in mediating sigma-2 ligand-induced cell death. Cell viability and caspase-3 assays were performed in control, TMEM97 knockout (KO), PGRMC1 KO, and TMEM97/PGRMC1 double KO cell lines treated with several sigma-2 ligands. The data showed that knockout of TMEM97, PGRMC1, or both did not affect the concentrations of sigma-2 ligands that induced 50% of cell death (EC50), suggesting that cytotoxic effects of these compounds are not mediated by TMEM97 or PGRMC1. Sigma-1 receptor ligands, (+)-pentazocine and NE-100, did not block sigma-2 ligand cytotoxicity, suggesting that sigma-1 receptor was not responsible for sigma-2 ligand cytotoxicity. We also examined whether the alternative, residual binding site (RBS) of 1,3-Di-o-tolylguanidine (DTG) could be responsible for sigma-2 ligand cytotoxicity. Our data showed that the binding affinities (K i) of sigma-2 ligands on the DTG RBS did not correlate with the cytotoxicity potency (EC50) of these ligands, suggesting that the DTG RBS was not fully responsible for sigma-2 ligand cytotoxicity. In addition, we showed that knocking out TMEM97, PGRMC1, or both reduced the initial internalization rate of a sigma-2 fluorescent ligand, SW120. However, concentrations of internalized SW120 became identical later in the control and knockout cells. These data suggest that the initial internalization process of sigma-2 ligands does not appear to mediate the cell-killing effect of sigma-2 ligands. In summary, we have provided evidence that sigma-2 receptor/TMEM97 and PGRMC1 do not mediate sigma-2 ligand cytotoxicity. Our work will facilitate elucidating mechanisms of sigma-2 ligand cytotoxicity.

Synthesis and evaluation of an AZD2461 [18F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant.

Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer's and Parkinson's. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC50 = 3.9 ±â€¯1.2 nM), which was further evaluated as a potential 18F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [18F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.

Altering Nitrogen Heterocycles of AZD2461 Affords High Affinity Poly(ADP-ribose) Polymerase-1 Inhibitors with Decreased P-Glycoprotein Interactions.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics with enhanced selectivity and cytotoxicity in BRCA1/2 mutant cancer cells. AZD2461, a congener of FDA approved olaparib, is a potent PARPi with high affinity for PARP-1 and nonsubstrate for P-glycoprotein (P-gp), an attractive characteristic for cancer therapeutics. Analogues of AZD2461 were synthesized and profiled in BRCA1 functional and nonfunctional cell lines, revealing compounds (2, 3, and 5) of low cytotoxicity and excellent PARP-1 affinities (∼4-8 nM). In comparison to AZD2461, these agents were found to be less stimulating of P-gp, suggesting that these compounds may be excellent candidates for neurological applications where blood brain barrier penetrance is sought.

Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity.

Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 ± 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 ± 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.

RINITIS MEDICAMENTOSA: UN ESTUDIO OBSERVACIONAL

La rinitis medicamentosa es una enfermedad producida por el uso abusivo de descongestivos nasales. Objetivos: identificar las características demográficas del uso prolongado de descongestivos en nuestra población y la prevalencia de la rinitis medicamentosa. Materiales y Métodos: estudio retrospectivo, descriptivo, realizado por jóvenes alergistas de la ciudad de Córdoba. Resultados: se incluyeron 260 pacientes con diagnóstico de Rinitis Crónica, el 17%usaban descongestivos tópicos, el 13% lo utilizaban en forma prolongada y predominó en el sexo masculino. Conclusión: Se identificó un uso prolongado de descongestivos tópicos y alta prevalencia de rinitis medicamentosa.

Drug rhinitis is a disease caused by the abusive use of nasal decongestants. Objectives: to identify the demographic characteristics of the prolonged use of decongestants in our population and the prevalence of drug rhinitis. Materials and Methods: a retrospective, descriptive study carried out by young allergists from the city of Córdoba. Results: 260 patients with chronic rhinitis were included, 17% used topical decongestants, 13% used it on a prolonged basis and predominated in males. Conclusion: A prolonged use of topical decongestants and high prevalence of drug rhinitis was identified.

Urticaria crónica y autoinmunidad tiroidea utilidad del testintradérmico de suero autólogo / Chronic urticaria and thyroid autoimmunity utility of autologous intradermal serum test

Introducción: La Urticaria Crónica (UC) es una patología de prevalencia creciente. La relación entre UC y autoinmunidad tiroidea tiene una asociación significativa. El test intradérmico de suero autólogo (TISA) es capaz de inducir un test positivoen la piel de pacientes con urticaria. Objetivo: Determinar la prevalencia de la enfermedad tiroidea autoinmune en pacientes que concurren a la consulta por UC. Correlacionar en pacientes con UC y enfermedad tiroidea autoinmune la positividad de TISA. Comparar resultados del TISA en pacientes con UC y controles sanos. Materiales y Métodos: Se estudiaron51 pacientes, 30 con UC y 21 pacientes sanos del grupo control. Edades: entre 22 y 77 años, desde 01/11/07 hasta el30/04/10. Se realizó historia clínica detallada; dosaje de hormonas tiroideas: hormona estimulante de tirotrofina (TSH), tiroxina libre (T4 libre); dosaje de anticuerpos antitiroideos: anticuerpo antiperoxidasa (ATPO), anticuerpo antitiroglobulina (ATG) y test de TISA. Resultados: Entre los pacientes con UC el 80 % (24) correspondieron al sexo femenino, la franja etaria predominantefue de 51 a 59 años. La mayoría de los pacientes fueron eutiroideos (50%), seguidos de hipotiroideos (30%) y porúltimo hipertiroideos (20%). La prevalencia de enfermedad tiroidea autoinmune en pacientes con UC fue de un 17%. El TISAresultó positivo en un 47% (14), de los sujetos con UC. En todos los pacientes con tiroiditis autoinmune el TISA resultó positivo. Sin embargo se encontró TISA positivo en 8 pacientes con disfunción tiroidea sin autoinmunidad y en un paciente del grupo control (sano). Conclusiones: Se objetivó una tendencia a la autoinmunidad en pacientes con UC. Un TISApositivo enpacientes sin autoinmunidad tiroidea, debería contemplar otros posibles autoanticuerpos y otros factores liberadores de histamina.Un TISA negativo es un marcador útil para determinar ausencia de anticuerpos funcionantes circulantes.

Introduction: Chronic urticaria (UC) is a disease of increasing prevalence. The relationship between UC and thyroid autoimmunityhas a significant association. The autologous intradermal serum test (TISA) is capable of inducing a positive test inthe skin of patients with urticaria. The chemical nature of the factors, defined UC as an antibody-mediated autoimmune disease.Objetive: Determine the prevalence of autoimmune thyroid disease in patients attending the consultation by UC.Correlate the TISA positivity in patients with UC and autoimmune thyroid disease. Compare results of the TISA in UC patientsand healthy controls. Material and Methods: 51 patients were studied, 21 and 30 with UC patients healthy control group.Age: between 22 and 77 years, from 01/11/07 to 04/30/10. It made detailed clinical history; dosing of thyroid hormones: thyrotrophin(TSH)- stimulating hormone, thyroxine l free thyroxine (free T4); dosing of antithyroid antibodies: antibody antiperoxidasa(ATPO), antibody antithyroglobulin (IGT) and test of TISA. Results: Among patients with UC 80% (24) werefemale, the predominant age Strip was 51 to 59 years. The majority of patients were eutiroideos (50%), followed by additivehypothyroid (30%) and finally hipertiroideos (20%). The prevalence of autoimmune thyroid disease in patients with UC was17%. The TISA resulted positive in a 47% (14) of the subjects with UC. The TISA was positive in all patients with autoimmunethyroiditis. However found positive TISA in 8 patients with thyroid without autoimmune dysfunction and a patient of(healthy) control group. Coclusions: We find a tendency to Autoimmunity in patients with UC. A positive TISA in patients withoutthyroid Autoimmunity should consider other possible autoantibodies and other histamine releasing factors. A negativeTISA is a marker that is useful to determine lack of circulating funcionantes antibodies.

Estudio de hipertensión renovascular en la Fundación Clínica Shaio: 1990-1993 / Renovascular hypertension study at Clínica Shaio

Se realizó un estudio de tipo descriptivo retrospectivo, en la Fundación Clínica Shaio de Bogotá, durante el período comprendido Enero de 1990 y Septiembre de 1993 con el fín de conocer el comportamiento de la HTA renovascular en la institución. Todos los pacientes seleccionados cumplían al menos un criterio de inclusión, según lo establecido. Se analizaron 30 pacientes en edades entre los 14 y 79 años, promedio 59+-17 años, el 70 por ciento eran mujeres.El 90 por ciento tenían aterosclerosis y el 10 por ciento displasia fibromuscular. La estenosis de la arteria renal fué del lado izquierdo (50 por ciento), lado derecho (33 por ciento) y bilateral (17 por ciento); el compromiso fué proximal al 70 por ciento, tercio medio en el 13 por ciento. El 16,7 por ciento de los casos no presentó síntoma, el síntoma más frecuente fué la angina (46,7 por ciento), claudicación MMII en el 16,7 por ciento, cefalea en el 13,3 por ciento, dolor lumbar 10 por ciento, y síncope en el 3,3 por ciento. Se encontró sólo abdominal en cuatro pacientes. La tensión arterial sistólica fué de 16+-22 mmHg y la diastólica promedio fué 94+-12 mmHg y en el seguimiento (n=22), las cifras tensionales en el seguimiento la tensión arterial sistólica fué de 137+-22 mmHg y en la diastólica de 83+-12 mmHg, disminución estadísticamente significativa (p<0.001). Los métodos diagnósticos utilizados fueron: arteriografía renal en el 100 por ciento fué sometido a tratamiento médico, el 10 por ciento a tratamiento quirúrgico y un paciente a cirugía y PTRA. Se presentaron complicaciones en el 16,7 por ciento (n=5). Al iniciar el estudio un paciente no recibía tratamiento antihipertensivo, el 36,6 por ciento recibían más de tres medicaciones