Use Of Pharmacological Agents Research Articles

65-OR: Effects of Treatment with Metformin and/or Sitagliptin on Beta-Cell Function and Insulin Resistance in Prediabetic Women with Previous Gestational Diabetes

Gestational diabetes (GDM) enhances the risk of type 2 diabetes (T2D) with 20-50% of women progressing to T2D within 10-years after pregnancy. Preventative strategies, including use of pharmacologic agents, are worth considering. We assessed, in a randomized double-blind study, the effect of 16-week therapy with sitagliptin (SITA, 100 mg qd), metformin (MET, 850 mg bid), and SITA+MET (50+850 mg bid) on beta-cell function and insulin sensitivity in women (n=40, age 30-49 y) with recent GDM and impaired glucose regulation (IGR: IFG and/or IGT). A 75gr OGTT and +125 mg/dl hyperglycemic clamp followed by 5 gr i.v. L-arginine were performed at baseline and study-end. Baseline characteristics were comparable in the 3 groups. At week 16, BMI declined in all groups (-1.2±0.2 Kg/m2; p<0.05). First phase(2-10 min) insulin secretion and arginine-stimulated C-peptide response increased with SITA+MET (1.0±0.2 to 1.3±0.3 ng/ml/min and 3.2±0.6 to 4.8±1.0 pmol/min, respectively, both p<0.05) while no changes occurred with MET and SITA. SITA+MET increased OGTT-based glucose sensitivity (55.7±11.3 to 108±56.2 pmol x min-1m-2 x mM-1; p=0.04) but no changes occurred with MET and SITA. No change occurred for rate sensitivity and potentiation factor in any group. SITA+MET increased insulin sensitivity (M/I: 2.2±0.5 to 4.6±1.3 mg/kg/min÷μIU/min/ml; p=0.04; OGIS: 351.9±11.4 to 375.7±9.6 ml x min-1m-2; p=0.08) but it was not affected by MET or SITA. Disposition Index increased with SITA+MET (10.8±1.1 to 13.6±1.6 μIU/ml/min÷mg/dl/min) and SITA (8.6±1.0 to 10.6±1.3; both p<0.05). Among SITA+MET women, 33% reverted to NGT compared to 14% with MET and 7% with SITA (p<0.05). This proof of concept study shows that SITA+MET is superior to SITA and MET monotherapy on beta-cell function and insulin sensitivity improvement in IGR women with previous GDM. It may offer a potential pharmacologic intervention to reduce risk of T2D in this high-risk population. Disclosure S. Barone: None. A. Dardano: None. A. Tura: None. J.J. Kurumthodathu: None. A. Bertolotto: Speaker's Bureau; Self; Abbott, Lilly Diabetes. C. Bianchi: None. L. Giusti: None. E. Lacaria: None. M. Romano: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. G. Daniele: None.

Regarding effectiveness of atropine use in children and adolescents with progressive myopia (literature review)

The issue of myopia prevention or myopia control is becoming more and more relevant every year. The approaches to myopia pathogenesis and myopia control have changed fundamentally, stereotypes have been dispelled, hypotheses and numerous studies are becom¬ing the basis of new scientific developments. However, the reality dictates the necessity to integrate the updated evidence based medicine data regarding myopia control into the clinical ophthalmological practice. The main reason that concerns the professional community is a growing prevalence of progressive my¬opia among children and adolescents around the world. The incidence of myopia among the adult population of European countries and the United States is estimat¬ed at 20-50%, whereas in Asian countries it amounts to 60-90%. In recent years, there was an increased interest towards the use of conservative methods of treatment in order to stabilize myopia, including the use of pharmacological agents. The publications from 1964 up until today were analyzed in the following review. They were focused on the results of studies that showed the ef¬fect of different concentrations of atropine on myopia progression in children and adolescents who had been observed during a maximum period of 5 years. Conclusion. According to numerous studies, low-concentration atropine (0.01%) is an effective mean to slow the progression of myopia and stabilize refraction. In addition, long-term therapeutic use of this particular concentration of atropine is associated with the least frequent occurrence of negative side effects.

Concise Review: Reduction of Adverse Cardiac Scarring Facilitates Pluripotent Stem Cell-Based Therapy for Myocardial Infarction.

Pluripotent stem cells (PSCs) are an attractive, reliable source for generating functional cardiomyocytes for regeneration of infarcted heart. However, inefficient cell engraftment into host tissue remains a notable challenge to therapeutic success due to mechanical damage or relatively inhospitable microenvironment. Evidence has shown that excessively formed scar tissues around cell delivery sites present as mechanical and biological barriers that inhibit migration and engraftment of implanted cells. In this review, we focus on the functional responses of stem cells and cardiomyocytes during the process of cardiac fibrosis and scar formation. Survival, migration, contraction, and coupling function of implanted cells may be affected by matrix remodeling, inflammatory factors, altered tissue stiffness, and presence of electroactive myofibroblasts in the fibrotic microenvironment. Although paracrine factors from implanted cells can improve cardiac fibrosis, the transient effect is insufficient for complete repair of an infarcted heart. Furthermore, investigation of interactions between implanted cells and fibroblasts including myofibroblasts helps the identification of new targets to optimize the host substrate environment for facilitating cell engraftment and functional integration. Several antifibrotic approaches, including the use of pharmacological agents, gene therapies, microRNAs, and modified biomaterials, can prevent progression of heart failure and have been developed as adjunct therapies for stem cell‐based regeneration. Investigation and optimization of new biomaterials is also required to enhance cell engraftment of engineered cardiac tissue and move PSCs from a laboratory setting into translational medicine.

English

INTRODUCTION: Acute kidney injury following receipt of iodinated contrast (CI-AKI) has been referred to as contrast induced nephropathy. There are various preventive measures for CI-AKI like 1. use of less nephrotoxic contrast agents, 2. use of pharmacological agents to counteract the toxic effects of contrast media, 3. administration of IV fluids to expand the intravascular space and enhance dieresis. This study shows whether ischemic preconditioning, transient brief episodes of ischemia before a subsequent prolonged ischemia / reperfusion injury is useful to reduce the incidence of CI-AKI. AIMS AND OBJECTIVES: To assess if remote ischemic preconditioning reduces the incidence of CI-AKI in patients with STEMI undergoing coronary angiogram. MATERIALS & METHODS: This is a prospective, single blind, randomized, sham-controlled parallel group study conducted among 100 randomly selected patients who are admitted in Govt. Rajaji Hospital, Madurai with STEMI. Patients are divided into two groups (test and control). Control group will undergo CAG without RIPC and those in the test group will undergo CAG after undergoing RIPC by three cycles of ischemia/ reperfusion of upper arm, achieved by 5 minute cuff inflation at 20 mm Hg above SBP followed by 5 minutes of complete cuff deflation. Both sets of patients are hydrated with normal saline infusion. Necessary haematological, biochemical, radiological investigations are performed and serum creatinine will be serially monitored in the next 72 hrs. RESULTS: Of the 50 patients in the control group 18 developed CI-AKI and of the 50 in test group 8 developed CI-AKI. This shows that RIPC was associated with a lower incidence of CIAKI and the difference was statistically significant. CONCLUSION: Not only was the incidence of CIAKI lower in RIPC group, but the mean rise in serum creatinine was also lower which would further reduce the duration of hospital stay and short term mortality. Thus RIPC can serve as a cost efficient tool in the lowering of occurrence of CI-AKI in patients undergoing contrast imaging.

Shining a Light: Integrating Protocols Into Clinical Practice for Treatment of Neonatal Abstinence Syndrome.

The epidemic use of opioids is negatively influencing the health of the American people. Pregnant women and their unborn babies have not escaped the ravages of substance use. A dramatic increase in maternal opioid use has led to an increasing number of infants experiencing withdrawal symptoms known as neonatal abstinence syndrome (NAS). The purpose of this article is to highlight best practice for the management of infants with opioid withdrawal. Review of available protocols and treatments revealed wide variation in the treatment of NAS and little use of standardized guidelines or protocols, despite current recommendations of the American Academy of Pediatrics. There is supporting evidence showing that the use of standardized protocols reduces the length of treatment and enhances outcomes in the neonatal population. Evidence-based strategies to address gaps in practice include developing strong protocols to identify infants at risk and implementing standardized plans when treating NAS. Consistent assessment, initial treatment with nonpharmacologic measures, and conservative use of pharmacologic agents are important elements to an NAS treatment protocol. In evaluating the current literature for best practice in the management of the newborn with opioid withdrawal, it is clear that evidence-based standardized protocols need to be in place for the best treatment of the mother-infant dyad, caring for both the infants with NAS as well as the mothers with opioid use disorder.

Chapter 2 - Behavioral and psychological symptoms in Alzheimer's dementia and vascular dementia

Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent and represent a significant burden for patients and their caregivers. Early recognition and management of these symptoms is crucial as they are associated with increased risk of institutionalization, impairments in daily functioning, reduced quality of life, and more rapid progression to severe dementia. This chapter will discuss the pathophysiology, proposed diagnostic criteria, clinical features, and management of BPSD, including apathy, depression, agitation/aggression, psychosis, and sleep disturbances. Apathy and depression are the most common overall, and apathy is associated with high symptom severity likely because of its greater persistence. Symptoms such as agitation, aggression, hallucinations, and delusions may be especially distressing and dangerous to patients and caregivers. Nonpharmacologic management should be considered first-line therapy in most cases due to the modest and inconsistent evidence base for pharmacologic agents and greater risk of harm. However, the judicious use of pharmacologic agents may be warranted when symptoms are dangerous and/or severely distressing.

The Bio-Psycho-Social Dimension in Women's Sexual Desire: 'Argumentum ad novitatem'.

Sexual desire includes complex motivation and drive. In the context of biological and cognitive- emotive state art of science, it is often a neglected field in medicine. In regard to the treatment, study on women's sexual function received less attention compared to the men's sexuality. In the past, this endeavor was relatively not well disseminated in the scientific community. Recently, there was a revolutionized surge of drug targets available to treat women with low sexual desire. It is timely to review the relevant biological approach, especially in the context of pharmacotherapy to understand this interesting clinical entity which was modulated by numerous interactive psychosocial inter-play and factors. The complex inter-play between numerous dimensional factors lends insights to understand the neural mechanism, i.e. the rewards centre pathway and its interaction with external psychosocialstimulus, e.g. relationship or other meaningful life events. The function of hormones, e.g. oxytocin or testosterone regulation was described. The role of neurotransmitters as reflected by the introduction of a molecule of flibenserin, a full agonist of the 5-HT1A and partial agonist of the D4 to treat premenopausal women with low sexual desire was deliberated. Based on this fundamental scientific core knowledge, we suggest an outline on know-how of introduction for sex therapy (i.e. "inner-self" and "outer-self") where the role of partner is narrated. Then, we also highlighted on the use of pharmacological agent as an adjunct scope of therapy, i.e. phosphodiasterase-5 (PDE-5) inhibitors and hormonal treatment in helping the patient with low sexual desire.

Correction of morphofunctional disorders with asialoerythropoietin and selective inhibitor of arginase II KUD975 in cases of ischemic kidney damage in the experiment

Introduction: Acute kidney injury (AKI), which is based on ischemic-reperfusion damage, is a widespread life-threatening condition and remains a serious public health problem with a high mortality rate among patients. Despite significant advances in various areas of medicine, the prevention and correction of ischemic-reperfusion kidney damage are still far from being at the desired level. Pharmacological preconditioning and the use of endothelioprotectors are promising areas in this field, therefore the purpose of this study was to analyze the nephroprotective properties of asialoerythropoietin and selective inhibitor of arginase II KUD975 in ischemic kidney damage in the experiment.Materials and methods: The study was performed on 260 white adult male Wistar rats, each weighing 180-220 g. Ischemic-reperfusion damage was simulated by applying a clamp on the renal leg for 40 minutes. To determine a degree of correction caused by morphofunctional disorders traditional functional, biochemical and morphological criteria were used.Results and discussion: When administering asialoerythropoietin and selective inhibitor of arginase II KUD975, there is observed an improvement in the glomerular filtration and microcirculation in the kidneys, decrease in the concentration of creatinine and urea, a decrease in fractional excretion of sodium and improvement in the histological pattern at different periods. The most pronounced nephroprotective effects are observed in the combined use of the test pharmacological agents, which are superior to such used in a monotherapy. The use of glibenclamide and L-NAME against the background of the correction of the pathology caused by asialoerythropoietin completely eliminates its positive effects. When glibenclamide and L-NAME are used against the background of correction of the pathology caused by the selective inhibitor of arginase II KUD975, its positive effects are completely eliminated by L-NAME. Glibenclamide does not eliminate positive effects.Conclusions: The results of the experiment prove the presence of pronounced nephroprotective properties of asialoerythropoietin and selective inhibitor of arginase II KUD975 in ischemic kidney damage in the experiment. The most pronounced effects are observed in the combined use of these pharmacological agents. The leading role in causing the positive effects from asialoerythropoietin is played by the activation of K+ATP channels and the activation of eNOS. The leading role in causing the positive effects from the selective inhibitor of arginase II KUD975 is played by the activation of eNOS.

Prevalence, pattern and clinical implications of transfusion transmissible viral infections among paediatric haemophiliacs in northern Nigeria

Abstract Background Scarcity of FVIII concentrate compels caregivers in poor countries to use multiple transfusions of fresh whole blood (FWB), fresh frozen plasma and cryoprecipitate for managing haemophilia A. FWB is the most frequently transfused blood product due to ease of production and its ability to simultaneously stop active bleeding and treat anaemia. Iron deficiency anaemia is common among haemophiliacs in poor tropical countries such as Nigeria, due to the combined effects of bleeding, malnutrition, and haemorrhagic parasitic diseases. Multiple FWB transfusion is usually initiated at local sub-tertiary hospitals before eventual referral to tertiary hospitals. The Nigerian blood transfusion service is underdeveloped, donor screening is rudimentary and transfusion safety is poor. The prevalence of transfusion transmissible viral infections (TTVIs), including HIV, and hepatitis B and C viruses (HBV and HCV), is therefore predicted to be high among Nigerian haemophiliacs. Aims To determine prevalence and pattern of TTVIs (HIV, HBV, HCV infections) among paediatric haemophiliacs who have received multiple FWB transfusions in Nigeria. Materials and methods Retrospective analyses of demographic and clinical data, disease severity, number of previous transfusions of FWB, and prevalence and pattern of TTVIs (HIV, HBV and HCV infections) of newly referred haemophiliacs as seen in five tertiary hospitals in northern Nigeria. Prevalence rates of TTVIs were expressed as percentages. Comparisons of parameters (age, disease severity and number of previous transfusions) between patients with and without TTVIs were performed using Students t-test for mean values and Fisher’s exact test for percentages, with p-values of less than 0.05 taken as significant. Results Of 97haemophiliacs studied, 24 (24.7%) were infected with TTVIs. The pattern and frequencies of TTVIs among the infected patients revealed HBV infection in 10 (41.7%), HIV-1 infection in five (20.8%), HCV infection in four (16.7%), HBV and HIV co-infection in three (12.5%), and HBV and HCV co-infection in two (8.3%). In comparison with haemophiliacs without TTVIs, haemophiliacs with TTVIs had a significantly lower mean age (4.9 vs. 7.8; p=0.007); a higher proportion of severe disease (62.5% vs. 26%; p=0.009), and a higher mean number of transfusions per patient (27.5 vs. 15.3; p=0.006). Conclusions The prevalence of TTVIs among haemophiliacs in Nigeria is high, and the risk is correlated with disease severity and number of previous transfusions. There is need for the national transfusion service to be upgraded and for standard haemophilia care centres with an adequate supply of FVIII concentrates for optimal care to be set up. Haemophilia healthcare providers in Nigeria can minimise multiple transfusions by incorporating regular screening and treatment of haemorrhagic parasitic diseases, iron supplementation, and the use of pharmacological agents in the standard of care for haemophilia.

Characterization of purinergic receptor expression in ARPKD cystic epithelia

Polycystic kidney diseases (PKDs) are a group of inherited nephropathies marked by formation of fluid-filled cysts along the nephron. Growing evidence suggests that in the kidney formation of cysts and alteration of cystic electrolyte transport are associated with purinergic signaling. PCK/CrljCrl-Pkhd1pck/CRL (PCK) rat, an established model of autosomal recessive polycystic kidney disease (ARPKD), was used here to test this hypothesis. Cystic fluid of PCK rats and their cortical tissues exhibited significantly higher levels of ATP compared to Sprague Dawley rat kidney cortical interstitium as assessed by highly sensitive ATP enzymatic biosensors. Confocal calcium imaging of the freshly isolated cystic monolayers revealed a stronger response to ATP in a higher range of concentrations (above 100μM). The removal of extracellular calcium results in the profound reduction of the ATP evoked transient, which suggests calcium entry into the cyst-lining cells is occurring via the extracellular (ionotropic) P2X channels. Further use of pharmacological agents (α,β-methylene-ATP, 5-BDBD, NF449, isoPPADS, AZ10606120) and immunofluorescent labeling of isolated cystic epithelia allowed us to narrow down potential candidate receptors. In conclusion, our ex vivo study provides direct evidence that the profile of P2 receptors is shifted in ARPKD cystic epithelia in an age-related manner towards prevalence of P2X4 and/or P2X7 receptors, which opens new avenues for the treatment of this disease.

Pharmacologic prevention of postoperative delirium after on-pump cardiac surgery

Background:Postoperative delirium is a prevalent and disabling mental disorder in patients undergoing on-pump cardiac surgery. There is some evidence that the use of pharmacological interventions may reduce the risk of developing of postoperative delirium. Therefore, the aim of this meta-analysis was to determine the effect of pharmacologic agents for the prevention postoperative delirium after cardiac surgery.Methods:Randomized controlled trials (RCTs) were identified through a systematic literature search of electronic databases and article references up to October 2016. End points included incidence of postoperative delirium, severity of postoperative delirium, cognitive disturbances of postoperative delirium, duration of postoperative delirium, length of stay in intensive care unit (ICU) and hospital, and short-term mortality.Results:A total of 14 RCTs with an aggregate of 14,139 patients were included. The results of the present meta-analysis show that pharmacologic agents significantly decrease postoperative delirium [relative risk (RR), 0.83; 95% confidence interval (95% CI), 0.75–0.91, P < .00001] and duration of postoperative delirium (RR = −0.37, 95% CI = −0.47 to −0.27, P < .00001) after on-pump cardiac surgery. In addition, subgroup analysis shows that dexamethasone and dexamethasone were associated with a trend toward a reduction in postoperative delirium (RR, 0.45; 95% CI, 0.30–0.66, P < .0001; RR, 0.80; 95% CI, 0.68–0.93, P = .003, respectively). However, our results fail to support the assumption that pharmacologic prophylaxis is associated with a positively reduction in short-term mortality, length of ICU, or hospital stay.Conclusion:This meta-analysis suggests that the perioperative use of pharmacologic agents can prevent postoperative delirium development in patients undergoing cardiac surgery. However, there remain important gaps in the evidence base on a few small studies with multiple limitations. Further large-scale, high-quality RCTs are needed in this area.

Atomoxetina no Tratamento da Perturbaça?o da Hiperatividade - De?fice de Atença?o: Casuística de um Hospital Tercia?rio Português

INTRODUÇÃO: A perturbação da hiperatividade - défice de atenção (PHDA) é a doença neurocomportamental mais comum em idade pediátrica, sendo frequentemente necessário na sua abordagem terapêutica o uso de medidas farmacológicas. A atomoxetina, inibidor seletivo da recaptação pré-sináptica de noradrenalina, é um fármaco não estimulante aprovado desde 2002 para o tratamento da PHDA na criança e no adolescente. O objetivo deste trabalho foi avaliar, num hospital terciário, o perfil de prescrição de atomoxetina, incluindo o motivo de prescrição, comorbilidades, dosagem, eficácia e eventuais efeitos adversos.MÉTODOS: Efetuamos um estudo retrospetivo de todos os doentes com o diagnóstico de PHDA, que iniciaram tra-tamento com atomoxetina num período de 24 meses. RESULTADOS: A amostra consistiu em 43 doentes, dos quais 39 completaram pelo menos 2 meses de tratamento com atomoxetina, tendo-se obtido sucesso terapêutico em 71,8% dos doentes, com um bom perfil de segurança (apenas 3 doentes descontinuaram o fármaco por efeitos adversos).CONCLUSÃO: Os autores realçam a segurança e a eficácia da atomoxetina no tratamento da PHDA, na amostra es-tudada, sobretudo após a ocorrência de efeitos adversos ou em situações de baixa eficácia do tratamento com psi-coestimulantes.

Implementation of a Smoking Cessation Education Program in the Emergency Department.

Tobacco use is a major threat to public health. Current guidelines suggest that healthcare professionals in the emergency department provide routine smoking cessation screening and interventions. Evidence suggests that an educational intervention among registered nurses in the emergency department may increase education and referral for smoking cessation of patients who use tobacco products. An educational module regarding smoking cessation counseling was provided to registered nurses in the emergency department at a private hospital in South Florida. A pre- and postintervention self-reported survey evaluated changes in nurses asking about tobacco use; advising to quit; assessing readiness, assisting, and arranging follow-up for patients who smoke to quit; and encouraging pharmacological agents. All participating nurses screened for tobacco use most of the time before and after the intervention. However, the number of nurses who assessed readiness, assisted, arranged follow-up for patients and encouraged the use of pharmacological agents increased significantly in the postsurvey. Study findings agree with previous research indicating that nurses routinely screen for tobacco and advise to quit. However, implementing smoking cessation education and referral resources may better equip registered nurses in the emergency department to take an active role initiating follow-up interventions for patients who screen positive for tobacco use. Educational interventions among these nurses can increase knowledge of and utilization of existing resources to help patients quit.

Pregabalin treatment for neuropathic pain may damage intervertebral disc tissue.

The aim of the present study was to determine whether pharmaceutical preparations with pregabalin (PGB) as an active ingredient, which are widely prescribed by clinicians, exert toxic effects on human primary nucleus pulposus (NP) and annulus fibrosis (AF). Primary human cell cultures were obtained from intact (n=6) and degenerated (n=6) tissues resected from the two groups of patients. Different doses of PGB were applied to these cultures and cells were subjected to molecular analyses at 0, 24 and 48 h. Cell vitality, toxicity and proliferation were assessed using a spectrophotometer. The expression of chondroadherin (CHAD), a (member of the NP-specific protein family), hypoxia-inducible factor-1α (HIF-1α) and type II collagen (COL2A1) was measured using reverse transcription-quantitative polymerase chain reaction. The results revealed that cell intensity increased in a time-dependent manner and cell vitality continued in the cultures without pharmaceuticals. Cell proliferation was suppressed in the PGB-treated cultures independent from the dose and duration of application. PGB was demonstrated to suppress the expression of CHAD and HIF-1α. In contrast, COL2A1 gene expression was not revealed in any experimental group. The present study utilized an in vitro model and the PGB active ingredient used herein may not be representative of clinical applications; however, the results demonstrated that PGB has a toxic effect on NP/AF cell cultures containing primary human intervertebral disc tissue. In summary, the use of pharmacological agents containing PGB may suppress the proliferation and differentiation of NP/AF cells and/or tissues, which should be considered when deciding on an appropriate treatment regime.

Actualización 2017 Guí­as prácticas para el ayuno preoperatorio. ¿Alguna novedad?

Actualización 2017 de las "Guías Prácticas de Ayuno Preoperatorio y el Uso de Agentes Farmacológicos para reducir el riesgo de aspiración pulmonar publicado por la ASA (American Society of Anesthesiologists) en 2011.

Targeting the Adenosinergic Axis in Chronic Lymphocytic Leukemia: A Way to Disrupt the Tumor Niche?

Targeting adenosine triphosphate (ATP) metabolism and adenosinergic signaling in cancer is gaining momentum, as increasing evidence is showing their relevance in tumor immunology and biology. Chronic lymphocytic leukemia (CLL) results from the expansion of a population of mature B cells that progressively occupies the bone marrow (BM), the blood, and peripheral lymphoid organs. Notwithstanding significant progress in the treatment of these patients, the cure remains an unmet clinical need, suggesting that novel drugs or drug combinations are needed. A unique feature of CLL is its reliance on micro-environmental signals for proliferation and cell survival. We and others have shown that the lymphoid niche, an area of intense interactions between leukemic and bystander non-tumor cells, is a typically hypoxic environment. Here adenosine is generated by leukemic cells, as well as by cells of myeloid origin, acting through autocrine and paracrine mechanisms, ultimately affecting tumor growth, limiting drug responses, and skewing the immune cells towards a tolerant phenotype. Hence, understanding the mechanisms through which this complex network of enzymes, receptors, and metabolites functions in CLL, will pave the way to the use of pharmacological agents targeting the system, which, in combination with drugs targeting leukemic cells, may get us one step closer to curing these patients.

Purinergic Receptors Profile in the ARPKD Cystic Epithelia

Polycystic kidney diseases (PKD) are a group of inherited nephropathies marked with the formation of fluid‐filled cysts along the nephron. Growing evidence suggests that autocrine and paracrine effects of purinergic signaling via P2 receptors could detrimentally contribute to cyst expansion. However, little is known about purinergic signaling in renal cyst epithelium, which is characterized by loss of polarity, dedifferentiation and other abnormalities which can lead to purinergic signaling remodeling. We have proposed that ATP via associated intracellular signaling can contribute to cystogenesis by modulation of calcium influx. PCK/CrljCrl‐Pkhd1pck/CRL (PCK) rat, an established model of ARPKD, was used here to test this hypothesis. The cystic fluid of PCK rats and their cortical tissues exhibited significantly higher levels of ATP compared to Sprague Dawley (SD) rat kidney cortical interstitium as assessed by highly sensitive for ATP enzymatic biosensors (211±55 vs 1082±147 nM for SD and PCK cortex correspondingly, and 2,078±391 nM for cystic fluid). Confocal calcium imaging of the freshly isolated cystic monolayers revealed a stronger response to ATP in a higher range of concentrations (above 100 μM). The removal of extracellular calcium results in the absence of ATP evoked transient, which pointed towards the extracellular (ionotropic) calcium entry in cyst‐lining cells rather than the metabotropic P2Y‐mediated internal depot. Application of iso‐PPADS (a non‐selective P2X antagonist) resulted in partial blockade of ATP response (calcium release after ATP was 30.1 ± 0.9, 22.2 ± 1.8 and 19.5 ± 3.2 a.u. in control, after incubation with iso‐PPADS, and after washout, respectively) indicating the contribution of P2X4 purinoreceptor in the cystic monolayer. Next, to specifically assess the role of P2X7 in the ATP‐mediated calcium influx, we employed AZ10606120, a potent P2X7 receptor antagonist. Application of AZ10606120 (5 μM) resulted in a bunted calcium response to ATP (32.4 ± 2.2, 13.5 ± 6.4, and 11.1 ± 3.1 a.u. of total calcium release in control, after incubation with AZ10606120, and after washout, respectively), which corroborates the commonly hypothesized role of P2X7 in cyst development. Further use of pharmacological agents (α,β‐methylene‐ATP, 5‐BDBD, and NF449) allowed to narrow down potential candidate receptors and suggested a significant involvement of the P2X4 and/or P2X7 signaling axis in the regulation of cytosolic calcium level in the cystic epithelia. In conclusion, our ex vivo study provides direct evidence that the profile of P2 receptors is altered in the ARPKD cystic epithelia towards the prevalence of P2X4 and/or P2X7 receptors, which opens new avenues for the treatment of this disease.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pharmacotherapy in Acutely Anemic Jehovah's Witnesses: An Evidence-Based Review.

To determine the pharmacological treatment methods available to anemic Jehovah's Witnesses (JW). MEDLINE and PubMed were searched from inception through February 2018 using the search terms Jehovah's Witnesses, treatment, erythropoietin, hemoglobin-based oxygen carrier, Sanguinate, Hemopure, bleeding, and anemia. All clinical trials, cohort studies, case-control studies, and observational trials involving pharmacotherapy in anemic JW patients were evaluated. Case reports and bibliographies were also analyzed for inclusion. Two studies involving the use of erythropoietin (EPO) and one study involving recombinant factor VIIa were included. Information was also included from other pharmacotherapeutic modalities that had case report data only. Current published evidence is limited with regard to evidence-based management of JW patients. High-dose EPO, intravenous iron supplementation, and hemostatic agents have demonstrated good clinical outcomes in case reports. EPO doses as high as 40 000 units daily have been advocated by some experts; however, pharmacokinetic studies do not support dose-dependent effects. Hemoglobin-based oxygen carriers (HBOCs) are currently not Food and Drug Administration approved. They are available through expanded access programs and may represent a lifesaving modality in the setting of severe anemia. There are currently not enough data to make definitive recommendations on the use of pharmacological agents to treat severe anemia in the JW population. Further evidence utilizing EPO and HBOCs will be beneficial to guide therapy.

Abstract P3-12-13: Breast atypical hyperplasia and guideline compliance

Abstract Background: Atypical hyperplasia of the breast is a high-risk benign lesion that is found in approximately 10% of benign breast biopsies[1]and confers a risk for future breast cancer[2]. The American Society of Clinical Oncology guideline states that pharmacologic risk reduction with the use of a selective estrogen receptor modulator or an aromatase inhibitor should be discussed with women with a 5-year projected absolute risk of breast cancer of 1.7% or higher[3]. The NCCN guideline for risk reduction recommends consideration of risk-reduction interventions, including the use of pharmacologic agents in women with a 5-year risk of 1.7% or higher and a life expectancy of 10 years or longer [4] .The majority of women with atypical hyperplasia meet this risk criterion with their cumulative risk of approximately 1% per year. Method: We retrospectively reviewed excisional biopsy pathology reports between January 2016 and June 2016 with the diagnosis of atypical ductal or lobular hyperplasia to identify patients with pure atypical hyperplasia. Medical records of these patients were then reviewed to identify the percentage of patients referred to a medical oncologist for chemoprevention discussion and the percentage of patients who received chemoprevention following excisional biopsy. Results: Two hundred seventy six patients with the diagnosis of atypical ductal or lobular hyperplasia were identified. Two hundred and sixteen patients were excluded from the analysis due to the presence of other histologies such as carcinoma in situ and invasive carcinoma. Medical records of the remaining sixty patients with pure atypical hyperplasia were reviewed. Eighteen patients' charts were unavailable for review. All of the remaining forty two patients had a 5-year breast cancer risk of 1.7% or higher. Five of these patients (8.3%) were referred to a medical oncologist for chemoprevention discussion. Two of these five patients (2.3%) received chemoprevention with tamoxifen. For patients who were not referred to medical oncologist, there was one documented discussion of chemoprevention with patient by her surgical oncologist. One patient underwent prophylactic bilateral mastectomies, and therefore, chemoprevention was not recommended. Conclusion: Multidisciplinary strategies need to be implemented to bridge the gap between guidelines and clinical practices which may lead to improved patient outcomes.

Oral Fluid Drug Testing in Pain Management Practice: Factors to Consider Before Choosing the Alternative Biological Matrix.

As the use of pharmacological agents, particularly opioid analgesics, has increased in the past 2 decades, so have the substance abuse risks, along with the prevalence of overdose deaths, addiction, and illicit drug use. Accordingly, close monitoring of patients to ensure medication compliance and to identify improper drug use becomes a critical task for pain-management practitioners. Oral fluid is an emerging biological matrix for clinical drug testing. It offers noninvasive, less hazardous, and directly observable sample collection with minimal potential for adulteration. Oral fluid can be collected multiple times in a short period and shows a stronger correlation with blood than urine concentrations. Usability of oral fluid testing had been limited by the sensitivity of analytical methods. The volume of oral fluid samples is typically much smaller than that of urine samples. Furthermore, oral fluid drug concentrations can be 10- to 100-fold lower than urine concentrations depending on analytes. Recent advances in analytical technologies lead to the growing popularity of oral fluid testing and subsequent need for scientific data to aid in interpretation of oral fluid test results. This review presents preanalytical, analytical, and postanalytical considerations associated with oral fluid drug testing for those contemplating the implementation of this alternative biological matrix in pain-management practice. Comparison with urine testing, collection procedure, drug stability, available technologies, scope of analysis, and drug disposition are discussed. As with other monitoring tools, oral fluid testing has advantages and limitations. The most important consideration is staying informed to use the testing within its capability.