Alpha Antagonists Research Articles

Reduced risk of suicidal behaviours associated with the treatment of hidradenitis suppurativa with tumour necrosis factor alpha antagonists: results from the US FDA Adverse Events Reporting System pharmacovigilance database.

Hidradenitis suppurativa (HS) is a chronic, recurrent condition that presents as painful, suppurating lesions in the apocrine gland-bearing skin regions. HS has been associated with increased suicidal behaviours (SB), independent of any treatment. TNF-alpha antagonists are used to treat moderate-to-severe HS and have also been associated with SB, a factor that could confound the decision to use the TNF-α antagonists in the moderately to severely affected HS patients, who may already be experiencing increased SB risk. To determine presence or absence of a safety signal for SB when HS is treated with TNF-α antagonists. We calculated the reporting odds ratios (ROR) with 95% CI of SB associated with treatment for HS with TNF-α antagonists vs. the reference group of all other treatments for HS in the US Food and Drug Administration pharmacovigilance database from 1 January 2004 to 31 March 2019. A second analysis excluded isotretinoin (which has been used to treat HS and has also been associated with SB) from the reference group. There was a signal for decreased risk of SB with TNF-α antagonists (ROR=0.1959, 95% CI 0.1247-0.3079; z=7.071, P<0.0001] vs. all other HS treatments; the ROR did not change significantly after isotretinoin was excluded from the reference group. Treatment of HS with TNF-α antagonists is associated with a decreased risk of SB.

Abstract P6-03-18: The accumulation of IGFBP-1 results in EGFR/MAPK activation and drives the development of tamoxifen resistance in breast cancer cells

Abstract Insulin-like growth factor (IGF) system plays a significantly role in cellular processes, including proliferation, survival, and mitogenesis. The IGF system consists of two soluble ligands, IGF-1 and IGF-2; two transmembrane receptors, IGF-1R and IGF-2R; and six high affinity IGF binding proteins, IGFBPs 1-6. Evidence shows that the IGF system is involved in breast cancer. For example, at least 50% of breast cancer tumors have elevated IGF-1R signaling; the level of circulating IGF-1 is found positively associated with the incident of estrogen receptor positive breast cancer. Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα-positive breast cancer. However, tamoxifen resistance also occurs, and its exact mechanism is not well understood. Recently, we discovered that the accumulation of IGFBP-1 was stimulated by tamoxifen treatment, which subsequently prevented the activation of IGF-1R and inhibited the proliferation in MCF-7 cells. As a result, we hypothesized that the accumulation of IGFBP-1 due to the long-term tamoxifen exposure would result in tamoxifen resistance. In order to mimic the accumulation of IGFBP-1 after tamoxifen treatment, we employed MCF-7 and T-47D breast cancer cells to generate stable cell lines with IGFBP-1 overexpression. We found that the expression of IGF-1R was largely reduced in both MCF7-BP1 and T47D-BP1 cells, which was also observed in tamoxifen resistant MCF-7 and T-47D cells. Furthermore, we demonstrated that both MCF7-BP1 and T47D-BP1 were not responsive to tamoxifen, and epidermal growth factor receptor (EGFR) signaling pathway was significantly upregulated, as shown by higher levels of EGFR, phospho-EGFR (pEGFR), and phospho-Erk (pErk). Also, we found that the inhibition of Erk phosphorylation by MEK1 inhibitor PD98059 sensitized the stable cells to tamoxifen, showing that elevated pErk was protective against tamoxifen. Lastly, the transient knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 resulted in significantly lower level of pErk and increased sensitivity to tamoxifen, further showing the role of IGFBP1 accumulation in the establishment of tamoxifen resistance and the activation of EGFR/MAPK pathway. Citation Format: Yan Zheng. The accumulation of IGFBP-1 results in EGFR/MAPK activation and drives the development of tamoxifen resistance in breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-18.

Predictors of long-term outcomes of radiologically defined perianal fistulizing Crohn's disease treated with antitumor necrosis factor-alpha agents based on Parks' classification.

Perianal fistulizing Crohn's disease (PFCD) leads to significant disability. Data assessing healing of complex PFCD based on pelvic MRI using Parks' classification remains sparse. We aimed to assess the frequency of closure of fistula tract on MRI in patients treated with antitumor necrosis factor alpha antagonists and identify predictors of poor response. We retrospectively identified patients registered in the Saudi Inflammatory Bowel Disease Information System registry, who were diagnosed as PFCD based on MRI and treated with infliximab or adalimumab. Fistulae were classified based on Parks' classification and response to treatment was determined as full, partial, or no response, after at least 12 months of treatment. Out of 960 patients, 61 had complex PFCD that required treatment with an anti-TNF agent. The median age was 27 years (range: 14-69 years) and the median duration of disease was 6.2 ± 5.8 years. A full response to treatment was achieved in 27 (44.4%), whereas 10 patients (16.3%) had partial response and 24 (39.3%) had no response. On univariable analysis, a statistically significant association was observed between poor fistula response and low BMI, rectal involvement, fistulae classification, and the presence of an abscess. According to multivariable regression, only low BMI predicted poor fistulae outcome (odds ratio = 1.37, 95% confidence interval: 0.69-0.98). Less than half of this cohort of patients with PFCD achieved complete radiological fistula healing with anti-TNF therapy. Low BMI appears to be the only predictor of poor outcome.

Severe asthma in the US population and eligibility for mAb therapy

Severe asthma in the US population and eligibility for mAb therapy

Psychotropic-Induced Priapism in a Treatment-Refractory Patient: A Case Report

Purpose: A case report of multiple episodes of priapism associated with the use of 4 different psychotropic medications. Summary: A 34-year-old African American male with treatment-refractory schizoaffective disorder suffered priapism on 6 separate occasions. His medical history is relatively unremarkable, with the exception of possible undiagnosed thalassemia. All incidences were potentially attributable to psychotropic medications, with chlorpromazine, risperidone, trazodone, and quetiapine being the most likely culprits. The onset of priapism ranged from hours after a single injection of chlorpromazine, to years after multiple injections of risperidone, with nothing to indicate a medication dose or duration relationship to priapism. While on clozapine, fluphenazine, haloperidol, lurasidone, and olanzapine at varying times, the patient did not appear to develop priapism. The commonality of high-affinity alpha-1 antagonism with these psychotropics may be to blame. No pharmacokinetic or pharmacodynamic interactions were noted, which would have produced elevations in the levels of these psychotropics, nor was the patient on any phosphodiesterase type 5 (PDE-5) inhibitors or antihypertensives known to cause priapism. Depending on the offending agent, the Naranjo et al’s Adverse-Reaction Probability Scale scores ranged from 5 to 8 (probable). Conclusion: A man suffered from multiple episodes of priapism attributed to psychotropic medications. This is not the first case to describe this effect, but will give clinicians a timeline of events and medications that did and did not appear to elicit priapism in a patient with treatment-refractory schizoaffective disorder. Knowledge of which psychotropic medications may be more likely to induce priapism is crucial to preventing long-term penile damage.

Pharmacokinetics of dexmedetomidine during administration of vatinoxan in male neutered cats anesthetized with isoflurane

Dexmedetomidine is an alpha-2 adrenoceptor agonist, and vatinoxan is an alpha-2 antagonist believed to poorly cross the blood-brain barrier in cats. Dexmedetomidine-vatinoxan combinations are of interest in anesthetized cats because the anesthetic sparing effect of dexmedetomidine may be preserved while vatinoxan attenuates the adverse cardiovascular effects of dexmedetomidine. The aim of this study was to characterize the pharmacokinetics of dexmedetomidine in cats during administration of isoflurane and vatinoxan. Six healthy adult male castrated cats were anesthetized with isoflurane in oxygen. Vatinoxan was administered using a target-controlled infusion system intended to maintain a plasma concentration of 4 µg/ml. Dexmedetomidine, 35 µg/kg was administered intravenously over 5 min. Plasma dexmedetomidine and vatinoxan concentrations were measured at selected time points ranging from prior to 8 hr after dexmedetomidine administration using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed-effect modeling. A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three-compartment volumes (ml/kg), the metabolic clearance and the two intercompartment distribution clearances (ml min-1 kg-1 ) were 168 (259), 318 (35), 1,425 (18), 12.4 (31), 39.1 (18), and 29.6 (17), respectively. Mean ± standard deviation plasma vatinoxan concentration was 2.6 ± 0.6 µg/ml.

627 Carvedilol vs. Endoscopic Variceal Ligation in Primary Prevention of First Variceal Hemorrhage Episode: A Systematic Review and Meta-Analysis

INTRODUCTION: Either a non-selective beta blocker or endoscopic variceal ligation (EVL) is recommended for the primary prevention of a first variceal hemorrhage episode in patients with medium or large sized varices. Carvedilol has been used for this purpose because of its additional alpha-1 antagonist effect and fewer hemodynamic complications. However, data supporting this recommendation are based on two previous randomized controlled trials. More studies have been published since these trials to investigate the benefit of carvedilol. We wanted to compare carvedilol with EVL in patients with esophageal varices to prevent the first variceal hemorrhage episode and to reduce mortality. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2019. Included studies were randomized controlled trials that investigated the efficacy of carvedilol compared to EVL to prevent the first variceal bleeding and to reduce mortality. The first variceal bleeding episode was defined as melena and/or hematemesis with endoscopic evidence of bleeding stigmata or recent variceal hemorrhage. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate pooled risk ratio (RR) and 95% confidence intervals. RESULTS: Four randomized controlled trials from 2009 to 2018 involving 556 patients (276 patients in the carvedilol group and 280 patients in the EVL group) were included in this meta-analysis. The mean age was 50 years. Compared to EVL, carvedilol did not significantly decrease the first variceal bleeding incidence or 1-year mortality (pooled RR 1.11 (0.56-2.19), P = 0.767, I2 = 53% and 1.22 (0.78-1.91), P = 0.38, I2 = 0%, respectively) (Figures 1 and 2). Serious adverse events that were intolerable and required specific therapy leading to discontinuation of the treatment arm was reported in 4 studies and did not show any significant difference between the carvedilol group and the EVL group (pooled RR 1.14 (0.78-1.68), P = 0.49, I2 = 6.8%) (Figure 3). CONCLUSION: Our study demonstrated a non-significant difference between carvedilol and EVL to prevent first variceal bleeding or decrease mortality. There was no difference in serious side effects. More randomized controlled trials with larger sample sizes and long term follow up are required to better understand the potential benefit of carvedilol. Our analysis supports the benefit of carvedilol as primary prophylaxis of variceal hemorrhage in cirrhotic patients.

Effects of the Alpha-1 Antagonist Prazosin on KOR Agonist-Induced Reinstatement of Alcohol Seeking.

BackgroundStress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488.MethodsWe trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression.ResultsPrazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area.ConclusionsThese findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.

Latent tuberculosis infection in patients with autoimmune diseases treated with Infliximab and Etanercept

Introduction: Latent tuberculosis infection (LTI) in patients receiving biological therapies is a reality, but this has not been studied in depth in Colombia. Objective: To determine the prevalence of LTI in patients with autoimmune diseases receiving treatment with Infliximab / Etanercept in a referral health center in Cali, Colombia, between the years 2011-2017. Methodology: A retrospective observational study was conducted. We reviewed the ‘Registry of patients exposed to tumor necrosis factor-alpha (TNF-α) antagonist drugs in Fundación Valle del Lili’. Patients diagnosed with a chronic inflammatory disease were included who received treatment with Infliximab, Etanercept, or both and followed at least two years. Design: Retrospective observational study. We reviewed the ‘Registry of patients exposed to tumor necrosis factor alpha (TNF-α) antagonist drugs in Fundación Valle del Lili’. Patients diagnosed with a chronic inflammatory disease were included who received treatment with Infliximab, Etanercept or both and followed at least a period of 2 years. Results: We included 82 patients; the median age was 47.5 years (IQR=28-60 years), 76% were female, 2% had intimate contact with tuberculosis, 15% were older than 65 years. The 56% had a diagnosis of rheumatoid arthritis as an indication of therapy, and 2% presented infection by hepatitis C virus. The median PPD was 12 mm (IQR=10-17 mm). The prevalence was 3.8% for LTI. Conclusion: The conversion to LTI shows an important prevalence, so it is convenient to perform a routine follow-up of patients receiving therapies with Infliximab and Etanercept.

Leishmaniasis and tumor necrosis factor alpha antagonists in the Mediterranean basin. A switch in clinical expression.

BackgroundTumor necrosis factor alpha (TNF-α) blockers are recognized as a risk factor for reactivation of granulomatous infections. Leishmaniasis has been associated with the use of these drugs, although few cases have been reported.MethodologyWe performed a retrospective observational study including patients with confirmed leishmaniasis acquired in the Mediterranean basin that were under TNF-α blockers therapy at the moment of the diagnosis. Patients diagnosed in our hospital from 2008 to 2018 were included. Moreover, a systematic review of the literature was performed and cases fulfilling the inclusion criteria were also included.Principal findingsForty-nine patients were analyzed including nine cases from our series. Twenty-seven (55.1%) cases were male and median age was 55 years. Twenty-five (51%) patients were under infliximab treatment, 20 (40.8%) were receiving adalimumab, 2 (4.1%) etanercept, one (2%) golimumab and one (2%) a non-specified TNF-α blocker. Regarding clinical presentation, 28 (57.1%) presented as cutaneous leishmaniasis (CL), 16 (32.6%) as visceral leishmaniasis (VL) and 5 (10.2%) as mucocutaneous leishmaniasis (MCL). All VL and MCL patients were treated with systemic therapies. Among CL patients, 13 (46.4%) were treated with a systemic drug (11 received L-AmB, one intramuscular antimonials and one miltefosine) while 14 (50%) patients were given local treatment (13 received intralesional pentavalent antimonials, and one excisional surgery). TNF-α blockers were interrupted in 32 patients (65.3%). After treatment 5 patients (10.2%) relapsed. Four patients with a CL (3 initially treated with local therapy maintaining TNF-α blockers and one treated with miltefosine) and one patient with VL treated with L-AmB maintaining TNF-α blockers.ConclusionsThis data supports the assumption that the blockage of TNF-α modifies clinical expression of leishmaniasis in endemic population modulating the expression of the disease leading to atypical presentations. According to the cases reported, the best treatment strategy would be a systemic drug and the discontinuation of the TNF-α blockers therapy until clinical resolution.

Therapeutic drug monitoring of biologics in psoriasis.

Biologics are an important component of the armamentarium of drugs in the treatment of moderate to severe psoriasis. There is increasing evidence that therapeutic drug monitoring (TDM) encompassing the measurement of trough concentrations and anti-drug antibodies (ADA), together with clinical response is emerging as a valuable tool for clinical decision making. It aids in targeted dose adjustments in patients with low drug concentrations, monitoring of adherence and assessment of patients who lose response to biologics or do not respond at all. The high prevalence of psoriasis, its impact on patients’ lives and costs spent on therapy motivate an evidence-based and cost-effective utility of biologics. We performed a literature review on the TDM of TNF alpha antagonists (adalimumab, infliximab, etanercept), IL12/23 antagonists (ustekinumab, guselkumab, tildrakizumab), IL17A inhibitors (secukinumab, ixekizumab) and biosimilars used in the treatment of psoriasis. Although establishing target therapeutic ranges for biologics is ideal, this has only been explored in adalimumab. We also propose a treatment algorithm for the practical application of TDM depending on drug trough concentrations, presence/absence of anti-drug antibodies and clinical response of patients. The practice of TDM is recommended in routine clinical practice where possible.

Molecular Dynamics Simulation Estrogen Receptor Alpha againts Andrographolide as Anti Breast Cancer

Breast cancer is the most common cancer suffered by women with 1.67 million new cases in the world by 2012 with a mortality rate of 12.9%. Tamoxifen is a standard therapy for breast cancer but can cause endometrial and thromboembolic cancer. Andrografolid is an active compound from Andrographis paniculata which has antiproliferation activity of MCF-7 breast cancer cells with IC50 was 61.11 μM. The purpose of this study was to design andrographolide modification structures as human estrogen receptor alpha (hER-α) antagonists. Molecular docking simulation results showed that the andrographolide and AND5 (best andrographolide derivative) have free binding energy (ΔG) values were -9.65 kcal/mol and -12.43 kcal/mol, respectively, and hydrogen bonds were formed with Gly521, Asp351, and Met343. The ΔG value of ANDS was lower than tamoxifen (-11.40 kcal/mol). Pharmacophore modeling results showed that andrographolide and AND5 had a high pharmacophore-fit value of 46.39% and 63.47%, respectively. Molecular dynamics simulation using MM-PBSA calculation method, showed that the hERα-AND5 system has a value of ΔGTOTAL = -50.52 kcal/mol compared to the hERα-estradiol system as an agonist with a value of ∆GTOTAL = -40.86 kcal/mol . These results suggested that AND5 has better affinity for hERα compared to estradiol so that AND5 is a very promising anti breast cancer agent.Keywords: Andrographolide, molecular dynamics, breast cancer, molecular docking, estrogen receptor alpha

Acute prazosin administration does not reduce stressor reactivity in healthy adults.

Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the norepinephrine alpha-1 receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test cross-species neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders. We hypothesized that acute administration of prazosin, a noradrenergic alpha-1 antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task. We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which 64 healthy adults (32 female) completed the NPU task at two visits (2mg prazosin vs. placebo). A single acute dose of 2mg prazosin did not reduce stress reactivity in a healthy adult sample. Neither NPU startle potentiation nor self-reported anxiety was reduced by prazosin (vs. placebo) during unpredictable (vs. predictable) stressors. Further research is needed to determine whether this failure to translate preclinical neuroscience to human laboratory models is due to methodological factors (e.g., acute vs. chronic drug administration, brain penetration, study population) and/or suggests limited clinical utility of noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.

Soluble Epoxide Hydrolase Inhibitor t-AUCB Promotes Murine Brown Adipogenesis: Role of PPAR Gamma and PPAR Alpha (P21-069-19)

ObjectivesBrown adipose tissue has recently emerged as a novel target for obesity treatment and prevention. In contrast to the lipid storing function of white adipocytes, brown adipocytes are responsible for dissipating energy as heat, a process involving uncoupling protein 1 (UCP1). Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that converts epoxy fatty acids (EpFAs) into less active diols. By stabilizing endogenous EpFAs, potent small molecule sEH inhibitors have been shown to be beneficial for many chronic diseases. Several recent papers have reported that sEH inhibitors are able to reduce diet-induced obesity, possibly by upregulating UCP1 expression. In the current study, we sought to study the mechanisms by which sEH inhibitor acts on brown preadipocytes. MethodsThe effects of a potent sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), on murine brown adipocyte differentiation were evaluated by lipid accumulation and expression of brown adipocyte marker genes. PPAR alpha and PPAR gamma activation by t-AUCB was measured by their respective transactivation assays. The roles of PPARs were further studied by pharmacological antagonism and knockdown experiments by small RNA interference. ResultsWe report that sEH expression was increased during murine brown adipocyte differentiation. t-AUCB dose-dependently promoted brown adipocyte differentiation. Moreover, we demonstrate that t-AUCB activated PPAR alpha, but not PPAR gamma. t-AUCB-induced upregulation of thermogenic gene Ucp1 and Pgc1 alpha and the general differentiation marker Fabp4 were significantly attenuated by the antagonist of PPAR alpha, GW6471. In contrast, they were only partially attenuated by the antagonist of PPAR gamma, GW9662, and specific knockdown of PPAR gamma. ConclusionsOur findings suggest that sEH may regulate brown adipogenesis and sEH pharmacological inhibition by t-AUCB promotes brown adipogenesis, possibly through activation of PPAR alpha. Funding SourcesThe work is supported by NIH 1R15DK114790-01A1 (to LZ), R00DK100736 (to AB) and R01ES002710 (to BDH).

The in vivo developmental toxicity of diethylstilbestrol (DES) in rat evaluated by an alternative testing strategy

In the present study, we evaluated an alternative testing strategy to quantitatively predict the in vivo developmental toxicity of the synthetic hormone diethylstilbestrol (DES). To this end, a physiologically based kinetic (PBK) model was defined that was subsequently used to translate concentration–response data for the in vitro developmental toxicity of DES, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose–response data for developmental toxicity. The previous studies showed that the PBK model-facilitated reverse dosimetry approach is a useful approach to quantitatively predict the developmental toxicity of several developmental toxins. The results obtained in the present study show that the PBK model adequately predicted DES blood concentrations in rats. Further studies revealed that DES tested positive in the ES-D3 differentiation assay and that DES-induced inhibition of the ES-D3 cell differentiation could be counteracted by the estrogen receptor alpha (ERα) antagonist fulvestrant, indicating that the in vitro ES-D3 cell differentiation assay was able to mimic the role of ERα reported in the mode of action underlying the developmental toxicity of DES in vivo. In spite of this, combining these in vitro data with the PBK model did not adequately predict the in vivo developmental toxicity of DES in a quantitative way. It is concluded that although the EST qualifies DES as a developmental toxin and detects the role of ERα in this process, the ES-D3 cell differentiation assay of the EST apparently does not adequately capture the processes underlying DES-induced developmental toxicity in vivo.

Phase 1/1b multicenter trial of TPST-1120, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist as a single agent (SA) or in combination in patients with advanced solid tumors.

TPS2665 Background: Tumor cells initially favor glucose metabolism via aerobic glycolysis. As tumors rapidly proliferate and metastasize, glucose stores are depleted and facilitated by a hypoxic tumor microenvironment (TME) and metabolic reprogramming shifts intracellular metabolism(IcM) towards fatty acid oxidation (FAO). Fatty acids support metabolism of suppressive immune cells in the TME in addition to tumor growth. PPARα is a ligand-activated nuclear transcription factor which regulates lipid metabolism and FAO. TPST-1120 is a first in class, oral selective PPARα antagonist that blocks transcription of PPARα target genes leading to an intracellular metabolism shift from FAO to glycolysis. Reduction of fatty acids in the TME leads to direct killing of tumor cells dependent on FAO, skews macrophages from immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells. TPST-1120 also restores thrombospondin-1, a known natural inhibitor of angiogenesis, to homeostatic levels within the TME. TPST-1120 has an IC50 of 0.04 nM with &gt; 35 fold selectivity over other PPAR isoforms. Preclinical studies in multiple tumor models show efficacy of TPST-1120 as a SA and in combination(combo) with an anti-PD1 monoclonal antibody (mAb) and chemotherapy. Methods: We have initiated a phase 1/1b multicenter, open label Dose Escalation (DEs) and Dose Expansion (DEx) trial to evaluate TPST-1120 as a SA and in combo with nivolumab, an anti-PD1 mAb; docetaxel, a chemotherapeutic agent and cetuximab, an anti-EGFR mAb. Objectives: 1) evaluate safety and tolerability of continuous dosing of TPST-1120 2) identify a recommended phase 2 dose (RP2D) and 3) evaluate efficacy. Eligibility: 1) patients with select advanced solid tumors who have failed 1 and up to 5 prior therapies. This phase 1/1b adaptive design has 4 DEs arms, 1 SA arm and 3 combination arms in which TPST-1120 is combined with nivolumab, docetaxel or cetuximab. The RP2D of TPST-1120 to proceed to DEx will be determined by safety and biomarkers during DEs. The DEx arms have 8 histology-specific cohorts, 4 SA arms and 4 combo arms and will follow a 2-stage expansion design. Biomarker analyses include gene expression profiling of PPARα-associated genes, tumor markers of immune modulation and serum lipid profiling. The total sample size is up to 338 pts. This trial is accruing at U.S sites. Clinical trial information: NCT03829436.

Su1857 – Comparative Safety and Effectiveness of Tumor Necrosis Factor Alpha Antagonists and Vedolizumab in Older IBD Patients: A Multicenter Study

Su1857 – Comparative Safety and Effectiveness of Tumor Necrosis Factor Alpha Antagonists and Vedolizumab in Older IBD Patients: A Multicenter Study

Disparities in care among patients presenting to the emergency department for urinary stone disease.

To determine whether patients with ureteral stones received different standard of care in the emergency department (ED) according to various sociodemographic factors. We conducted a retrospective study of patients presenting to EDs in a large tertiary-care hospital in the Bronx, New York with a diagnosis of ureteral stones. Electronic chart review was used to assess each patient's ED course and to gather socio-demographic information. The primary outcomes of interest were administration of pain medication, prescription of alpha-1 antagonists to facilitate stone passage, and whether or not patients received CT scan or ultrasound. Associations of these outcomes with age categories, sex, race/ethnicity, BMI category, socioeconomic status and insurance status were examined using multivariate logistic regression models. 1200 patients were included in this analysis of which 616 (51%) were women. A large proportion of patients were minorities: 40% Hispanic, 15% non-Hispanic Black, and 20% other/multiracial. Patients aged 55-64years and those 65 or older were less likely to receive pain medication compared to patients < 35years (OR = 0.48, 95% CI 0.27-0.86, p = 0.01 and OR = 0.46, 95% CI 0.21-1.00, p = 0.05, respectively). Women were less likely than men to undergo any form of diagnostic imaging (OR = 0.52, 95% CI 0.35-0.76, p = 0.001). Similarly, patients in the lowest quintile of SES received less imaging than patients in the highest SES group (OR = 0.50, 95% CI 0.27-0.90, p = 0.02). Finally, women were less likely to receive alpha blockade compared to men (OR = 0.68, 95% CI 0.49-0.92, p = 0.014). Multiple disparities exist among patients presenting to the emergency department for ureteral stones.

Estrogen Receptor Covalent Antagonists: The Best Is Yet to Come.

The development of tamoxifen and subsequent estrogen receptor alpha (ERα) antagonists represents a tremendous therapeutic breakthrough in the treatment of breast cancer. Despite the ability of ERα antagonists to increase survival rates, resistance to these therapies is an all-too-common occurrence. The majority of resistant tumors, including those with hotspot mutations in the ligand-binding domain of ERα, remain dependent on ERα signaling, indicating that either a more potent or novel class of antagonist could have clinical benefit. With this thought in mind, we developed a novel ERα antagonist that exhibits enhanced potency due to its ability to covalently target a unique cysteine in ER. This review describes the design of this antagonist, H3B-5942, and discusses opportunities for future improvements, which could reduce the risk of escape mutations to this therapeutic modality.

Dibutyltin dichloride is a potent PPAR alpha antagonist

Organotins are endocrine disruptors and a widely distributed environmental chemical. The best‐studied organotin is tributyltin (TBT), which has been shown to bind to PPAR gamma/RXR alpha and induces adipogenesis in different mammalian cells. Dibutyltin (DBT) is another organotin used as a stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from TBT in vivo. Recently, we demonstrated that DBTs are PPARγ partial agonists and that DBT chloride and dilaurate are also partial RXRα agonists. Additionally, DBTs induce adipogenesis in a PPARγ‐dependent manner and repress inflammatory genes in preadipocyte cell culture. However, the role of DBTs on PPAR alpha is still unknown. In the present study, we investigate the effect of dibutyltins pharmacological effects on PPAR alpha in mammalian cells. In reporter gene assay using HeLa cells, we observed that dibutyltins do not display an agonist effect on PPAR alpha. Therefore, we decided to explore the antagonistic effects on PPARα. In the cell‐based reporter gene assay, treatment with PPAR alpha agonist (bezafibrate) induced a 3.3‐fold activation on PPAR alpha. On the other hand, DBT dilaurate and DBT dichloride produced a dose‐dependently inhibition of the PPAR alpha transcription transactivation induced by bezafibrate. These effects were not due to the cytotoxicity. Next, we compared the antagonistic results of DBT dilaurate and DBT dichloride to GW6471, a well‐known synthetic specific PPAR alpha antagonist. Transfected cells were treated with vehicle, an increasing concentration of DBT dilaurate, DBT dichloride or GW6471 in the presence of Bezafibrate (10μM). Bezafibrate activation in the absence of antagonist was considered as 100%. The percentage of GW6471, DBT dilaurate, and DBT dichloride were calculated in comparison to bezafibrate. DBT dilaurate and DBT dichloride showed a dose‐dependent inhibition of bezafibrate induced PPARα transcriptional activity. The median inhibitory concentration (IC50) of DBT dilaurate (4.1μM) was significantly higher than GW647, which displayed an IC50 value of 0.13μM. However, IC50 of DBT dichloride upon PPAR alpha was significantly lower (0.26μM) and similar to GW647. Therefore, DBT dilaurate was considered as a weak antagonist, while the dibutyltin dichloride displayed a potent antagonist effect on PPAR alpha. Next, to further characterize these effects on a physiological assay, we analyzed the catalase activity induced by WKY14643, a PPAR alpha agonist in the presence and absence of DBT dilaurate and DBT dichloride in HepG2 and HFF‐1 cells. As was observed with GW647, DBT dilaurate and DBT dichloride inhibited the catalase activity induced by WKY14643 in a dose‐dependent manner. These results showed for the first time that DBT dilaurate and dichloride display a PPAR alpha antagonist effect.Support or Funding InformationNational Council for Scientific and Technological Development–Grant number: CNPq 486613/2013‐5 and Fundacao de Apoio a Pesquisa do Distrito Federal ‐ FAPDF ‐ Edital 04/2017.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.