Chronic Regimen Research Articles

Vascular Function in Continuous‐Flow Left Ventricular Assist Device Recipients: Effect of a 6‐Week Pulsatility Treatment Regimen.

Vascular function is further diminished in chronic heart failure patients implanted with a continuous‐flow left ventricular assist device (LVAD), which contributes to vascular‐related adverse events. A single pulsatility treatment has been documented to recover vascular function, however, the impact of a chronic treatment regimen is unknown.MethodsEleven LVAD recipients and ten well‐matched controls, received unilateral, 45‐minute, arm pulsatility treatment, created by intermittent cuff inflation and deflation (2‐second duty cycle), distal to the elbow, three days a week for 6 weeks. Vascular function was assessed by percent brachial artery flow mediated dilation (%FMD) (Doppler ultrasound).ResultsAt baseline, %FMD was not different between LVAD recipients (4.2±0.3%) and controls (4.4±0.4 %), while LVAD recipients exhibited an attenuated %FMD/Shear (LVAD: 0.09±0.01; Controls: 0.14±0.01 %/s−1, p<0.05) and a longer time‐to‐peak dilation (LVAD: 85±6; Controls: 51±5 s, p<0.05). Pulsatility index (PI) was lower in the LVAD recipients compared to controls (LVAD: 2±1; Controls: 13±2 AU, p<0.05). Importantly, during the pulsatility treatment, the PI level was not different between groups (LVAD: 28±5; Controls: 34±5 AU). Although time‐to‐peak dilation was not altered by 6‐weeks of pulsatility treatment, %FMD (LVAD: 7.9±0.5; Controls: 7.3±0.7 %) and %FMD/Shear (LVAD: 0.16±0.02; Controls: 0.26±0.03 %/s−1) improved significantly. Notably, %FMD/Shear in the LVAD recipients recovered to the baseline level of controls. All measures returned to baseline levels after a 6‐week washout period.ConclusionsA 6‐week pulsatility treatment regimen restored vascular function in LVAD recipients, demonstrating the efficacy of a pulsatility targeted intervention to potentially mitigate vascular related adverse events in this population.Support or Funding InformationCOI: Dr. Stavros G. Drakos serves on the Steering Committee of the Abbott‐sponsored INTELLECT‐2 LVAD. Funding: This research was supported by the National Institutes of Health (1T322HL13945, R01HL118313) and the U.S. Veteran’s Administration (E6910‐R, E1697‐R, E1433‐P, E9275‐L, E1572‐P, and I01RX001311).

Observational Study Relapsed or Refractory Chronic Lymphocytic Leukemia Venetoclax-based Regimens Outside Clinical Trials in Italy

Observational Study Relapsed or Refractory Chronic Lymphocytic Leukemia Venetoclax-based Regimens Outside Clinical Trials in Italy

Effectiveness of interventions targeting self-regulation to improve adherence to chronic disease medications: a meta-review of meta-analyses

ABSTRACTAdherence to chronic disease medication regimens depends in part on successful self-regulation. However, the overall benefit of interventions targeting self-regulatory mechanisms is not well-understood. Accordingly, we conducted a meta-review of meta-analyses assessing the effect of interventions targeting self-regulation on medication adherence. For this meta-review, meta-analyses appearing between January 2006 and March 2019 were eligible if they included experimental trials that assessed the effect of an intervention targeting self-regulation on adherence to chronic disease medication. A systematic literature search of multiple databases for published and unpublished literature identified 16,001 abstracts. Twelve meta-analyses met eligibility criteria and had variable quality according to AMSTAR 2 item completion (M = 50%; range: 31–66%). Overall, meta-reviews showed small to medium effect sizes for interventions that targeted self-monitoring, provided personalised feedback on adherence, or involved complete self-management. Other interventions, such as goal setting, barrier identification and problem solving, and stress management showed little evidence of improving adherence. Only a limited number of self-regulation intervention components were able to be evaluated. Additional research is needed to advance the understanding of the efficacy of adherence interventions focussed on self-regulation by expanding the scope of self-regulation elements targeted (e.g., emotion regulation).

The stair-step approach in treatment of anovulatory PCOS patients.

Clomiphene citrate (CC) is a widely accepted first-line treatment for anovulatory patients with polycystic ovarian syndrome (PCOS). The current practice is to prescribe CC with gradual dose increments until ovulation is achieved. Typically, progesterone withdrawal bleeding is induced between each dose increment and before the commencement of gonadotropin therapy in CC-resistant patients. It has been recently suggested that dose increments of CC can be administered once failure to induce ovulation at a certain dose has been documented, without induction of progesterone withdrawal bleeding, and this approach has been nicknamed the clomiphene-citrate stair-step (CC-SS) protocol. The same principle has been found feasible before introducing gonadotropin therapy in CC-resistant PCOS patients. Our objective was to review the world literature on the CC-SS protocol and to summarize our own experience with extending the CC-SS approach to initiation of gonadotropin therapy. Studies on CC-SS protocol (n = 4) have found that this approach leads to a significant reduction of the time to ovulation and to an increased ovulation rate. In our own retrospective case series, 18 CC-resistant PCOS patients initiated gonadotropin stimulation without induction of progesterone withdrawal bleeding, using the chronic low-dose regimen. The time to ovulation in the study group was 54.2 ± 6.2 days, while the estimated time to ovulation calculated according to the traditional approach was approximately 110 days. The clinical pregnancy rate was 44% (8/18), and all pregnancies were singletons. One patient miscarried; hence, the live birth rate was 38.9% (7/18). In summary, the CC-SS approach and its extension to the initiation of gonadotropin therapy results in considerable reduction of the time to ovulation, and favorable ovulation rates and reproductive outcome. Large-scale confirmation of these findings by properly designed randomized controlled trials may lead to a change of practice in the treatment of anovulatory infertility in PCOS patients, allowing simplification of treatment and a shorter time to ovulation and pregnancy.

Angiotensin-Converting Enzyme Inhibitor Induced Angioedema Occurring after 8 Years of Taking Lisinopril: A Case Report

Angiotensin-converting enzyme inhibitor induced angioedema (AIIA) can vary from mild to life-threatening. A vast majority of cases of AIIA occur within a month of starting an angiotensin-converting enzyme-inhibitor (ACE-I). We present a 48-year-old male who presented with respiratory failure secondary to AIIA, after being on lisinopril for over 8 years. He had no previous complications secondary to lisinopril and aside from smoking, carried no risk factors for AIIA. Despite conventional treatment for angioedema, he had a prolonged stay in the Medical Intensive Care Unit (MICU). Following discharge, there hasn’t been a recurrence of AIIA since the discontinuation of lisinopril. The case is intended to caution that AIIA remains possible even late into a chronic regimen of ACE-I. This is a risk that shouldn’t be neglected, even with sparse risk factors or longer duration of ACE-I use. Conventional treatment is not currently in line with proposed etiologies of AIIA. We advocate for more clinical trials involving pharmaceutical agents targeting bradykinin accumulation.

Chronic opioid pretreatment potentiates the sensitization of fear learning by trauma

Despite the large comorbidity between PTSD and opioid use disorders, as well as the common treatment of physical injuries resulting from trauma with opioids, the ability of opioid treatments to subsequently modify PTSD-related behavior has not been well studied. Using the stress-enhanced fear learning (SEFL) model for PTSD, we characterized the impact of chronic opioid regimens on the sensitization of fear learning seen following traumatic stress in mice. We demonstrate for the first time that chronic opioid pretreatment is able to robustly augment associative fear learning. Highlighting aversive learning as the cognitive process mediating this behavioral outcome, these changes were observed after a considerable period of drug cessation, generalized to learning about multiple aversive stimuli, were not due to changes in stimulus sensitivity or basal anxiety, and correlated with a marker of synaptic plasticity within the basolateral amygdala. Additionally, these changes were not observed when opioids were given after the traumatic event. Moreover, we found that neither reducing the frequency of opioid administration nor bidirectional manipulation of acute withdrawal impacted the subsequent enhancement in fear learning seen. Given the fundamental role of associative fear learning in the generation and progression of PTSD, these findings are of direct translational relevance to the comorbidity between opioid dependence and PTSD, and they are also pertinent to the use of opioids for treating pain resulting from traumas involving physical injuries.

The Relationship Between Cumulative Exogenous Corticosteroid Exposure and Volumes of Hippocampal Subfields and Surrounding Structures.

Glucocorticoids are a class of hormones that include naturally occurring cortisol and corticosterone, as well as prescription drugs commonly used to manage inflammatory, autoimmune, and allergic conditions. Adverse effects, including neuropsychiatric symptoms, are common. The hippocampus appears to be especially sensitive to the effects of glucocorticoids. However, to our knowledge, no studies to date have examined hippocampal subfields in humans receiving glucocorticoids. We examined patients on chronic glucocorticoid regimens to determine relationships between dose and duration of treatment, and hippocampal subfields, and related regions volumes. The study included adult men and women receiving at least 5 mg daily of prednisone equivalents for at least 6 months. Volumes of brain regions were measured via magnetic resonance imaging. A multivariate general linear model was used for analysis, with brain volumes as dependent variables and age, sex, and cumulative corticosteroid exposure, as predictors. The study population consisted of 81 adult outpatients (43 male) on corticosteroids (mean dose, 7.88 mg; mean duration, 76.75 months). Cumulative glucocorticoid exposure was negatively associated with left and right hippocampal dentate gyrus/CA3 volume. In subsequent subgroup analysis, this association held true for the age group older than the median age of 46 years but not for the younger age group. This finding is consistent with previous studies showing detrimental effects of elevated glucocorticoids on the hippocampus but further suggests that the dentate gyrus and CA3 regions are particularly vulnerable to those effects, which is consistent with animal models of chronic stress but has not been previously demonstrated in humans.

Pediatric heart transplantation in the current era.

To provide an international perspective and current review of pediatric heart transplantation (PHTx). Waitlist survival and long-term outcomes in PHTx continue to improve. Strategies to maximize donor pool utilization include ABO incompatible listing for infants and expanded donor-to-recipient weight ranges. However, there is a high degree of practice variation internationally, from listing strategies and donor acceptance practices to chronic immunosuppression regimens, long-term graft surveillance, and consideration for retransplantation. Common indications for PHTx include end-stage congenital heart disease and cardiomyopathy. Current median graft survival among PHTx recipients ranges from 13 to 22 years. Common morbidities include infection, rejection, renal dysfunction, coronary allograft vasculopathy, and posttransplant lymphoproliferative disease. International registry data, collaborative initiatives to standardize management, and multicenter studies continue to improve knowledge and advancement of the field.

Brain Reward Function after Chronic and Binge Methamphetamine Regimens in Mice Expressing the HIV-1 TAT Protein.

Methamphetamine abuse and human immunodeficiency virus (HIV) are common comorbidities. HIV-associated proteins, such as the regulatory protein TAT, may contribute to brain reward dysfunction, inducing an altered sensitivity to methamphetamine reward and/or withdrawal in this population. These studies examined the combined effects of TAT protein expression and, chronic and binge methamphetamine regimens on brain reward function. Transgenic mice with inducible brain expression of the TAT protein were exposed to either saline, a chronic, or a binge methamphetamine regimen. TAT expression was induced via doxycycline treatment during the last week of methamphetamine exposure. Brain reward function was assessed daily throughout the regimens, using the intracranial self-stimulation procedure, and after a subsequent acute methamphetamine challenge. Both methamphetamine regimens induced withdrawal-related decreases in reward function. TAT expression substantially, but not significantly increased the withdrawal associated with exposure to the binge regimen compared to the chronic regimen, but did not alter the response to acute methamphetamine challenge. TAT expression also led to persistent changes in adenosine 2B receptor expression in the caudate putamen, regardless of methamphetamine exposure. These results suggest that TAT expression may differentially affect brain reward function, dependent on the pattern of methamphetamine exposure. The subtle effects observed in these studies highlight that longer-term TAT expression, or its induction at earlier stages of methamphetamine exposure, may be more consequential at inducing behavioral and neurochemical effects.

Supporting Physicians and Practice Teams in Efforts to Address the Opioid Epidemic.

Primary care physicians and practice teams increasingly recognize the need to take a role in addressing the growing epidemic of opioid use disorder (OUD) and opioid-related drug overdose deaths, but face considerable challenges in doing so. Through its work supporting practice transformation efforts, sharing innovations, and connecting key sectors within communities, the Network for Regional Healthcare Improvement and several of its member regional health improvement collaboratives have identified innovative ways to support physicians and practice teams in transforming practice in ways that address a spectrum of issues related to opioid use. These strategies include efforts to prevent, identify, and treat opioid addiction, including reducing inappropriate prescribing; improving opioid prescribing safety; compassionately tapering chronic and/or high-dose opioid regimens; appropriately screening for and identifying OUD; initiating treatment with evidence-based medications for OUD within practice settings; and prescribing life-saving naloxone to reverse opioid overdose. By outlining specific initiatives and practice transformation efforts that several regional health improvement collaboratives across the country have implemented to support clinicians and their teams, this article offers examples of how clinicians can get support from collaboratives in their region to implement practice improvement efforts to advance this critically important work.

Tualang honey and DHA-rich fish oil reduce the production of pro-inflammatory cytokines in the rat brain following exposure to chronic stress.

ObjectivesThe aim of the present study was to investigate the effects of Tualang honey (TH), DHA-rich fish oil, and their combination on the concentrations of selected pro-inflammatory cytokines in rat brains following exposure to chronic stress.MethodsFifty male Sprague–Dawley rats were divided into (i) control, (ii) stress-exposed, (iii) stress-exposed and treated with TH (1 g/kg body weight twice daily via oral gavage), (iv) stress-exposed and treated with DHA-rich fish oil (450 mg/kg body weight twice daily via oral gavage), and (v) stress-exposed and treated with a combination of TH and DHA-rich fish oil. The chronic stress regimen consisted of a combination of restraint stress and a swim stress test for 28 days. The concentrations of selected pro-inflammatory cytokines in brain homogenates (TNF-α, IL6, and IFN-γ) were measured by ELISA.ResultsThe concentrations of TNF-α, IL6, and IFN-γ in brain homogenates from the DHA, TH, and TH + DHA-treated groups were significantly lower compared to the control and stress-only-exposed groups (p < 0.05), but no difference was observed between treatment groups.ConclusionConsumption of DHA-rich fish oil and TH can be effective in lowering pro-inflammatory cytokine levels in the brains of rats under chronic stress conditions. However, consuming these agents together does not provide additional benefits compared to taking them separately.

Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival

Vascularized composite allotransplantation (VCA), such as hand and face transplantation, is emerging as a potential solution in patients that suffered severe injuries. However, adverse effects of chronic high-dose immunosuppression regimens strongly limit the access to these procedures. In this study, we developed an in situ forming implant (ISFI) loaded with rapamycin to promote VCA acceptance. We hypothesized that the sustained delivery of low-dose rapamycin in proximity to the graft may promote graft survival and induce an immunoregulatory microenvironment, boosting the expansion of T regulatory cells (Treg). In vitro and in vivo analysis of rapamycin-loaded ISFI (Rapa-ISFI) showed sustained drug release with subtherapeutic systemic levels and persistent tissue levels. A single injection of Rapa-ISFI in the groin on the same side as a transplanted limb significantly prolonged VCA survival. Moreover, treatment with Rapa-ISFI increased the levels of multilineage mixed chimerism and the frequency of Treg both in the circulation and VCA-skin. Our study shows that Rapa-ISFI therapy represents a promising approach for minimizing immunosuppression, decreasing toxicity and increasing patient compliance. Importantly, the use of such a delivery system may favor the reprogramming of allogeneic responses towards a regulatory function in VCA and, potentially, in other transplants and inflammatory conditions.

The AT1 Receptor Antagonist Losartan Does Not Affect Depressive-Like State and Memory Impairment Evoked by Chronic Stressors in Rats.

The present study investigated the effect of the treatment with the angiotensin II type 1 receptor (AT1) antagonist losartan in the depressive-like state and memory impairment evoked by exposure to either homotypic (i.e., repeated exposure to the same type of stressor) or heterotypic (i.e., exposure to different aversive stimuli) chronic stressors in rats. For this, male Wistar rats were subjected to a 10 days regimen of repeated restraint stress (RRS, homotypic stressor) or chronic variable stress (CVS, heterotypic stressor) while being concurrently treated daily with losartan (30 mg/kg/day, p.o.). Depressive-like state was evaluated by analysis of the alterations considered as markers of depression (decreased sucrose preference and body weight and coat state deterioration), whereas cognitive non-emotional performance was tested using the novel object recognition (NOR) test. Locomotor activity was also evaluated in the open field test. Both RRS and CVS impaired sucrose preference and caused coat state deterioration, whereas only CVS impaired body weight gain. Besides, RRS impaired short-term memory (but not long-term memory) in the NOR test. Neither depressive-like state nor memory impairment evoked by the chronic stressors was affected by the treatment with losartan. Nevertheless, CVS increased the locomotion, which was inhibited by losartan. Taken together, these results provide evidence that the chronic treatment with losartan does not affect the depressive-like state and memory impairment evoked by either homotypic or heterotypic chronic stress regimens in rats.

Effect of chronic variable stress on sensitization to amphetamine in high and low sucrose-consuming rats.

Individual vulnerability to stress manifests in the interaction of innate properties and environment. There is a growing interest in the individual variability in vulnerability to stress and how it contributes to the development of psychiatric disorders. Intake of palatable substances is often measured in animal models. We have previously demonstrated that the consumption of sucrose solution is a stable trait in rats. The present study aimed to compare the sensitivity of rats with high vs low liquid sucrose consumption to chronic variable stress and the stress effect on behavioural sensitization to amphetamine. Male Wistar rats were subjected to a chronic stress regimen and subsequent repeated treatment with amphetamine (1 mg/kg, intraperitoneally). Fifty-kHz ultrasonic vocalizations, locomotor activity and stereotypies were measured. In no-stress baseline conditions, the behavioural response to acute amphetamine was similar in rats with high vs low sucrose consumption. Prior chronic stress potentiated the effect of amphetamine only in rats with high sucrose consumption. Behavioural sensitization to repeated administration of amphetamine was observed in non-stressed rats with lower sucrose preference, but not in the respective stressed group that had increased monoamine turnover in the nucleus accumbens. In contrast, in rats with high sucrose preference the amphetamine sensitization effect was prevalent in stressed rats, but not in non-stressed animals. Chronic stress can change the psychostimulant effect but this depends on the inherent reward sensitivity of the animal. Trait-wise, sucrose intake reflects vulnerability to chronic stress and may interact with the development of addiction.

PB2317 CHOICE OF VENOUS ACCESS FOR CHRONIC RED CELL EXCHANGE IN CHILDREN WITH SICKLE CELL DISEASE

Background:Among the options of chronic transfusion regimen in sickle cell anemia (SCA), red cell exchange (RCE) is the most efficient method.In pediatrics, permanent venous accesses minimize venous punctions and improve the quality of life. Port‐a‐cath (PAC) are the devices with the least infectious complications.The recommended size of the PAC is related to the patient's age and weightPatients with SCA have a higher risk of thrombotic complications.Aims:Our objective is to select the most versatile and small PACs, to reduce thrombotic risk, which allow adequate flows to perform RCE.Methods:Selection of PAC marketed in Europe with one and two lumen, depending on the size of the reservoir, catheter, speed and availability in EuropeEx vivo analysis of the maximum flows tolerated by the ”Spectra Optia“ machine during the RCE procedure, using expired red blood cell concentrates and Gripper needles of 19 and 20G.Implantation of the device and analysis of the efficacy of the procedure in 2 patients with SCA in a chronic transfusion regimen for 2 yearsResults:After a first screening, the Cardiva PHS Medical 10.5fr double‐lumen PACs were analyzed; Bard 9.5 fr and Vortex Angyodinamics 11.4 fr. As a PAC of single lumen, the Smart Port CT mini Angyodinamics of 6.6 fr was analyzed, in order to use an extraction PAC and a return one for the same vessel.The catheters that showed better results were those of Angyodinamics, using Gripper of 19G and reaching flows of 25‐30 ml / min.Among these PACs, we selected the 6.6 fr of single lumen for the following reasons: smaller reservoir (more suitable for small and thin children), separate devices that allow only one of them to be replaced if a light is obstructed and because a Single‐light PAC could be sufficient if in the future Spectra Optima allows the unipuncture mode.In vivo, we successfully implanted the 2 PAC of single lumen selected in 2 patients of more than 40 kg, in which we were able to perform RCE every 6 weeks, during the last 2 years. The procedure is performed in an average of 3 hours. There have been no complications of thrombosis, obstruction or infection to date.Summary/Conclusion:The exvivo test allowed to discard devices not suitable for the procedure and to select a single lumen PAC model of 6.6 fr that allows sufficient flows to perform the chronic RCE in pediatric patients of any age and weight, minimizing the associated infectious and thrombotic risks to permanent accesses in patients with ACF.

Muted responses to Ag accumulation by plankton to chronic and pulse exposure to silver nanoparticles in a boreal lake

Silver nanoparticles (AgNPs) are an emerging class of contaminants with the potential to impact ecosystem structure and function. AgNPs are antimicrobial, suggesting that microbe-driven ecosystem functions may be particularly vulnerable to AgNP exposure. Predicting the environmental impacts of AgNPs requires in situ investigation of environmentally relevant dosing regimens over time scales that allow for ecosystem-level responses. We used 3000 L enclosures installed in a boreal lake to expose plankton communities to chronic and pulse AgNP dosing regimens with concentrations mimicking those recorded in natural waters. We compared temporal patterns of plankton responses, Ag accumulation, and ecosystem metabolism (i.e., daily ecosystem respiration, gross primary production, and net ecosystem production) for 6 weeks of chronic dosing and 3 weeks following a pulsed dose. Ag accumulated in microplankton and zooplankton, but carbon-specific Ag was nonlinear over time and generally did not predict plankton response. Ecosystem metabolism did not respond to either AgNP exposure type. This lack of response corresponded with weak microplankton responses in the chronic treatments but did not reflect the stronger microplankton response in the pulse treatment. Our results suggest that lake ecosystem metabolism is somewhat resistant to environmentally relevant concentrations of AgNPs and that organismal responses do not necessarily predict ecosystem-level responses.

Chronic unpredictable stress influenced the behavioral but not the neurodegenerative impact of paraquat

The impact of psychological stressors on the progression of motor and non-motor disturbances observed in Parkinson's disease (PD) has received little attention. Given that PD likely results from many different environmental “hits”, we were interested in whether a chronic unpredictable stressor regimen would act additively or possibly even synergistically to augment the impact of the toxicant, paraquat, which has previously been linked to PD. Our findings support the contention that paraquat itself acted as a systemic stressor, with the pesticide increasing plasma corticosterone, as well as altering glucocorticoid receptor (GR) expression in the hippocampus. Furthermore, stressed mice that also received paraquat displayed synergistic motor coordination impairment on a rotarod test and augmented signs of anhedonia (sucrose preference test). The individual stressor and paraquat treatments also caused a range of non-motor (e.g. open field, Y and plus mazes) deficits, but there were no signs of an interaction (neither additive nor synergistic) between the insults. Similarly, paraquat caused the expected loss of substantia nigra dopamine neurons and microglial activation, but this effect was not further influenced by the chronic stressor. Taken together, these results indicate that paraquat has many effects comparable to that of a more traditional stressor and that at least some behavioral measures (i.e. sucrose preference and rotarod) are augmented by the combined pesticide and stress treatments. Thus, although psychological stressors might not necessarily increase the neurodegenerative effects of the toxicant exposure, they may promote co-morbid behaviors pathology.

Chronic aerobic exercise: Lack of effect on brain CB1 receptor levels in adult rats

IntroductionExercise programs have been shown to be effective for both reducing risk for, and intervention following, substance abuse behaviors in both clinical and preclinical studies. Less is known, however, regarding the underlying neurobiological substrates involved in these changes in drug seeking behavior. In this study, we assessed cannabinoid receptor (CB1) levels throughout the brain which are key in endocannabinoid signaling following chronic aerobic exercise. MethodsMale and female Lewis young adult rats were grouped into exercise and sedentary groups at 8 weeks of age. Exercise rats ran on a treadmill at 10 m/min, 5 days/week, for 6 weeks, whereas sedentary rats remained in their home cage. Rats were euthanized after 6 weeks, and in vitro receptor autoradiography was performed using [3H] SR141716A to quantify CB1 receptors throughout the brain. ResultsExercise rats did not show significantly different [3H] SR141716A binding levels as compared to sedentary rats; however, an overall sex effect was found, where males had 29% higher [3H] SR141716A binding within the pyramidal layer of the hippocampus when compared to females. The chronic aerobic exercise regimen did not produce any changes in CB1 receptor levels. ConclusionsThe present study found that chronic exercise during young adulthood did not alter cannabinoid CB1 receptor levels in the brain. Therefore, previously reported decreased cocaine preference in parallel treated cohorts did not involve exercise induced changes in CB1 levels which is key for endocannabinoid signaling.

A phase II study of myeloablative allogeneic hematopoietic stem cell transplantation (aHSCT) for acute lymphoblastic leukemia (ALL) in older patients using fludarabine and total body irradiation (Flu/TBI).

TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI (12 Gy) is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing aHSCT, but with less NRM confering survival benefit over Cy/TBI 12 Gy. Methods: This study is a single center, single-arm phase II clinical trial of Flu 40 mg/m2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. Patients aged 40-65 years with ALL in CR, KPS ≥ 70, adequate organ function, and having HLA-matched sibling or unrelated donor will be eligible. The primary endpoint of the study is 1-year DFS post-transplant. Secondary endpoints include 1-year overall survival (OS), incidence and severity of acute and chronic GVHD, immune reconstitution and regimen related toxicity. The study has just finished accrual (January 2019) enrolling a total of 16 patients. This number of patients was pre-determined to give a probability ≤ 0.05 of concluding that the 1-year DFS rate exceeds 45%, and a probability of at least 0.80 of concluding that the 1-year DFS rate exceeds 45% (expecting 1-year DFS of 75%). Clinical trial information: NCT01991457.

Comparative Behavioral Studies of Rimonabant and a Peripherally Restricted CB1 Receptor Antagonist

In recent years, cannabinoid subtype 1 receptor (CB1R) antagonists have been developed to treat obesity and metabolic syndrome. Unfortunately, rimonabant (SR141716A) the first marketed drug produced CNS‐related adverse effects including depression and suicidal ideation and was withdrawn from the market. Recent data suggest that blockade of peripheral CB1R receptors can mitigate symptoms associated with metabolic syndrome independent of CNS effects. Therefore, CNS‐sparing CB1R antagonists that have limited transport across the blood‐brain‐barrier are under development. We have developed several potent, selective and drug‐like small molecule inverse agonists of CB1R with vastly reduced brain exposure (e.g. RTI‐1092915). As part of an integrated drug discovery program it was deemed prudent to evaluate lead compounds for evidence of possible neuropsychiatric side effects.First, a behavioral battery was performed in rats to assess the effects of rimonabant after acute and chronic dosing regimens. Rimonabant (vehicle, 3, 10 mg/kg) was administered i.p. 30 minutes prior to the simultaneous assessment of locomotor activity, grooming, feeding, and defecation. Rimonabant significantly decreased food consumption, decreased measures of locomotor activity, increased scratching and wet‐dog shakes, and increased defecation. Subsequently, animals were dosed daily but were always tested in a drug‐free state, as not to test the acute effects of the drug on top of the background of chronic dosing. The highest dose of rimonabant tested significantly decreased marble burying behavior, presumably anxiolysis, while there were trends for anxiogenic effects in the light‐dark box. In an attempt to clarify these results, behavioral tests including forced swim test and preference in two‐bottle choice for sucrose were performed, however there was no effect of treatment. Chronic treatment with rimonabant also significantly attenuated weight gain in these animals despite having ad libitum food.A similar battery of behaviors was performed to directly compare rimonabant (10 mg/kg) to RTI‐ 1092915 (3 mg/kg; a dose previously shown to reduce alcoholic steatosis). There were no significant effects with RTI‐1092915 while rimonabant again acutely decreased food intake, weight gain and locomotor activity. The chronic dosing of rimonabant, but not RTI‐1092915, significantly decreased time spent near an intruder animal in a social interaction paradigm.Our preliminary data suggests that certain behaviors, either after acute or chronic dosing, could be used to distinguish peripherally restricted and CNS penetrant CB1R antagonists. Specifically, social interaction could be used to assess the negative impact of chronic treatment with centrally‐acting CB1R antagonists. Finally, RTI‐1092915 shows no or mitigated negative effects in the behaviors tested. Therefore, RTI‐1092915 may be a lead candidate to treat metabolic syndrome and liver diseases through inhibition of peripheral CB1R receptors.Support or Funding InformationNIH DK100414, AA023256This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.