Chronic Regimen Research Articles

Abstract 14230: Effects of Oral Carbon Monoxide on Doxorubicin-Induced Cardiotoxicity

Introduction: Doxorubicin (DOX) and other anthracyclines comprise important anticancer drugs. However, anthracycline treatment-related cardiotoxicity is a major clinical problem for which there are currently no effective treatments. Low-dose carbon monoxide (CO) presents an exciting and promising approach to preventing anthracycline cardiotoxicity. Endogenous CO is generated in the body by heme oxygenase enzymes during the degradation of heme. There is a literature precedent that supports low-dose CO in providing cardioprotection without reducing DOX efficacy. Hypothesis: the present study aimed to test an oral formulation of CO (HBI-002) to attenuate DOX-induced cardiotoxicity. Methods: Male C57BL/6, 10 to 12-week-old mice were subjected to acute (single dose, 20mg/kg, i.p.), and chronic (ten doses, 2mg/kg, i.p., every other day) DOX regimens in combination with HBI-002 (10ml/kg) or vehicle (10ml/kg). Animals were sacrificed after one hour of single DOX injection to evaluate serum tissue damage markers, such as creatine kinase (CK), lactate dehydrogenase (LDH), and heme. Moreover, cardiac function was evaluated after seven days of single DOX injection and after a chronic DOX regimen by echocardiography. Results: Here, we show that after DOX injection, HBI-002 can prevent a rapid and early release of excess serum CK (Vehicle: 2547 ± 260 U/L vs. HBI-002: 1122 ± 168 U/L; p<0.05 ), LDH (Vehicle: 1390 ± 103 U/L vs. HBI-002: 1122 ± 168 U/L; p<0.05 ), and heme (Vehicle: 47.5 ± 6.7 uM vs. HBI-002: 5.3 ± 2.7 uM; p<0.05 ) levels. Moreover, we observed that HBI-002 prevented a decrease in the ejection fraction after seven days of a single dose of DOX (Vehicle: 54.3 ± 1.3% vs. HBI-002: 64.7 ± 7.5%; p<0.05 ), as well as after DOX chronic regimen (Vehicle: 44.5 ± 3.6% vs. HBI-002: 61.6 ± 5.4%; p<0.05 ). Finally, HBI-002 attenuated DOX-induced mortality compared to the vehicle-treated group. Conclusions: Collectively, these findings support HBI-002 as a promising cardioprotective agent against DOX toxicity and warrant further development as a therapeutic.

The Role of Hemoglobin and Hemolysis on Transcranial Doppler Velocities in Children with Sickle Cell Disease: Data from a Natural History Cohort

Background: Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events that can impact neurocognitive development and quality of life (Colombatti 2016). Transcranial Doppler ultrasound (TCD) is a validated screening tool to identify pediatric SCD patients with the highest risk of stroke to start on a preventive chronic blood transfusion regimen (Estcourt 2020; Inusa 2019). High TCD velocities are an indication to start disease-modifying treatments or consider disease-curative options in children with SCD (Khemani 2019). However, real-world pediatric data on the correlation between hematological variables and TCD results are scarce (Salama 2020). We aimed to evaluate the distribution of TCD velocities in a pediatric natural history cohort and investigate their correlation with hematological variables and treatments.Methods: We performed a retrospective analysis on data from a prospective pediatric cohort followed from January 1,2009, to December 31, 2020 (censoring date). Standard care includes annual TCD from 2 years of age. We used transcranial Doppler imaging (TCDi) and classified results according to STOP criteria, considering terminal internal carotid artery (TICA) and middle cerebral artery (MCA) time-averaged maximum mean velocities (TAMMVs). Only complete exams with right and left measures available for both vessels were included. Hematological, clinical, and treatment variables were available from the natural history cohort database. Patients were divided according to genotype: HbSS/HbSβ 0 or HbSC/HbSβ +.Two-sample and Welch t-tests for unequal variances were used to compare mean hemoglobin (Hb) values and hemolysis markers in patients with and without abnormal/conditional TCDi results. Fisher and chi-square tests were used to compare categorical variables. Linear regression models were used to assess the effects of MCA and TICA TAMMVs as continuous variables on Hb. Odds ratios (ORs) for neurological events at different Hb levels were estimated using generalized estimated equations (GEE) with a binomial distribution, logistic function, and exchangeable correlation structure, allowing for correlation among repeated observations for the same patient. Multivariable GEE including characteristics and treatment variables were used to evaluate the association between neurological events and Hb.Results: Of the 182 SCD patients in the cohort, 169 had assessments of cerebral vasculopathy, and 155 had evaluable TCDi (583 exams). The median follow-up of the entire cohort was 79.8 months (range: 2.1-298.6 months) (interquartile range [IQR]: 36.9-126.3 months). The median age at the censoring date was 13.4 years (IQR: 9.1-17.5 years); 130 were HbSS/HbSβ 0, and 25 were HbSC/HbSβ +. Basic demographic characteristics of the cohort are in Table 1. The distribution of TCDi results was significantly different between genotypes (P<0.0001): in the HbSC/HbSβ + group (70 exams), 14 were normal (20.0%), and 56 were low (80.0%); in the HbSS/HbSβ 0 group (513 exams), 8 were abnormal (1.6%), 56 were conditional (10.9%), 311 were normal (60.6%), and 138 were low (26.9%). Only 37/138 (26.8%) low TCDi results were confirmed as stenosis at the nearest MRA. Patients with abnormal/conditional TCDi results had lower Hb (8.4 vs 8.9 g/dL, P≤0.0001) and higher reticulocyte counts (317,766 vs 262,750/mm 3, P≤0.0001), lactate dehydrogenase (843 vs 690 U/L, P=0.0012), and aspartate aminotransferase (61 vs 54 U/L, P=0.0007) compared with patients with normal/low results.We detected a linear correlation between TICA/MCA TAMMVs and Hb (Figure 1A and 1B). Univariate analysis showed significant inverse correlation between abnormal/conditional TCDi results and Hb considered as a continuous variable (OR: 0.484, P<0.001). In the multivariate analysis, the correlation between TCDi results and Hb remained significant; moreover, the risk of presenting abnormal/conditional TCDi results decreased with age (OR: 0.833, P<0.0064).Conclusions: This analysis from our natural history cohort shows a significant inverse correlation between Hb and MCA and TICA velocities, supporting the beneficial effect of higher Hb levels in reducing TAMMV. Disease-modifying therapies increasing Hb and reducing hemolysis could be helpful in reducing TAMMV in children with SCD.Funding: This study was supported by Global Blood Therapeutics. [Display omitted] DisclosuresAgodoa: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Beaubrun: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Biffi: BlueBirdBio: Consultancy, Other: Advisory Board. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding.

Nrf2 Plays a Key Role in Iron-Overload Cardiomyopathy

Cardiomyopathy due to iron-overload is a severe complication of patients undergoing chronic transfusion regimen such as β-thalassemia and myelodysplastic syndromes. Previous studies have shown the key role of Nrf2, a redox-related transcriptional factor, in both β-thalassemia erythropoiesis and iron homeostasis (Matte A et al. ARS 2018, 2019; Lim PJ et al Nat Metab, 2019). Here, we compared Nrf2 knockout male mice (Nrf2 -/-) and C57BL-6J as wild-type (WT) controls, with a focus on cardiac function. Nrf2 -/- mice were characterized by a mild chronic hemolytic anemia associated with ineffective erythropoiesis, similar to what observed in murineβ-thalassemia (Toya SCM et al., Blood, 2019). Aging Nrf2 -/- mice developed systolic and diastolic dysfunction, associated with increased cardiac oxidative stress, degradation of the calcium-dependent SERCA2A transporter and activation of metalloproteinase MMP9, involved in both SERCA2A degradation and heart remodeling. In Nrf2 -/- mice, we observed increased plasma NTBI, heart iron deposition and elevated expression of cardiac ferroportin when compared to WT animals. Moreover, cardiac Hamp mRNA levels were down-regulated in aging Nrf2 -/- mice when compared to WT mice. This pattern was consistent with progressive cardiac iron overload in absence of Nrf2. Interestingly, activation of TGF-b receptor and PDGF-B-related pathway as well as increased collagen deposition were observed in hearts from 12 months old Nrf2 -/- mice. Taken together our data suggest an aging-associated development of iron-overload cardiomyopathy in mice genetically lacking Nrf2. To evaluate the role of Nrf2 in iron overload cardiomyopathy, Nrf2 -/- and WT mice were exposed to dietary iron supplementation (2.5% w/w carbonyl iron for 28 days). Nrf2 -/- mice developed cardiac hypertrophy which was accompanied by a worsening in collagen deposition and persistent activation of PDGF-B pathway. This was associated with inflammatory vasculopathy. The biologic importance of Nrf2 is supported by the cardiac activation of Nrf2, degradation of SERC2A and activation of TGF-b receptor and PDGF-B pathway in a mouse model of beta thalassemia intermedia, the Hbb3th/+ mice. Collectively our data support the crucial role of Nrf2 in the protection of cardiomyocytes against iron cytotoxicity which significantly develops in aging as well as in β-thalassemia. DisclosuresVinchi: Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vifor Pharma: Research Funding; PharmaNutra: Research Funding; Novartis: Research Funding. Ghigo: Kither Biotech: Other: Board member and Co-Founder. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board.

Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease.

After identification of lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 (NB-360), an inhibitor with a pKa of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.

DHA-rich fish oil and Tualang honey reduce chronic stress-induced oxidative damage in the brain of rat model

BackgroundExposure to chronic stress induces oxidative damage which alters the dynamic balance between antioxidant and pro-oxidant activities in the brain. Tualang honey (TH) is a Malaysian wild multifloral honey which has been shown to contain high amount antioxidants. DHA-rich fish oil is a form of omega-3 fatty acids found in fish which also possesses some antioxidant activity. This study aimed to evaluate anti-stress activity of DHA-rich fish oil, TH and their combination on several parameters of oxidative stress in chronic stress rat model. 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), (iv) stress-exposed and treated with DHA-rich fish oil (450 mg/kg body weight twice daily), 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. ResultsDHA-rich fish oil and TH significantly (p < 0.05) supressed stress-induced elevation of serum corticosterone and lipid peroxidation, and caused a significant increase in total antioxidant capacity. For glutathione status, only TH significantly reduced stress-induced elevation of oxidised glutathione (GSSG) and normalised GSH/GSSG ratio. Conclusion: Both DHA-rich fish oil and TH have protective effects against brain oxidative stress but consuming these substances together does not seem to provide an additional benefit compared to consuming them separately.

The emergence of insulin resistance following a chronic high-fat diet regimen coincides with an increase in the reinforcing effects of nicotine in a sex-dependent manner

The present study assessed the sex-dependent effects of insulin resistance on the reinforcing effects of nicotine. Female and male rats received a chronic high-fat diet (HFD) or regular diet (RD) for 8 weeks. A subset of rats then received vehicle or a dose of streptozotocin (STZ; 25 mg/kg) that induces insulin resistance. To assess insulin resistance, glucose levels were measured 15, 30, 60, 120, and 180 min after an insulin injection (0.75 U/kg). Nine days later, the rats were given extended access to intravenous self-administration (IVSA) of nicotine (0.015, 0.03, 0.06 mg/kg) in an operant box where they consumed their respective diet ad libitum and performed responses for water deliveries. Each nicotine dose was delivered for 4 days with 3 intermittent days of abstinence in their home cage. The day after the last IVSA session, physical signs were compared following administration of mecamylamine (3.0 mg/kg) to precipitate nicotine withdrawal. The results revealed that there were no changes in insulin resistance or nicotine intake in HFD alone rats regardless of sex. Insulin resistance was observed in HFD-fed rats that received STZ, and the magnitude of this effect was greater in males versus females. Our major finding was that nicotine intake was greater among HFD + STZ female rats as compared to males. Lastly, the physical signs of withdrawal were similar across all groups. Our results suggest that females diagnosed with disorders that disrupt insulin signaling, such as diabetes may be at risk of greater vulnerability to nicotine use due to enhanced reinforcing effects of this drug.

Commentary: Management of Refractory Pain After Total Joint Replacement

Chronic refractory pain after total joint replacement is debilitating and a source of dissatisfaction for patients. The management of pain following total joint replacement varies during the acute postoperative period compared to the 3 months postoperative at which point the pain is considered chronic pain. Acute postoperative pain relief programs have seen promising results with multimodal pain control through the use of combinations of opioids, acetaminophen, nonsteroidal anti-inflammatory drugs, gabapentinoids and ketamine. The addition of regional blocks to the multimodal regimen has improved acute postoperative pain control following total joint replacements. On the other hand, chronic pain can be successfully managed with options including genicular nerve radioablation therapy (GN-RFA), neuromuscular electrical stimulation (NMES), transcutaneous electrical nerve stimulation (TENS), and peripheral subcutaneous field stimulation (PSFS). While there is still minimal data on chronic pain relief regimens, meta-analyses and case reports have demonstrated the effectiveness and promising outcomes. This paper aims to evaluate the current medications and treatment options for managing refractory pain following TJA.

Multifunctional Arylsulfone and Arylsulfonamide-Based Ligands with Prominent Mood-Modulating Activity and Benign Safety Profile, Targeting Neuropsychiatric Symptoms of Dementia

The current pharmaceutical market lacks therapeutic agents designed to modulate behavioral disturbances associated with dementia. To address this unmet medical need, we designed multifunctional ligands characterized by a nanomolar affinity for clinically relevant targets that are associated with the disease pathology, namely, the 5-HT2A/6/7 and D2 receptors. Compounds that exhibited favorable functional efficacy, water solubility, and metabolic stability were selected for more detailed study. Pharmacological profiling revealed that compound 11 exerted pronounced antidepressant activity (MED 0.1 mg/kg), outperforming commonly available antidepressant drugs, while compound 16 elicited a robust anxiolytic activity (MED 1 mg/kg), exceeding comparator anxiolytics. In contrast to the existing psychotropic agents tested, the novel chemotypes did not negatively impact cognition. At a chronic dose regimen (25 days), 11 did not induce significant metabolic or adverse blood pressure disturbances. These promising therapeutic-like activities and benign safety profiles make the novel chemotypes potential treatment options for dementia patients.

Associations of Medication Regimen Complexity with COPD Medication Adherence and Control.

IntroductionMedication adherence is often low among people with chronic obstructive pulmonary disease (COPD) and medication regimen complexity may be a contributing factor. In this study, we sought to examine the role of medication regimen complexity in COPD medication adherence among patients with multimorbidity.MethodsWe performed cross-sectional analysis of data on COPD patients in primary care and pulmonary practices in New York City and Chicago (n=400). Regimen complexity was represented by the medication regimen complexity index (MRCI) and simple medication count. Adherence was measured by self-report and inhaler dose counts. Disease control measures included the COPD severity score (COPDSS) and the Medical Research Council (MRC) severity index.ResultsMean age of study participants was 69 years, 66% had MRC grades 4 or 5, and 45% had low medication adherence. MRCI scores did not differ significantly between those with and without adequate medication adherence. Patients with higher MRCI scores were more likely to have severe COPD (OR 5.00, 95% CI 1.46–17.1, p=0.01) and dyspnea grades 3 or 4 (OR 2.27, 95% CI 1.03–5.03, p=0.04). Significant associations of medication count with COPD severity were also observed.DiscussionThese findings demonstrate that among patients with COPD and comorbid hypertension and diabetes, higher medication regimen complexity is associated with worse COPD control but not with COPD medication adherence.

Interrogating the impact of combination antiretroviral therapies on HIV‐associated neurocognitive disorders

Although the advent of Combination Antiretroviral Therapy (cART) has greatly reduced the prevalence of HIV-Associated Dementia, the most severe form of HIV-Associated Neurocognitive Disorder (HAND), the incidence of the milder forms of HAND have risen. The explanations proposed include persistent central nervous system (CNS) viraemia and the neurotoxicity of chronic cART regimens. Nonetheless, controversies in HAND prevalence estimates, alongside a lack of consensus on the significance of CNS Penetration Effectiveness (CPE) have added to the complexity of elucidating the role of cART in HAND. The present review will evaluate the evidence underlying these explanations, as well as highlighting the need for improved trial designs and the incorporation of emerging biomarkers and neuroimaging tools. A review of the current literature investigating cART neurotoxicity, controversies in HAND prevalence estimates, CNS Penetration Effectiveness, and neuroprotective adjuvant therapies. Ultimately, the inadequacy of cART in achieving complete preservation of the CNS underscores the imminent need for neuroprotective adjuvant therapies, where the efficacy of combining multiple adjuvant classes presents a potential therapeutic frontier which must be interrogated.

Metformin generates profound alterations in systemic and tumor immunity with associated antitumor effects

BackgroundMetformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can...

Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360.

Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Aβ levels in mice, rats, and dogs in acute and chronic treatment regimens.

Putative Anti-Immobility Action of Acute Insulin Is Attributable to an Increase in Locomotor Activity in Healthy Wistar Rats

Background/Aims: Anti-immobility actions of insulin in diabetic rats that are subjected to the forced swim test (FST) have been reported. In this test, low doses of antidepressants exert actions after long-term treatment, without affecting locomotor activity in healthy rats. Few studies have compared acute and chronic actions of insulin with antidepressants in healthy rats. Methods: We hypothesized that if insulin exerts a true anti-immobility action, then its effects must be comparable to fluoxetine in both a 1-day treatment regimen and a 21-day treatment regimen in healthy, gonadally intact female Wistar rats. Results: The results showed that low levels of glycemia were produced by all treatments, including fluoxetine, and glycemia was lower in proestrus-estrus than in diestrus-metestrus. None of the treatments or regimens produced actions on indicators of anxiety in the elevated plus maze. Insulin in the 1-day regimen increased the number of crossings and rearings in the open field test and caused a low cumulative immobility time in the FST. These actions disappeared in the 21-day regimen. Compared with the other treatments, fluoxetine treatment alone or combined with insulin produced a longer latency to the first period of immobility and a shorter immobility time in the chronic regimen in the FST, without affecting locomotor activity, and more pronounced actions were observed in proestrus-estrus (i.e., a true anti-immobility effect). Conclusion: These results indicate that insulin does not produce a true antidepressant action in healthy rats. The purported antidepressant effects that were observed were instead attributable to an increase in locomotor activity only in the 1-day regimen.

BCLA CLEAR – Medical use of contact lenses

The medical use of contact lenses is a solution for many complex ocular conditions, including high refractive error, irregular astigmatism, primary and secondary corneal ectasia, disfiguring disease, and ocular surface disease. The development of highly oxygen permeable soft and rigid materials has extended the suitability of contact lenses for such applications. There is consistent evidence that bandage soft contact lenses, particularly silicone hydrogel lenses, improve epithelial healing and reduce pain in persistent epithelial defects, after trauma or surgery, and in corneal dystrophies. Drug delivery applications of contact lens hold promise for improving topical therapy. Modern scleral lens practice has achieved great success for both visual rehabilitation and therapeutic applications, including those requiring retention of a tear reservoir or protection from an adverse environment. This report offers a practical and relevant summary of the current evidence for the medical use of contact lenses for all eye care professionals including optometrists, ophthalmologists, opticians, and orthoptists. Topics covered include indications for use in both acute and chronic conditions, lens selection, patient selection, wear and care regimens, and recommended aftercare schedules. Prevention, presentation, and management of complications of medical use are reviewed.

Driveline Infections after Implantation of a Left Ventricular Assist Device

<h3>Purpose</h3> After implantation of a Left Ventricular Assist Device (LVAD), driveline infection (DLI) remains a common complication. Early recognition and treatment of these infections is of great importance in the prevention of morbidity and mortality. We sought to investigate DLI in LVAD patients, focusing on the incidence, pathogenic profile and antimicrobial therapy. <h3>Methods</h3> Data from 160 LVAD patients in chronic follow-up have been retrospectively collected. They underwent LVAD implantation between March 2007 and February 2018 . Implanted devices were HeartWare (Medtronic) in 28 patients, HeartMate II (Abbott) in 118 patients and HeartMate 3 (Abbott) in 14 patients. Variables examined include wound cultures (WC) of the driveline exit site, inflammatory parameters and antimicrobial therapy. DLI was defined based on the INTERMACS Adverse Events definitions. Chronic antibiotic treatment, defined as an antibiotic treatment that will last as long as the driveline is in place, was started once the patient showed recurrent of DLI with systemic effect. <h3>Results</h3> DLI occurred frequently and at a constant risk in time (figure1). At one year 48% had a first infection, 25% already a second infection and 19% is already on chronic antibiotic therapy. At 3 years these numbers increased to 80%, 56% and 36% respectively. The most common bacterial pathogens to cause driveline infection included Staphylococcus aureus (37%), Staphylococcus epidermidis (11%) and Streptococcus spp. (10%). <h3>Conclusion</h3> DLI occurred frequently and at a constant risk in time. At three years of follow-up, 80% of the patients had already at least one DLI and approximately 35% of the patients are on a chronic antibiotic regimen. The most common pathogen causing DLI is Staphylococcus. In case of a clinical suspicion of infection, blind antibiotic treatment of these infections should focus on Staphylococcus until a specific pathogen is isolated from the WC.

Considerations for and Mechanisms of Adjunct Therapy in COPD.

Inhaled bronchodilators and corticosteroids, when indicated, form the backbone of COPD therapy. However, over the last decade there has been an emergence of adjunct therapies in oral or inhaled form that are now part of the therapeutic approach to COPD. While these therapies have shown to be beneficial when used in the appropriate instances, there are particular considerations that need to be minded when using these therapies. This review article discussed the mechanism of roflumilast, macrolide antibiotics, other chronic antibiotic regimens, vitamin D supplementation, oral corticosteroids, n-acetylcysteine, and nebulized hypertonic saline, the clinical data behind each of these therapies, adverse events associated with therapy, and the expert recommendations for their utilization. Our goal is to provide a brief but informative and clinically useful review of commonly encountered therapies used in advanced COPD.

Discovery of a macromolecular complex mediating the hunger suppressive actions of cocaine: Structural and functional properties.

Cocaine not only increases brain dopamine levels but also activates the sigma1 receptor (σ1 R) that in turn regulates orexigenic receptor function. Identification of interactions involving dopamine D1 (D1 R), ghrelin (GHS-R1a ), and σ1 receptors have been addressed by biophysical techniques and a complementation approach using interfering peptides. The effect of cocaine on receptor functionality was assayed by measuring second messenger, cAMP and Ca2+ , levels. The effect of acute or chronic cocaine administration on receptor complex expression was assayed by in situ proximity ligation assay. In silico procedures were used for molecular model building. σ1 R KO mice were used for confirming involvement of this receptor. Upon identification of protomer interaction and receptor functionality, a unique structural model for the macromolecular complex formed by σ1 R, D1 R, and GHS-R1a is proposed. The functionality of the complex, able to couple to both Gs and Gq proteins, is affected by cocaine binding to the σ1 R, as confirmed using samples from σ1 R-/- mice. The expression of the macromolecular complex was differentially affected upon acute and chronic cocaine administration to rats. The constructed 3D model is consistent with biochemical, biophysical, and available structural data. The σ1 R, D1 R, and GHS-R1a complex constitutes a functional unit that is altered upon cocaine binding to the σ1 R. Remarkably, the heteromer can simultaneously couple to two G proteins, thus allowing dopamine to signal via Ca2+ and ghrelin via cAMP. The anorexic action of cocaine is mediated by such complex whose expression is higher after acute than after chronic administration regimens.

Intermittent fasting promotes anxiolytic-like effects unrelated to synaptic mitochondrial function and BDNF support

Anxiety disorders are linked to mitochondrial dysfunction and decreased neurotrophic support. Since anxiolytic drugs target mitochondria, non-pharmacological approaches to improve mitochondrial metabolism such as intermittent fasting (IF) may cause parallel behavioral benefits against anxiety disorders. Here, we investigated whether a chronic IF regimen could induce anxiolytic-like effects concomitantly to modulation in mitochondrial bioenergetics and trophic signaling in mice brain. A total of 44 Male C57BL/6 J mice (180 days old) were assigned to two dietary regimens: a normal, ad libitum diet (AL group) and an alternate-day fasting (IF group), where animals underwent 10 cycles of 24 h food restriction followed by 24 h ad libitum access. Animals underwent the open field test, dark/light box and elevated plus maze tasks. Isolated nerve terminals were obtained from mice brain and used for mitochondrial respirometry, hydrogen peroxide production and assessment of membrane potential dynamics, calcium handling and western blotting. We showed that IF significantly alters total daily food intake and food consumption patterns but not body weight. There were no differences in the exploratory and locomotory parameters. Remarkably, animals from IF showed decreased anxiety-like behavior. Mitochondrial metabolic responses in different coupling states and parameters linked with H2O2 production, Ca2+ buffering and electric gradient were not different between groups. Finally, no alterations in molecular indicators of apoptotic death (Bax/Bcl-2 ratio) and neuroplasticity (proBDNF/BDNF and synaptophysin were observed). In conclusion, IF exerts anxiolytic-like effect not associated with modulation in synaptic neuronergetics or expression of neurotrophic proteins. These results highlight a potential benefit of intermittent fasting as a nutritional intervention in anxiety-related disorders.

A scoping review of research on Canadian team-based primary care pharmacists

An ageing population with an increasing prevalence of chronic disease and complex medication regimens has placed a strain on healthcare systems in Canada. A limited number of team-based primary care pharmacists are integrated into primary care clinics across the country, working alongside other members of the health care team to identify and resolve drug therapy problems and improve outcomes. While many studies have been completed in the area, the extent of research on integrated team-based primary care pharmacists in Canada is unknown. The objectives of this work were to describe the literature that exists surrounding pharmacists in a primary health care team setting in Canada. A scoping review of research focusing on pharmacists in team-based primary health care settings in Canada was performed. Thematic analysis was then performed to categorize the identified studies. The search identified 874 articles, of which 93 met inclusion criteria relevant to the objective. From these 93 studies, 4 themes and 23 subthemes were identified, with some studies having more than one theme or subtheme. Themes identified were the following: primary care pharmacist scope of practice (n = 79 studies), collaboration/communication within the primary care setting (n = 26), chronic disease management (n = 24) and 'other' (n = 15). This research quantified and categorized 93 studies on pharmacists in interprofessional primary care teams in Canada. As this is an expanding role for pharmacists in Canada, understanding the current state of the literature is an important consideration when developing future team-based primary care roles.

Consistency of chronic obstructive pulmonary disease regimens for patients visiting community pharmacies with the Global Initiative for Chronic Obstructive Lung Disease recommendations

ObjectiveDespite evidence-based Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations, outcomes are poor. GOLD uses chronic obstructive pulmonary disease (COPD) assessment test (CAT) scores with exacerbation history to categorize COPD severity into A, B, C, and D severity groups. Therapy is group-specific; monotherapy/dual long-acting bronchodilators (LABDs) therapy is preferred to inhaled corticosteroids (ICS). Pharmacist-accessible data could be used to identify evidence-based interventions to improve outcomes. The primary objective was to analyze previously collected data to compare the consistency of patient-described COPD regimens with GOLD therapeutic recommendations to identify potential pharmacist interventions. MethodsCross-sectional, nonrandomized design using a written questionnaire and CAT scores. Dispensing data from 35 Missouri community pharmacies initially identified participants aged 40 years or older with 1 or more COPD medications dispensed in the past year. Those self-reporting COPD, emphysema, or chronic bronchitis completed a demographic survey with medication history, including oral corticosteroid and antibiotic use, and CAT scores. Proportion of days covered (PDC) was calculated for any COPD maintenance medication dispensed over 1 year. The participants’ COPD was categorized into A, B, C, and D severity groups. The reported medication regimens were categorized into consistent with, escalated from, or less than initial first-line/alternative recommended therapy for the A, B, C, and D severity groups. ResultsThe participants totaled 709 (group A: 6%; group B: 35%; group C: 4%; group D: 55%). Of the regimens, 41% were consistent with, 34% were escalated from, and 24% were less than initial first-line/alternative GOLD recommendations. Most (96%) of the participants were highly symptomatic. Regimens containing ICS: (67.5%); ICS plus LABD (37.2%) exceeded dual LABD (4.2%). The average PDC was 0.43 ± 0.37; only 28.7% were adherent (PDC ≥ 0.80). ConclusionsParticipants with self-reported COPD were highly symptomatic and nonadherent; undertreatment was noted. Community pharmacists could provide therapeutic interventions consistent with GOLD A, B, C, and D severity groups, promote dual LABD versus ICS therapies, and optimize adherence.