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1.
J Dent Educ ; 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38551244

ABSTRACT

PURPOSE: The American Dental Association advocates for dentists' education on therapeutic and legal issues related to medical cannabis. It is important to understand current knowledge of cannabis and cannabinoids and to have a practical knowledge assessment instrument. This exploratory study is the first of its kind to assess dental students' knowledge of cannabis and aims to determine if there is a need for more instruction regarding cannabis in a dental school's curriculum. METHODS: Predoctoral dental students at the University at Buffalo School of Dental Medicine were recruited to participate. A validated, anonymous 22-item online survey was adapted and administered to students in all 4 years of the dental program. There was a total of 56 knowledge points. RESULTS: The average knowledge score was 21.6 points (SD = 5.2, range: 7-34), corresponding to 38.5% (SD = 9.2) of the answers correct. There were no overall differences in knowledge by gender, years in dental school, or by any reported source of formal education on cannabis. Those who reported doing their own research had higher knowledge scores. Most participants knew that there is an endogenous cannabinoid system (72.3%) and that Tetrahydrocannabinol (THC) is responsible for the "high" experienced with cannabis (76.6%). Most participants reported that they did not know the effective doses of THC (58.2%) and Cannabidiol (CBD) (66.7%); few provided an answer for THC (34%) or CBD (17%) in the acceptable range of 2-10 mg. CONCLUSION: Dental students did not have adequate knowledge on cannabis and cannabinoids. Given the rapid expansion of cannabis legalization, additional efforts are needed to integrate cannabis topics into coursework and learning experiences.

2.
Clin Pharmacol Drug Dev ; 8(7): 871-883, 2019 10.
Article in English | MEDLINE | ID: mdl-31268250

ABSTRACT

GPR109A (HM74A), a G-protein-coupled receptor, is hypothesized to mediate lipid and lipoprotein changes and dermal flushing associated with niacin administration. GSK256073 (8-chloro-3-pentyl-1H-purine-2,6[3H,7H]-dione) is a selective GPR109A agonist shown to suppress fatty acid levels and produce mild flushing in short-term clinical studies. This study evaluated the effects of GSK256073 on lipids in subjects with low high-density lipoprotein cholesterol (HDLc). Subjects (n = 80) were randomized (1:1:1:1) to receive GSK256073 5, 50, or 150 mg/day or matching placebo for 8 weeks. The primary end point was determining the GSK256073 exposure-response relationship for change from baseline in HDLc. No significant exposure response was observed between GSK256073 and HDLc levels. GSK256073 did not significantly alter HDLc levels versus placebo, but rather revealed a trend at the 150-mg dose for a nonsignificant decrease in HDLc (-6.31%; P = .12) and an increase in triglycerides (median, 24.4%; 95% confidence interval, 7.3%-41.6%). Flushing was reported in 21%, 25%, and 60% of subjects (5, 50, and 150 mg, respectively) versus 24% for placebo. Results indicated that selective activation of the GPR109A receptor with GSK256073 did not produce niacin-like lipid effects. These findings add to the increasing evidence that niacin-mediated lipoprotein changes occur predominantly via GPR109A-independent pathways.


Subject(s)
Cholesterol, HDL/analysis , Dyslipidemias/drug therapy , Flushing/chemically induced , Xanthines/administration & dosage , Aged , Drug Administration Routes , Dyslipidemias/metabolism , Female , Humans , Male , Middle Aged , Niacin/adverse effects , Receptors, G-Protein-Coupled/agonists , Treatment Outcome , Xanthines/adverse effects , Xanthines/pharmacology
3.
Clin Kidney J ; 12(1): 129-138, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30746140

ABSTRACT

BACKGROUND: This study assessed the short-term safety and efficacy of daprodustat (an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor) to achieve a target hemoglobin in patients with anemia of chronic kidney disease (CKD). METHODS: Patients (n = 252) with Stages 3-5 CKD not receiving dialysis were enrolled in this 24-week, multicenter trial [hemoglobin entry criteria: 8-10 g/dL (Cohort 1) or 8-11 g/dL (Cohort 2) for recombinant human erythropoietin (rhEPO)-naïve participants; 9-10.5 g/dL (Cohort 1) or 9-11.5 g/dL (Cohort 2) for rhEPO users]. rhEPO-naïve participants were randomized 3:1 to daprodustat (1, 2 or 4 mg) or control (rhEPO per standard of care). rhEPO users were randomized 1:1 to daprodustat 2 mg or control. Study medication was titrated to maintain hemoglobin 9-10.5 g/dL (Cohort 1) or 10-11.5 g/dL (Cohort 2). Hemoglobin, iron metabolism markers and safety parameters were measured every 4 weeks. RESULTS: Mean hemoglobin levels at Week 24 were 10.2 g/dL (Cohort 1) and 10.9 g/dL (Cohort 2) in the daprodustat group and 10.7 g/dL (Cohort 1) and 11.0 g/dL (Cohort 2) in the control group. Participants had hemoglobin levels within the target range a median of 82% and 66% of the time between Weeks 12 and 24 in the daprodustat and control groups, respectively. The adverse event profile was consistent with clinical events in the CKD population. CONCLUSIONS: Daprodustat effectively maintained target hemoglobin over 24 weeks in CKD patients with anemia who were rhEPO naïve or had switched from existing rhEPO therapy.

4.
Clin Kidney J ; 12(1): 139-148, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30746141

ABSTRACT

BACKGROUND: This study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease. METHODS: Participants (n = 216) with baseline hemoglobin levels of 9-11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10-11.5 g/dL. The primary outcome was characterization of the dose-response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks. RESULTS: Over the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from -0.29 (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and -0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were ∼14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population. CONCLUSIONS: Daprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks.

5.
Skelet Muscle ; 8(1): 38, 2018 12 10.
Article in English | MEDLINE | ID: mdl-30526662

ABSTRACT

Following publication of the original article [1], the authors flagged that there is a discrepancy with the Availability of data and materials statement on page 12 of the article.

6.
Skelet Muscle ; 8(1): 35, 2018 11 13.
Article in English | MEDLINE | ID: mdl-30424786

ABSTRACT

BACKGROUND: In muscular dystrophy and old age, skeletal muscle repair is compromised leading to fibrosis and fatty tissue accumulation. Therefore, therapies that protect skeletal muscle or enhance repair would be valuable medical treatments. Hypoxia-inducible factors (HIFs) regulate gene transcription under conditions of low oxygen, and HIF target genes EPO and VEGF have been associated with muscle protection and repair. We tested the importance of HIF activation following skeletal muscle injury, in both a murine model and human volunteers, using prolyl hydroxylase inhibitors that stabilize and activate HIF. METHODS: Using a mouse eccentric limb injury model, we characterized the protective effects of prolyl hydroxylase inhibitor, GSK1120360A. We then extended these studies to examine the impact of EPO modulation and infiltrating immune cell populations on muscle protection. Finally, we extended this study with an experimental medicine approach using eccentric arm exercise in untrained volunteers to measure the muscle-protective effects of a clinical prolyl hydroxylase inhibitor, daprodustat. RESULTS: GSK1120360A dramatically prevented functional deficits and histological damage, while accelerating recovery after eccentric limb injury in mice. Surprisingly, this effect was independent of EPO, but required myeloid HIF1α-mediated iNOS activity. Treatment of healthy human volunteers with high-dose daprodustat reduced accumulation of circulating damage markers following eccentric arm exercise, although we did not observe any diminution of functional deficits with compound treatment. CONCLUSION: The results of these experiments highlight a novel skeletal muscle protective effect of prolyl hydroxylase inhibition via HIF-mediated expression of iNOS in macrophages. Partial recapitulation of these findings in healthy volunteers suggests elements of consistent pharmacology compared to responses in mice although there are clear differences between these two systems.


Subject(s)
Enzyme Inhibitors/therapeutic use , Glycine/analogs & derivatives , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Muscle Contraction , Muscle, Skeletal/drug effects , Myalgia/drug therapy , Quinolones/therapeutic use , Adolescent , Adult , Animals , Cells, Cultured , Enzyme Inhibitors/pharmacology , Glycine/pharmacology , Glycine/therapeutic use , Humans , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal/injuries , Muscle, Skeletal/metabolism , Myalgia/etiology , Quinolones/pharmacology
7.
PLoS One ; 12(9): e0184049, 2017.
Article in English | MEDLINE | ID: mdl-28880966

ABSTRACT

There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague-Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45-52% of plasma level) and brain (1-4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47-64%), cognitive dysfunction (60-75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury.


Subject(s)
Behavior, Animal , Brain Injuries/drug therapy , Brain Injuries/etiology , Cognition Disorders/drug therapy , Glycine/analogs & derivatives , Motor Activity , Prolyl-Hydroxylase Inhibitors/therapeutic use , Quinolones/therapeutic use , Stroke/complications , Administration, Oral , Animals , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain Injuries/blood , Brain Injuries/physiopathology , Cognition Disorders/etiology , Erythropoietin/blood , Erythropoietin/genetics , Glycine/administration & dosage , Glycine/pharmacokinetics , Glycine/pharmacology , Glycine/therapeutic use , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Infarction, Middle Cerebral Artery/blood , Infarction, Middle Cerebral Artery/complications , Infarction, Middle Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/physiopathology , Male , Motor Activity/drug effects , Organ Specificity/drug effects , Prolyl Hydroxylases/metabolism , Prolyl-Hydroxylase Inhibitors/administration & dosage , Prolyl-Hydroxylase Inhibitors/pharmacology , Quinolones/administration & dosage , Quinolones/pharmacokinetics , Quinolones/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Sensation/drug effects , Stroke/blood , Stroke/physiopathology , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/genetics
8.
Am J Nephrol ; 45(2): 127-135, 2017.
Article in English | MEDLINE | ID: mdl-27978511

ABSTRACT

BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. METHODS: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated. RESULTS: Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL. CONCLUSION: Daprodustat 4-10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels.


Subject(s)
Anemia/drug therapy , Barbiturates/therapeutic use , Glycine/analogs & derivatives , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Prolyl-Hydroxylase Inhibitors/therapeutic use , Renal Insufficiency, Chronic/therapy , Aged , Anemia/etiology , Barbiturates/pharmacology , Dose-Response Relationship, Drug , Double-Blind Method , Erythropoietin/blood , Female , Glycine/pharmacology , Glycine/therapeutic use , Hemoglobins/analysis , Humans , Japan , Male , Middle Aged , Prolyl-Hydroxylase Inhibitors/pharmacology , Renal Dialysis , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Treatment Outcome , Vascular Endothelial Growth Factor A/blood
10.
JAMA ; 315(15): 1591-9, 2016 Apr 19.
Article in English | MEDLINE | ID: mdl-27043082

ABSTRACT

IMPORTANCE: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE: To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. DESIGN, SETTING, AND PATIENTS: LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS: Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS: In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE: Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02145468.


Subject(s)
Cyclopropanes/therapeutic use , Myocardial Infarction/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aged , Algorithms , C-Reactive Protein/analysis , Cyclopropanes/adverse effects , Double-Blind Method , Drug Administration Schedule , Female , Hospitalization , Humans , Male , Middle Aged , Myocardial Infarction/enzymology , Myocardial Infarction/mortality , Myocardial Ischemia/prevention & control , Myocardial Ischemia/surgery , Myocardial Revascularization , Protein Kinase Inhibitors/adverse effects , Pyridines/adverse effects , Recurrence , Secondary Prevention , Treatment Failure
11.
JACC Heart Fail ; 4(7): 559-566, 2016 07.
Article in English | MEDLINE | ID: mdl-27039125

ABSTRACT

OBJECTIVES: This study sought to determine if glucagon-like peptide (GLP)-1 ameliorates myocardial metabolic abnormalities in chronic heart failure. BACKGROUND: Albiglutide (GSK716155) is a GLP-1 agonist indicated for type 2 diabetes. METHODS: We performed a randomized, placebo-controlled study evaluating 12 weeks of albiglutide in New York Heart Association II or III subjects with ejection fraction <40%. Subjects received weekly placebo (n = 30) or albiglutide 3.75 mg (n = 12), 15 mg (n = 13), or 30 mg (n = 27). The primary comparison was between albiglutide 30 mg and placebo. Assessments included echocardiography, 6-minute-walk test, and peak oxygen consumption. In a subgroup of patients, myocardial glucose and oxygen use were assessed. Endpoints are reported as change from baseline ± SE. RESULTS: Albiglutide 30 mg compared with placebo did not improve change from baseline in left ventricular ejection fraction (2.4% [1.1%] vs. 4.4% [1.1%]; p = 0.22), 6-min walk test (18 [12] m vs. 9 [11] m; p = 0.58), myocardial glucose use (p = 0.59), or oxygen use (p = 0.25). In contrast, albiglutide 30 mg versus placebo improved change from baseline in peak oxygen consumption (0.9 [0.5] ml/kg/min vs. -0.6 [0.5] ml/kg/min; p = 0.02). Albiglutide was well tolerated. CONCLUSIONS: Although there was no detectable effect of albiglutide on cardiac function or myocardial glucose use, there was a modest increase in peak oxygen consumption, which could have been mediated by noncardiac effects. (A Multi-center, Placebo-controlled Study to Evaluate the Safety of GSK716155 and Its Effects on Myocardial Metabolism, Myocardial Function, and Exercise Capacity in Patients With NYHA Class II/III Congestive Heart Failure; NCT01357850).


Subject(s)
Exercise Tolerance , Glucagon-Like Peptide 1/analogs & derivatives , Heart Failure/drug therapy , Incretins/therapeutic use , Stroke Volume , Adult , Aged , Carbon Radioisotopes , Chronic Disease , Echocardiography , Female , Fluorodeoxyglucose F18 , Glucagon-Like Peptide 1/therapeutic use , Glucose/metabolism , Heart Failure/diagnostic imaging , Heart Failure/metabolism , Heart Failure/physiopathology , Humans , Male , Middle Aged , Myocardium/metabolism , Oxygen Consumption , Positron Emission Tomography Computed Tomography , Quality of Life , Radiopharmaceuticals , Walk Test
12.
J Am Soc Nephrol ; 27(4): 1234-44, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26494831

ABSTRACT

Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dose-dependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD.


Subject(s)
Anemia/drug therapy , Barbiturates/therapeutic use , Glycine/analogs & derivatives , Aged , Anemia/blood , Anemia/etiology , Erythropoietin/therapeutic use , Female , Glycine/therapeutic use , Hemoglobins/analysis , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Male , Middle Aged , Renal Dialysis , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/therapy , Single-Blind Method , Time Factors
13.
PLoS One ; 10(6): e0130894, 2015.
Article in English | MEDLINE | ID: mdl-26098939

ABSTRACT

Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (↑64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (↑14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (↑106%, p<0.05) and lactate (↑121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (↑14%, p<0.05) and decreased fatty acid oxidation (↓15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner.


Subject(s)
Cardiotonic Agents/pharmacology , Energy Metabolism/drug effects , Glucagon-Like Peptide 1/pharmacology , Myocardium/metabolism , Reperfusion Injury/metabolism , Animals , Carbon Isotopes/metabolism , Cardiotonic Agents/administration & dosage , Cyclic AMP/metabolism , Energy Metabolism/physiology , Fatty Acids/metabolism , Glucagon-Like Peptide 1/administration & dosage , Glucose/metabolism , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Myocytes, Cardiac/metabolism , Oxygen Consumption/physiology , Rats
14.
Vasc Med ; 19(6): 473-82, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25377872

ABSTRACT

Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). This multicenter, randomized, placebo-controlled study evaluated the safety and efficacy of GSK1278863 (an oral PHD inhibitor) in subjects with PAD. The study assessed two active treatment paradigms: single dosing and subchronic daily dosing (300 mg single dose and 15 mg daily for 14 days, respectively). Neither regimen improved exercise performance compared with placebo (change from baseline in the 6-minute walk test (6MWT; feet), (GSK1278863, placebo): single dose (-46, -44), p=0.96; repeat dose (9, 8), p=0.99; change in number of contractions to onset of claudication (goniometry): single dose (4, -1), p=0.053; repeat dose (-2, 1), p=0.08). A calf-muscle biopsy substudy showed no increases in mRNA or protein levels of HIF target genes. More subjects receiving GSK1278863 than placebo experienced adverse events, particularly following the 300 mg single dose. Thus, assessing the safety of GSK1278863 in this setting would require a larger population exposed to the agent for a longer duration. These data do not support a benefit of GSK1278863 in PAD using the regimens tested. CLINICALTRIALSGOV IDENTIFIER NCT01673555:


Subject(s)
Intermittent Claudication/drug therapy , Peripheral Arterial Disease/drug therapy , Prolyl-Hydroxylase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Exercise Test , Female , Humans , Male , Middle Aged , Muscle, Skeletal/drug effects , Quality of Life , Time Factors , Treatment Outcome , Walking/physiology
15.
Lancet ; 384(9949): 1187-95, 2014 Sep 27.
Article in English | MEDLINE | ID: mdl-24930728

ABSTRACT

BACKGROUND: p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial. METHODS: From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962. FINDINGS: Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ. INTERPRETATION: p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes. FUNDING: GlaxoSmithKline.


Subject(s)
Cyclopropanes/administration & dosage , Myocardial Infarction/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyridines/administration & dosage , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aged , Area Under Curve , Double-Blind Method , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , Magnetic Resonance Angiography , Male , Middle Aged , Myocardial Infarction/mortality , Treatment Outcome
16.
PLoS One ; 9(1): e83094, 2014.
Article in English | MEDLINE | ID: mdl-24475026

ABSTRACT

BACKGROUND: We explored the theorized upregulation of platelet-activating factor (PAF)- mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials. METHODS AND RESULTS: Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0-10 µg/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9-27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination. CONCLUSIONS: Lp-PLA2 inhibition does not enhance platelet aggregation. TRIAL REGISTRATION: 1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257.


Subject(s)
Lipoproteins/metabolism , Phospholipase A2 Inhibitors/pharmacology , Platelet Aggregation/drug effects , Acetamides/pharmacology , Adult , Analysis of Variance , Cross-Over Studies , Dose-Response Relationship, Drug , Humans , Male , Models, Biological , New South Wales , Phospholipase A2 Inhibitors/metabolism , Platelet Aggregation/physiology , Quinolones/pharmacology
17.
Proc Natl Acad Sci U S A ; 111(4): 1551-6, 2014 Jan 28.
Article in English | MEDLINE | ID: mdl-24453217

ABSTRACT

Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain- or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC50, 3-21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells as well as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management.


Subject(s)
Cardiomegaly/genetics , TRPC Cation Channels/antagonists & inhibitors , Animals , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation , Rats , TRPC Cation Channels/genetics , TRPC6 Cation Channel
18.
Genes Dev ; 27(23): 2576-89, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24298057

ABSTRACT

B-class ephrins, ligands for EphB receptor tyrosine kinases, are critical regulators of growth and patterning processes in many organs and species. In the endothelium of the developing vasculature, ephrin-B2 controls endothelial sprouting and proliferation, which has been linked to vascular endothelial growth factor (VEGF) receptor endocytosis and signaling. Ephrin-B2 also has essential roles in supporting mural cells (namely, pericytes and vascular smooth muscle cells [VSMCs]), but the underlying mechanism is not understood. Here, we show that ephrin-B2 controls platelet-derived growth factor receptor ß (PDGFRß) distribution in the VSMC plasma membrane, endocytosis, and signaling in a fashion that is highly distinct from its role in the endothelium. Absence of ephrin-B2 in cultured VSMCs led to the redistribution of PDGFRß from caveolin-positive to clathrin-associated membrane fractions, enhanced PDGF-B-induced PDGFRß internalization, and augmented downstream mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK) activation but impaired Tiam1-Rac1 signaling and proliferation. Accordingly, mutant mice lacking ephrin-B2 expression in vascular smooth muscle developed vessel wall defects and aortic aneurysms, which were associated with impaired Tiam1 expression and excessive activation of MAP kinase and JNK. Our results establish that ephrin-B2 is an important regulator of PDGFRß endocytosis and thereby acts as a molecular switch controlling the downstream signaling activity of this receptor in mural cells.


Subject(s)
Ephrin-B2/metabolism , Receptor, Platelet-Derived Growth Factor beta/metabolism , Signal Transduction , Animals , Cell Membrane/metabolism , Cells, Cultured , Ephrin-B2/genetics , Female , Male , Mice , Mutation , Myocytes, Smooth Muscle/pathology , Protein Transport
19.
Cardiovasc Diabetol ; 12: 148, 2013 Oct 14.
Article in English | MEDLINE | ID: mdl-24125539

ABSTRACT

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. METHODS: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 µg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C(min)). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. RESULTS: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. CONCLUSIONS: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.


Subject(s)
Cardiotonic Agents/pharmacology , Glucagon-Like Peptide 1/pharmacology , Immunoconjugates/pharmacology , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Peptide Fragments/pharmacology , Serum Albumin/immunology , Single-Domain Antibodies/pharmacology , Animals , Cardiotonic Agents/administration & dosage , Cardiotonic Agents/blood , Cardiotonic Agents/pharmacokinetics , Disease Models, Animal , Exenatide , Glucagon-Like Peptide 1/administration & dosage , Glucagon-Like Peptide 1/blood , Glucagon-Like Peptide 1/pharmacokinetics , Glucagon-Like Peptide-1 Receptor , Immunoconjugates/administration & dosage , Immunoconjugates/blood , Immunoconjugates/pharmacokinetics , Injections, Subcutaneous , Male , Myocardial Contraction/drug effects , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardium/metabolism , Myocardium/pathology , Peptide Fragments/administration & dosage , Peptide Fragments/blood , Peptide Fragments/pharmacokinetics , Peptides/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Glucagon/agonists , Receptors, Glucagon/genetics , Single-Domain Antibodies/administration & dosage , Single-Domain Antibodies/blood , Venoms/pharmacology , Ventricular Function, Left/drug effects
20.
Sci Transl Med ; 5(207): 207ra141, 2013 Oct 16.
Article in English | MEDLINE | ID: mdl-24132636

ABSTRACT

Percutaneous coronary intervention is first-line therapy for acute coronary syndromes (ACS) but can promote cardiomyocyte death and cardiac dysfunction via reperfusion injury, a phenomenon driven in large part by oxidative stress. Therapies to limit this progression have proven elusive, with no major classes of new agents since the development of anti-platelets/anti-thrombotics. We report that cardiac troponin I-interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes ischemia/reperfusion injury, oxidative stress, and myocyte death. TNNI3K-mediated injury occurs through increased mitochondrial superoxide production and impaired mitochondrial function and is largely dependent on p38 mitogen-activated protein kinase (MAPK) activation. We developed a series of small-molecule TNNI3K inhibitors that reduce mitochondrial-derived superoxide generation, p38 activation, and infarct size when delivered at reperfusion to mimic clinical intervention. TNNI3K inhibition also preserves cardiac function and limits chronic adverse remodeling. Our findings demonstrate that TNNI3K modulates reperfusion injury in the ischemic heart and is a tractable therapeutic target for ACS. Pharmacologic TNNI3K inhibition would be cardiac-selective, preventing potential adverse effects of systemic kinase inhibition.


Subject(s)
MAP Kinase Kinase Kinases/antagonists & inhibitors , Myocardial Ischemia/enzymology , Myocardial Ischemia/physiopathology , Oxidative Stress , Protein Kinases/metabolism , Ventricular Remodeling , Acute Coronary Syndrome/complications , Acute Coronary Syndrome/enzymology , Acute Coronary Syndrome/pathology , Acute Coronary Syndrome/physiopathology , Animals , Cell Death/drug effects , Disease Models, Animal , Energy Metabolism/drug effects , Enzyme Activation/drug effects , Gene Deletion , Heart Failure/complications , Heart Failure/enzymology , Heart Failure/physiopathology , Humans , MAP Kinase Kinase Kinases/metabolism , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Myocardial Ischemia/complications , Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/pathology , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Superoxides/metabolism , Up-Regulation/drug effects , Ventricular Dysfunction, Left/complications , Ventricular Dysfunction, Left/enzymology , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/physiopathology , Ventricular Remodeling/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism
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