Dose-dependent Increase In Heart Rate Research Articles

Mechanism of and strategy to mitigate liraglutide-mediated positive chronotropy

AimAn adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. Main methodsExperiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. Key findingsLG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during β-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. SignificanceLG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than β-blockade.

104-OR: Novel GIP/GLP-1/Glucagon Receptor Agonist LY3437943: A First-in-Human Dose Study in Healthy Subjects

Multifunctional incretins are in clinical development for several metabolic conditions. Novel LY3437943 has potent agonist activity on glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon receptors. The primary objective of this randomized, double-blind, placebo (PBO)-controlled, Phase 1, first in human study was to assess safety and tolerability of single-ascending doses of LY3437943. Forty-five healthy subjects were randomized (6:2) to subcutaneous LY3437943 (6 rising dose levels) or PBO. Vital signs, ECGs, laboratory data and adverse events (AEs) were monitored to assess safety and tolerability. LY3437943 pharmacokinetics (PK) as well as change from baseline (BL) in fasting insulin, C-peptide and weight were measured. Appetite was assessed using a visual analog scale (VAS). The most common treatment-emergent AEs were gastrointestinal, including vomiting (with higher doses), abdominal distention and nausea, which were dose-dependent, mostly mild in severity, occurred within 4 days of dosing and resolved within a week of onset. Dose-dependent increases in heart rate and decreases in systolic blood pressure were observed, which returned to near BL by Day 29. Mean terminal half-life of LY3437943 ranged from 134-165 h (∼7 days) across the 6 doses, supporting once-weekly dosing. Dose-dependent increases in mean fasting insulin and C-peptide, with maximum levels observed at 24 and 48 h, returned to near BL by Day 15. Dose-dependent weight loss was statistically significant with the 3 highest doses vs. PBO (up to 3.5 kg at the highest dose). Weight loss was maintained up to Day 43 following single administration of the two highest doses. Overall VAS score significantly increased with higher doses vs. PBO, reflecting decreased appetite. Triple-agonist peptide LY3437943 had a safety and tolerability profile similar to other incretins in Phase 1 trials with PK and pharmacodynamic outcomes that support further clinical evaluation. Disclosure S. Urva: Employee; Self; Eli Lilly and Company. Y. Du: None. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. T. Coskun: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. C. Benson: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company

Effect of altrenogest supplementation on endogenous progesterone production in embryo recipient mares in a commercial embryo transfer program

To determine the physiologic and behavioral effects and pharmacokinetic profile of hydromorphone administered intravenously (IV) to horses.Prospective, randomized, crossover study.A group of six adult healthy horses weighing 585.2 ± 58.7 kg.Each horse was administered IV hydromorphone (0.025 mg kg–1; treatment H0.025), hydromorphone (0.05 mg kg–1; treatment H0.05) or 0.9% saline in random order with a 7 day washout period. For each treatment, physiologic, hematologic, abdominal borborygmi scores and behavioral data were recorded over 5 hours and fecal output was totaled over 24 hours. Data were analyzed using repeated measures anova with significance at p < 0.05. Blood samples were collected in treatment H0.05 for quantification of plasma hydromorphone and hydromorphone-3-glucuronide and subsequent pharmacokinetic parameter calculation.Hydromorphone administration resulted in a dose-dependent increase in heart rate (HR) and systolic arterial pressure (SAP). HR and SAP were 59 ± 17 beats minute–1 and 230 ± 27 mmHg, respectively, in treatment H0.05 at 5 minutes after administration. No clinically relevant changes in respiratory rate, arterial gases or temperature were observed. The borborygmi scores in both hydromorphone treatments were lower than baseline values for 2 hours. Fecal output did not differ among treatments and no evidence of abdominal discomfort was observed. Recorded behaviors did not differ among treatments. For hydromorphone, mean ± standard deviation for volume of distribution at steady state, total systemic clearance and area under the curve until the last measured concentration were 1.00 ± 0.29 L kg–1, 106 ± 21 mL minute–1 kg–1 and 8.0 ± 1.5 ng hour mL–1, respectively.Hydromorphone administered IV to healthy horses increased HR and SAP, decreased abdominal borborygmi and did not affect fecal output.

Pharmacokinetics and pharmacodynamics of hydromorphone hydrochloride in healthy horses

ObjectivesTo determine the physiologic and behavioral effects and pharmacokinetic profile of hydromorphone administered intravenously (IV) to horses. Study designProspective, randomized, crossover study. AnimalsA group of six adult healthy horses weighing 585.2 ± 58.7 kg. MethodsEach horse was administered IV hydromorphone (0.025 mg kg–1; treatment H0.025), hydromorphone (0.05 mg kg–1; treatment H0.05) or 0.9% saline in random order with a 7 day washout period. For each treatment, physiologic, hematologic, abdominal borborygmi scores and behavioral data were recorded over 5 hours and fecal output was totaled over 24 hours. Data were analyzed using repeated measures anova with significance at p < 0.05. Blood samples were collected in treatment H0.05 for quantification of plasma hydromorphone and hydromorphone-3-glucuronide and subsequent pharmacokinetic parameter calculation. ResultsHydromorphone administration resulted in a dose-dependent increase in heart rate (HR) and systolic arterial pressure (SAP). HR and SAP were 59 ± 17 beats minute–1 and 230 ± 27 mmHg, respectively, in treatment H0.05 at 5 minutes after administration. No clinically relevant changes in respiratory rate, arterial gases or temperature were observed. The borborygmi scores in both hydromorphone treatments were lower than baseline values for 2 hours. Fecal output did not differ among treatments and no evidence of abdominal discomfort was observed. Recorded behaviors did not differ among treatments. For hydromorphone, mean ± standard deviation for volume of distribution at steady state, total systemic clearance and area under the curve until the last measured concentration were 1.00 ± 0.29 L kg–1, 106 ± 21 mL minute–1 kg–1 and 8.0 ± 1.5 ng hour mL–1, respectively. Conclusions and clinical relevanceHydromorphone administered IV to healthy horses increased HR and SAP, decreased abdominal borborygmi and did not affect fecal output.

Blocking properties of terguride at the 5-HT2 receptor subtypes mediating cardiovascular responses in the rat.

In vitro studies have suggested that terguride blocks the contractile and relaxant responses produced by 5-hydroxytryptamine (5-HT) via 5-HT2A/2B receptors. This study has now investigated terguride's blocking properties on central/peripheral 5-HT2 receptors in anaesthetized or pithed rats. Male Wistar anaesthetized/pithed rats were cannulated for recording blood pressure and heart rate and for i.v. administration of several compounds. In both groups of rats, i.v. bolus injections of 5-HT or (±)-DOI (a 5-HT2 receptor agonist; 1-1000 μg/kg) produced dose-dependent increases in diastolic blood pressure and heart rate. These responses were dose-dependently antagonized by terguride (10-3000 μg/kg). In anaesthetized rats, i.v. bolus injections of BW723C86 (a 5-HT2B receptor agonist; 1-1000 μg/kg) produced dose-dependent increases in diastolic blood pressure and not dose-dependent increases in heart rate, while in pithed rats, these responses were attenuated. The vasopressor responses elicited by BW723C86 in anaesthetized rats were dose-dependently blocked by terguride (10-300 μg/kg), whereas its the tachycardic responses were dose-independently blocked. These results, taken together, suggest that terguride behaved as an antagonist at the 5-HT2 receptors located in the central nervous system and (or) the systemic vasculature. This is the first evidence demonstrating that terguride can block central/peripheral 5-HT2 receptors mediating cardiovascular responses in anaesthetized or pithed rats.

Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 after single subcutaneous administration in healthy subjects.

To evaluate the pharmacodynamics, pharmacokinetics and safety of single subcutaneous (s.c.) injection of ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in healthy subjects. A total of 51 healthy volunteers were enrolled in this double-blind, placebo-controlled study investigating RG7697 doses ranging from 0.03 to 5 mg. Adverse events (AEs) were monitored and drug concentrations, fasting glycaemic variables, vital signs, ECG, antibody formation and routine laboratory variables were assessed. A meal tolerance test (MTT) was performed at the same time on day -1 (baseline) and day 1. RG7697 was generally well tolerated in healthy participants after s.c. injections up to 3.6 mg. Tolerability was limited by gastrointestinal AEs (nausea and vomiting) at the highest dose. There was a small dose-dependent increase in heart rate. No episodes of hypoglycaemia occurred. RG7697 concentrations peaked at 2 to 4 hours post-dose with a half-life of 19 to 25 hours. During MTT, RG7697 at doses ≥1.8 mg, reduced glucose maximum plasma concentration (Cmax ; -46%) without affecting overall glucose area under the curve (AUC). Its effect on insulin was more pronounced, with reductions in both Cmax (-64%) and AUC (-51%). Pharmacodynamic variables were well correlated to RG7697 average plasma concentration during MTT, with IC50 (average concentration required for 50% reduction) values of 49 and 24.5 ng/mL for glucose and insulin, respectively. Single s.c. injections of RG7697 up to 3.6 mg were generally well tolerated. Evidence of glycaemic effect and pharmacokinetic profiles consistent with once-daily dosing render this drug candidate suitable to be further tested in multiple-dose clinical trials in patients with type 2 diabetes.

Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study

BackgroundRegadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed. Method and ResultsHealthy males and females were randomized to receive intravenous regadenoson [100 μg (3 doses), 200 μg (3 doses), or 400 μg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects. ConclusionRepeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

How the heart speaks to the brain: neural activity during cardiorespiratory interoceptive stimulation.

Prominent theories emphasize key roles for the insular cortex in the central representation of interoceptive sensations, but how this brain region responds dynamically to changes in interoceptive state remains incompletely understood. Here, we systematically modulated cardiorespiratory sensations in humans using bolus infusions of isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline. To identify central neural processes underlying these parametrically modulated interoceptive states, we used pharmacological functional magnetic resonance imaging (phMRI) to simultaneously measure blood-oxygenation-level dependent (BOLD) and arterial spin labelling (ASL) signals in healthy participants. Isoproterenol infusions induced dose-dependent increases in heart rate and cardiorespiratory interoception, with all participants endorsing increased sensations at the highest dose. These reports were accompanied by increased BOLD and ASL activation of the right insular cortex at the highest dose. Different responses across insula subregions were also observed. During anticipation, insula activation increased in more anterior regions. During stimulation, activation increased in the mid-dorsal and posterior insula on the right, but decreased in the same regions on the left. This study demonstrates the feasibility of phMRI for assessing brain activation during adrenergic interoceptive stimulation, and provides further evidence supporting a dynamic role for the insula in representing changes in cardiorespiratory states.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'.

Cardiorespiratory effects of isoflurane in Asiatic black bears (Ursus thibetanus) anesthetized with intramuscular medetomidine and zolazepam/tiletamine.

The objective of this study was to determine the dose-dependent effects of isoflurane on various cardiovascular parameters and the stable range of isoflurane concentrations in Asiatic black bears (Ursus thibetanus). Seven Asiatic black bears were intramuscularly injected with medetomidine, zolazepam and tiletamine (MZT) to induce anesthesia, and anesthesia was maintained by administering isoflurane in 100% oxygen (4 l/min) without mechanical ventilation. Several cardiovascular parameters were measured at five end-tidal isoflurane concentrations (0.5, 1.0, 1.5, 2.0, and 2.5%). Blood was collected from the femoral artery before administration of isoflurane and after each administration for immediate blood gas analysis. Isoflurane produced dose-dependent increases in heart rate, respiratory rate, minute volume, end-tidal carbon dioxide (CO2) partial pressure and the partial pressure of arterial CO2, and dose-dependent decreases in non-invasive blood pressure and tidal volume. Rectal temperature, oxygenation and acid-base balance were unaffected by isoflurane. All parameters in this study were in a clinically acceptable range at all times. The data show that the combination of MZT and isoflurane is suitable for general anesthesia in Asiatic black bears with spontaneous breathing during prolonged procedures. End-tidal isoflurane concentrations of 0.5 to 2.5% can be used in Asiatic black bears without adverse side effects.

Cardiorespiratory dose-response relationship of isoflurane in Cinereous vulture (Aegypius monachus) during spontaneous ventilation.

Anesthesia is an inevitably important component of diagnosis and treatments examining the health condition of wild animals. Not only does anesthesia become an essential tool in minimizing stress of the patients and providing an opportunity to deliver accurate and safe procedures, but it also ensures the safety of the medical crew members. This study was conducted to investigate the dose-response cardiorespiratory effects of isoflurane during spontaneous ventilation in ten cinereous vultures. Each bird was administered isoflurane at initial concentration of 1.0, 1.5, 2.0, 2.5 and 3.0 and then an end-tidal isoflurane concentrations (ETiso) of 1.0% for an equilibration period of 15 min in the given order. At the end of the equilibration period, the direct blood pressure (BP), heart rate (HR), respiratory rate (RR) and end tidal CO2 partial pressure (PETCO2) were recorded, and blood gas analysis was performed. Increasing isoflurane concentrations during spontaneous ventilation led to dose-dependent increases in HR and PETCO2, with minimal changes in RR, decreased arterial BP and respiratory acidosis. Overall, isoflurane for anesthesia of spontaneously breathing cinereous vultures is a suitable choice for diagnostic or surgical procedures.

First Clinical Experience with ONO-4232: A Randomized, Double-blind, Placebo-controlled Healthy Volunteer Study of a Novel Lusitropic Agent for Acutely Decompensated Heart Failure

PurposeThe aim of this study was to evaluate the safety, tolerability, and pharmacokinetic parameters of up to 15 dose levels of ONO-4232, a selective agonist for the EP4 subtype of the prostaglandin E2 receptor, with a dual left ventricular lusitropic and venodilatory action, in healthy, adult, male and female volunteers. MethodsIn this randomized, single-center, double-blind, placebo-controlled, single-dose, sequential-group escalation, first in human study, ONO-4232 (0.001, 0.003, 0.01, 0.02, 0.04, 0.08, 0.12, 0.15, 0.18, or 0.27 ng/kg/min) or placebo was administered as a continuous intravenous infusion over 3 hours. Safety, tolerability, and pharmacokinetic data were collected during dosing and over a period of 3 days (Day –1 to Day 2), and at the follow-up visit (Day 7 [±2 days]). FindingsFifty-seven subjects received ONO-4232 and 19 subjects received placebo. Ten of the planned 15 cohorts (dose range, 0.001–0.27 ng/kg/min) were conducted. A total of 34 treatment-emergent adverse events (TEAEs) were reported in 23 subjects. Overall, the majority of TEAEs were mild. No serious TEAEs or deaths were reported and no subjects discontinued due to adverse events. The most frequently reported TEAE was infusion site erythema. A decrease in systolic blood pressure from baseline occurred for ONO-4232 subjects compared with placebo that was statistically significant for the 0.08 ng/kg/min dose, and a dose-dependent increase in heart rate starting at 0.04 ng/kg/min and achieving statistical significance compared with placebo at 0.15 ng/kg/min and above. More orthostatic events occurred in the higher-dose groups and the dose escalation was terminated due to increasing occurrences of orthostatic hypotension/intolerance. Plasma concentrations of ONO-4232 reached steady state approximately 2 hours after the start of infusion and then declined rapidly after the end of infusion, and systemic exposure appeared to increase in a dose-proportional manner. Approximately 30% of the administered dose of ONO-4232 was excreted in the urine. ImplicationsIn healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure.

P.2.c.021 Levomilnacipran in the treatment of major depressive disorder: an analysis of efficacy and safety data from two phase III studies

The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic parameters of up to 15 dose levels of ONO-4232, a selective agonist for the EP4 subtype of the prostaglandin E2 receptor, with a dual left ventricular lusitropic and venodilatory action, in healthy, adult, male and female volunteers.In this randomized, single-center, double-blind, placebo-controlled, single-dose, sequential-group escalation, first in human study, ONO-4232 (0.001, 0.003, 0.01, 0.02, 0.04, 0.08, 0.12, 0.15, 0.18, or 0.27 ng/kg/min) or placebo was administered as a continuous intravenous infusion over 3 hours. Safety, tolerability, and pharmacokinetic data were collected during dosing and over a period of 3 days (Day –1 to Day 2), and at the follow-up visit (Day 7 [±2 days]).Fifty-seven subjects received ONO-4232 and 19 subjects received placebo. Ten of the planned 15 cohorts (dose range, 0.001–0.27 ng/kg/min) were conducted. A total of 34 treatment-emergent adverse events (TEAEs) were reported in 23 subjects. Overall, the majority of TEAEs were mild. No serious TEAEs or deaths were reported and no subjects discontinued due to adverse events. The most frequently reported TEAE was infusion site erythema. A decrease in systolic blood pressure from baseline occurred for ONO-4232 subjects compared with placebo that was statistically significant for the 0.08 ng/kg/min dose, and a dose-dependent increase in heart rate starting at 0.04 ng/kg/min and achieving statistical significance compared with placebo at 0.15 ng/kg/min and above. More orthostatic events occurred in the higher-dose groups and the dose escalation was terminated due to increasing occurrences of orthostatic hypotension/intolerance. Plasma concentrations of ONO-4232 reached steady state approximately 2 hours after the start of infusion and then declined rapidly after the end of infusion, and systemic exposure appeared to increase in a dose-proportional manner. Approximately 30% of the administered dose of ONO-4232 was excreted in the urine.In healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure.

Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers

Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 agonist oral Δ9tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers and compare these with dronabinol's effects. Participants (4 female; 10 male) smoking marijuana 6.6 (standard deviation = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over seven sessions, the time-dependent subjective, cognitive and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect and/or 'high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol, and effects were more dose-related, suggesting improved bioavailability. Nabilone was well tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence.

Acute Effects of COREXIT EC9500A on Cardiovascular Functions in Rats

These studies characterized cardiovascular responses after an acute inhalation exposure to COREXIT EC9500A, the oil dispersant used in the Deepwater Horizon oil spill. Male Sprague-Dawley rats underwent a single 5-h inhalation exposure to COREXIT EC9500A (average exposure level 27.12 mg/m3) or air. On d 1 and 7 following the exposure, rats were implanted with indwelling catheters and changes in heart rate and blood pressure were assessed in response to increasing levels of adrenoreceptor agonists. A separate group of rats was euthanized at the same time points, ventral tail arteries were dissected, and vascular tone along with dose-dependent responses to vasoconstricting and dilating factors were assessed in vitro. Agonist-induced dose-dependent increases in heart rate and blood pressure were greater in COREXIT EC9500A-exposed than in air-exposed rats at 1 d but not 7 d after the exposure. COREXIT EC9500A exposure also induced a rise in basal tone and reduced responsiveness of tail arteries to acetylcholine-induced vasodilation at 1 d but not 7 d following the exposure. These findings demonstrate that an acute exposure to COREXIT EC9500A exerts transient effects on cardiovascular and peripheral vascular functions.

Mephedrone, a new designer drug of abuse, produces acute hemodynamic effects in the rat

Mephedrone (4-methylmethcathinone) is a new and popular drug of abuse widely available on the Internet and still legal in some parts of the world. Clinical reports are now emerging suggesting that the drug displays sympathomimetic toxicity on the cardiovascular system but no studies have yet explored its cardiovascular effects. Therefore we examined the effects of mephedrone on the cardiovascular system using a combination of in vitro electrophysiology and in vivo hemodynamic and echocardiographic measurements. Patch clamp studies revealed that mephedrone, up to 30 μM, had little effect on the major voltage-dependent ion channels of the heart or on action potentials recorded in guinea pig myocytes. Subcutaneous administration of mephedrone (3 and 15 mg/kg) to conscious telemetry-implanted rats produced dose-dependent increases in heart rate and blood pressure which persisted after pre-treatment with reserpine. Echocardiographic analysis demonstrated that intravenous injection of mephedrone (0.3 and 1 mg/kg) increased cardiac function, including cardiac output, ejection fraction, and stroke volume, similar to methamphetamine (0.3 mg/kg). We conclude that mephedrone is not directly pro-arrhythmic, but induces substantial increases in heart rate, blood pressure and cardiac contractility and this activity contributes to the cardiovascular toxicity in people who abuse the drug.

Acute effects of COREXIT® EC9500A on cardiovascular function

The goal of these studies was to characterize cardiovascular responses after an acute inhalation exposure to COREXIT® EC9500A, the oil dispersant used in the Deepwater Horizon oil spill response. Male Sprague Dawley rats underwent a single 5 h exposure to COREXIT® EC9500A (N= 5 exposures, average exposure level 27.12 mg/m3) or air. On days 1 and 7 following the exposure, rats were implanted with indwelling catheters and changes in heart rate and blood pressure were assessed in response to increasing levels of adrenoreceptor agonists. Separate groups of rats were euthanized at the same time points, ventral tail arteries were dissected, and vascular tone along with dose‐dependent responses to vasoconstricting and dilating factors were assessed in vitro. Agonist‐induced dose‐dependent increases in heart rate and blood pressure where greater in COREXIT® EC9500A than air exposed rats 1 but not 7 days after the exposure. COREXIT® EC9500A exposure also induced an increase in basal tone and a reduced responsiveness of tail arteries to acetylcholine‐mediated vasodilation 1 day following the exposure. These findings demonstrate that an acute exposure to COREXIT® EC9500A had transient effects on cardiovascular and peripheral vascular function.

Effects of crustacean cardioactive peptide on the hearts of two Orthopteran insects, and the demonstration of a Frank–Starling-like effect

Like vertebrate cardiovascular systems, the dorsal vessel of the Orthopteran insects Baculum extradentatum and Locusta migratoria is under myogenic as well as neural control, through the action of neurotransmitters, neuromodulators and neurohormones. It was previously shown that the excitatory neuropeptide, crustacean cardioactive peptide (CCAP), triggers an increase in heart rate in B. extradentatum, and CCAP-like immunoreactivity is present in the innervation to the heart in many insects. In the present study, CCAP resulted in a dose-dependent increase in heart rate and hemolymph flow velocity, or cardiac output, in B. extradentatum. In contrast, CCAP led to a significant increase in stroke volume and cardiac output in L. migratoria without modifying heart rate or aortic contraction frequency. Hemolymph flow through the excurrent ostia of L. migratoria, small openings or valves on the posterior aorta and anterior heart, was inhibited with increasing concentrations of CCAP, with complete inhibition seen at 10 −7 M CCAP. In the locust, CCAP increases the volume of hemolymph in the dorsal vessel by the synchronous closing of the excurrent ostia, resulting in more forceful heart contractions and increased stroke volume and cardiac output, without modifying heart rate through a physiological mechanism analogous to the Frank–Starling mechanism in vertebrates. Therefore, crustacean cardioactive peptide alters the contractile properties of cardiac tissue in both B. extradentatum and L. migratoria, allowing for an increase in blood flow and circulation.

The physiologic responses to epinephrine during cooling and after rewarming in vivo

IntroductionThe purpose of our study was to determine whether hypothermia has any effects on physiological hemodynamic responses to epinephrine (Epi), and whether rewarming reverses these effects.MethodsSprague-Dawley rats were instrumented to measure mean arterial pressure (MAP), and left ventricular (LV) pressure-volume changes were recorded by using a Millar pressure-volume conductance catheter. Core temperature was reduced from 37°C to 28°C and returned to 37°C by using both internal and external heat exchangers. Two groups of rats were infused with either saline (n = 7), or Epi 0.125 μg/min continuously (n = 7). At 33°C, 30°C, and 28°C, the Epi infusion was temporarily increased from 0.125 to 1.25 μg/min.ResultsBefore cooling, Epi infusion in both groups resulted in a significant, dose-dependent increase in heart rate (HR), stroke volume (SV), cardiac output (CO), LV dP/dtmax (maximum derivative of systolic pressure over time), but only Epi infusion at 1.25 μg/min caused elevation of MAP. During cooling to 30°C, Epi infusion at 0.125 μg/min caused a significant elevation of central hemodynamic variables, whereas MAP remained unchanged. In contrast, Epi infusions at 1.25 μg/min caused a significant elevation of MAP during cooling to 28°C but no increases in central hemodynamics. After rewarming, all hemodynamic variables returned to baseline in both groups, but only the saline-treated animals displayed the prehypothermic hemodynamic dose responses to Epi infusions.ConclusionsThis study shows that hypothermia causes a change in the physiological hemodynamic response to Epi, which is not reversed by rewarming.

Central ECG analysis of resminostat, a new oral histone deacetylase inhibitor (HDACi), in clinical development as anticancer compound.

e13609 Background: Resminostat (4SC-201) is a new, specific, potent, pan-HDAC inhibitor with broad anti-tumor activity in preclinical models and promising clinical characteristics. Methods: 19 patients with advanced solid tumors were treated in a first-in-human trial at increasing oral daily dose levels from 100 mg to 800 mg in repeated 14-day cycles consisting of 5 consecutive treatment days followed by a 9-day rest period. Cardiac function was monitored by pulse rate, blood pressure, troponin levels, and continuous ECG telemetry during the first treatment day. In addition, standard 12-lead rest ECGs were conducted frequently to aid in the determination of potential effects on QT interval prolongation. An intensive profile consisting of 18 single ECGs was performed from day 1 to 5 during cycle 1, and a reduced number of ECGs in the following cycles, if there were no clinically relevant findings. Subsequent to the on-site clinical assessment, ECGs were sent to a core lab for further analysis by a trained cardiologist. PR, QRS, and QT intervals and heart rate (HR) were measured in lead II across 3 consecutive beats using markers for the respective ECG intervals. Results: No signal for drug-induced prolongation of QTc was observed. A dose-dependent increase in HR with a maximum mean increase of up to 22 beats per minute and a corresponding shortening of the PR and QT interval was found. HR correction with Fridericia's formula did not reveal consistent changes in QTc. The incidence of QTcF outliers was very small. The results suggest that resminostat does not affect the duration of myocardial repolarization. At doses ≥ 400 mg, unspecific flattening of the T-wave and slight depression of the ST-segment were observed frequently. However, in some patients such findings were already observed at baseline. No dose-limiting toxicities were seen with regard to cardiac safety in all dose cohorts. Conclusions: Central analysis of phase I ECG measurements did not reveal a drug- induced prolongation of the QTc interval. Drug administration was frequently associated with moderate increases in HR. At higher doses ≥ 400 mg unspecific changes in T-wave morphology and slight ST-segment depression were observed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration 4SC AG 4SC AG 4SC AG 4SC AG

The effect of different dosing schedules of UCN-01 on its pharmacokinetics and cardiohaemodynamics in dogs.

7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-infinity) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0-22 and 0.65 mgkg(-1)) and 24-h infusion (0.81 to 6.48 mgkg(-1)), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14+/-1.12 to 8.32+/-1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666+/-0.149 L h(-1) kg(-1). There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-infinity and slope0-3 h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs.