Comparative Analgesic and Mental Effects of Increasing Plasma Concentrations of Dexmedetomidine and Alfentanil in Humans

2004 ◽  
Vol 101 (3) ◽  
pp. 744-752 ◽  
Author(s):  
Martin S. Angst ◽  
Bhamini Ramaswamy ◽  
M Frances Davies ◽  
Mervyn Maze
Keyword(s):  
Plasma Concentration ◽  
Receptor Agonist ◽  
Plasma Concentrations ◽  
Analgesic Efficacy ◽  
Intrathecal Administration ◽  
Experimental Models ◽  
Sedation Score ◽  
Systemic Administration ◽  
Double Blind ◽  
Cognitive Speed

Background In animals, systemic and intrathecal administration of the alpha2 -adrenergic receptor agonist dexmedetomidine results in robust antinociceptive effects in models of heat pain. In humans, systemically administered dexmedetomidine is approved for sedating patients in the intensive care unit. However, whether systemic administration of dexmedetomidine in humans produces significant analgesia at doses causing sedation but not unconsciousness remains controversial. Methods This study in human volunteers used a placebo-controlled, double-blind, and randomized design to examine whether dexmedetomidine at doses causing mild to severe sedation produces analgesia in experimental models of heat and electrical pain. Results were compared to the effects of the mu-opioid receptor agonist alfentanil. A computer-controlled infusion provided four median step-up plasma concentrations of dexmedetomidine (0.09, 0.24, 0.54, and 1.23 ng/ml) and alfentanil (13.4, 33.8, 67.8, and 126.1 ng/ml). Results Sedative and cognitive effects of dexmedetomidine were dose-dependent, resulting in a median sedation score of 95 of 100 and slowing of cognitive speed (reaction time, trail-making test) by a factor of about two at the highest plasma concentration. Dexmedetomidine did not attenuate heat or electrical pain. Alfentanil caused severe sedation (median sedation score 88 of 100) and slowed cognitive speed by a factor of approximately 1.4 at the highest plasma concentration. Alfentanil attenuated heat and electrical pain dose dependently. Conclusion This study documents that systemic dexmedetomidine lacks analgesic efficacy for heat and electrical pain at doses causing mild to severe sedation. These results provide further evidence suggesting that systemic administration of dexmedetomidine lacks broad analgesic activity in models of acute pain at doses not rendering humans unconscious.

scholarly journals Comparison of pharmacokinetics of omega-3 fatty acid supplements in monoacylglycerol or ethyl ester in humans: a randomized controlled trial

2020 ◽  
Author(s):  
Laurie Chevalier ◽  
Mélanie Plourde
Keyword(s):  
Plasma Concentration ◽  
Ethyl Ester ◽  
Controlled Trial ◽  
Plasma Concentrations ◽  
Controlled Clinical Trial ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Post Dose ◽  
Double Blind ◽  
Omega 3 Fatty Acid

Abstract Background A diet low in omega-3 fatty acids (n-3 FA) results in low plasma concentrations of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the two main long chain n-3 FA. n-3 FA supplements on the market are esterified in triglycerides (TG) or ethyl ester (EE); the latter is absorbed less than other esterification forms. The objective of this study was to test and compare the pharmacokinetics of n-3 FA esterified in monoacylglycerides (MAG), a predigested form, with the EE form. Methods This study was a randomized, double-blind, crossover, controlled, clinical trial. Ten men and ten women between 18 and 60 years old were recruited. Participants received a single oral dose of 3 g of n-3 FA esterified in EE or MAG. Eleven blood samples were collected over 24 h post-dose. Plasma total lipids were extracted, methylated, and analyzed using gas chromatography. Results After receiving the MAG form, plasma EPA and DHA peaked at a concentration 3 and 2.5 times higher, respectively, than with the EE form. When provided in MAG form, n-3 FA plasma concentration during the absorption phase was on average 3–5 times higher than in EE form. When n-3 FAs were provided esterified in MAG, their concentration 24 h post-dose was higher than in EE. Males had a lower n-3 FA plasma concentration than females when n-3 FAs were provided in EE but there was no sexe difference when provided in MAG. Conclusions Plasma concentration of DHA and EPA was higher when provided in MAG than EE form.

Pharmacodynamics of Orally Administered Sustained- release Hydromorphone in Humans

2001 ◽  
Vol 94 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Martin S. Angst ◽  
David R. Drover ◽  
Jörn Lötsch ◽  
Bhamini Ramaswamy ◽  
Sujata Naidu ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Sustained Release ◽  
Analgesic Effect ◽  
Time Course ◽  
Plasma Concentrations ◽  
Experimental Pain ◽  
Immediate Release ◽  
Double Blind ◽  
Sustained Release Formulation ◽  
Analgesic Effects

Background The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo. Methods Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times. Results The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed. Conclusion A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.

scholarly journals Analgesic efficacy and associated plasma concentration of tramadol and O-desmethyltramadol following oral administration post ovariohysterectomy in dogs

2015 ◽  
Author(s):  
Elizabeth M Goudie-DeAngelis ◽  
Kerry J Woodhouse
Keyword(s):  
Plasma Concentration ◽  
Postoperative Pain ◽  
Pain Score ◽  
Short Form ◽  
Plasma Concentrations ◽  
Analgesic Efficacy ◽  
Pain Scale ◽  
Clinical Pain ◽  
Drug Plasma ◽  
Significant Difference

Tramadol is used in both human and veterinary medicine to treat postoperative pain. The purpose of this study was to evaluate tramadol as a sole postoperative analgesic and to compare drug plasma concentration to clinical pain score. A high or low dose of tramadol was randomly assigned and administered to 14 mixed breed female dogs after ovariohysterectomy. The Short-Form of the Glasgow Composite Measure Pain Scale was used for pain evaluation post-operatively. Plasma was collected for evaluation of tramadol and O-desmethyltramadol concentrations. The effect of weight and dose on pain scores as well as how pain score correlated with plasma concentration of tramadol and O-desmethyltramadol was evaluated. A significant difference in pain score was noted between doses when weight classes were pooled. The plasma concentrations did not correlate with pain score. Based on our results, the use of tramadol as a sole analgesic agent provides inadequate postoperative pain control.

Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects

2021 ◽  
Author(s):  
Jeongjun Kim ◽  
Jinho Choi ◽  
Hwankyu Kang ◽  
Jiye Ahn ◽  
Jane Hutchings ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Drug Candidate ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve ◽  
Exponential Decline ◽  
Potent Drug

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 – 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 – 800 mg), telacebec plasma concentration reached the maximal plasma concentration (C max ) in average 2.0 – 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration vs. time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for C max . Moderate delay in T max (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis , support further investigation of telacebec for the treatment of tuberculosis.

A multiple-dose double-blind randomized study to evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy of the TRPV1 antagonist JNJ-39439335 (mavatrep)

2018 ◽  
Vol 18 (2) ◽  
pp. 151-164 ◽  
Author(s):  
Prasarn Manitpisitkul ◽  
Christopher M. Flores ◽  
John A. Moyer ◽  
Gary Romano ◽  
Kevin Shalayda ◽  
...  
Keyword(s):  
Adverse Events ◽  
Knee Osteoarthritis ◽  
Multiple Dose ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Analgesic Efficacy ◽  
Heat Pain ◽  
Double Blind ◽  
Cold Pain ◽  
Thermal Burns

Abstract Background and aims: This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2). Methods: Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2–50 mg; part 2: 10–50 mg): n=6; placebo: n=2] and follow-up (total study duration ~10 weeks). Results: Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%). Conclusions: JNJ-39439335 (doses 2–50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain. Implications: Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.

κ-Opioid modulation of vasopressin secretion in conscious rats

1991 ◽  
Vol 129 (3) ◽  
pp. 411-416 ◽  
Author(s):  
T. Wells ◽  
M. L. Forsling
Keyword(s):  
Plasma Concentration ◽  
Receptor Agonist ◽  
Plasma Concentrations ◽  
Endogenous Opioids ◽  
Inhibitory Influence ◽  
Conscious Rat ◽  
Opioid Receptor Agonist ◽  
Basal Plasma ◽  
Vasopressin Secretion ◽  
Prior Administration

ABSTRACT A series of studies has been performed in the conscious rat to investigate the effect of the intracerebroventricular (i.c.v.) administration of the selective κ-opioid receptor agonist, U50 488H, on arginine vasopressin (AVP) secretion stimulated by i.c.v. administration of hypertonic NaCl. Similarly, the effect of the i.c.v. administration of morphine and the i.v. administration of naloxone on AVP secretion was investigated. The response of AVP to an i.c.v. injection of hypertonic NaCl was potentiated by naloxone at a dose of 0·4 mg/kg, but a higher dose (1·2 mg/kg) was required to increase the basal plasma concentration of AVP. Prior treatment with U50 488H or morphine attenuated the increase in plasma concentrations of AVP stimulated by i.c.v. injection of hypertonic NaCl from 13·92±4·44 to 1·22±0·34 and 1·78±0·74 pmol/l respectively (n = 7; P<0·05). Prior administration of U50 488H also attenuated the potentiating effect of naloxone on AVP secretion stimulated by i.c.v. injection of hypertonic NaCl. These results indicate that basal AVP secretion is under tonic inhibitory control by dynorphin, and that μ-and κ-opioid receptors mediate an inhibitory influence of endogenous opioids on osmoreceptor-mediated AVP secretion. Journal of Endocrinology (1991) 129, 411–416

scholarly journals Peritoneal Nebulization of Ropivacaine during Laparoscopic Cholecystectomy: Dose Finding and Pharmacokinetic Study

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Massimo Allegri ◽  
Martina Ornaghi ◽  
Catherine E. Ferland ◽  
Dario Bugada ◽  
Yash Meghani ◽  
...  
Keyword(s):  
Laparoscopic Cholecystectomy ◽  
High Performance ◽  
Controlled Trial ◽  
Plasma Concentrations ◽  
Analgesic Efficacy ◽  
Postoperative Nausea And Vomiting ◽  
Dose Finding ◽  
Morphine Consumption ◽  
Double Blind ◽  
Postoperative Morphine

Background. Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods. Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results. Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups (P>0.05). Conclusions. There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested.

scholarly journals Analgesic efficacy and associated plasma concentration of tramadol and O-desmethyltramadol following oral administration post ovariohysterectomy in dogs

2015 ◽  
Author(s):  
Elizabeth M Goudie-DeAngelis ◽  
Kerry J Woodhouse
Keyword(s):  
Plasma Concentration ◽  
Postoperative Pain ◽  
Pain Score ◽  
Short Form ◽  
Plasma Concentrations ◽  
Analgesic Efficacy ◽  
Pain Scale ◽  
Clinical Pain ◽  
Drug Plasma ◽  
Significant Difference

Tramadol is used in both human and veterinary medicine to treat postoperative pain. The purpose of this study was to evaluate tramadol as a sole postoperative analgesic and to compare drug plasma concentration to clinical pain score. A high or low dose of tramadol was randomly assigned and administered to 14 mixed breed female dogs after ovariohysterectomy. The Short-Form of the Glasgow Composite Measure Pain Scale was used for pain evaluation post-operatively. Plasma was collected for evaluation of tramadol and O-desmethyltramadol concentrations. The effect of weight and dose on pain scores as well as how pain score correlated with plasma concentration of tramadol and O-desmethyltramadol was evaluated. A significant difference in pain score was noted between doses when weight classes were pooled. The plasma concentrations did not correlate with pain score. Based on our results, the use of tramadol as a sole analgesic agent provides inadequate postoperative pain control.

A Double-blind, Randomized Comparison of IV Lorazepam versus  Midazolam for Sedation of ICU Patients via  a Pharmacologic Model

2001 ◽  
Vol 95 (2) ◽  
pp. 286-298 ◽  
Author(s):  
Juliana Barr ◽  
Katayoun Zomorodi ◽  
Edward J. Bertaccini ◽  
Steven L. Shafer ◽  
Eran Geller
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Sedation Score ◽  
Surgical Intensive Care Unit ◽  
Population Pharmacokinetic ◽  
Surgical Intensive Care ◽  
Double Blind ◽  
Icu Patients ◽  
Intravenous Infusions

Background Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients. Methods With Institutional Review Board approval, 24 consenting adult surgical patients were given either lorazepam or midazolam in a double-blind fashion (together with either intravenous fentanyl or epidural morphine for analgesia) through target-controlled intravenous infusions titrated to maintain a moderate level of sedation for 12-72 h postoperatively. Moderate sedation was defined as a Ramsay Sedation Scale score of 3 or 4. Sedation scores were measured, together with benzodiazepine plasma concentrations. Population pharmacokinetic and pharmacodynamic parameters were estimated using nonlinear mixed-effects modeling. Results A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation &gt; or = ss) = 50%) values for midazolam (sedation score [SS] &gt; or = n, where n = a Ramsay Sedation Score of 2, 3, ... 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively. Conclusions The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.

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