Analgesic and Respiratory Depressant Effects of R-dihydroetorphine

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. Methods The authors performed a population pharmacokinetic–pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. Results R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. Conclusions Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Download Full-text

The Pharmacokinetics of Milrinone in Pediatric Patients after Cardiac Surgery

Anesthesiology ◽

10.1097/00000542-199904000-00014 ◽

1999 ◽

Vol 90 (4) ◽

pp. 1012-1018 ◽

Cited By ~ 64

Author(s):

James M. Bailey ◽

Bruce E. Miller ◽

Wei Lu ◽

Steven R. Tosone ◽

Kirk R. Kanter ◽

...

Keyword(s):

Cardiac Surgery ◽

Plasma Concentration ◽

Cardiac Index ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Plasma Concentrations ◽

Compartment Model ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Loading Dose

Background Milrinone has been shown to increase cardiac output in children after cardiac surgery, but pharmacokinetic analysis has not been used to identify effective dose regimens. The purpose of this study was to characterize the pharmacokinetics of milrinone in infants and children and to apply the results to the issue of dosing. Methods Twenty children were studied after they underwent repair of congenital cardiac defects. Control hemodynamic measurement was made after the children were separated from cardiopulmonary bypass, and each patient was given a loading dose of 50 microg/kg progressively in 5 min. Hemodynamic measurements were recorded again at the end of the loading dose and when a blood sample was taken to determine milrinone plasma concentrations. Further blood samples were taken during the next 16 h for milrinone plasma concentration analysis. The pharmacokinetics of milrinone were analyzed using the population pharmacokinetic program NONMEM. Results The loading dose of milrinone resulted in a mean decrease in mean blood pressure of 12% and a mean increase in cardiac index of 18% at a mean peak plasma concentration of 235 ng/ml. The pharmacokinetics of milrinone were best described by a three-compartment model. In the optimal model, all volumes and distribution clearances were proportional to weight, and weight-normalized elimination clearance was proportional to age; ie., Cl1 = 2.5 x weight x (1 + 0.058 x age) where Cl1 is expressed as ml/min, and the units of weight and age are kg and months, respectively. Conclusions A loading dose of 50 microg/kg effectively increases cardiac index in children after cardiac surgery. Simulations indicate that the peak plasma concentration can be maintained by following the loading dose of 50 microg/kg with an infusion of approximately 3 microg x kg(-1) x min(-1) for 30 min and then a maintenance infusion, which may require adjustment for age.

Download Full-text

DOSE-DEPENDENT PHARMACOKINETICS OF RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR (tPA) IN ANESTHETIZED DOGS FOLLOWING INTRAVENOUS INFUSION

10.1055/s-0038-1644399 ◽

1987 ◽

Cited By ~ 1

Author(s):

K L L Fong ◽

C S Crysler ◽

B A Mico ◽

K E Boyle ◽

G A Kopia ◽

...

Keyword(s):

Steady State ◽

Plasma Concentration ◽

Plasminogen Activator ◽

Dose Range ◽

Plasma Concentrations ◽

Tissue Type ◽

Tissue Type Plasminogen Activator ◽

Arterial Blood ◽

Type Plasminogen Activator ◽

Dose Dependent

The pharmacokinetics of SK&F recombinant two-cha1n tissue-type plasminogen activator (tPA) following Intravenous (i.v.) infusion were characterized in anesthetized, open chested mongrel dogs in which artificial Intracoronary thrombi were formed. SK&F tPA was Infused at rates of 0.5, 1, 2, 4, and 8 μg/kg/min (n=3 to 5 per dose) for 90 min and arterial blood samples were withdrawn during and after Infusion for determination of functionally active tPA concentrations using a modified and validated S-2251 chromogenlc assay. At all doses studied, steady state active tPA plasma concentrations were achieved 10-20 min after the onset of Infusion. Upon cessation of Infusion, active tPA plasma concentrations declined rapidly with a t1/2 of 2-3 min. The active tPA plasma concentration at steady state (Css) and the area under the tPA plasma concentration-time curve (AUC) Increased linearly with dose in the range of 0.5-4 μg/kg/min. However, as the dose was Increased 2-fold from 4 to 8 μg/kg/min, the AUC and the Css Increased 2.5 fold. The systemic clearance ranged from 15-16 ml/min/kg at doses of 0.5-4 μg/kg/min but decreased to 11.7 ml/min/kg at the 8 μg/kg/min dose. With exceptions in 3 dogs, the volume of distribution at steady state approached or slightly exceeded the blood volume. Plasma tPA antigen concentrations were also determined in the dogs receiving the 2 μg/kg/min dose. At steady state, active tPA accounted for 40-60% of the total tPA antigen. The post-infusion t1/2 of the tPA antigen was considerably longer (13.46 ± 5.94 min) than that of active tPA. These results suggested that non-plasminogen activating metabolites (e.g., tPA-inhlbltor complex(es)) are present in the plasma of dogs receiving tPA. It 1s also concluded from the present study that (1) distribution of the i.v. administered tPA molecule was limited primarily to the Intravascular space, and (2) tPA may display dose-dependent pharmacokinetics within the optimum thrombolytic dose range.

Download Full-text

The Measurement of Heparin and Other Therapeutic Sufphated Polysaccharides in Plasma, Serum and Urine

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660086 ◽

1985 ◽

Vol 54 (03) ◽

pp. 630-634 ◽

Cited By ~ 19

Author(s):

J Dawes ◽

C V Prowse ◽

D D Pepper

Keyword(s):

Biological Fluids ◽

Anticoagulant Activity ◽

Dose Range ◽

Plasma Concentrations ◽

Heparin Therapy ◽

Competitive Binding Assay ◽

First Order Kinetics ◽

Activity Measurements ◽

Heparin Activity ◽

Dose Dependent

SummaryThe competitive binding assay described will specifically and accurately measure concentrations of administered heparin in biological fluids with a sensitivity of 60 ng ml-1. Neither endogenous glycosaminoglycans, nor plasma proteins such as ATIII and PF4 interfere in the assay. Semi-synthetic highly sulphated heparinoids and LMW heparin can also be measured. Using this assay heparin clearance followed simple first-order kinetics over the dose range 100-5,000 units, but the half-life was strongly dose-dependent. There was good correlation with heparin activity measurements by APTT and anti-Xa clotting assays. Plasma concentrations were measurable for at least 5 h following subcutaneous injection of 10,000 units of heparin. Excretion in the urine could be followed after all but the lowest intravenous dose. This assay, used in conjunction with measurements of heparin anticoagulant activity, will be valuable in the elucidation of mechanisms of action of heparin and the heparinoids, and in the assessment and management of problems related to heparin therapy.

Download Full-text

Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz203 ◽

2019 ◽

Vol 74 (8) ◽

pp. 2335-2340 ◽

Cited By ~ 3

Author(s):

Christoph Dorn ◽

David Petroff ◽

Nancy Neumann ◽

Alexander Kratzer ◽

Nahed El-Najjar ◽

...

Keyword(s):

Drug Exposure ◽

Peak Plasma ◽

Subcutaneous Tissue ◽

Plasma Concentrations ◽

Surgical Patients ◽

Pharmacokinetic Analysis ◽

Controlled Clinical Trial ◽

Morbidly Obese ◽

Obese Patients ◽

Tissue Pharmacokinetics

Abstract Objectives To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. Methods Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. Results Thirteen obese patients (BMI 38–50 kg/m2) and 14 non-obese patients (BMI 0–29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). Conclusions Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.

Download Full-text

Pharmacokinetic-Pharmacodynamic Assessment of the Hepatic and Bone Marrow Toxicities of the New Trypanoside Fexinidazole

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02515-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 7

Author(s):

James A. Watson ◽

Nathalie Strub-Wourgraft ◽

Antoine Tarral ◽

Isabela Ribeiro ◽

Joel Tarning ◽

...

Keyword(s):

Bone Marrow ◽

Chagas Disease ◽

Plasma Concentrations ◽

Bone Marrow Suppression ◽

Population Pharmacokinetic ◽

Phase 2 ◽

Content Type ◽

Platelet Counts ◽

Exposure Response ◽

Dose Dependent

ABSTRACT Fexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease. During the course of a dose ranging assessment in patients with chronic indeterminate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases were observed and clinical investigations were suspended. We retrospectively analyzed all available pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in patients with Chagas disease and g-HAT to assess the determinants of toxicity. A population pharmacokinetic model was fitted to plasma concentrations (n = 4,549) of the bioactive fexinidazole sulfone metabolite, accounting for the majority of the bioactive exposure, from three phase 1 studies, two g-HAT phase 2/3 field trials, and one Chagas disease phase 2 field trial (n = 462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver-related pharmacodynamic outcomes in Chagas disease patients. Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure dependent and, thus, dose dependent in patients with Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in patients with g-HAT. In contrast, no evidence of hepatotoxicity was observed in patients with g-HAT. Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease patients. Regimens of shorter duration should be evaluated in clinical trials with patients with Chagas disease. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.

Download Full-text

Phase I and Pharmacokinetic Study of Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.4.927 ◽

2000 ◽

Vol 18 (4) ◽

pp. 927-927 ◽

Cited By ~ 187

Author(s):

J. Zujewski ◽

I.D. Horak ◽

C.J. Bol ◽

R. Woestenborghs ◽

C. Bowden ◽

...

Keyword(s):

Peak Plasma ◽

Performance Status ◽

Dose Range ◽

Plasma Concentrations ◽

Oral Drug ◽

Total Daily Dose ◽

Pharmacokinetic Data ◽

Metastatic Colon Cancer ◽

Phase Ii Trials ◽

Farnesyl Protein Transferase

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1,000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Download Full-text

Pharmacokinetics of Rapacuronium in Infants and Children with Intravenous and Intramuscular Administration

Anesthesiology ◽

10.1097/00000542-200002000-00018 ◽

2000 ◽

Vol 92 (2) ◽

pp. 376-376 ◽

Cited By ~ 8

Author(s):

Lynne M. Reynolds ◽

Andrew Infosino ◽

Ronald Brown ◽

Jim Hsu ◽

Dennis M. Fisher

Keyword(s):

Plasma Concentration ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Pediatric Anesthesia ◽

Infants And Children ◽

Intramuscular Administration ◽

Pharmacokinetic Analysis ◽

Intravenous Route ◽

Population Pharmacokinetic ◽

In Infants And Children

Background A nondepolarizing muscle relaxant with an onset and offset profile similar to succinylcholine is desirable for pediatric anesthesia. The onset and offset of rapacuronium are rapid in children. In the current study, the authors determined its pharmacokinetic characteristics in children. In addition to administering rapacuronium by the usual intravenous route, the authors also gave rapacuronium intramuscularly to determine uptake characteristics and bioavailability. Methods Forty unpremedicated patients aged 2 months to 3 yr were anesthetized with halothane, 0.82-1.0% end-tidal concentration. When anesthetic conditions were stable, rapacuronium was injected either into a peripheral vein (2 mg/kg for infants, 3 mg/kg for children) or a deltoid muscle (2.8 mg/kg for infants, 4.8 mg/kg for children). Four venous plasma samples were obtained from each subject 2-240 min after rapacuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak plasma concentration with intramuscular administration. Results Plasma clearance was 4.77 ml x kg(-1) x min(-1) + 8.48 ml/min. Intramuscular bioavailability averaged 56%. Absorption from the intramuscular depot had two rate constants: 0.0491 min(-1) (72.4% of absorbed drug) and 0.0110 min(-1) (27.6% of the absorbed drug). Simulation indicated that plasma concentration peaks 4.0 and 5.0 min after intramuscular rapacuronium in infants and children, respectively, and that, at 30 min, less than 25% of the administered dose remains to be absorbed from the intramuscular depot. Conclusions In infants and children, rapacuronium's clearance and steady state distribution volume are less than in adults. After intramuscular administration, bioavailability is 56%, and plasma rapacuronium concentrations peak within 4 or 5 min.

Download Full-text

Antidipsogenic effects of eel bradykinins in the eelAnguilla japonica

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.4.r1090 ◽

2001 ◽

Vol 281 (4) ◽

pp. R1090-R1096 ◽

Cited By ~ 8

Author(s):

Yoshio Takei ◽

Takamasa Tsuchida ◽

Zhihong Li ◽

J. Michael Conlon

Keyword(s):

Dose Range ◽

Plasma Concentrations ◽

Plasma Osmolality ◽

Physiological Role ◽

Kinin System ◽

Arterial Blood ◽

Dependent Inhibition ◽

High Conservation ◽

Kallikrein Kinin System ◽

Sustained Increase

A peptide with bradykinin (BK)-like immunoreactivity was isolated from an incubate of heat-denatured eel plasma with porcine pancreatic kallikrein. The purified peptide had the following amino acid sequence: Arg-Arg-Pro-Pro-Gly-Ser-Trp-Pro-Leu-Arg. This decapeptide, named eel [Arg0]BK, was identical to two previously identified BK homologs from cod and trout. High conservation of the BK sequence among distant teleost species suggests an important function in this vertebrate group. Bolus intra-arterial injections of eel [Arg0]BK, BK, and [Arg0]-des-Arg9-BK (1–10 nmol/kg) caused significant ( P < 0.05) inhibition of drinking in seawater-adapted eels. The potency of the inhibition was ranked in the following order: [Arg0]BK > [Arg0]-des-Arg9-BK = BK. The BK peptides also produced an immediate, transient increase followed by a sustained increase in arterial blood pressure and an initial decrease followed by an increase in heart rate. Strong tachyphylaxis occurred for the cardiovascular effect but not for the antidipsogenic effect. The order of the potency of the cardiovascular actions, [Arg0]BK > BK > [Arg0]-des-Arg9-BK, was different from that of the antidipsogenic action. Slow infusions of eel [Arg0]BK in the dose range 1–1,000 pmol · kg−1 · min−1 produced concentration-dependent inhibition of drinking without changes in arterial pressure, plasma osmolality, and hematocrit. At the infusion rate of >100 pmol · kg−1 · min−1, plasma concentrations of angiotensin II, a potent dipsogenic hormone in eels, increased, suggesting an interaction of the kallikrein-kinin and renin-angiotensin systems. In mammals, BK is dipsogenic and vasodepressor, so that our data demonstrate opposite effects on fluid and cardiovascular regulation of BK in the eel and suggest a new physiological role for the kallikrein-kinin system in teleost fish.

Download Full-text

Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05317-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5294-5299 ◽

Cited By ~ 53

Author(s):

Gautam Baheti ◽

Jennifer J. Kiser ◽

Peter L. Havens ◽

Courtney V. Fletcher

Keyword(s):

Rate Constant ◽

Sequential Analysis ◽

Plasma Concentrations ◽

Elimination Rate ◽

Distribution Volume ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Response Model ◽

Indirect Response Model ◽

Indirect Response

ABSTRACTThe relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n= 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h−1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (Emax), the TFV concentration producing 50% ofEmax(EC50), and the intracellular elimination rate constant (kout) of 300 fmol/106cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h−1, respectively. The estimatedkoutgave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

Download Full-text