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1.
J Clin Pharmacol ; 56(12): 1528-1537, 2016 12.
Article in English | MEDLINE | ID: mdl-27225334

ABSTRACT

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP-4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ∼2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Heterocyclic Compounds, 2-Ring/administration & dosage , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Pyrans/administration & dosage , Pyrans/pharmacokinetics , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Healthy Volunteers , Humans , Male , Middle Aged
2.
Gynecol Obstet Invest ; 77(4): 211-6, 2014.
Article in English | MEDLINE | ID: mdl-24686129

ABSTRACT

AIM: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. METHODS: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m(2)) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. RESULTS: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m(2), at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). CONCLUSION: Estradiol and weight in part explain the variation in paracetamol clearance in young women.


Subject(s)
Acetaminophen/pharmacokinetics , Analgesics, Non-Narcotic/pharmacokinetics , Body Weight , Estradiol/blood , Acetaminophen/administration & dosage , Adult , Analgesics, Non-Narcotic/administration & dosage , Biomarkers/blood , Cesarean Section , Chromatography, High Pressure Liquid , Contraceptives, Oral, Hormonal/pharmacology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Injections, Intravenous , Linear Models , Metabolic Clearance Rate/drug effects , Postpartum Period , Pregnancy , ROC Curve
3.
Eur Rev Med Pharmacol Sci ; 18(5): 599-604, 2014.
Article in English | MEDLINE | ID: mdl-24668698

ABSTRACT

OBJECTIVES: Because of the extensive variability in paracetamol clearance in young women, published data were pooled with newly collected observations in search of covariates of paracetamol pharmacokinetics (PK) within this specific population. SUBJECTS AND METHODS: PK estimates and clinical characteristics [pregnant, weight, exposure to oral contraceptives (OC)] in young women following IV loading dose (2 g paracetamol) were pooled, using a non-compartmental linear disposition model in individual time-concentration profiles. Data were reported by median and range. Rank correlation was used to link clearance (l/h) to weight, Mann Whitney U test to compare clearance (l/h.m-2) between subgroups (pregnant, OC exposure). Finally, a multiple regression model with clearance (l/h) in all women and all non-pregnant women was performed. RESULTS: Based on 73 paracetamol PK estimates, a 8-fold variability in clearance (range 7.1-62.2 l/h) was documented, in part explained by a correlation (r2=0.36) between clearance (l/h) and weight. Clearance (l/h and l/h.m-2) and distribution volume (l) at delivery (n=36) were higher compared to non-pregnant observations. In non-pregnant women, women on OC (n=20) had a higher paracetamol clearance (l/h.m-2) compared to women (n=17) not on OC (p = 0.023). Weight (p = 0.0043) and pregnancy (p = 0.02) were independent variables (r=0.56) of paracetamol clearance (l/h). In non-pregnant women, weight (p = 0.009) and OC exposure (p = 0.03) were independent variables (r=0.51). CONCLUSIONS: Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women.


Subject(s)
Acetaminophen/administration & dosage , Acetaminophen/blood , Body Weight/physiology , Contraceptives, Oral/administration & dosage , Contraceptives, Oral/blood , Pregnancy/blood , Administration, Intravenous , Adult , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/blood , Body Weight/drug effects , Cohort Studies , Delivery, Obstetric , Drug Interactions/physiology , Female , Humans , Pregnancy/drug effects , Young Adult
4.
J Psychopharmacol ; 25(3): 314-28, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20147571

ABSTRACT

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.


Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , GABA-A Receptor Agonists/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Hydrocarbons, Fluorinated/pharmacology , Adolescent , Adult , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/adverse effects , Binding Sites , Brain/metabolism , Chlordiazepoxide/administration & dosage , Chlordiazepoxide/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , GABA-A Receptor Agonists/administration & dosage , GABA-A Receptor Agonists/adverse effects , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/adverse effects , Humans , Hydrocarbons, Fluorinated/administration & dosage , Hydrocarbons, Fluorinated/adverse effects , Male , Mice , Middle Aged , Positron-Emission Tomography , Protein Binding , Protein Subunits , Rats , Rats, Sprague-Dawley , Saimiri , Species Specificity , Tissue Distribution , Young Adult
5.
J Psychopharmacol ; 25(3): 329-44, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20156926

ABSTRACT

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.


Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , GABA-A Receptor Agonists/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Hydrocarbons, Fluorinated/pharmacology , Adolescent , Adult , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/adverse effects , Disease Models, Animal , Dose-Response Relationship, Drug , GABA-A Receptor Agonists/administration & dosage , GABA-A Receptor Agonists/adverse effects , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/adverse effects , Humans , Hydrocarbons, Fluorinated/administration & dosage , Hydrocarbons, Fluorinated/adverse effects , Male , Mice , Middle Aged , Protein Subunits , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Saimiri , Species Specificity , Time Factors , Young Adult
6.
J Clin Pharmacol ; 49(3): 281-90, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19246728

ABSTRACT

The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC(0-2) [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.


Subject(s)
Migraine Disorders/drug therapy , Nitric Oxide Synthase Type II/antagonists & inhibitors , Sulfones/pharmacokinetics , Sulfones/therapeutic use , Adult , Area Under Curve , Female , Half-Life , Humans , Male , Nitrates/blood , Nitric Oxide/blood , Nitric Oxide/metabolism , Sulfones/pharmacology , Tyrosine/analogs & derivatives , Tyrosine/blood
7.
Br J Anaesth ; 100(4): 525-32, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18303070

ABSTRACT

BACKGROUND: Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited. METHODS: A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score. RESULTS: In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h(-1) (70 kg)(-1) (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h(-1) (70 kg)(-1) (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability. CONCLUSIONS: Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited micro-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.


Subject(s)
Analgesics, Opioid/blood , Infant, Premature/blood , Tramadol/blood , Aging/blood , Creatine/blood , Cytochrome P-450 CYP2D6/genetics , Genotype , Humans , Infant , Infant, Newborn , Models, Biological , Prospective Studies , Tramadol/analogs & derivatives
8.
J Pharmacol Exp Ther ; 325(1): 248-55, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18216286

ABSTRACT

The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP(8-37) (1200 ng . min(-1) . dl(-1) forearm), indomethacin (5 mug . min(-1) . dl(-1) forearm), and N(G)-monomethyl-l-arginine (l-NMMA; 0.2 mg . min(-1) dl(-1) forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP(8-37) inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.


Subject(s)
Calcitonin Gene-Related Peptide/pharmacology , Capsaicin/pharmacology , Peptide Fragments/pharmacology , Skin/blood supply , Vasodilation/drug effects , Adolescent , Adult , Calcitonin Gene-Related Peptide/administration & dosage , Cross-Over Studies , Drug Antagonism , Forearm , Humans , Laser-Doppler Flowmetry , Middle Aged , Pharmacokinetics , Receptors, Calcitonin Gene-Related Peptide , Regional Blood Flow , Single-Blind Method
9.
Clin Pharmacol Ther ; 83(6): 840-7, 2008 Jun.
Article in English | MEDLINE | ID: mdl-17882161

ABSTRACT

Laropiprant is a selective antagonist of the prostaglandin D(2) (PGD(2)) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T(max)=0.8-2.0 h) and the terminal half-life is approximately 12-18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD(2)-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.


Subject(s)
Indoles/adverse effects , Indoles/pharmacokinetics , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/metabolism , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Headache/blood , Headache/chemically induced , Humans , Indoles/therapeutic use , Male , Middle Aged
10.
Br J Anaesth ; 99(6): 864-70, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17965417

ABSTRACT

BACKGROUND: To document covariates which contribute to inter-individual variability in propofol pharmacokinetics in preterm and term neonates. METHODS: Population pharmacokinetics were estimated (non-linear mixed effect modelling) based on the arterial blood samples collected in (pre)term neonates after i.v. bolus administration of propofol (3 mg kg(-1), 10 s). Covariate analysis included postmenstrual age (PMA), postnatal age (PNA), gestational age, weight, and serum creatinine. RESULTS: Two hundred and thirty-five arterial concentration-time points were collected in 25 neonates. Median weight was 2930 (range 680-4030) g, PMA 38 (27-43) weeks, and PNA 8 (1-25) days. In a three-compartment model, PMA was the most predictive covariate for clearance (P<0.001) when parameterized as [CL(std).(PMA/38)(11.5)]. Standardized propofol clearance (CL(std)) at 38 weeks PMA was 0.029 litre min(-1). The addition of a fixed value in neonates with a PNA of >/=10 days further improved the model (P<0.001) and resulted in the equation [CL(std).(PMA/38)(11.5) +0.03] for neonates >/=10 days. Values for central volume (1.32 litre), peripheral volume 1 (15.4 litre), and peripheral volume 2 (1.29 litre) were not significantly influenced by any of the covariates (P>0.001). CONCLUSIONS: PMA and PNA contribute to the inter-individual variability of propofol clearance with very fast maturation of clearance in neonatal life. This implicates that preterm neonates and neonates in the first week of postnatal life are at an increased risk for accumulation during either intermittent bolus or continuous administration of propofol.


Subject(s)
Anesthetics, Intravenous/blood , Infant, Newborn/blood , Propofol/blood , Aging/blood , Anesthetics, Intravenous/administration & dosage , Body Weight/physiology , Creatinine/blood , Drug Administration Schedule , Female , Gestational Age , Humans , Infant, Premature/blood , Male , Metabolic Clearance Rate/physiology , Models, Biological , Propofol/administration & dosage
11.
Cephalalgia ; 27(7): 843-6, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17668468

ABSTRACT

Interictal serum C-reactive protein (CRP) was measured in 50 young adult patients with migraine and compared with 50 controls. The median CRP level was 1.42 mg/l in patients with migraine and 0.90 mg/l in controls (P = 0.03). This finding supports the role of inflammation in migraine, but needs confirmation in larger controlled studies. Prospective studies may establish whether measurements of CRP can identify patients with migraine at risk for cardiovascular events.


Subject(s)
Biomarkers/blood , C-Reactive Protein/metabolism , Migraine with Aura/blood , Migraine without Aura/blood , Adult , Age Distribution , Cross-Sectional Studies , Female , Humans , Inflammation/blood , Inflammation/epidemiology , Male , Migraine with Aura/epidemiology , Migraine with Aura/immunology , Migraine without Aura/epidemiology , Migraine without Aura/immunology , Risk Factors
12.
Br J Clin Pharmacol ; 64(5): 580-90, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17578484

ABSTRACT

AIMS: Part I: to establish the dose and appropriate application site of capsaicin on the human forearm in order to produce a robust and reproducible dermal blood flow (DBF) response. Part II: to evaluate the within-subject arm-to-arm and period-to-period reproducibility. METHODS: Both parts consisted of two study visits. In part I, placebo and 100, 300 and 1000 microg capsaicin were applied at four predefined sites on the volar surface of both forearms. Placebo and capsaicin doses were randomized and balanced by site between subjects. Changes in DBF were assessed by laser Doppler perfusion imaging up to 60 min after capsaicin application. In part II, only 1000 microg capsaicin was applied on the proximal forearm and changes in DBF assessed up to 30 min (t(30)). DBF response was expressed as percent change from baseline +/- SD and the corresponding AUC(0-30). Reproducibility assessment included calculation of the concordance correlation coefficient (CCC). RESULTS: Part I (n = 12 subjects): compared with placebo, 300 and 1000 microg capsaicin increased DBF (P < 0.05) at all time points except at 10 min. This increase was reproducible at the two most proximal sites from the 30-min time point onwards when compared between arms (CCC >or= 0.8, i.e. substantial to almost perfect reproducibility). In part II (n = 11), t(30) averaged 390 +/- 120% and arm-to-arm reproducibility was almost perfect (CCC = 0.91) for AUC(0-30). CONCLUSIONS: Capsaicin induces a reproducible within-subject arm-to-arm increase in DBF. We provide a non-invasive pharmacodynamic model in humans to test antagonists of mediators involved in capsaicin-induced dermal vasodilation, including calcitonin gene-related peptide antagonists.


Subject(s)
Capsaicin/pharmacology , Forearm/blood supply , Sensory System Agents/pharmacology , Skin/blood supply , Adolescent , Adult , Analysis of Variance , Blood Flow Velocity/drug effects , Dose-Response Relationship, Drug , Humans , Laser-Doppler Flowmetry , Male , Middle Aged , Piperazines/pharmacology , Quinazolines/pharmacology , Reproducibility of Results , Treatment Outcome
13.
Eur J Clin Pharmacol ; 63(2): 135-41, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17200838

ABSTRACT

INTRODUCTION: Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D(2) is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD(2) reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD(2) (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD(2) can be a useful tool for evaluating DP-receptor antagonists. OBJECTIVE: The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD(2) induced nasal congestion in healthy volunteers. METHODS: To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD(2) were performed to determine the PD(75), which is the intranasal dose of PGD(2) that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry. RESULTS: Following treatment with MK-0524, the PD(75) (mean+/-SD) was significantly shifted from 15.8 +/- 18.3 mug/nostril during the placebo period to more than 512 mug/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen. CONCLUSION: Whether this >45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.


Subject(s)
Indoles/pharmacology , Nasal Obstruction/drug therapy , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Rhinitis, Allergic, Seasonal/drug therapy , Administration, Oral , Adult , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , Male , Nasal Obstruction/chemically induced , Prostaglandin D2/physiology , Rhinomanometry
14.
Cephalalgia ; 26(1): 56-63, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16396667

ABSTRACT

The forearm vascular response to nitric oxide (NO) and calcitonin gene-related peptide (CGRP) was investigated in 10 migraine patients and 10 matched control subjects. Changes in forearm blood flow (FBF) during intrabrachial infusion of: (i) serotonin (releasing endogenous NO), (ii) sodium nitroprusside (SNP, exogenous NO-donor), and (iii) CGRP were measured using venous occlusion plethysmography. Flow-mediated dilation (FMD) of the brachial artery, a measure for the endogenous release of NO reactive to occlusion, was measured using ultrasound and expressed as percentage change vs. baseline diameter. FBF ratio (i.e. FBF in the infused over the control arm) at baseline (1.1 +/- 0.1) did not differ between both populations. Serotonin, SNP and CGRP induced a dose-dependent increase (P < 0.001) in FBF ratio in controls (to 2.8 +/- 0.3, 6.7 +/- 1.4 and 6.9 +/- 1.2 at the highest dose, respectively) and migraineurs (2.5 +/- 0.4, 5.6 +/- 0.8 and 6.5 +/- 1.3, respectively); these ratios did not differ between both groups. FMD was comparable in control subjects (5.8 +/- 1%) and migraine patients (5.2 +/- 1%). Based on the forearm vascular response to NO and CGRP, migraine patients do not display generalized changes in vascular function.


Subject(s)
Calcitonin Gene-Related Peptide/administration & dosage , Migraine Disorders/physiopathology , Nitric Oxide/metabolism , Regional Blood Flow/drug effects , Regional Blood Flow/physiology , Adult , Brachial Artery/physiology , Female , Forearm/blood supply , Humans , Ischemia/metabolism , Ischemia/physiopathology , Male , Migraine Disorders/etiology , Migraine Disorders/metabolism , Nitric Oxide Donors/administration & dosage , Nitroprusside/administration & dosage , Plethysmography , Serotonin/administration & dosage , Serotonin Agents/administration & dosage , Vasodilation/drug effects
15.
Eur J Clin Pharmacol ; 61(5-6): 341-6, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15983826

ABSTRACT

OBJECTIVE: To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK1)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting. METHODS: This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10-12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1-3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day -1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily. RESULTS: The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC(0-24 h) and C(max). However, compared with placebo, trough S(-) warfarin concentrations decreased on days 5-8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011). CONCLUSION: These data are consistent with a significant induction of CYP2C9 metabolism of S(-) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7-10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.


Subject(s)
Anticoagulants/pharmacokinetics , Antiemetics/pharmacology , Morpholines/pharmacology , Warfarin/pharmacokinetics , Anticoagulants/blood , Anticoagulants/pharmacology , Antiemetics/administration & dosage , Aprepitant , Area Under Curve , Aryl Hydrocarbon Hydroxylases/biosynthesis , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP2C9 , Double-Blind Method , Drug Interactions , Enzyme Induction , Female , Humans , International Normalized Ratio , Male , Metabolic Clearance Rate , Morpholines/administration & dosage , Prothrombin Time , Time Factors , Warfarin/blood , Warfarin/pharmacology
16.
Cephalalgia ; 23(2): 96-104, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12603365

ABSTRACT

As migraine is associated with an increased risk for ischaemic stroke and peripheral vasospastic disorders, it was hypothesized that interictal vascular changes may be present in migraine patients. Using ultrasound and applanation tonometry, the cardiovascular properties of migraine patients were compared with those of matched control subjects. Vascular parameters of the carotid arteries, cardiac output and systemic vascular resistance did not differ between both groups. Right temporal artery diameter was larger in migraine patients (mean difference 101 micro m; 95% confidence interval (CI) 9/194 micro m; P = 0.033). At the brachial artery, migraine patients displayed a smaller distension (difference -24 micro m; 95% CI -45/-4 micro m; P = 0.021) and a decreased compliance (difference -0.025 mm2/kPa; 95% CI -0.047/-0.003 mm2/kPa; P = 0.024). Thus, migraine patients display an increased peripheral arterial stiffness. The presence of these interictal vascular changes suggests that migraine might be part of a more generalized vascular disorder.


Subject(s)
Migraine Disorders/diagnosis , Migraine Disorders/physiopathology , Adult , Blood Pressure , Brachial Artery/diagnostic imaging , Brachial Artery/physiopathology , Brain/blood supply , Brain/physiopathology , Cardiac Output , Carotid Artery, Common/diagnostic imaging , Carotid Artery, Common/physiopathology , Cerebrovascular Circulation , Female , Femoral Artery/diagnostic imaging , Femoral Artery/physiopathology , Humans , Male , Middle Aged , Migraine Disorders/diagnostic imaging , Migraine Disorders/epidemiology , Norway/epidemiology , Temporal Arteries/diagnostic imaging , Temporal Arteries/physiopathology , Ultrasonography , Vascular Resistance
17.
Aliment Pharmacol Ther ; 16(9): 1683-8, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12197849

ABSTRACT

BACKGROUND: Aspirin is widely used as an anti-thrombotic drug; however, it has been suggested that enteric-coated formulations of aspirin may be less bioavailable and less effective as anti-thrombotic agents. AIM: To assess the effect of a formulation of enteric-coated, low-dose (81 mg) aspirin on serum generated thromboxane B2 and platelet aggregation in healthy subjects. METHODS: Twenty-four subjects participated in a double-blind, randomized, placebo-controlled, parallel-group, multiple-dose study. Twelve subjects in each of two groups received a daily oral dose of enteric-coated aspirin (81 mg) or matching placebo for 7 days. Serum thromboxane B2 and platelet aggregation (using 1 mm arachidonic acid and 1 microg/mL collagen as agonists) were measured 1-3 days prior to day 1, on day 1 (prior to therapy) and 4 h after the last dose on day 7. RESULTS: After seven daily doses of enteric-coated aspirin, the mean percentage inhibition from baseline of ex vivo generated serum thromboxane B2 was 97.4%, compared with a 7.8% increase after placebo treatment. The mean percentage inhibition of arachidonic acid- and collagen-induced platelet aggregation was 97.9% and 70.9%, respectively, following enteric-coated aspirin, compared with - 1.0% and 2.7%, respectively, after placebo. CONCLUSIONS: The anti-platelet effects of multiple, daily, low-dose aspirin (as assessed by inhibition of serum thromboxane B2 and platelet aggregation) are not adversely affected by enteric coating.


Subject(s)
Aspirin/pharmacology , Blood Platelets/drug effects , Platelet Aggregation Inhibitors/pharmacology , Adolescent , Adult , Aspirin/administration & dosage , Blood Platelets/physiology , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/administration & dosage , Tablets, Enteric-Coated , Thromboxane B2/biosynthesis , Thromboxane B2/blood
18.
Eur J Clin Pharmacol ; 58(5): 303-8, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12185552

ABSTRACT

OBJECTIVE: To compare the sensitivity of three non-invasive techniques for detecting serotonin (5-HT)(1B/1D)-receptor agonist-induced peripheral vascular effects in humans: the measurement of (1) systolic (SBP) and diastolic (DBP) blood pressures, (2) dorsal hand vein (DHV) diameter and (3) toe-arm systolic blood pressure gradient (DeltaSBP(toe-arm)). METHODS: A double-blind, placebo-controlled, three-way, cross-over study was performed in 12 healthy male volunteers. According to a randomly assigned allocation schedule, subjects were administered sumatriptan 3 mg, sumatriptan 6 mg or placebo subcutaneously. Measurements were performed at baseline, every 5 min for 30 min and at 40 min and 60 min after drug administration. SBP and DBP were recorded using a semi-automated oscillometric device. DHV diameter was measured using a linear variable differential transformer. DeltaSBP(toe-arm) was calculated after measuring toe and arm SBP with a strain-gauge technique. Sensitivity was evaluated with responsiveness statistics. RESULTS: Based on weighted mean and compared with placebo, sumatriptan 3 mg and 6 mg increased SBP by 3.3 mmHg ( P=0.023) and 6.4 mmHg ( P<0.001) and DBP by 5.0 mmHg ( P=0.006) and 7.5 mmHg ( P<0.001), respectively. Sumatriptan 3 mg and 6 mg decreased DHV diameter by 36% ( P=0.015) and 40% ( P=0.005), respectively. DeltaSBP(toe-arm) did not change. Peak changes were observed within 10-15 min after drug administration. The rank order of responsiveness was: BP > DHV diameter > DeltaSBP(toe-arm.) CONCLUSIONS: Clinically relevant doses of subcutaneous sumatriptan increased blood pressure and decreased DHV diameter without affecting DeltaSBP(toe-arm). The increase in blood pressure appeared to be dose dependent. Compared with DHV diameter and DeltaSBP(toe-arm), blood pressure measurement appeared to be the most sensitive technique for detecting selective 5-HT(1B/1D)-receptor agonist-induced peripheral vascular effects in humans.


Subject(s)
Arm/blood supply , Blood Pressure/drug effects , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Toes/blood supply , Adult , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Hand/blood supply , Humans , Male , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Sensitivity and Specificity , Sumatriptan/administration & dosage , Sumatriptan/pharmacology , Veins
19.
Br J Clin Pharmacol ; 52(1): 45-51, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11453889

ABSTRACT

AIMS: To investigate the peripheral vascular effects and pharmacokinetics of dihydroergotamine (DHE) 0.5 mg after a single subcutaneous administration in humans. METHODS: A double-blind, placebo-controlled cross-over study was performed in 10 healthy male subjects. A wash-out period of 2 weeks separated the two study periods. During each period, just before and at regular intervals after drug administration, vascular measurements were performed and venous blood samples were drawn. Vessel wall properties were assessed at the brachial artery, by ultrasound and applanation tonometry. Blood pressure and heart rate were recorded with an oscillometric device. Forearm blood flow was measured with venous occlusion plethysmography. For all parameter-time curves the area under the curve (AUC) was calculated. Differences in AUC after placebo and DHE (DeltaAUC) were analysed and the time-course of the difference assessed. DHE pharmacokinetics were analysed according to a two-compartment open model with an absorption phase. RESULTS: AUC for blood pressure, heart rate and forearm vascular resistance did not change after DHE. Brachial artery diameter and compliance decreased (P < 0.01); DeltaAUC (95% confidence interval) equalled -8.81 mm h (-12.97/-4.65) and -0.98 mm2 kPa(-1) h (-1.61/-0.34), respectively. Diameter decreased (P < 0.05) from 1 until 24 h after DHE (peak decrease 9.7% at 10 h); compliance from 2 until 32 h (24.8% at 2 h). Time to reach maximum plasma concentration of DHE averaged 0.33 +/- 0.08 h (+/- s.e.mean); terminal half-life was 5.63 +/- 1.15 h. CONCLUSIONS: DHE decreased diameter and compliance of the brachial artery whereas forearm vascular resistance remained unchanged. Thus, DHE acts on conduit arteries without affecting resistance arteries. Furthermore, a discrepancy was demonstrated between the plasma concentrations of DHE which rapidly reach peak levels and quickly decline, and its long lasting vasoconstrictor activity.


Subject(s)
Brachial Artery/drug effects , Dihydroergotamine/pharmacokinetics , Vasoconstrictor Agents/pharmacokinetics , Adult , Area Under Curve , Arteries/drug effects , Arteries/metabolism , Arterioles/drug effects , Arterioles/metabolism , Blood Flow Velocity , Blood Pressure/drug effects , Brachial Artery/metabolism , Cross-Over Studies , Dihydroergotamine/pharmacology , Double-Blind Method , Half-Life , Heart Rate/drug effects , Humans , Injections, Subcutaneous , Male , Vasoconstrictor Agents/pharmacology
20.
Clin Pharmacol Ther ; 68(4): 418-26, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11061582

ABSTRACT

OBJECTIVES: Second-generation triptans are believed to have fewer cardiovascular effects than sumatriptan. This was investigated in vivo by comparing the vascular effects of equipotent therapeutic dosages of selective 5-HT1B/1D-receptor agonists. METHODS: Sixteen patients with migraine headaches completed a double-blind, placebo-controlled, four-way crossover study. With ultrasonography and applanation tonometry used 1.5 hours after the oral intake of sumatriptan (50 mg), rizatriptan (10 mg), zolmitriptan (2.5 mg), or placebo arterial vessel wall properties, blood flow and pressure waveforms were measured in common carotid, brachial, and temporal arteries. At the brachial artery, flow-induced vasodilation (an endothelium-dependent process) was evaluated, and blood pressures were recorded. RESULTS: Mean arterial pressure, 91 +/- 2 mm Hg after placebo, increased (P < .05) by 4% to 6% after administration of each triptan. Each active treatment decreased (P < .001) both brachial and carotid artery diameter. Isobaric compliance of the brachial artery, 0.077 +/- 0.010 mm2/kPa after placebo, decreased (P < .01) by 11% +/- 8%, 11% +/- 11%, and 23% +/- 7% after administration of sumatriptan, rizatriptan, and zolmitriptan, respectively. Isobaric compliance of the carotid artery was 1.31 +/- 0.10 mm2/kPa after placebo (no change). Zolmitriptan was the only triptan that decreased temporal artery diameter significantly (by 12% +/- 3%, P < .001). The resistance of the temporal artery vascular bed increased after administration of sumatriptan (by 26% +/- 11%, P < .05) and zolmitriptan (by 40% +/- 9%, P = .001). Flow-induced vasodilation was unaffected. CONCLUSIONS: Selective 5-HT1B/1D-receptor agonists induce vasoconstriction and decrease compliance of conduit arteries. These effects are more pronounced at muscular (temporal, brachial) compared with elastic (carotid) arteries. Resistance is only increased at the temporal artery vascular bed, suggesting cranioselectivity for resistance vessels. Endothelial function is not differently affected by any of the triptans tested.


Subject(s)
Carotid Artery, Common/drug effects , Migraine Disorders/drug therapy , Oxazolidinones/pharmacology , Serotonin Receptor Agonists/pharmacology , Sumatriptan/pharmacology , Triazoles/pharmacology , Vasoconstrictor Agents/pharmacology , Adult , Analysis of Variance , Blood Flow Velocity/drug effects , Blood Pressure/drug effects , Brachial Artery/drug effects , Carotid Artery, Common/diagnostic imaging , Carotid Artery, Common/physiopathology , Cross-Over Studies , Double-Blind Method , Female , Humans , Male , Middle Aged , Migraine Disorders/diagnostic imaging , Migraine Disorders/physiopathology , Temporal Arteries/drug effects , Tryptamines , Ultrasonography , Vascular Resistance/drug effects , Vasodilation/drug effects
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