1. The ocular hypotensive effect of 0.025% bromocriptine and 0.25% timolol eye drops was compared in nine healthy human volunteers, using non-contact tonometry. 2. Considering all post-dosing measurements compared with placebo and including the baseline values as continuous independent variables, using multiple linear regression analysis, both bromocriptine and timolol had a significant ocular hypotensive effect (P less than 0.0001) in the treated eye with a significant but lesser effect in the contralateral eye. 3. In the concentrations used, timolol was more efficacious than bromocriptine in lowering intraocular pressure (P less than 0.025). 4. Using other forms of vehicles for bromocriptine to improve efficacy and studying the ocular hypotensive effect of topical application of other dopamine-2-receptor agonists such as pergolide and lisuride was suggested.
1. The interaction of ranitidine hydrochloride (150 mg twice daily for 15 doses) with single doses (0.15, 0.3 and 0.6 g kg-1) of ethanol was investigated in a placebo controlled study in 24 male subjects. Ethanol was given 1 h after a standard breakfast to maximise a drug ethanol effect if there is one. A balanced incomplete block design was used in that each subject received two of the three ethanol doses in the presence or absence of ranitidine. Blood samples (n = 18) were taken for 8 h after dosing and blood ethanol concentrations (BAC) were determined by head space analysis using a validated gas liquid chromatographic method. 2. At the lowest dose of ethanol studied the pharmacokinetic profile was largely first order but at the higher doses the usual zero order kinetics were seen. Using the technique of simultaneous fitting across all doses the Km and Vmax constants were similar and close to literature value of 100 mg l-1 and 200-300 mg h l-1 respectively. 3. Ranitidine, in common with other H2-receptor antagonists tested under the same experimental conditions, caused a small rise in BAC. However this was only evident at the smallest dose of ethanol studied and in common with many other publications, no effects were seen at the higher doses. The mean rise in blood ethanol following the 0.15 g kg-1 dose was 2.6 mg dl-1 (13.3 mg dl-1 for placebo and 15.9 mg dl-1 for ranitidine) and this change is of no clinical relevance.
To investigate whether dorzolamide modifies peripapillary retinal haemodynamics in juvenile primary open-angle glaucoma (JPOAG) patients treated with timolol.
In 40 JPOAG subjects, before and after dorzolamide coadministration with timolol, the following examinations were achieved: intraocular pressure (IOP), blood pressure (BP), ocular perfusion pressure (OPP), heart rate (HR), visual field and retinal flowmetry.
Adjunctive therapy with dorzolamide induced the following modifications: IOP reduction [1.75 mmHg, 95% confidence interval (CI) 1.23, 2.26; P < 0.05], OPP increase (5.09 mmHg, 95% CI 2.97, 7.20; P < 0.02) and retinal blood flow improvement (35.0 arbitrary units, 95% CI 12.20, 57.80; P < 0.03). BP, HR and visual field indices did not change.
Dorzolamide, in association or in fixed combination with timolol, significantly improves retinal blood flow in JPOAG patients.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Mothers are using medicines during pregnancies; the extent varies across the world and is generally difficult to compare.
• In this registry-based study, we examined more than 100 000 Norwegian pregnancies and described the drug prescription pattern of both fathers and mothers around conception and during pregnancy (mothers).
WHAT THIS STUDY ADDS
• In every trimester of pregnancy, about 30% of the mothers was dispensed a drug.
• The total drug exposure did not seem to diminish throughout pregnancy.
• One-quarter of the fathers was dispensed drugs during the last 3 months prior to conception.
The primary aim of this study was to describe the use of prescribed drugs in both mothers and fathers before and during pregnancy in Norway.
This population-based cohort study was based on data retrieved from the Medical Birth Registry of Norway and the Norwegian Prescription Database. These registries cover the entire population of Norway. Information on >100 000 births during 2004–2006 in the birth registry was linked to prescription data. Prescriptions issued to mothers just prior to, during and after the pregnancies as well as prescriptions to fathers just prior to conception were identified.
Among mothers, 83% were prescribed drugs during the period 3 months prior to estimated conception until 3 months after giving birth. The mothers who received drugs were prescribed on average 3.3 different Anatomical Therapeutic Chemical (ATC) codes (range 1–38). During pregnancy, 57% were prescribed drugs. In the first trimester, 33% of mothers were dispensed drugs, while the figure was 29% for mothers in the last trimester. Among fathers, 25% used prescribed drugs during the 3 months prior to conception, with on average 1.9 different ATC codes (range 1–22).
Large proportions of both fathers and mothers were dispensed drugs prior to conception or during pregnancy. While there is a high awareness of the issues involved in maternal drug use in pregnancy, possible teratogenic effects of drug use in fathers shortly before conception should be further explored.
To assess the translation of pharmacokinetic-pharmacodynamic (PK-PD) relationships for heart rate effects of PF-00821385 in dog and man.
Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5-120 mg kg(-1), n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK-PD models were fitted using nonlinear mixed effects.
Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm microM(-1)[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm microM(-1) (95% CI 0.54, 1.14) in man.
The preclinical translational of concentration-response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed.
1 Acute thrombosis was induced in the carotid arteries of anaesthetized rabbits by local electrical stimulation (1 mA for 2 min) of the vessel wall. Histological findings confirmed the platelet-rich composition of the thrombus. Platelet accumulation at the stimulus site was quantitated with 111Indium-labelling of autologous platelets. 2 In rabbits injected intravenously with either the thromboxane synthetase inhibitor dazoxiben 2 mg/kg or aspirin 10 mg/kg, accumulation of labelled platelets was considerably reduced. Animals which received vehicle injection only, showed no such reduced thrombus formation. 3 In separate experiments in anaesthetized rabbits, the levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha in clotting blood were measured in blood samples taken from animals which had received the above drug treatments. Aspirin markedly reduced the production of both arachidonate metabolites. In contrast, dazoxiben almost totally inhibited TXB2 production but caused a 3.5-fold increase in the levels of 6-keto PGF1 alpha. 4 These findings demonstrate an antithrombotic effect and confirm the mechanistic selectivity of a thromboxane synthetase inhibitor.
To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET(A)) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect.
Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET(A) antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose-response (dose range 0.08-13.33 microg kg(-1) min(-1)), (2) a randomized study to confirm dose-response (placebo, 2.5, 6.67 and 15 microg kg(-1) min(-1)), and (3) a delayed administration study (15.7 microg kg(-1) min(-1)) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first.
Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800-2000 ng ml(-1)). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml(-1)) were well below pharmacologically active concentrations as determined in studies 1 and 2.
S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.
What is already known about this subject:
• The topical second generation anti-histamine azelastine hydrochloride (AZE) and the potent corticosteroid fluticasone propionate (FP) are well established first-line treatments in allergic rhinitis (AR). • MP29-02, a novel intranasal AZE and FP formulation, has been shown to control AR symptoms faster and better than standard intranasal AZE or FP. • The systemic bioavailabilities of marketed AZE and FP nasal spray products have been established at about 40% and 1% only, respectively. • For new combination medicinal products such as MP29-02, the determination of possible pharmacokinetic (PK) drug-drug interactions between both active components and formulation-based bioavailability alterations is essential.
What this study adds:
• This paper provides for the first time information on potential drug-drug interactions, AZE and FP bioavailability and disposition characteristics of each component administered by the novel nasal spray formulation MP29-02. • The studies employed highly sensitive FP and AZE LC-MS/MS assays and could therefore be conducted with recommended therapeutic doses, thereby circumventing previously recognized draw-backs that required nasal bioavailability studies to be conducted using supra-therapeutic doses. • No significant PK drug-drug interaction between the active components AZE and FP was noted for MP29-02. • AZE bioavailabilty was equivalent when MP29-02 data were compared with MP29-02-AZE-mono and Astelin®. • Increased FP exposure was observed with MP29-02-based products compared with FP-BI. FP serum concentrations were generally very low with all investigational products suggesting no clinically meaningful pharmacodynamic differences in terms of systemic safety.
To determine azelastine hydrochloride (AZE) and fluticasone propionate (FP) bioavailabilities of the novel nasal spray combination product MP 29-02, compared with MP29-02-based products containing only AZE (MP29-02-AZE-mono), FP (MP29-02-FP-mono), marketed AZE and FP single entity products (Astelin® and FP Boehringer-Ingelheim; FP-BI).
Two randomized, three period, six sequence, three treatment crossover studies were conducted in healthy subjects. Study 1 administered 200 µg FP as MP29-02, MP29-02-FP-mono or FP-BI. Study 2 administered 548 µg AZE as MP29-02, MP29-02-AZE-mono or Astelin®. Each dose consisted of two sprays/nostril. Serum FP and plasma AZE were followed over 24 (FP) and 120 h (AZE) and quantified by LC-MS/MS. Peak (C(max) ) and total exposures AUC(0,t(last) ) were compared between the treatments by anova.
Study 1: Average FP C(max) was very low with all products (≤ 10 pg ml(-1) ). FP AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-FP-mono and MP29-02 : FP-BI ratios (%) were 93.6 (83.6, 104.7) and 161.1 (137.1, 189.3). Corresponding ratios for C(max) were 91.0 (82.5, 100.4) and 157.4 (132.5, 187.1). Study 2: AZE AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-AZE-mono and MP29-02 : Astelin® ratios (%) were 98.8 (91.0, 107.4) and 105.5 (95.6, 116.4). Corresponding outcomes for C(max) were 102.7 (92.1, 114.4) and 107.3 (92.6, 124.3).
No interactions of AZE and FP were found with the MP29-02 formulation. Azelastine bioavailability was similar for MP29-02 and Astelin®. Maximum and total FP exposure was higher for MP29-02-based products compared with FP-BI. FP concentrations were generally very low with all investigational products and did not suggest clinically meaningful differences concerning systemic safety.
To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr).
In this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min(-1); n= 6); mild RI (CLcr 51 to < or =80 ml min(-1); n= 6); moderate RI (CLcr >30 to 50 ml min(-1); n= 6); and severe RI (CLcr < or =30 ml min(-1); n= 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data.
PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66-3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CL(R)) clearance rates decreased with deteriorating renal function, whereas area under the concentration-time curve (AUC(0-infinity)) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CL(R) correlated with CLcr (r= 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group.
PD 0200390 pharmacokinetic parameters (CL/F, CL(R) and AUC(0-infinity)) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.
To investigate the effect of age and gender on the tolerability, safety and pharmacokinetics (PK) of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite.
Forty-two subjects were assigned to one of the following three groups: young men, elderly men and elderly women. The PK, safety and tolerability of an intravenous infusion of 1500 mg tomopenem and its resultant major metabolite (open beta-lactam ring) were assessed.
Minor differences in exposure of both tomopenem and the major metabolite were seen. The area under the curve (AUC) of tomopenem was 22% higher in elderly men compared with young men, and 19% higher in elderly women relative to the elderly men. Total clearance of tomopenem decreased with decreasing creatinine clearance. In the two male groups, renal clearance values of tomopenem were similar (3.52 and 3.67 l h(-1)) and higher than in the elderly female group (2.83 l h(-1)). The mean half-lives ranged from 2.03 (healthy young men) to 2.41 h (elderly men). The difference in AUC of tomopenem can be explained by differences in the mean creatinine clearances of 116 (young men), 101 (elderly men) and 84.7 (elderly women) ml min(-1) 1.73 m(-2), respectively.
While some PK parameters were statistically different among the three groups, the differences were mostly minor and unlikely to be clinically meaningful. The difference in the PK can be largely attributed to the difference in creatinine clearance of these groups.
(i) To model the effects of the monoclonal antibody ATM-027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase I data in order to evaluate the predictive performance of the model by comparison with the actual trial results.
Based on the data from one phase I and one phase II study in multiple sclerosis (MS) patients, models were developed to characterize the pharmacokinetics and pharmacodynamics of the monoclonal antibody ATM-027 and its effects on Vβ5.2/5.3+ T cells. The pharmacodynamic variables were the number of target T cells and the expression of its receptor. The latter was modelled in both a categorical and continuous way. The modelling was performed with a nonlinear mixed effects approach using the software NONMEM. The joint continuous models were used to simulate the phase II trial from the phase I data.
The pharmacokinetics of ATM-027 were characterized by a two-compartment model with a total volume of distribution of 5.9 litres and a terminal half-life of 22.3 days (phase II parameter estimates) in the typical patient. Continuous receptor expression was modelled using an inhibitory sigmoidal Emax-model. Similar results from the phase I and phase II data were obtained, and EC50 was estimated to be 138 and 148 µg litre−1, respectively. Categorical receptor expression was modelled using a proportional odds model, and the EC50 values obtained were highly correlated with those from the continuous model. The numbers of target T cells were also modelled and treatment with ATM-027 decreased the number of cells to 25.7% and 28.9% of their baseline values in the phase I and II trials, respectively. EC50s for the decrease in the number of T cells were 83 µg litre−1 and 307 µg litre−1, respectively. Simulations of the phase II trial from the phase I models gave good predictions of the dosing regimens administered in the phase II study.
All aspects of effects of the monoclonal antibody ATM-027 on Vβ5.2/5.3+ T cells were modelled and the phase II trial was simulated from phase I data. The effects of categorizing a continuous scale were also evaluated.
Endothelin-1 (ET-1) has been implicated in the pathophysiology of a number of cardiovascular diseases for which endothelin receptor antagonists are currently under clinical development. We have previously reported that systemic administration of the combined endothelin A/B receptor antagonist, TAK-044, abolishes the forearm vasoconstriction caused by intrabrachial ET-1 infusion for at least 3 h. In this study we investigated whether TAK-044 can inhibit ET-1 mediated forearm vasoconstriction for longer periods.
Eighteen subjects were recruited to a randomized, placebo-controlled, single-blind, three-way, crossover study. Subjects were divided into three groups of six. Groups received 25 mg, 50 mg or 100 mg TAK-044 on two separate occasions, 6 and 10 h before the start of a 2 h intrabrachial infusion of ET-1 (5 pmol min(-1)). On a third occasion subjects received only placebo before intra-arterial ET-1 infusion. Forearm vasoconstriction to ET-1 was measured by venous occlusion plethysmography.
In the placebo phase, ET-1 caused significant, slowly-progressive local forearm vasoconstriction of approximately 30% (P<0.01) in all three groups. All three doses of TAK-044, administered at both timepoints, tended to blunt the vasoconstriction caused by ET-1. When the responses from all three groups were combined, TAK-044 significantly reduced ET-1 mediated vasoconstriction compared with placebo -9% (95% CI -15 to -3; P=0.01) at 8 h and by -9% (95% CI -17 to -2; P=0.01) 12 h after dosing.
TAK-044 attenuated, but did not abolish, local ET-1 mediated vasoconstriction, for up to 12 h after administration. Vasoconstriction to local intra-arterial administration of ET-1 appears to represent a safe and reproducible pharmacodynamic index of systemic endothelin receptor antagonism in humans.
* The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. * However, as yet few validated or qualified biomarkers are used in early-stage drug development in terms of clinical pharmacology and disease pathophysiology.
* This first-time-in-human study provides evidence of the pharmacological activity of LC15-0444 in humans, by using dipeptidyl peptidase IV activity and active glucagon-like peptide-1 concentrations. * LC15-0444 possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen.
LC15-0444 is a selective and competitive inhibitor of dipeptidyl peptidase (DPP) IV with potential for the treatment of Type 2 diabetes. The aim was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles after multiple oral ascending doses of LC15-0444 in healthy male subjects.
A dose block-randomized, double-blind, placebo-controlled, parallel group study was performed in three groups with 10 subjects (eight for active drug; two for placebo) per group; each group received 200, 400 or 600 mg of LC15-0444 once daily for 10 days. Blood and urine samples were collected up to 24 h after the first dosing and up to 72 h after the last dosing.
The LC15-0444 concentration-time profiles exhibited characteristics of multicompartment disposition. No dose- or time-dependent change in PK parameters was observed. Mean elimination half-life was in a range 16.6-20.1 h in the dose groups. Mean renal clearance and fraction of unchanged drug excreted in urine was 18.6-21.9 and 0.40-0.48 l h(-1), respectively. In the steady state, mean accumulation ratios by dose groups were between 1.22 and 1.31. More than 80% inhibition of DPP IV activity from baseline was sustained for >24 h in all dose groups.
This study provides evidence of the pharmacological activity of LC15-0444 in humans. LC15-0444 possesses PK and PD characteristics that support a once-daily dosing regimen.
AIMS To evaluate the pharmacology and tolerability of PF-04457845, an orally available fatty acid amide hydrolase-1 (FAAH1) inhibitor, in healthy subjects.
Double-blind, randomized, placebo-controlled single and multiple rising dose studies and an open-label, randomized, food effect study were conducted. Plasma and urine PF-04457845 concentrations, plasma fatty acid amide concentrations and FAAH1 activity in human leucocytes were measured. Tolerability, including effects on cognitive function, were assessed.
PF-04457845 was rapidly absorbed (median t(max) 0.5-1.2 h). Exposure increased supraproportionally to dose from 0.1 to 10 mg and proportionally between 10 and 40 mg single doses. The pharmacokinetics appeared dose proportional following 14 days once daily dosing between 0.5 and 8 mg. Steady-state was achieved by day 7. Less than 0.1% of the dose was excreted in urine. Food had no effect on PF-04457845 pharmacokinetics. FAAH1 activity was almost completely inhibited (>97%) following doses of at least 0.3 mg (single dose) and 0.5 mg once daily (multiple dose) PF-04457845. Mean fatty acid amide concentrations increased (3.5- to 10-fold) to a plateau and then were maintained following PF-04457845. FAAH1 activity and fatty acid amide concentrations returned to baseline within 2 weeks following cessation of dosing at doses up to 4 mg. There was no evidence of effects of PF-04457845 on cognitive function. PF-04457845, at doses up to 40 mg single dose and 8 mg once daily for 14 days, was well tolerated.
PF-04457845 was well tolerated at doses exceeding those required for maximal inhibition of FAAH1 activity and elevation of fatty acid amides.
MK-4076 or sodium 1-(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl) 3-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl) cycloproprane) acetate is a novel, potent, and specific LTD4-receptor antagonist. The safety, tolerability and plasma drug profiles of single oral doses of MK-0476 (capsules) were evaluated in 18 healthy male volunteers assigned to one of the two parallel 9-subject panels. Under fasting conditions, increasing single doses of 20 to 800 mg were administered in a first part of the study and in a second part, 200 mg MK-0476 was given either as a solution, under fasting conditions, or as capsules, after a standard breakfast. All volunteers completed the study. Side effects, reported by the investigator to be related to study drug, were mild and transient. No laboratory abnormalities were noted. In the evaluated dose range of MK-0476 (20 to 800 mg) the median value of tmax ranged from 2 to 4 h, while the apparent t1/2 value averaged 4 to 5 h. The median tmax value of the 200 mg capsule dose was not significantly different from the median tmax of the 200 mg oral solution dose indicating that neither disintegration nor dissolution is a rate-limiting step for the absorption of MK-0476 from capsules. There was a statistically significant increase in the AUC (geometric mean ratio of fed/fast was 2.52 with 95% confidence interval of 1.25, 5.06) and in Cmax (geometric mean ratio of fed/fast was 1.36 with 95% confidence interval of 0.60, 3.04) when MK-0476 was given together with a breakfast, suggesting an increase in bioavailability.(ABSTRACT TRUNCATED AT 250 WORDS)
To use non-linear mixed effects modelling and simulation techniques to predict whether PF-04878691, a toll-like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a 'proof of concept' (POC) study in chronic hepatitis C (HCV) patients.
A population pharmacokinetic-pharmacodynamic (PKPD) model was developed using available 'proof of pharmacology' (POP) clinical data to describe PF-04878691 pharmacokinetics (PK) and its relationship to 2',5'-oligoadenylate synthetase (OAS; marker of pharmacology) and lymphocyte levels (marker of safety) following multiple doses in healthy subjects. A second model was developed to describe the relationship between change from baseline OAS expressed as fold change and HCV viral RNA concentrations using clinical data available in HCV patients for a separate compound, CPG-10101 (ACTILON™), a TLR9 agonist. Using these models the antiviral efficacy and safety profiles of PF-04878691 were predicted in HCV patients.
The population PKPD models described well the clinical data as assessed by visual inspection of diagnostic plots, visual predictive checks and precision of the parameter estimates. Using these relationships, PF-04878691 exposure and HCV viral RNA concentration was simulated in HCV patients receiving twice weekly administration for 4 weeks over a range of doses. The simulations indicated that significant reductions in HCV viral RNA concentrations would be expected at doses > 6 mg. However at these doses grade ≥ 3 lymphopenia was also predicted.
The model simulations indicate that PF-04878691 is unlikely to achieve POC criteria and support the discontinuation of this compound for the treatment of HCV.
1. The pharmacokinetic and pharmacodynamic properties of a novel 2-indolealkanoic acid derivative (MK-0591), a potent inhibitor of leukotriene biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days were administered. 2. After the single-dose administration following overnight fasting, Cmax and AUC of MK-0591 in plasma increased in a dose-dependent manner, while elimination half-life remained constant (11.2-13.2 h) irrespective of dose. Food intake decreased Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple-dose administration before meals, there were no significant differences in the pharmacokinetic parameters between the first and last days, indicating a lack of significant accumulation of MK-0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the study. 3. Ionophore-stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single-dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore-stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK-0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)
The aims of the study were to assess the trend of older and newer anti-epileptic drugs (AEDs) in the elderly population and to analyze the effects of a health-policy intervention with regard to AED use in general practice in a setting in Southern Italy.
Data were extracted from the 'Caserta-1' Local-Health-Unit Arianna database in the years 2004-07. Patients aged over 65 years, receiving at least one AED prescription and registered in the lists of 88 general practitioners, were selected. The use of older and newer AEDs was calculated as 1 year prevalence and incidence of use and defined daily dose (DDD) per 1000 inhabitants day(-1) . Sub-analyses by gender, age and indication of use were performed.
Most of AED users were treated because of neuropathic pain (64.8%). However, the main indication of use for older AEDs (57.8%) was epilepsy, whereas newer AEDs (79.5%) were used for neuropathic pain. Prevalence and incidence of newer AED use increased until 2006, followed by a reduction in 2007. Newer AEDs, particularly gabapentin and pregabalin, were used in the treatment of more patients than older AEDs. However phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period.
An increasing use of AEDs has been observed during 2004-07, mostly due to the prescription of newer compounds for neuropathic pain. The fall in the use of newer AEDs during 2007 coincides with revised re-imbursement criteria for gabapentin and pregabalin. The large use of phenobarbital in the elderly should be considered in the light of a risk of adverse drug reactions.
What is already known about this subject:
* Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. * CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. * A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm.
What this study adds:
* This study shows that the novel oral CGRP receptor antagonist, telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. * This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.
To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine.
A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of telcagepant 300 mg, telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 microg capsaicin per 20 microl water-ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before ('baseline'), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF.
Geometric mean plasma concentrations after dosing with 300 mg and 800 mg telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC(90) for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm.
Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.
1. The new intravenous bisphosphonate drug aminohydroxypropylidine bisphosphonate (APD) is effective in treating the hypercalcaemia of malignant disease, but the optimum dose regimen is not yet established. We have treated twenty-seven patients with malignant hypercalcaemia (corrected calcium greater than 3.00 mmol l-1) with intravenous APD, comparing three regimens of drug administration. 2. Patients were randomly allocated to receive a single dose of APD 30 mg on day 1 (group A, n = 9), two consecutive doses of 30 mg on days 1 and 2 (group B, n = 9) or a single 60 mg dose on day 1 (group C, n = 9). The patients were severely hypercalcaemic, and in nine (33%) the corrected serum calcium was higher than 4.00 mmol l-1 and all were severely ill: three patients died within 48 h of receiving the initial dose and seven died within the first week. 3. Serum calcium levels fell by day 7 in all patients: in group A, from 3.91 +/- 0.40 (s.d.) mmol l-1 to 2.91 +/- 0.49; in group B, from 3.59 +/- 0.33 to 2.63 +/- 0.23 mmol l-1; and in group C, from 3.71 +/- 0.43 to 2.66 +/- 0.39 mmol l-1. Complete response, defined by a nadir calcium (on days 5-12) below 2.60 mmol l-1 occurred in eleven of 24 surviving patients (4/9 in group A, 4/7 in group B, and 3/8 in group C). The remaining patients showed a partial response with serum calcium falling at least 0.25 mmol l-1.(ABSTRACT TRUNCATED AT 250 WORDS)
NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure.
A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured.
Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg x kg(-1) body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (+/- s.d.) AUC(0,infinity) (capsule 602 +/- 154 vs solution 602 +/- 146 microg x ml(-1) h) or t1/2 (capsule 55 +/- 13 vs solution 54 +/- 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,infinity) and Cmax increased linearly with dose. Following administration of 1 mg NTBC x kg(-1) in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol x ml(-1). Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol x ml(-1) following a dose of 4 mg x kg(-1) body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione x kg(-1), but returned to background levels during the following 24 h period.
NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use.
E7070 is a novel, sulphonamide anticancer agent currently under clinical development for the treatment of solid tumours. The aim of this study was to develop and validate limited sampling strategies for the prediction of E7070 exposure in two different treatment schedules for phase II studies using the Bayesian estimation approach.
Data from two phase I dose finding studies were used in which E7070 was administered either as a single 1 h infusion or as a daily 1 h infusion for 5 days. Plasma concentration-time data from 75 patients were randomly divided into an index data set, used for the development of the strategies, and a validation data set. Population pharmacokinetic parameters were derived on the basis of the index data set. The D-optimality algorithm was used for the selection of optimal time points for both treatment schedules. The developed strategies were compared by assessment of their predictive performance of exposure, expressed as AUC (area under the plasma concentration vs time curve), in the validation data set.
The developed population pharmacokinetic model comprised three compartments, with saturable distribution to one peripheral compartment and both linear and saturable elimination from the central compartment. For the 1 h infusion, a four sample strategy was selected which resulted in unbiased and accurate predictions of AUC (bias 0.74%, precision 13%). A five sample strategy was generated for the daily times five schedule yielding unbiased (bias 3.2%) and precise (12% precision) predictions of AUC.
Optimal sampling strategies were developed and validated for estimation of E7070 exposure in two different treatment schedules. Both schedules enabled accurate and unbiased predictions of AUC.
1 The immediate and residual effects on performance of benzodiazepines differ, and the differences are important in the use of these drugs. 2. Diazepam and its hydroxylated metabolites, temazepam and oxazepam, each possess hypnotic activity, and have effects on performance limited to the sleep period. The demethylated metabolite of diazepam, nordiazepam, and its precursor, potassium clorazepate, which also possess hypnotic activity, have a longer duration of action, although the next day anxiolytic effect is accompanied by only minimal effects on performance. The 1.5 benzodiazepine, clobazam, seems to have minimal immediate effects on performance. 3 Diazepam and its hydroxylated metabolites, temazepam and oxazepam, would be useful in the management of insomnia without psychopathology in those cases in which residual effects on performance must be avoided. Nordiazepam and potassium clorazepate would be appropriate for insomnia secondary to day-time anxiety, and clobazam may be useful as a day-time anxiolytic. 4 It is emphasized that more work needs to be carried out on the effects of anxiolytics on performance before one can be certain that ingestion during the day would be without any deleterious effects on skilled work.
1 A high pressure liquid chromatographic (HPLC) assay has been developed for the measurement of chlordiazepoxide and its metabolites, N-desmethylchlordiazepoxide and demoxepam in microgram concentrations in human plasma. 2 Another metabolite was detected in appreciable amounts in the plasma from patients receiving high doses of chlordiazepoxide after the first 3 days of treatment. 3 Preliminary studies would indicate that this metabolite is N-desmethyldiazepam. 4 A modified HPLC system, using a microparticulate column was developed to separate N-desmethyldiazepam from chlordiazepoxide and its other metabolites in plasma.
1 The structures and chemistry of the 1,4- and 1,5-benzodiazepines are compared. These two groups of drugs differ in respect to basicity, lipophilicity and electronic charge distribution. 2 The 1,4-benzodiazepine diazepam has a weakly basic imine group in contrast to the acid methylene protons of clobazam. 3 The imine function of diazepam is more lipophilic than the carboxamide group of clobazam with its rather hydrophilic character. 4 Diazepam and clobazam differ in electronic charge distribution and hence in the location of the chemically reactive centres, the imine partial structure in diazepam and the malonic acid portion of clobazam.
1 The immediate effects on human performance of the 1,5-benzodiazepine, clobazam (20 mg), and the 1,4-benzodiazepines, chlordiazepoxide hydrochloride (20 mg) and diazepam (10 mg), were studied by adaptive tracking and measurement of reaction time. Each drug was ingested at 09.00 h and performance was measured at 09 h 30 min (0.5 h), 11 h 30 min (2.5 h), 14 h 30 min (5.5 h) and 18 h 30 min (9.5 h after ingestion). 2 With diazepam decrements in performance on adaptive tracking were observed at 0.5 h and 2.5 h and performance was enhanced at 9.5 h after ingestion. With clobazam performance at individual times did not differ significantly from control, but there was evidence of an improvement in performance during the day. There was no evidence of impaired performance on adaptive tracking after chlordiazepoxide hydrochloride. 3 Reaction time was slowed at 0.5 h and 2.5 h after diazepam and chlordiazepoxide hydrochloride. A decrease in reaction time was observed at 9.5 h after diazepam. No changes in reaction time were observed after clobazam. 4 The subjects as a group differentiated correctly between performance decrements on adaptive tracking after diazepam and the absence of performance decrements after clobazam and chlordiazepoxide hydrochloride. The persistence of the decrement in performance after diazepam was accurately assessed. 5 It is evident that the nature and persistence of impaired performance and the ability to appreciate impaired performance vary considerably between the benzodiazepines, and that the choice of a benzodiazepine should include careful consideration of performance sequelae.
1 The effect of the 1,5-benzodiazepines, clobazam (10 and 20 mg) and triflubazam (20 and 40 mg), on sleep was studied in six healthy males using electroencephalography for sleep measures and analogue scales for subjective assessments of well being and sleep quality. The effect of clobazam was limited to the night of ingestion. There was some evidence from subjective assessments that the effect of triflubazam may have persisted beyond the night of ingestion. 2 No effect of clobazam or triflubazam was observed on total sleep time, stage shifts in the first 6 h or latency to the first rapid eye movement period of sleep. With clobazam sleep onset latency was shortened (P less than 0.05), but this effect was not seen with triflubazam. The latency to stage 3 was shortened by both drugs. There was evidence of reduced duration of awake (stage 0) activity and drowsy (stage 1) sleep with both drugs. 3 The percentage stage 1 sleep was reduced by clobazam (10 and 20 mg) and by triflubazam (20 mg) (P less than 0.05), though the effect was not significant with triflubazam (40 mg). Clobazam (20 mg) increased the percentage stage 2 sleep (P less than 0.05), but reduced the percentage stage 3 (P less than 0.01) and stages 3 + 4 (P less than 0.05) sleep. There were no other effects on percentage of total sleep time occupied by various sleep stages or in duration (min) of sleep stages, except that the duration (min) of sleep stages, except that the duration (min) of stage 2 sleep in the second 2 h interval of sleep was increased with clobazam (20 mg) (P less than 0.01). 4 Subjects reported impaired sleep with triflubazam (40 mg) (P less than 0.05), and a sense of less wakefulness the morning after ingestion of clobazam (10 and 20 mg) (P less than 0.01) and triflubazam (40 mg) (P less than 0.05).
1 The effects of clobazam, a new anxiolytic agent (a 1,5-benzodiazepine) on car-driving ability and other tests of psychomotor performance were investigated in a double-blind, cross-over study v. placebo in normal volunteers. 2 Clobazam (20 mg) or placebo was given nightly for six nights to ten volunteers and subjective ratings of sleep and subjective and objective assessments of behaviour and psychomotor performance on the morning following drug ingestion were recorded. 3 Clobazam significantly improved the subjective ratings of sleep induction and quality of induced sleep. 4 Clobazam did not significantly impair performance in a variety of psychomotor tests and car-driving ability. 5 The validity of the measures used and the relevance of the findings to real life car-driving situations are discussed.
1 The methodology of clinical trails of anxiolytic drugs carried out in general practice conditions is discussed. Particular problems include: the selection of suitable patients; placebo effects; the influence of non-specific variables such as life-events; and patient compliance. 2 Clobazam, a novel 1,5 benzodiazepine, and diazepam were compared with placebo in a double-blind group comparative trial in general practice, which was designed to avoid as many confounding variables as possible. Anxiety-reducing effects were evaluated and at the same time the effects of the drugs on psychomotor performance were examined. 3 Both clobazam and diazepam produced significant improvements in anxiety ratings on the Hamilton Anxiety Scale and the Morbid Anxiety Inventory, whereas placebo did not. 4 The placebo group demonstrated a significant improvement in performance on a pursuit rotor and digit symbol substitution test (DSST), whereas the diazepam group's performance did not change. The clobazam group showed improvement in both tests, significantly so in the DSST. This suggests that diazepam produces impairment in performance, which had negated the practice effects seen in the placebo group, whereas clobazam did not seem to produce similar impairment.
Steady state carbamazepine (CBZ) plasma concentrations were similar in 15 epileptics receiving monotherapy and in 24 patients taking CBZ in combination with one other anticonvulsant. The ratio of CBZ 10, 11-epoxide (CBZ-E) to the parent drug was significantly higher (P less than 0.01) in those patients taking concomitant phenytoin (n = 9), phenobarbitone or primidone (n = 9), and valproic acid (n = 6) than in the patients receiving CBZ alone. In the monotherapy group, there was a significant correlation between CBZ-E/CBZ ratio and the concentration of the parent drug (P less than 0.05). If CBZ-E has equipotent anticonvulsant properties to CBZ in man as is the case in animal models, routine CBZ-E concentrations may provide further refinement in the therapeutic drug monitoring of CBZ.
1. The relationships between saliva, free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZ-EP) were studied in 24 chronically medicated epileptic patients. Four patients were taking CBZ alone, while 20 were taking one or more additional anticonvulsant drugs. 2. The free fraction of CBZ in plasma ranged from 0.19 to 0.33 (mean 0.24) while the saliva:plasma (S:P) concentration ratios ranged from 0.20 to 0.35 (mean 0.27). The free fraction of CBZ-EP in plasma ranged from 0.16 to 0.50 (mean 0.32), while the S:P ratios ranged from 0.14 to 0.70 (mean, 0.43). The plasma protein binding and S:P ratios of these compounds appeared to be independent of age, sampling time and concurrently administered anticonvulsant drugs. 3. Significant linear relationships between saliva and total plasma concentrations and between saliva and free plasma concentrations were observed for both compounds (P less than 0.001). However, salivary concentrations of CBZ and CBZ-EP were significantly more reliable as predictors of their respective free plasma concentrations than of their respective total plasma concentrations (P less than 0.01). 4. It is concluded that measurement of CBZ and CBZ-EP in the saliva of chronically medicated epileptic patients provides a more reliable estimate of the pharmacodynamically active, free concentrations of these compounds in plasma.
1 Carbamazepine (CBZ) brain and plasma concentrations were measured in twenty-one patients undergoing brain surgery for tumour removal. The drug was administered prophylactically at doses ranging from 6.9 to 14.8 mg/kg for 4-5 days before the intervention. 2 In seventeen cases where sample were collected 10-14 h after dosing, CBZ brain levels ranged from 2.2-14.5 microgram/g. A significant linear relationship (p less than 0.01) was observed between brain and plasma concentrations with a brain/plasma ratio of 1.1 +/- 0.1. 3 Carbamazepine 10,11-epoxide (CBZ-Epox), present in all samples, could be quantified in three brain specimens. Its brain concentrations ranged from 1.5-2.7 microgram/g with a brain/plasma ratio of 1.1-1.2. 4 Parieto-occipital areas tended to show higher CBZ concentrations while lower values were found in temporal regions. Very low CBZ levels were found in two gliomas while in meningiomas CBZ levels were similar to those observed in normal tissue. 5 The data, showing a linear relationship between brain and plasma concentrations of both CBZ and its epoxide, give additional significance to the plasma level monitoring of antiepileptic drugs.
The serum levels of carbamazepine (CBZ) and its 10,11-epoxide metabolite (CBZ-E) were determined in seven subjects after a single dose of CBZ (400 mg) in the control state and during co-administration of erythromycin (500 mg three times daily for 10 days). Erythromycin treatment was associated with a decrease in CBZ clearance and a prolongation of CBZ half-life, while CBZ-E levels were markedly reduced. These data provide evidence that erythromycin inhibits the conversion of CBZ to its epoxide metabolite.
The effect of the valpromide isomer valnoctamide (VCD, 200 mg three times daily for 8 days), an over-the-counter tranquillizer, on the elimination kinetics of a single oral dose of carbamazepine-10, 11-epoxide (CBZ-E, 100 mg) was investigated in healthy subjects. During VCD treatment, the half-life of CBZ-E was prolonged significantly compared with control (19.7 +/- 6.7 h vs 6.9 +/- 2.0 h, means +/- s.d., P less than 0.01), and its oral clearance decreased four-fold (from 109.6 +/- 30.7 to 28.8 +/- 11.1 ml h-1 kg-1, P less than 0.01). These findings indicate that VCM, like valpromide, strongly inhibits epoxide hydrolase in vivo.
The binding of carbamazepine and carbamazepine 10,11-epoxide to serum, albumin and alpha 1-acid glycoprotein (AAG) was determined and compared at drug concentrations ranging from 0.5 to 400 mg/l using equilibrium dialysis and liquid chromatography. The total binding of carbamazepine in serum was determined primarily by albumin and to a lesser extent (20-30%) by AAG. Modified Scatchard plots for carbamazepine binding in serum were biphasic, suggesting the presence of two binding sites on serum protein. Association constants characterizing the first (k1 = 2.4 X 10(4) l/mol) and second (k2 = 4.6 X 10(2) l/mol) binding sites agreed with those measured for AAG and albumin respectively. Modified Scatchard plots for carbamazepine 10,11-epoxide binding in serum were linear and serum binding was largely accounted for by binding to albumin. The epoxide metabolite did not bind to AAG. Carbamazepine binding to AAG was drug concentration-dependent over the concentration range considered to be therapeutic, while the percent binding values for carbamazepine and epoxide binding to albumin and serum from a normal individual were constant over this range. Computer simulations showed that physiological extremes in AAG and albumin concentrations can result in a range of carbamazepine unbound fractions of 0.17 to 0.47. These data suggest that normal variations in concentrations of both proteins may be the principal cause of interpatient variability in serum protein binding of carbamazepine.
The single oral dose pharmacokinetics of carbamazepine-10, 11-epoxide (CBZ-E) were investigated in six normal volunteers during a control session and during concurrent treatment with valpromide (VPM) (300 mg twice daily for 8 days). VPM caused a prolongation of the CBZ-E half-life from 6.4 +/- 1.4 to 20.5 +/- 6.3 h and decreased CBZ-E clearance from 73.5 +/- 20.0 to 23.5 +/- 4.0 ml h-1 kg-1 (P less than 0.01). These results suggest that the elevation of plasma CBZ-E levels in patients receiving carbamazepine and VPM in combination is due to inhibition of epoxide hydrolase in the liver.
Concentrations of carbamazepine (CBZ) and its 10,11-epoxide metabolite (CBZ-E) were measured in simultaneously collected plasma and mixed saliva samples from 15 children (aged 1-13 years). Saliva concentrations of CBZ and CBZ-E were measured in hourly samples taken from six of these children during dose intervals whilst on different dose or dose-frequency regimens. Saliva and plasma CBZ (r = 0.91; P less than 0.001) and CBZ-E (r = 0.91; P less than 0.001) concentrations were significantly correlated. The mean +/- s.d. steady state CBZ-E/CBZ concentration ratio in the six children was 0.40 +/- 0.21 and was similar at all times within the 12 h dose interval. The mean +/- s.d. percentage fluctuation of the combined CBZ + CBZ-E (103.0 +/-28.9) was significantly less than that of CBZ-E (145.5 +/- 52.8) but not CBZ (109.6 +/- 31.1). If CBZ and CBZ-E have equipotent anticonvulsant activity in man, the contribution of CBZ-E approximates to 30% of total anticonvulsant effect in children taking CBZ alone.
1 BM 10.188 (Doxaminol, Boehringer Mannheim, GmbH) is a recently developed beta-sympathomimetic agent which has shown promising positive inotropic activity in experimental animal models. It is a dibenzoxepine derivative. 2 The effects of 20 mg oral BM 10.188 on systolic time intervals and standard echocardiographic parameters have been studied in six normal healthy male volunteers. 3 When assessed by repeated measured analysis of variance, QS2 and LVET shortened significantly (P less than 0.005) in the 8 h period following BM 10.188. Mean maximum shortening values were: QS2, 25.7 +/- 25.6 (s.d.) ms at 155 min and LVET, 10.7 +/- 9.5 (s.d.) ms at 155 min. There was a corresponding small but significant increase of 4.2 +/- 3.9 (s.d.) ml in stroke volume at 6 h (P less than 0.025). 4 These results indicate that in normal volunteers, BM 10.188 exhibits effects on noninvasive cardiological indices similar to those observed after cardiac glycosides.
The plasma elimination rate of antipyrine, as measured by the salivary concentration decay, and the urinary excretion of antipyrine and its primary metabolites 4-hydroxy-antipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxy-antipyrine were studied in 5 healthy volunteers, who received 250, 500 and 1000 mg antipyrine orally in a cross-over design. The mean antipyrine half-life and metabolic clearance were 11.5 ± 2.5 h (range 10.2-16.9 h) and 3.4 ± 0.9 l/h (range 1.7-4.2 l/h) respectively after 500 mg. These values were not significantly different after 250 or 1000 mg P>0.1; paired t-test). In 52 h urine 3.3±1.2% 1.2% of the dose of 500 mg antipyrine was excreted unchanged as antipyrine, 28.5±2.2% as 4-hydroxy-antipyrine, 16.5±6.0% as norantipyrine, 35.1±7.2% as 3-hydroxymethyl-antipyrine and 3.3±0.8% as 3-carboxy-antipyrine. The values obtained at the other dose levels were not significantly different (P>0.1; paired t-test). At all dose levels 4-hydroxy-antipyrine and norantipyrine were excreted in urine entirely as glucuronides. After 500 mg antipyrine, 3-hydroxymethyl-antipyrine was excreted as glucuronide to the extent of 58±9% of the total excreted amount. This percentage was not significantly different at the other dose levels. 3-Carboxy-antipyrine was excreted in the free form at all three dose levels. From 12h of drug intake onwards, the urinary excretion rate curves of antipyrine and all its metabolites declined mono-exponentioally with about the same half-life as the parent compound in saliva. The half-lives calculated from the excretion rate curves of 4-hydroxy-antipyrine, norantipyrine and 3-hydroxymethyl-antipyrine correlated significantly with the half-life of antipyrine in plasma. At all dose levels a relative delay in urinary excretion of 3-hydroxymethyl-antipyrine was observed compared to the urinary excretion of antipyrine and the other metabolites. The ratios of the cumulative amounts of metabolites excreted in 24 h were essentially the same as those measured in the 52 h samples.
To investigate whether the administration of tenofovir diproxil fumarate 300 mg once daily alters the plasma pharmacokinetics of the saquinavir hard gel/ritonavir combination in HIV-1 infected individuals.
On day 1, 12 h pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg given twice daily) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Tenofovir diproxil fumarate 300 mg given once daily was then added to the regimen and blood sampling was repeated at days 3 and 14. Saquinavir and ritonavir concentrations were measured by HPLC-MS/MS, and tenofovir concentrations by HPLC with UV detection.
Following the addition of tenofovir diproxil fumarate to the regimen, saquinavir and ritonavir plasma concentrations were not significantly different compared with day 1. Thus the geometric mean ratios (95% confidence intervals) for the area under the concentration-time curve were 1.16 (0.97, 1.59) and 0.99 (0.87, 1.30) for saquinavir and 1.05 (0.92, 1.28) and 1.08 (0.97, 1.30) for ritonavir, on days 3 and 14, respectively.
Tenofovir diproxil fumarate did not alter the pharmacokinetics of saquinavir hard gel/ritonavir.
To evaluate the effect of a 3-day regimen of ibuprofen 600 mg x 4 on acute postoperative swelling and pain and other inflammatory events after third molar surgery compared with a traditional regimen of paracetamol 1000 mg x 4.
A controlled, randomized, double-blind, cross-over study where 36 patients (26 females, 10 males) with mean age 23 (range 19-27) years acted as their own controls. All patients were subjected to surgical removal of bilateral third molars. After one operation the patients received tablets of ibuprofen 600 mg x 4 for 3 days. After the other operation they received an identical regimen of paracetamol 1000 mg tablets. Swelling was objectively measured (mm) with a standardized face bow and the patients scored their pain intensity (PI) on a 100-mm visual analogue scale.
There was no statistically significant difference between paracetamol and ibuprofen treatment with respect to effect on acute postoperative swelling. Swelling after paracetamol on the third postoperative day was 1.8% less than that after ibuprofen. Mean (95% CI) difference between treatments was -0.3 (-4.7, 4.1) mm. On the sixth postoperative day swelling after ibuprofen was 2.3% less than that after paracetamol. Mean (95% CI) between treatments was 0.2 (-2.4, 2.8) mm. There was no statistically significant difference in pain intensity between the paracetamol and the ibuprofen regimen on the day of surgery. The mean (95% CI) difference between the treatments for summed pain intensity on the day of surgery (SUMPI 3.5-11) was 3.31 (-47.7, 54.3) mm. Two patients developed fibrinolysis of the blood clot (dry socket) after receiving ibuprofen while none did this after paracetamol treatment. There was no noticeable difference between treatments with respect to appearance of haematomas/ecchymoses or adverse effects which all were classified as mild to moderate.
A 3-day regimen of ibuprofen 600 mg x 4 daily does not offer any clinical advantages compared with a traditional paracetamol regimen 1000 mg x 4 daily with respect to alleviation of acute postoperative swelling and pain after third molar surgery.
The effect of the timing of a standard meal relative to a single oral dose of 200 mg ibopamine, on the appearance of its pharmacologically active metabolite, epinine, in plasma was investigated in a randomised crossover study in 12 healthy volunteers. After a 12 h fast, ibopamine was administered either in the fasting state (no meal), or 1 h before, 0.5 h before, immediately after, 2 h after or 3 h after a standardised meal. Blood samples taken immediately before and at intervals for 3 h after dosing were analysed for free epinine. Maximum concentration (Cmax), time to Cmax(tmax), and area under the concentration-time curve (AUC) for free epinine in plasma were calculated. When compared with the fasting state, Cmax and AUC0-3h were significantly reduced when ibopamine was given immediately after or 2 h after a meal. AUC was also reduced for ibopamine given 0.5 h before a meal. tmax was significantly delayed when ibopamine was given immediately after, or 2 or 3 h after a meal. Thus, administration of ibopamine with or shortly after a meal reduced the rate and extent of appearance of free epinine in plasma. The clinical significance of reduced epinine levels on acute dosing in the presence of food is unknown.
GS-101 (GeneSignal, Epalinges, Switzerland) is an antisense oligonucleotide that inhibits the expression of the scaffold protein insulin receptor substrate-1 (IRS-1). Inhibition of IRS-1 results in the prevention of neovascular growth and was shown to prevent the angiogenic process in preclinical in vitro and in vivo experiments. There is therefore a strong therapeutic rational for targeting angiogenesis in pathological neovascularization. We aimed to investigate the safety, tolerability and bioavailability of GS-101 eye drops.
This was a Phase I open-label study. The investigation was performed in two steps. Local ocular tolerability was first assessed with the application of one single low dose in one eye. After no signs of intolerance were observed in the subjects, the dose escalation phase of the study was initiated, and the remaining subjects received three times daily escalating doses of GS-101 in one eye for 14 days.
The 14 healthy volunteers tolerated well 14 days' continued use of escalating doses of GS-101 from 43 to 430 microg per day. Other than itching, experienced also in the control eye by one subject and determined to be unrelated to the study treatment, no signs of intolerance were observed.
The tolerability profile obtained from this study suggests that GS-101 is safe for human use. Further clinical evaluations in diseases related to abnormal angiogenesis are being targeted. In particular, the neovascularization-related orphan indications of corneal graft rejection, retinopathy of pre-maturity and neovascular glaucoma are currently under Phase II clinical investigation and are showing promising results.
1. SK&F 101468, a non phenolic indolone derivative, has been characterised preclinically as a novel, potent and specific dopamine D2-receptor agonist. 2. Its tolerability and effects on serum prolactin were investigated in 14 healthy male volunteers in a study of the first administration of SK&F 101468 to man. 3. Doses between 80 micrograms and 2.5 mg caused statistically significant (P less than 0.05) lowering of basal and food stimulated serum prolactin, relative to placebo, over a 6 h post treatment period. 4. SK&F 101468 was well tolerated up to 1 mg with symptoms of nausea and postural hypotension at higher doses.
1. We have investigated the effect of repeated s.c. Org 10172 (a low molecular weight heparinoid; Lomoparan) treatment (1000 anti-Xa units twice daily for 5 days) on antipyrine (500 mg orally) metabolism, and the effect of enzyme induction by pentobarbitone (100 mg for 12 days) on the pharmacokinetics and pharmacodynamics of Org 10172 following an intravenous bolus injection of 3250 anti-Xa units. 2. Org 10172 treatment caused a small increase in the formation rates of all antipyrine metabolites (P less than 0.05), while the overall kinetics of antipyrine did not change significantly. 3. Oxidative enzyme induction by pentobarbitone, as demonstrated by an increased clearance of antipyrine, was associated with an increase in the area under the anti-thrombin activity vs time curve (P less than 0.05). No influence was seen on the kinetics of plasma anti-Xa and thrombin generation inhibiting (TGI) activity. 4. The pharmacodynamics of Org 10172, as determined by clotting tests, was not influenced by enzyme induction. 5. The clinical relevance of these observations is likely to be limited.
ORG 10172 is a heparinoid with mean molecular weight 6500 daltons. Intravenous bolus injections of ORG 10172 were compared with placebo and heparin injections in 91 separate studies in 83 healthy male subjects. 6400 units ORG 10172 produced a mean maximum change of 14.7 s in kaolin cephalin time (c.f. greater than 120 s for 5000 units heparin). Changes in prothrombin time were minimal (1.6 s for 6400 units ORG 10172 and 4.5 s after 5000 units heparin). A dose-related increase in bleeding time occurred after ORG 10172 and at high doses (greater than 3200 units) some secondary bleeding, which was never serious, occurred at between 1 and 4 h after incision. A dose-dependent reduction in ex vivo platelet adhesiveness was found at 10 min after ORG 10172 injection. ORG 10172 promoted a much smaller release of lipoprotein lipase as compared with heparin. The effect of ORG 10172 on plasma factor Xa activity (one measure of its action) was described by a biexponential decay with a mean distribution half-life of 2.34 (s.e. mean 0.16) h and mean disposition half-life of 17.6 (s.e. mean 1.1) h. It thus has a much longer duration of effect than heparin. There was a linear relationship of plasma anti-Xa response to increasing dose although there was some variability only partly explained by differences in body weight or surface area. ORG 10172 administration by bolus intravenous injection was well tolerated and there was no evidence of adverse effects on clinical chemistry or haematology tests.
1. In a cross-over study a new low molecular weight heparinoid Org 10172 was administered to 12 elderly male and female volunteers. It was well tolerated and no adverse effects occurred. 2. The absolute bioavailability of Org 10172 as measured by plasma anti-Xa activity, glycosaminoglycuronans with no affinity to antithrombin III (NoA-GAG) and thrombin generation inhibiting activity approached 100% in both sexes. 3. The half-life of elimination of its anti-Xa activity (19.2 +/- 6.1 h) was similar to that found previously in young volunteers. Org 10172 was further characterised by a rapid disappearance from the circulation of its anti-thrombin activity (t1/2 1.8 +/- 0.6 h) and of the NoA-GAG (t1/2 3.5 +/- 2.1 h). 4. Its thrombin generation inhibiting activity was of intermediate duration (t1/2 elimination 6.2 +/- 4.0 h).
1. The effects of an intravenous injection of a conventional high molecular weight heparin (HMWH) were compared with those of a low molecular weight heparinoid (Org 10172). A bolus injection of HMWH (5000 iu) was associated with: (a) a small but significant prolongation of bleeding time (BT); (b) a significant fall in PRP platelet count; (c) significantly enhanced platelet aggregation; and (d) significantly increased platelet thromboxane A2 (TXA2) release. These changes were not observed following the intravenous injection of Org 10172 (3200 anti Xa U). 2. These experiments were repeated following the oral administration of acetylsalicylic acid (ASA). HMWH again caused some enhancement of platelet aggregation despite the ASA-mediated inhibition of platelet aggregation and TXA2 release. Administration of Org 10172 to subjects taking ASA did not alter any of the platelet function indices. 3. In additional control experiments the injection of 5000 iu of HMWH was associated with a significant fall in PRP but not whole blood platelet counts. This finding suggests that the fall in PRP platelet count is a methodological artefact. 4. The HMWH also induced a significantly greater increase in serum non-esterified fatty acid (NEFA) concentrations than Org 10172. 5. The present findings indicate that Org 10172 is a less potent stimulator of platelet aggregation and lipolysis than HMWH. 6. The minor prolongation of the BT after HMWH is not compatible with enhanced aggregation but may be a consequence of alterations in the activity of coagulation factors and vascular-platelet interactions or of ongoing platelet activation accompanied by granule depletion. 7. The different effects of the two anticoagulants assessed suggests a therapeutic advantage in favour of Org 10172, especially in patients with hyperactive platelets.