Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

The bioavailability of doxycycline

The bioavailability of doxycycline (Doxy-Diolan 100 tablets, test, active substances: 100 mg doxycyclin per tablet) was compared with that of another commercially available tablet-formulation containing the same active substance (reference). In a cross-over study, 16 young healthy male volunteers were administered in fasting state orally by one tablet containing 100 mg active substance. The concentrations of doxycycline were determined in plasma and saliva by a high-performance liquid chromatographic assay. Mean maximum plasma concentration (cmax +/- standard deviation) of doxycycline were 1.57 +/- 0.40 micrograms/ml (test) and 1.59 +/- 0.38 micrograms/ml (reference), respectively, and were reached 1.47 +/- 0.55 h and 1.66 +/- 0.57 h after administration. Plasma half-lives were 16.6 +/- 2.9 h and 16.8 +/- 3.0 h, the areas under the plasma concentration-time curves (AUC0-00) 29.3 +/- 4.5 mg/l.h and 29.7 +/- 4.4 mg/l.h. The concentration of doxycycline in saliva were low, median maximum concentrations of 50 ng/ml were measured 1-2 h after administration. The statistical evaluation revealed bioequivalence between both drugs.     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

The plasma pharmacokinetics of iophenoxic and iopanoic acids in goat.

1. The comparative plasma pharmacokinetics of two organic iodine-containing compounds were evaluated in the goat for their suitability as markers in wildlife studies. 2. After oral administration of a single dose, the plasma elimination half-life for iopanoic acid was considerably more rapid (t1/2 of 1-2 days) than that of iophenoxic acid (t1/2 of 81 days). 3. Similar peak plasma concentrations were obtained after administration of iophenoxic acid (1.5 mg/kg) and iopanoic acid (25 mg/kg); however, the AUC0----infinity for iopanoic acid at doses of 25, 50, and 100 mg/kg were 201 +/- 39, 604 +/- 225, and 1292 +/- 721 (micrograms h/ml +/- SD), respectively, which were less than the value of 36,600 +/- 6387 for the oral administration of iophenoxic acid at 1.5 mg/kg. 4. Iophenoxic acid was chosen as a suitable marker because of its persistence at detectable concentrations in the plasma for 5 months.     

The influence of renal function on clinical pharmacokinetics of moxonidine

Investigations were carried out on 24 hypertensive or borderline hypertensive patients with different degrees of renal function. Eight had normal renal function [glomerular filtration rate (GFR) greater than 90 ml/min], 8 moderate (GFR 30 to 60 ml/min) and 8 severe renal impairment (GFR less than 30 ml/min). All patients were given moxonidine 0.3mg once daily for 7 days and both pharmacokinetic and pharmacodynamic data were determined. During moxonidine treatment plasma elimination half-life, area under the plasma concentration-time curve (AUC) and apparent total clearance (CLT) showed statistically significant differences among patients in the 3 groups. Elimination half-life was 2.6 +/- 0.9 hours in patients with a GFR greater than 90 ml/min and increased to 6.9 +/- 3.7 hours in those with a GFR less than 30 ml/min (mean +/- SD; p = 0.012). Correspondingly, AUC0-24 h rose from 5.4 +/- 2.7 to 17.2 +/- 7.9 micrograms/L . h (p = 0.001), and CLT decreased from 1150 +/- 602.l ml/min to 369 +/- 227.6 ml/min (p = 0.001). These data suggest that once-daily administration of 0.3mg moxonidine may be appropriate in patients with impaired renal function. Independent of renal function, moxonidine was well tolerated in 22 of 24 patients. No deterioration in renal function as a consequence of the use of moxonidine was found. Thus, in patients with renal failure, dosage of moxonidine should be individually titrated according to the desired clinical response, as is recommended for hypertensive patients without renal impairment.     

Pharmacokinetics of mitoxantrone in patients after 2 h and 24 h intra-arterial administration

The pharmacokinetic parameters of mitoxantrone in patients with liver metastasis after intra-arterial 2 h and 24 h infusion (dosage 12 mg/m2) were investigated. Peak plasma concentrations were 305 +/- 60 ng/ml at 2 h infusion and 244 +/- 89 ng/ml at 24 h infusion. These peak plasma concentrations occurred at 0.9 +/- 0.8 h during 2 h infusion and 5.5 +/- 3.4 h during 24 h infusion. No significant difference between both intra-arterial administrations in elimination half-life (50-223 h at 2 h infusion, 58-246 h at 24 h infusion) and area under the plasma concentration-time curve (AUC0-72 = 11.6 micrograms/ml.h for 2 h infusion, AUC0-72 = 11.2 micrograms/ml.h for 24 h infusion) could be found. The results indicate that no change of availability in the central compartment at infusion of mitoxantrone over a period of 24 h could be achieved. The 2 h infusion lead to sufficient plasma levels with pharmacokinetic parameters of mitoxantrone similar to 24 h infusion and showed a good clinical picture with mild toxicity.     

Pharmacokinetics and bioequivalence study of a generic amlodipine tablet formulation in healthy male volunteers

Two different tablets containing amlodipine besylate (CAS 111470-99-6) (Vazkor 10 mg tablet as test preparation and 10 mg tablet of the originator product as reference preparation) were investigated in 18 healthy male volunteers in order to compare the bioavailability and prove the bioequivalence between both treatments after oral single dose administration. The study was performed according to an open-label, randomized, two-period cross-over design with a wash-out phase of 21 days. Blood samples for pharmacokinetic profiling were taken up to 144 h post-dose, and amlodipine plasma concentrations were determined with a validated LC-MS/MS method. Maximum plasma concentrations (Cmax) of 6,183.7 pg/ml (test) and 5,366.7 pg/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 267,231.0 pg x h/ml (test) and 266,061.7 ng x h/ml (reference) were calculated. The median tmax was 5.6 h (test) and 6.1 h (reference). Plasma elimination half-lives (t 1/2) were 46.46 h (test) and 45.34 h (reference). Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA); 90% confidence intervals were between 93.20%-107.16% (AUC(0-infinity) and 103.36%-123.13% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.     

Pharmacokinetic profile and bioavailability of a new pharmaceutical formulation of isosorbide-5-mononitrate sustained-release formulation

The pharmacokinetic profile and the bioavailability of a new galenic formulation of isosorbide-5-mononitrate sustained released capsules (Olicard 40 retard) was tested under standardized conditions. 12 healthy, male volunteers (mean age 24.9 +/- 3.0 years) in a randomized, intraindividual crossover design (wash-out phase: 6 days) received the isosorbide-5-mononitrate sustained-release capsules (testformulation) and a standard-release formulation of the same active substance as single dose (40 mg each). Venous blood sampling for analysing the plasma concentration of isosorbide-5-mononitrate was done before and at 21 fixed times after medication. The AUC0----36h of the concentration/time curve was calculated using the linear trapezoidal rule and the AUC0----infinity extrapolated after computing the half-life of the terminal elimination phase. The leading variable was the AUC0----infinity. For the sustained-release preparation an AUC0----36h of 5764.5 +/- 909 ng/ml.h was measured, an AUC0----infinity of 5863.9 +/- 981.9 ng/ml.h was calculated, with a peak maximum (Cmax) of 472.5 +/- 29.7 ng/ml after 2.9 +/- 0.5 h (tmax). For the standard-release formulation an AUC0----36h of 5679.8 +/- 690.3 ng/ml.h was measured, an AUC0----infinity of 5688.7 +/- 695.7 ng/ml.h was calculated, with a peak maximum (Cmax) of 842.4 +/- 100.2 ng/ml after 1.2 +/- 0.2 h (tmax). The bioavailability of the standard-release formulation was postulated to be 100%. The non-parametric calculation of the bioavailability-ratio (geometric Walsh-averages) was 101.47% (95% confidence limits 85.24% to 121.09%). There was no statistically significant difference between the both galenical formulations, the sustained-release preparation has no influence on the total amount of resorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of pramiracetam in healthy volunteers after oral administration.

The pharmacokinetics of pramiracetam was assessed using an HPLC method after oral administration of two different formulations of 600 mg (a solution and a tablet) of pramiracetam to 11 fasting volunteers. The mean kinetic parameters were: t1 = 4.7 +/- 2.4 - 4.3 +/- 2.2 h, AUC = 57.6 +/- 43.6 - 47.2 +/- 33.9 micrograms h/ml, Cmax = 6.80 +/- 3.2 - 5.80 +/- 3.3 micrograms/ml for the solution and the tablet respectively. The plasma profile of pramiracetam proved to be not highly affected by the formulation, only that the absorption rate was faster after oral administration of the drug in solution than after administration as a tablet. The half-life was very variable between subjects [2-8 hours], but less variable within subjects and it was unaffected by the formulation.     

Neurohormonal and blood pressure responses to low-dose infusion of an orally active renin inhibitor, Ro 42-5892, in salt-replete men.

Renin inhibitors are an alternative means of blockade of circulating and tissue-based renin-angiotensin systems (RAS). We studied a new renin inhibitor, Ro 42-5892, by low-dose (0.1 mg/kg) intravenous (i.v.) infusion in 10 min (fast) or 6 h (slow) or placebo in a double-blind cross-over study to assess the relationship between drug concentration and response. Fasting salt-replete normotensive male volunteers (n = 9) aged 18-32 years were studied supine. There were no significant changes in blood pressure (BP) or heart rate (HR) between drug and placebo infusion. Drug concentration peaked (482 +/- 140 ng/ml) at the end of the fast infusion or showed a sustained plateau (25.9 +/- 6.1 ng/ml) with the slow infusion (mean time to peak 121 +/- 99 min). Both fast (135.2 +/- 26 ng/ml/h2) and slow (121.0 +/- 31.1 ng/ml/h2) infusions had similar area under the curve (AUC)0-24-values. Plasma renin activity (PRA) was dramatically reduced by both strategies, but AUC0-10 for PRA was significantly less for slow (1.7 +/- 0.6 ngAI/ml/h2) than fast (4.9 +/- 2.5 ngAI/ml/h2) infusions. Mean peak plasma active renin (AR) concentration was increased by both fast (102.2 +/- 65.9 pg/ml) and slow (195.2 +/- 110.5 pg/ml) infusions as compared with placebo (49.9 +/- 18.6 pg/ml). Similarly, AUC0-10 for AR was greater for slow (990.2 +/- 582.1 pg/ml/h) than fast (512.4 +/- 189.4 pg/ml/h) infusions. Plasma angiotensin-converting enzyme (ACE) activity was unaltered. Our results indicate that protracted low concentrations of Ro 42-5892 may provide more effective and long-lasting inhibition of renin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab).

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration (C(max)) for the latter, while the time to peak (T(max)) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C(max) by 18% and AUC by 21%, and slightly delayed T(max) from 5 to 6h. During fractional dosing, morning and evening C(max) reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC(0-24 h) on the last day to AUC(infinity) on the first day, was 82.1% (confidence limits 71.7-94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC(0-24 h, s.s.) of 5.55+/-1.78 and 5.71+/-1.08 microg h/ml).     

Determination of the transdermal bioavailability of a newly developed diclofenac sodium patch in comparison with a reference preparation

Two different transdermal diclofenac (CAS 15307-86-5) formulations (Olfen Patch 140 mg diclofenac sodium as test preparation and 180 mg diclofenac epolamine plaster, equivalent to 140 mg diclofenac sodium, as reference preparation) were investigated in 24 healthy male and female volunteers in order to compare the transdermal bioavailability between both treatments following topical multiple dose administration. Subjects were applied 2 plasters of test and reference formulation at a dose interval of 12 h for 4 consecutive days. Test and reference preparation were administered in randomised sequence at a marked spot at the left upper arm under non-fasting conditions. For determination of diclofenac concentrations, pre-dose (trough) values were taken during steady-state build-up and during the period of switch-over between both preparations on days 1-3 and 5-7. Blood samples for pharmacokinetic profiling were taken on days 4 and 8 at pre-defined time points up to 24 h following drug administration (after the 7th resp. 15th dose). Treatments were not separated by a wash-out phase. Considering the short half-life of diclofenac, it was appropriate that a switch-over design was chosen without wash-out periods between treatments. Diclofenac plasma concentrations were determined by means of a validated LC-MS/MS method (limit of detection: 0.06 ng/ml; lower limit of quantification: 0.15 ng/ml). For the test preparation, maximum plasma concentrations of 3.36 ng/ml (C(max, 0-12)), 3.73 ng/ml (C(max, 12-24)) and 3.84 ng/ml (C(max, 0-24)) as well as areas under the plasma concentration-time curve (AUC) of 31.11 ng x h/ml (AUC(0-12), 34.83 ng x h/ml (AUC(12.24)) and 65.94 ng x h/ml (AUC(0-24)) were determined. For the reference preparation, these values were 1.55 ng/ml (C(max, 0-12)), 1.45 ng/ml (C(max, 12-24) and 1.57 ng/ml (C(max, 0-24)) as well as 13.28 ng x h/ml (AUC(0-12)), 12.68 ng x h/ml (AUC(12-24)) and 25.96 ng x h/ml (AUC(0-24)). For the test preparation, peak-to-trough fluctuations (% PTF) of 34.78% (% PTF(0-12)), 38.50% (% PTF(12-24)) and 43.68% (% PTF(0-24)) were observed. Corresponding values for the reference preparation were 35.82% (% PTF(0-12), 31.36% (% PTF(12-24)) and 40.55% (% PTF(0-24)). In order to evaluate comparable bioavailability of both preparations, 90% confidence intervals of the test/reference ratios were determined. Thereby, for all dose intervals considered and all AUC parameters calculated, the extent of diclofenac absorption from the test preparation markedly exceeds those values obtained for the reference preparation. Likewise, maximum plasma concentrations, as a measure for the rate of absorption, were higher after the test preparation. With respect to peak-to-trough fluctuation of plasma diclofenac levels, both plaster preparations were comparable for the morning dose interval 0-12 h as well as for the 0-24 h period.     

Plasma pharmacokinetics of desmopressin following sublingual administration: an exploratory dose-escalation study in healthy male volunteers

OBJECTIVE: Desmopressin is usually administered intranasally in the treatment of central diabetes insipidus or nocturnal enuresis. The sublingual administration of desmopressin is expected to be an alternative to the intranasal route with advantages to children and to patients with allergic rhinitis or chronic rhinosinusitis. Therefore, the present study was carried out to explore the time-versus-concentration profile of desmopressin in plasma after sublingual administration to healthy volunteers. SUBJECTS AND METHODS: A total of 16 healthy male volunteers were enrolled in this open, exploratory, 1-period, randomized, dose-escalation study. Volunteers received a single sublingual dose of either 20, 40, 80, 160, 240 or 320 microg of desmopressin acetate. Desmopressin plasma concentrations were measured over a 12-hour period using a validated radioimmunoassay method. Safety and tolerability were assessed simultaneously. RESULTS: Plasma concentrations of desmopressin were below the lower limit of quantification (LLOQ) of 5 pg/ml for doses lower than 80 microg. For the doses of 160 - 320 microg the time-versus-concentration profiles were higher than the LLOQ. The area under the curve from 0 - 12 h (AUC0-12h) was 54.66 +/- 25.92 pg x h/ml after the 160 microg dose, 104.38 +/- 79.10 pg x h/ml following the 240 microg dose and 133.18 +/- 181.84 pg x h/ml following the 320 microg dose. Given the data from previous experiments, the time-versus-concentration profile of desmopressin in plasma after a sublingual dose of 240 microg appeared to be in the range of previously published data on an intranasal dose of 20 microg. Sublingual administration of desmopressin proved to be safe and was well tolerated by all volunteers. CONCLUSION: A very high inter-individual variability in desmopressin plasma concentrations was detected after sublingual administration. A sublingual dose of 240 microg of desmopressin appeared to result in a pharmacokinetic profile comparable to 20 microg administered intranasally. These data, however, need to be verified in a separate well-designed prospective clinical study.     

Pharmacokinetics of nifedipine derived from a new retard tablet formulation

A nifedipine retard tablet formation (Glopir, 20mg) was developed to reduce the number of daily doses required in the treatment of hypertension. The plasma pharmacokinetics of this oral formulation were examined, in a single study, on 12 healthy volunteers. Single 20 mg doses of nifedipine retard tablet (Glopir, GAP & Co. Athens, Greece) were given after an overnight fast and 10 blood samples were drawn during the first 24 h after administration. Plasma concentrations of nifedipine were measured by high performance liquid chromatography. The mean peak plasma nifedipine concentration was 27.6 ng/ml at a maximum time of 24 h, after tablet ingestion. The mean apparent nifedipine elimination half-life was 16.0 +/- 7.5 h and the mean area under the plasma concentration time curve (0-24 h) 404.1 +/- 134.0 ng/ml.h. The data suggest that the tablet form has properties of a sustained-release preparation, with slow accumulation and elimination phases and can appropriately be given in a twice-daily regimen.     

Single dose absorption profiles and bioavailability of two different salbutamol tablets

In a single dose cross-over experiment in twelve healthy adults a comparison of the absorption profiles and the relative bioavailability was made between a new salbutamol containing tablet (preparation A = Salbutax) and a commercially available and accepted formulation as reference (preparation B), both containing 4 mg salbutamol. Salbutamol plasma concentrations were measured frequently during a period of 16 h post dosing. Maximum salbutamol plasma concentrations after intake of product A and product B on an empty stomach were reached after 2.3 +/- 0.9 (= mean +/- S.D.) and 2.4 +/- 1.1 h, respectively, and accounted for 14.3 +/- 2.5 and 12.8 +/- 2.6 micrograms X l-1, respectively. The differences were not found to be significant (p greater than 0.05). The areas under the plasma concentration-time curves (AUC0----16), as obtained after administration of tablet A and tablet B, accounted for 73.5 +/- 14.0 and 65.0 +/- 11.8 micrograms X l-1 X h, respectively, the difference being marginally significant (p = 0.05). This results in a relative bioavailability of 114.3 +/- 15.7% for the product A 4-mg tablets. It is concluded that both products can be considered as having comparable bioavailability.     

Pharmacokinetics of three organic nitrates in Chinese healthy male volunteers

Eighteen Chinese male subjects completed a single-blind, randomized, three-treatment, three-period, cross-over study. In each treatment phase, subjects received a single dose of 20 mg isosorbide dinitrate (CAS 87-33-2, ISDN) intravenous infusion, 20 mg isosorbide 5-mononitrate (CAS 16051-77-7, 5-ISMN) tablet or 20 mg isosorbide 5-mononitrate intravenous infusion. Each consecutive dosing was separated by a washout period of 7 days. Following each dosing, venous blood samples were collected over a period of 16 h. Plasma concentrations of ISDN and its two active metabolites isosorbide 2-mononitrate (2-ISMN), 5-ISMN had been measured by a validated gas chromatographic method. Various pharmacokinetic parameters including AUC0-t, AUC0-infinity, Cmax, tmax, t1/2, Kelm and MRT were determined for the three formulations and found to be in good agreement with literature values. AUC0-t and AUC0-infinity of 5-ISMN tablet and intravenous infusion were 2694 +/- 496 ng x ml(-1) x h vs. 2548 +/- 556 ng x ml(-1) x h and 3266 +/- 624 ng x ml(-1) x h vs. 3178 +/- 769 ng x ml(-1) x h, respectively, and the relative bioavailability of 5-ISMN tablet was 105 +/- 20%. As compared with 5-ISMN intravenous infusion, ISDN can rapidly reach the plateau concentration and metabolize to its active metabolites 5-ISMN and 2-ISMN, which both have vasodilator effect. The results of this study suggest that as evaluated from the pharmacokinetic profiles of the three formulations, 5-ISMN tablet and ISDN intravenous infusion are ideal vasodilators and anti-angina drugs especially in acute conditions due to their rapid onset and long duration of action.     

Is epinephrine administration by sublingual tablet feasible for the first‐aid treatment of anaphylaxis? A proof‐of‐concept study

PURPOSE: In order to explore the feasibility of sublingual administration of epinephrine tablets as a non-invasive first-aid treatment for anaphylaxis, we studied epinephrine absorption from this dosage form in an animal model. METHODS: In a prospective, randomized, four-way crossover study, six rabbits received epinephrine 2.5 or 10 mg as a sublingual tablet, epinephrine 0.03 mg (0.3 ml) by intramuscular (IM) injection (positive control), and 0.9% NaCl (0.3 ml) IM (negative control). Pre- and post-dose blood samples were obtained for measurement of plasma epinephrine concentrations by HPLC-EC. RESULTS: After administration of epinephrine 2.5 mg as a sublingual tablet, the mean (+/-SEM) C(max) was 2369+/-392 pg/ml, and the t(max) was 20.8+/-5.7 min. After administration of epinephrine 10 mg sublingually, the C(max) was 10836+/-2234 pg/ml, and the t(max) was 21.7+/-5.4 min. After IM epinephrine, the C(max) was 6445+/-4233 pg/ml, and the t(max) was 15.8+/-4.7 min. After IM 0.9% NaCl, the C(max) (endogenous epinephrine) was 518+/-142 pg/ml. The t(max) after both of the sublingual epinephrine tablet doses did not differ significantly from the t(max) after IM epinephrine, and the C(max) after the 10 mg sublingual epinephrine tablet dose did not differ significantly from the C(max) after IM epinephrine. CONCLUSIONS: In this proof-of-concept study, administration of epinephrine as a sublingual tablet formulation resulted in rapid achievement of peak plasma epinephrine concentrations. Absorption studies in humans are needed. DEFINITIONS: HPLC-high performance liquid chromatography; EC - electrochemical detection; C(max) - maximum plasma epinephrine concentration after dosing; t(max) - time of maximum plasma epinephrine concentration.     

Intrapulmonary pharmacodynamics of high-dose levofloxacin in subjects with chronic bronchitis or chronic obstructive pulmonary disease

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in subjects with stable chronic lung disease. Three doses of 1000 mg levofloxacin were administered once daily to 16 adult subjects divided into four groups of 4 subjects each. Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed at 4 h, 8 h, 12 h and 24 h following administration of the last dose. Blood was obtained for drug assay prior to drug administration, at the end of the last infusion (maximum concentration (Cmax)) and at the time of BAL. Levofloxacin was measured using a high-performance liquid chromatographic tandem mass spectrometric (HPLC/MS/MS) technique. Plasma, epithelial lining fluid (ELF) and alveolar cell (AC) pharmacokinetics were derived using non-compartmental methods. Cmax/MIC(90) and area under the concentration-time curve for 0-24 h after the last dose (AUC(0-24 h)/MIC(90) ratios were calculated for respiratory pathogens with minimum inhibitory concentrations for 90% of the organisms (MIC(90)) of 0.03-2 microg/mL. The Cmax (mean+/-standard deviation), AUC(0-24h) and half-life were, respectively, 9.2+/-2.7 microg/mL, 130 microg h/mL and 8.7 h for plasma, 22.8+/-12.9 microg/mL, 260 microg h/mL and 7.0 h for ELF and 76.3+/-28.7 microg/mL, 1492 microg h/mL and 49.5 h for ACs. Levofloxacin concentrations were quantitatively greater in ACs than in ELF or plasma at all time points, however only the differences between AC concentration and ELF or plasma concentrations in the 4-h and 8-h time groups were statistically significant. Cmax/MIC(90) and AUC/MIC(90) ratios in ELF were, respectively, 11.4 and 130 for Mycoplasma pneumoniae, 22.8 and 260 for Streptococcus pneumoniae, 91.2 and 1040 for Chlamydia pneumoniae and 760 and 8667 for Haemophilus influenzae. In ACs the ratios were 38.2 and 746 for M. pneumoniae, 76.3 and 1492 for S. pneumoniae, 305 and 5968 for C. pneumoniae and 2543 and 49 733 for H. influenzae. In conclusion, Cmax/MIC(90) and AUC/MIC(90) ratios provide a pharmacokinetic rationale for once-daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of respiratory infection in patients with chronic lung disease.     

The I1-imidazoline agonist moxonidine decreases sympathetic tone under physical and mental stress

AIMS: Moxonidine is an I1-imidazoline receptor agonist that reduces blood pressure by inhibition of central sympathetic activity. The effects of the drug under physical and mental stress have not been studied in detail. METHODS: We investigated the effects of 0.4 mg moxonidine orally on sympathetic activity, blood pressure and heart rate in a double-blind, placebo-controlled crossover study in 12 healthy volunteers. The subjects underwent physical exercise test using bicycle ergometry and a mental stress test using an adaptive reaction test device. Potential association of parameters with the GNB3 C825T polymorphism was also assessed. RESULTS: Under resting conditions, moxonidine decreased plasma noradrenaline (NA: -66.1 +/- 12 pg ml(-1); P < 0.01 vs placebo) and adrenaline (A: -18.8 +/- 6 pg ml(-1); P < 0.05 vs placebo). Physical exercise evoked a significant increase in plasma NA and A (NA: 760 +/- 98 pg ml(-1); A: 97 +/- 9 pg ml(-1); P < 0.001 vs baseline), which was significantly reduced after pretreatment with moxonidine (NA: 627 +/- 68 pg ml(-1); P < 0.05 vs placebo; A: 42.8 +/- 4 pg ml(-1); P < 0.01 vs placebo). Maximal physical exercise capacity was not limited by moxonidine (NS). During the mental stress test, increases in NA (placebo: 146 +/- 24 pg ml(-1), moxonidine: 84 +/- 26 pg ml(-1); P < 0.01 vs placebo) and A (placebo: 22.8 +/- 9 pg ml(-1), moxonidine: 8.0 +/- 8 pg ml(-1); P < 0.01 vs placebo) were significantly reduced after pretreatment with moxonidine. Increases in blood pressure during mental stress were significantly lower after pretreatment with moxonidine (P < 0.05 vs placebo). There was no association of the response to moxonidine with GNB3 genotypes (NS). CONCLUSIONS: Moxonidine decreases total sympathetic tone under basal conditions as well as during physical exercise and mental stress without limiting absolute exercise capacity. Thus, moxonidine appears suitable for the treatment of patients with high SNS activity and hypertension induced by physical or mental stress. As the drug does not reduce exercise capacity, it may be considered as an alternative to beta-adrenoceptor blockers in selected patients.     

Effect of gender on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel blocker

PURPOSE: To determine the effect of gender on the pharmacokinetics of eslicarbazepine acetate, a novel voltage-gated sodium channel blocker in the development for the treatment of epilepsy and bipolar disorder. METHODS: Single-centre, open-label, parallel-group study in 12 female and 12 male healthy subjects. The study consisted of a single-dose (600 mg) period and a multiple-dose (600 mg, once-daily, for 8 days) period, separated by 4 days. RESULTS: Eslicarbazepine acetate was rapidly and extensively metabolized to eslicarbazepine (S-licarbazepine), the main active metabolite. Following a single-dose, arithmetic mean eslicarbazepine maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve over 24 h (AUC(0-24)) and from 0 to infinity (AUC(0-infinity)) were, respectively, 9.3 microg/ml, 128.5 microg h/ml and 171.9 microg h/ml in male subjects and 10.1 microg/ml, 150.1 microg h/ml and 205.0 microg h/ml in female subjects. At steady-state, C(max), AUC(0-24) and AUC(0-infinity) were 15.5 microg/ml, 207.8 microg h/ml and 295.8 microg h/ml in male subjects, and 16.8 microg/ml, 214.5 microg h/ml and 295.2 microg h/ml in female subjects. Steady-state plasma concentrations were attained at 4 to 5 days of administration in both groups.Eslicarbazepine C(max), AUC(0-24) and AUC(0-infinity) female:male geometric mean ratios (90%CI) were, respectively, 1.09 (0.94; 1.24), 1.16 (1.00; 1.33) and 1.17 (0.99; 1.38) following single-dose, and 1.10 (0.97; 1.25), 1.04 (0.92; 1.17) and 1.01 (0.88; 1.16) at steady-state. CONCLUSION: At steady-state, the pharmacokinetic profile of eslicarbazepine acetate was not affected by gender.