摘要:

Since the late 1970s, topical β‐adrenergic blockers have been the drugs of choice in treating ocular hypertension and associated glaucoma. The currently available drugs are timolol, betaxolol, levobunolol, metipranolol, and carteolol. All reduce intraocular pressure by decreasing the production of aqueous humor. Although these drugs are applied locally in the eye, they may enter the general circulation and reach concentrations high enough to cause systemic effects, including alterations in heart rate and rhythm, bronchoconstriction, dyslipidemia, and central nervous system abnormalities. Interactions with other drugs may also occur. Ocular β‐ blockers differ in β1‐selectivity (betaxolol is β1‐selective, whereas the other drugs are nonselective) and in intrinsic sympathomimetic activity (ISA) or partial agonist properties (only carteolol possesses ISA). These differences give betaxolol and carteolol potential advantages in minimizing certain side effects. The advantage of betaxolol vis‐à‐vis systemic side effects is more clearly established than that of carteolol. Further systematic study is needed to determine what advantages, if any, are conferred by the

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02042.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02043.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02044.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The cardiovascular actions of racemic atenolol (RSATN) have been well characterized in humans, but the actions of S(—)‐atenolol (SATN) when administered alone are unknown. In this study, responses of heart rate (HR) and Doppler‐derived aortic blood flow profiles to upright treadmill exercise were compared after oral administration of 50 mg SATN and 100 mg RSATN in eight healthy, adult, male volunteers. After a single‐blind, placebo run‐in period, subjects were randomly allocated in a double‐blind, crossover fashion to receive SATN and RSATN. Each study period was separated by a 7‐day washout period. Multiple submaximal exercise tests were performed and data were collected over the 24 hours after each treatment. Both SATN and RSATN significantly (P<.05) blunted peak exercise HR by 38±3 and 37±3 beats/mint, respectively. Aortic blood flow acceleration measured during peak exercise decreased after SATN and RSATN, by 13±4 and 13±3 m/sec2, respectively (P<.05). No difference in hemodynamic effect was observed between treatments. Pharmacodynamic parameters derived from plasma S(—)‐atenolol concentration‐effect (HR) curves after SATN, RSATN, and total atenolol plasma concentrations after RSATN did not differ significantly. Predicted maximum reductions in heart rate (Emax) and EC50for S(—)‐atenolol after SATN were 39.6±5.8 beats/min and 38.4±40.9 ng/ml versus 34.5±8 beats/min and 25.9±29.9 ng/ml for RSATN, respectively. The Emaxand EC50for total atenolol plasma concentrations after RSATN were 35.1± 8.4 beats/min and 50.2 ±68 ng/ml, respectively. These data indicate that, after a single dose: (1) the negative chronotropic and inotropic activities of 100 mg oral RSATN reside in the S(—)‐enantiomer and R(+)‐atenolol exerts no detectable cardiovascular activity, and (2) pharmacodynamic modeling of the total plasma concentration accurately describes

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02045.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

This study further characterized the impact of concentration‐dependent protein binding on the bioavailability and clinical use of the immediate‐release (IR) and controlled‐release (CR) dosage forms of disopyramide after single doses and during steady‐state conditions in ten healthy volunteers. Consistent with the clinical use of these products, steady state has incorporated an IR to CR conversion step. Side effects and electrocardiographic actions were quantitated using a visual analog scale and serial Holter monitor recordings, respectively. Significant decreases resulted in area under the curve for total disopyramide between single dose and steady state: IR, 47.8±13.6 versus 33.0±6.4 mg/Lxh (P<.05); and CR, 46.9±9.5 versus 31.7±5.9 mg/Lxh (P<.05). In contrast, there were no differences in area under the curve for unbound disopyramide between phases or products. During conversion, the mean IR peak significantly decreased (P<.05) to the nadir before the first CR dose for total (37%) and unbound (60%) concentrations. There were no major differences in change in QT interval or side effects detected between products or phases. These findings indicate that, because of concentration‐dependent protein binding, unbound, not total, concentrations should be used to estimate the bioavailability of disopyramide. Also, although the previously recommended conversion method (first CR dose 6 hours after the last IR dose) should provide an adequate transition in most, an alternative method (combined first CR with last IR dose) is indicated in se

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02046.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Dose proportionality of racemic bisoprolol and the stereoselectivity of its enantiomers were studied after single oral dosing of 5 to 40 mg of bisoprolol hemifumarate in eight healthy male volunteers in an open‐label, randomized, four‐way cross‐over trial. There were dose‐proportional increases in mean peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values for the racemate and the individual enantiomers. No statistically significant differences were detected between the mean half life (t1/2), Cmax, and time to reach Cmax(tmax) of the R‐ and S‐isomers at each of the four dose levels studied. These findings support dose proportionality and absence of stereoselective pharmacokinetics for bisoprolol in the dose ra

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02047.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The potential interaction between tirilazad mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium‐channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad mesylate as a 10‐minute intravenous infusion, and a combination of the two treatments according to a balanced 3‐way crossover design. No significant effects of nimodipine on tirilazad mesylate pharmacokinetic parameters were observed (P>.05). Values for tirilazad mesylate clearance (34.9±8.96 L/hr) and half‐life (29±7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad mesylate and nimodipine is detectable after single‐dose adm

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02048.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

A Bayesian method was used to evaluate nortriptyline (NTP) serum concentrations (Cps) and predict future Cps in two populations: five simulated groups (n = 20 each) with known clearance (CL) and volume of distribution (Vd), and an actual inpatient group (n = 20). The effects of weight, CL, Vd, and magnitude of Cps on absolute prediction error (APE) were evaluated. In simulated groups, Cps after two doses of NTP and for steady‐state were calculated for normal, increased, and decreased Vd and CL. In the actual patient group, Cps were measured in the first few days after starting NTP administration and again during maintenance therapy. The first Cps were used in the Bayesian program to estimate CL and Vd to predict the second Cps. In the simulated group, PE and APE differed significantly between normal and decreased values of CL. A large Vd resulted in less of a change in PE or APE in these subjects, but when combined with low CL led to the largest errors. In the actual patient group, PE was −5.9±19.2 ng/mL and APE was 15.4±12.6 ng/mL. In these patients, only body weight was correlated with the percent APE (r = 0.607, P =0.005). The Bayesian method performs well clinically, but increased Vd and decreased CL can lead to higher PE. Clinically, the only factor that predicted higher APE was obesity. This may reflect an effect on Vd, and in these patients, a high APE may

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02049.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The authors studied the antipyretic effect of three intramuscular doses of ketorolac (15, 30, and 60 mg), acetaminophen 650 mg PO, and placebo in healthy male volunteers using an endotoxin‐induced fever model. In this double‐blind, double‐dummy, parallel study, subjects were assigned randomly with equal probability to one of the above treatment groups. Thirty minutes after study medication administration, a 20 unit per kilogram dose of reference standard endotoxin (RSE) was administered intravenously, and temperature was determined every 15 minutes for an 8‐hour period. Compared with placebo, all active treatment groups demonstrated a statistically significant reduction in both adjusted area under the temperature‐by‐time curve (AAUC) and the maximum increase over baseline temperature (dTmax). Furthermore, the 30 mg intramuscular dose of ketorolac demonstrated approximately the same antipyretic activity as the 650 mg oral dose of acetaminophen, and there was a statistically significant dose response across the three ketorolac doses studied (P<.0001). The majority of side effects reported during this study were symptoms associated with fever, including chills, headache, myalgia, and dizziness, all of which are effects of RSE. The frequency of side effects tended to be less in the treatment groups with the greatest antipyret

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02050.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The potential for enhanced systemic absorption of intranasal triamcinolone acetonide was explored in patients with inflamed nasal mucosa. Twelve allergic rhinitis patients with documented nasal inflammation, and 12 healthy volunteers, each received a single, therapeutic, 400‐μg dose of triamcinolone acetonide in each nostril. Blood was obtained at fixed time points after the dose, and plasma concentrations of triamcinolone acetonide were determined by radioimmunoassay. There were no statistically significant differences in any of the derived pharmacokinetic parameters (maximum plasma triamcinolone acetonide concentrations[Cmax],time to maximum plasma triamcinolone concentrations[Tmax],elimination half‐life[t1/2],and area under the plasma concentration‐time curve[AUC0–12]from 0 to 12 hours) between treatment groups. A once‐a‐day, chronic regimen (6 weeks) of triamcinolone acetonide was also administered to five patients with allergic rhinitis. Pharmacokinetic parameters were similar to the parameters derived from healthy volunteers after acute administration. There was no evidence of drug accumulation. The results of this study indicate that acute and chronic intranasal administration of therapeutic doses of triamcinolone acetonide to patients with inflamed nasal mucosa does not result in enhanced systemic drug absorption or

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1994.tb02051.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY