Plasma timolol levels and systolic time intervals

Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.39). 07/1980; 28(2):159-166. DOI: 10.1038/clpt.1980.145

ABSTRACT The -blocking potency of timolol was compared with that of propranolol under steady-state conditions in eight healthy subjects. The effects on systolic time intervals in healthy subjects and patients (n = 6) with coronary artery disease were evaluated in relation to varying timolol dose schedules and plasma concentrations. The -blocking potency was assessed by the inhibition of exercise-induced tachycardia. Timolol was eight times as potent as propranolol. There was wide between-patient variation (2.6 to 13.8) in timolol plasma concentration, and correlation between dose and peak (r = 0.61, p < 0.01) or nadir (r = 0.5, p < 0.01). There was a relatively weak correlation between timolol plasma concentration and degree of -blockade (r = 0.45, p < 0.05) and a linear correlation with dose (r = 0.98, p < 0.001). In healthy subjects timolol and propranolol had variable effects on systolic time intervals but in patients with coronary artery disease equipotent doses prolonged the preejection period, isovolumetric contraction time, and the ratio of the preejection period over the left ventricular ejection time. In patients as well as in normal subjects, the data indicated considerable -blocking effects for both drugs at the end of a 12-hourly dosing schedule, suggesting that twice-daily timolol and propranolol may be clinically practical.

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    ABSTRACT: Therapeutic options for superficial infantile hemangiomas (IH) are limited. Recently, timolol maleate gel, a topical nonselective beta-blocker, has been reported as a potentially effective treatment for superficial IH. This study is an extension of a previously published pilot study designed to further investigate the efficacy and safety and to identify predictors of good response of topical 0.5% or 0.1% timolol maleate gel-forming solution. This was a retrospective cohort study including patients enrolled from five centers. Patients were included if they were treated with timolol maleate 0.1% or 0.5% gel-forming solution and had photographic documentation of the IH and at least one follow-up visit. Patients with concomitant active treatment using other IH treatments were excluded. The primary endpoint was change in the appearance of IH as evaluated using a visual analog scale (VAS). Data from 73 subjects were available for final analysis. Timolol maleate gel-forming solution 0.5% was used in 85% (62/73) of patients, the remainder being treated with 0.1%. The median age at treatment initiation was 4.27 months (interquartile range [IQR] 2.63-7.21 mos), and patients were treated for a mean of 3.4 ± 2.7 months. All patients except one improved, with a mean improvement of 45 ± 29.5%. Predictors of better response were superficial type of hemangioma (p = 0.01), 0.5% timolol concentration (p = 0.01), and duration of use longer than 3 months (p = 0.04). Sleeping disturbance was noted in one patient. This study further demonstrates the efficacy and tolerability of topical timolol maleate and gradual improvement with longer treatment in patients with superficial IH.
    Pediatric Dermatology 12/2011; 29(1):28-31. DOI:10.1111/j.1525-1470.2011.01664.x · 1.52 Impact Factor
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    ABSTRACT: It is a major goal of clinical pharmacology to understand the dose-effect relationship in therapeutics. Much progress towards this goal has been made in the last 2 decades through the development of pharmacokinetics as a discipline. The study of pharmacokinetics seeks to explain the time course of drug concentration in the body. Recognition of the crucial concepts of clearance and volume of distribution has provided an important link to the physiological determinants of drug disposition. Mathematical models of absorption, distribution, metabolism and elimination have been extensively applied, and generally their predictions agree remarkably well with actual observations. However, the time course of drug concentration cannot in itself predict the time course or magnitude of drug effect. When drug concentrations at the effect site have reached equilibrium and the response is constant, the concentration-effect relationship is known as pharmacodynamics. Mathematical models of pharmacodynamics have been used widely by pharmacologists to describe drug effects on isolated tissues. The crucial concepts of pharmacodynamics are potency — reflecting the sensitivity of the organ or tissue to a drug, and efficacy — describing the maximum response. These concepts have been embodied in a simple mathematical expression, the Emax model, which provides a practical tool for predicting drug response analogous to the compartmental model in pharmacokinetics for predicting drug concentration. The application of pharmacodynamics to the study of drug action in vivo requires the linking of pharmacokinetics and pharmacodynamics to predict firstly the dose-concentration, and then the concentration-effect relationship. This may be done directly by equating the concentration predicted by a pharmacokinetic model to the effect site concentration, but this simplistic approach is often not appropriate for various reasons, including delay in drug equilibrium with the receptor site, use of indirect measures of drug action, the presence of active metabolites, or homeostatic responses, thus often necessitating the use of more complex models. The relative pharmacodynamic bioavailability of different preparations of the same drug may be determined from the time course of a drug effect. Bioavailability determined in this way may differ markedly from bioavailability defined by measurements of drug concentration if active metabolites are formed or if effects are produced in the non-linear region of the concentration-effect relationship. The influence of changes in the extent of plasma protein binding may be important in the interpretation of drug concentration measurements since it is generally held that only the unbound fraction is pharmacologically active. Clear examples of this phenomenon are few, but this reflects the general paucity of adequate observations rather than casting doubt on the usual assumption. The design of rational dosing regimens for clinical therapeutics cannot be performed with a knowledge of pharmacokinelics alone. The time course of drug effect may be essentially independent of concentration when a dose produces near maximal effects throughout the dosing interval. If effects are between 20 and 80% of maximum, the response will decrease linearly even though concentrations are declining exponentially. Finally, at relatively small degrees of effect, the time course of drug effect and concentration will be in parallel. The usual ‘rule of thumb’ of dosing every half-life is a conservative strategy for limiting wide fluctuations in drug effect, but demands more from the patient in terms of dosing frequency than may be necessary to achieve consistent drug action. On the other hand, if therapeutic success is dependent more on cumulative response than moment to moment activity, the use of extended dosing intervals may markedly reduce the effectiveness of the same average dose. Considerations of these factors can be incorporated into a dosing scheme by combined application of the principles of pharmacokinelics and pharmacodynamics.
    Clinical Pharmacokinetics 12/1981; 6(6). DOI:10.2165/00003088-198106060-00002 · 5.49 Impact Factor
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    ABSTRACT:   Propranolol has become the treatment of choice of large and complicated infantile hemangiomas. There is a controversy concerning the safety of systemic propranolol. Here we show that topical use of the beta-blocker timolol can also inhibit the growth and promote regression of infantile hemangiomas. In this case series we treated 11 infantile hemangiomas in nine children including six preterm babies with the nonselective betablocker timolol. A timolol containing gel was manufactured from an ophthalmic formulation of timolol 0.5% eyedrops. This gel was applied using a standardized occlusive dressing (Finn-Chambers) containing approximately 0.25 mg of timolol. In all infants topical timolol was associated with growth arrest, a reduction in redness and thickness within the first 2 weeks. Seven hemangiomas showed almost complete resolution, and four became much paler and thinner. No data are available on the transdermal absorption of timolol. Even supposing complete absorption of timolol from the occlusive dressing, a maximum dose of 0.25 mg of timolol would result per day and hemangioma. Regression of infantile hemangiomas treated using 0.5% timolol gel in this case series occurred earlier than spontaneous regression which is generally not observed before the age of 9-12 months. The promising results need to be verified in prospective randomized trials on topical beta blocker administration for infantile hemangiomas which should address dose, duration, and mode of application.
    Pediatric Dermatology 04/2012; 30(2). DOI:10.1111/j.1525-1470.2012.01723.x · 1.52 Impact Factor