Duration Of Pharmacological Effect Research Articles

Detection and pharmacokinetics of salmeterol in thoroughbred horses following inhaled administration.

Salmeterol is a man-made beta-2-adrenergic receptor agonist used to relieve bronchospasm associated with inflammatory airway disease in horses. Whilst judicious use is appropriate in horses in training, they cannot race with clinically effective concentrations of medications under the British Horseracing Authority's Rules of Racing. Salmeterol must therefore be withdrawn prior to race day and pharmacokinetic (PK) studies used to establish formal detection time advice. Salmeterol xinafoate (Serevent Evohaler® ) was administered (0.1mg twice daily for 4.5days) via inhalation to six horses. Urine and blood samples were taken up to 103h postadministration. Hydrolysed samples were extracted using solid phase extraction. A sensitive Ultra high performance tandem mass spectrometry (UPLC-MS/MS) method was developed, with a Lower limit of quantification (LLOQ) for salmeterol of 10pg/mL in both matrices. The majority of salmeterol plasma concentrations, postlast administration, were below the method LLOQ and so unusable for PK analysis. Urine PK analysis suggested a half-life consistent with duration of pharmacological effect. Average estimated urine concentration at steady-state was obtained via PK modelling and used to estimate a urine concentration of 59±34pg/mL as a marker of effective lung concentration. From this, potential detection times were calculated using a range of safety factors.

Affinity of a Drug for and Residence Time at its Target

A major problem in drug designing and development is the difficulty in predicting efficacy in humans from in vitro data. For a long time, it was thought that an important contributor to the efficacy of a drug is its affinity for the target. This traditional view was challenged by accumulative evidence suggesting that thermodynamic equilibrium constants, such as Kd or Ki, in most cases do not reflect potency in vivo. A new concept was, therefore, introduced in 2006; the drug-residence time (tR) concept [1]. This has arisen from the fact that a drug can elicit its action as long as it remains bound to its target. The drug-residence time, which is the reciprocal of the rate constant for dissociation of the binary drug-target complex (koff), was suggested as an alternative perspective on drug optimization, with superior predictability for the duration of pharmacological effect and target selectivity. Nevertheless, recent studies revealed that long tR has predictability value only when koff is slower than the elimination rate of the drug from the target vicinity [2]. Therefore, pharmacokinetics as well as other factors, such as selectivity of targeting, biodynamics of the target, and endogenous ligands and signaling should be taken into account.

The use of lipid microtubes as a novel slow‐release delivery system for laryngeal injection

The potential utility of direct injection of bioactive substances in the treatment of vocal fold tissue fibrosis is limited by rapid clearance from the injection site. The objective of this study is to evaluate the potential of a lipid-based microtube delivery system to preserve the biological activity of injected substances and prolong their duration of pharmacological effects in the larynx. Prospective in vitro and case-control in vivo murine study Lipid-based microtubes were loaded with Texas red-dextran (MT-TR) and hepatocyte growth factor (MT-HGF). In vitro and in vivo (using a murine vocal fold injection model) release of MT-TR and MT-HGF were determined to assess duration of microtube-mediated delivery. The biologic effects of MT-HGF on fibroblasts were assessed after treatment in the presence of transforming growth factor (TGF)-β. In vitro release kinetics demonstrated slow release of MT-TR and MT-HGF, correlating with in vivo results demonstrating persistence of MT-HGF at 4 weeks postinjection. Bioefficacy was maintained, as MT-HGF was shown to inhibit TGF-β-mediated induction of procollagen mRNA levels in vitro 24 hours after treatment in fibroblast cells. Sustained release of HGF from microtubes at 6 days exacerbated the effects of TGF-β and increased levels of procollagen mRNA. Microtubes have significant potential utility as an efficacious means of sustained-release delivery of bioactive agents to the larynx. Atthough the role of HGF as an antifibrotic agent is questioned, its sustained bioefficacy after microtube encapsulation distinguishes microtubes from other delivery vehicles.

Quantitative Aspects of Intracellularly-Targeted Drug Delivery

Many pharmacological agents act intracellularly, need to be endocytosed, and reach the site of action in specific organelle to exert their action. The cell’s interior is highly compartmentalized, and complexity of the cellular endocytosis and trafficking pathways (1,2) leads to suboptimal magnitude and duration of pharmacological effects at the organelle of interest, as well as to non-specific effects due to exposure of additional organelles to the drug. Thus, attaining efficient and selective pharmacological effects for intracellularly acting drugs requires development of specialized drug delivery systems (DDS) that should be targeted to specific organelle and deliver the drug in a controlled fashion (3,4). For this purpose, particle or vesicle (liposome)-basedDDS can be used, and intracellular targeting can be achieved by decorating the drug or the DDS with organelle-specific targeting moieties. This approach relies on recognition of these moieties by the endogenous intracellular trafficking mechanisms andpreferential delivery of the drug or theDDS into specific organelle (3,4). Feasibility of targeted delivery of drugs and model compounds into individual organelles has been assessed in several studies (summarized in Table I). However, the quantitative aspects of this targeting, in terms of targeting efficiency and kinetics of drug delivery to the specific intracellular organelles, are not yet clear and should be intensively studied in order to pave the way to the clinical application of the intracellularly targeted DDSs. This commentary analyzes the existing approaches for intracellular drug targeting, their efficiency and limitations. For an introduction to intracellular drug delivery, the reader is referred to several excellent recent reviews (3,5). Delivery of DNA and RNA molecules is not in the scope of this commentary and will be mentioned only briefly.

Accumulation of Antibody-Target Complexes and the Pharmacodynamics of Clotting after Single Intravenous Administration of Humanized Anti-Factor IX Monoclonal Antibody to Rats

SB-249417, a humanized monoclonal antibody (Mab) specific for the Gla domain of Factor IX, inhibits activation of this zymogen and blocks the activity of Factor IXa on Factor X, the subsequent enzyme in the clotting cascade. In the present study, the pharmacokinetics and pharmacodynamics of SB-249417 were investigated in male Sprague-Dawley rats after IV administration of single doses of 10, 50, or 250 mg/kg. Blood samples were collected for up to six weeks to assess total plasma Mab concentration and activated partial thromboplastin time (aPTT). A PK/PD model was developed using an empirical relationship between aPTT and the concentration of free Factor IX (inhibitory Emax model). The model assumed natural synthesis and degradation of the endogenous zymogen that was interrupted by the complexation of Factor IX with the antibody. Following antibody administration, aPTT values increased 5-fold above baseline at the earliest sampling time in all dose groups. Higher doses led to a longer duration of prolonged clotting time. Estimates of model parameters yielded a Kd for antibody-antigen interaction (38 nM) that was similar to the in vitro value. The estimated degradation half-life of Factor IX (8 hr) was consistent with historical estimates. The PK/PD model predicted that the maximum concentration of antibody-Factor IX complex (Cmax) and the time to Cmax (Tmax) would increase with increasing dose. The extent of accumulation, up to 10-fold greater than the concentration of endogenous Factor IX at baseline, was confirmed by Western Blot analysis of Protein A extracts. Complex Tmax was similar to the duration of pharmacological effect and suggests effects persisted until Factor IX synthesis produced sufficient antigen to saturate the antibody.

Pharmacokinetic assessment of the effect of age on the disposition and pharmacologic activity of drugs.

Aging is associated with a number of physiologic changes. These include decreases in plasma albumin concentration, lean body mass and total body water, cardiac output, renal function (glomerular filtration and renal tubular secretion), and activity of drug metabolizing enzyme systems (reviewed in refs. 1–3). Superimposed upon these age-related changes, and difficult if not impossible to distinguish from these in a clinical setting, are the cumulative effects of environment (including smoking, medications, and diet) and disease. It is not surprising, therefore, that there is evidence suggesting age-dependent changes in the absorption, distribution, metabolism, and excretion of drugs. Such changes may be expected to result in corresponding modifications in the intensity and duration of pharmacologic effects but age may also affect the intrinsic response of receptor sites to drugs. Since the pertinent literature on pharmacokinetics related to advanced age has been reviewed thoroughly in several recent publications (1–3), the purpose of this presentation will be to focus on the pharmacokinetic principles that must be considered in the design, analysis, and interpretation of studies of the effect of age on the disposition and pharmacologic activity of drugs.

The pharmacological action and O-demethylation of glyceryl guaiacolate ether in male and female rats

The duration of pharmacologic effects and the plasma half-life of glyceryl guaiacolate ether (GGE) were shorter in adult male than in adult female rats. The sex-dependent variation resulted from a high activity of O-demethylase in male rats and a low activity in female rats. The kinetic data obtained on O-demethylase from liver microsomes of both male and female rats indicated that the Michaelis constants for the two sexes were similar. This, coupled with a greater maximal velocity value observed for the oxidation of GGE by O-demethylase of male rats, suggested a quantitative rather than a qualitative difference between the O-demethylase of male and female rats.

Estimation of methotrimeprazine in brain and correlation of brain levels with pharmacologic activity

A method for estimating methotrimeprazine in brain by ultraviolet spectrophotometry was developed which is based on extracting the compound from alkalinized tissue with 1 per cent butanol in cyclohexane and determining its absorbance in acid at 250 m μ . A high degree of specificity for methotrimeprazine was conveyed to the procedure by subjecting the organic solvent extract of tissue to several buffer washes. Following intravenous injection of the compound in mice, methotrimeprazine was found to be metabolized rapidly during the first hour, after which its rate of disappearance slowed considerably. Brain levels were maximal at 1 hr. and were still appreciable at 4 hr. The onset and duration of pharmacologic effects as measured by a loss in coordinated motor ability varied directly with the concentration of drug in the brain, suggesting that the parent compound is principally responsible for mediating the response.