Withdrawal Interval Research Articles

Multivariate meta-analysis of pharmacokinetic studies of ampicillin trihydrate in cattle

To investigate the feasibility of using multivariate cluster analysis to meta-analyze pharmacokinetic data obtained from studies of pharmacokinetics of ampicillin trihydrate in cattle and identify factors that could account for variability in pharmacokinetic parameters among studies. Data from original studies of the pharmacokinetics of ampicillin trihydrate in cattle in the database of the Food Animal Residue Avoidance Databank. Mean plasma or serum ampicillin concentration versus time data and potential factors that may have affected the pharmacokinetics of ampicillin trihydrate were obtained from each study. Noncompartmental pharmacokinetic analyses were performed, and values of pharmacokinetic parameters were clustered by use of multivariate cluster analysis. Practical importance of the clusters was evaluated by comparing the frequency of factors that may have affected the pharmacokinetics of ampicillin trihydrate among clusters. A single cluster with lower mean values for clearance and volume of distribution of ampicillin trihydrate administered PO, compared with other clusters, was identified. This cluster included studies that used preruminant calves in which feeding was withheld overnight and calves to which probenecid had been administered concurrently. Meta-analysis was successful in detecting a potential subpopulation of cattle for which factors that explained differences in pharmacokinetic parameters could be identified. Accurate estimates of pharmacokinetic parameters are important for the calculation of dosages and extended withdrawal intervals after extralabel drug administration.

A web-based decision support system to estimate extended withdrawal intervals

All drugs approved for use in food-producing animals have a withdrawal interval to prevent residues in food of animal origin that are potentially harmful to consumers. These withdrawal times must be appropriately extended if the drug is used in an extralabel manner. This paper describes a web-based application that was developed to facilitate the calculation of extended withdrawal intervals based on information in the databases maintained by members of the Food Animal Residue Avoidance Databank (FARAD) and using the Extrapolated Withdrawal Interval Estimator (EWE) algorithm. The implementation of this application was illustrated using a group of antimicrobials that are used in cattle and swine. The use of this application has been limited to staff veterinarians working for FARAD since limitations in the available pharmacokinetic data require that results are interpreted by personnel with in-depth knowledge of the pharmacokinetics of drugs in food-producing animals.

Feasibility of Using Half-Life Multipliers To Estimate Extended Withdrawal Intervals following the Extralabel Use of Drugs in Food-Producing Animals

Under the Animal Medicinal Drug Use Clarification Act of 1994, veterinarians are legally allowed to use drugs in food-producing animals in an extralabel manner. This could potentially lead to violative residues in food of animal origin. It is therefore essential that an appropriately extended withdrawal interval be established. Ideally, these extended withdrawal intervals should be calculated on the basis of the tissue half-life of the drug in the target animal. However, these data are not readily available for all drugs of extralabel use in food-producing animals. For this reason, the use of a half-life multiplier has been proposed as a simple alternative method to estimate the effective tissue half-life of a drug. Extended withdrawal intervals, estimated using various half-life multipliers, were compared with the withdrawal intervals calculated using actual tissue half-lives. For the group of drugs investigated, a half-life multiplier of 5 resulted in estimates of extended withdrawal intervals that were potentially inadequate to prevent violative tissue residues for drugs that had relatively long tissue half-lives, high tolerances, or both. This is possibly because fewer half-lives are required for these drugs to reach the target tissue concentrations following administration at label doses. Use of a smaller half-life multiplier (in this case 3) is therefore suggested to ensure that extended withdrawal intervals are adequate to prevent violative tissue residues.

Three-week thyroxine withdrawal thyroglobulin stimulation screening test to detect low-risk residual/recurrent well-differentiated thyroid carcinoma.

Measurement of serum TSH-stimulated thyroglobulin (Tg) is recognized as a sensitive method for detecting residual/recurrent well-differentiated thyroid carcinoma (WDTC) in patients previously treated by surgery and radioactive iodine (RAI) ablation therapy. WDTC patients who have an undetectable serum Tg on thyroid hormone therapy (THT) in the absence of Tg-antibody interference are considered to be at low risk for residual/recurrent disease. Traditional management has been to withdraw T4 for 4-6 weeks or T3 for 2 weeks to stimulate endogenous TSH. However, this prolonged THT withdrawal induces hypothyroidism and its concomitant morbidity. In the present study, we assess the efficacy of shortening the time of T4 withdrawal to only 3 weeks for detecting residual/recurrent WDTC as a sufficient serum TSH stimulus for obtaining a positive serum Tg result without a routine diagnostic whole body scan (WBS). Additionally, we have evaluated the impact of such a T4 withdrawal interval on quality of life and loss of employment time. A total of 181 patients with WDTC selected for study had previously been treated with a bilateral surgical thyroidectomy followed by RAI ablation therapy (average post-surgery to follow-up interval of 10.8 yr). All of the cohort had an undetectable (< 1 microg/l) serum Tg on THT without Tg-antibody interference. Serum TSH and Tg were measured before and after cessation of T4 therapy for 3 weeks. A serum Tg > or = 2 microg/l was considered positive for residual/recurrent disease. A quality of life questionnaire [Short-Form 36 (SF-36)] was administered before withdrawal, at peak TSH and after resumption of therapy. From the completed SF-36 questionnaires, the overall degree of functional impairment was not severe and did not result in loss of employment time. Moreover, this protocol identified three possible responses to the 3-week T4 withdrawal interval as follows: a) serum Tg undetectable with TSH > or = 25 mIU/l (approximately 75% of total cohort); b) serum Tg > or = 2 microg/l (approximately 10% of total cohort) which will require further investigation and treatment for residual/recurrent disease; c) undetectable serum Tg with inadequate TSH rise (approximately 15% of total cohort), which will require TSH stimulation by either longer T4 withdrawal or recombinant human TSH to exclude residual disease. We conclude that a stimulated serum Tg test performed 3 weeks after T4 withdrawal is a simple and cost-effective first-line screening test with minimal morbidity which is sufficient to evaluate low-risk WDTC patients for recurrent/residual carcinoma.

Extrapolated Withdrawal-Interval Estimator (EWE) Algorithm: A Quantitative Approach to Establishing Extralabel Withdrawal Times

The extralabel use of drugs can be defined as the use of drugs in a manner inconsistent with their FDA-approved labeling. The passage of the Animal Medicinal Drug Use Clarification Act (AMDUCA) in 1994 and its implementation by the FDA—Center for Veterinary Medicine in 1996 has allowed food animal veterinarians to use drugs legally in an extralabel manner, as long as an appropriate withdrawal period is established. The present study introduces and validates with simulated and experimental data the Extrapolated Withdrawal-Period Estimator (EWE) Algorithm, a procedure aimed at predicting extralabel withdrawal intervals (WDIs) based on the label and pharmacokinetic literature data contained in the Food Animal Residue Avoidance Databank (FARAD). This is the initial and first attempt at consistently obtaining WDI estimates that encompass a reasonable degree of statistical soundness. Data on the determination of withdrawal times after the extralabel use of the antibiotic oxytetracycline were obtained both with simulated disposition data and from the literature. A withdrawal interval was computed using the EWE Algorithm for an extralabel dose of 25 mg/kg (simulation study) and for a dose of 40 mg/kg (literature data). These estimates were compared with the withdrawal times computed with the simulated data and with the literature data, respectively. The EWE estimates of WDP for a simulated extralabel dose of 25 mg/kg was 39 days. The withdrawal time (WDT) obtained for this dose on a tissue depletion study was 39 days. The EWE estimate of WDP for an extralabel intramuscular dose of 40 mg/kg in cattle, based on the kinetic data contained in the FARAD database, was 48 days. The withdrawal time experimentally obtained for similar use of this drug was 49 days. The EWE Algorithm can obtain WDI estimates that encompass the same degree of statistical soundness as the WDT estimates, provided that the assumptions of the approved dosage regimen hold for the extralabel dosage regimen. Population models could be fitted to fragmentary data to predict residue concentrations in tissues, validate the EWE estimates, and obtain WDI estimates.

Striatal dopamine sensitization to d-amphetamine in periadolescent but not in adult rats

The neurobiological and behavioral facets of adolescence have been poorly investigated in relation to the vulnerability to psychostimulants. Periadolescent (33–43 days) and adult (>70 days) Sprague–Dawley rats underwent a 3-day treatment history with d-amphetamine (AMPH) at 0, 2, or 10 mg/kg (once a day). After a short 5-day-long withdrawal interval, freely moving animals were challenged with a 2-mg/kg AMPH dose and their behavior as well as in vivo intrastriatum dopamine (DA) release in the CNS were assessed. Microdialysis data indicated that AMPH-history periadolescent rats showed a prominent sensitization of AMPH-stimulated DA release, whereas no such change was found in adult subjects. As expected, acute AMPH administration strongly reduced time spent lying still and increased levels of cage exploration in animals of both ages. A treatment history of high AMPH dosage was associated with a marked sensitization of the exploratory behavior in adults, whereas it induced a quite opposite profile in periadolescents. The latter group only was also characterized by a compulsive involvement in the stereotyped head-bobbing response. These results indicate that differently from adults, marked alterations in neurobiological target mechanisms are observed in rats around periadolescence as a consequence of a quite mild regimen of intermittent AMPH exposure. Thus, a neurobiological substrate for an age-related increased vulnerability towards the addictive risks of these drugs is suggested.

Commentary

Penicillin G is a widely used antimicrobial in food-producing animals, and one of the most predominant drug residues in animal-derived food products. Due to reduced sensitivity of bacteria to penicillin, extralabel use of penicillin G is common, which may lead to violative residues in edible tissues and cause adverse reactions in consumers. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict drug residues in edible tissues and estimate extended withdrawal intervals for penicillin G in swine and cattle. A flow-limited PBPK model was developed with data from Food Animal Residue Avoidance Databank using Berkeley Madonna. The model predicted observed drug concentrations in edible tissues, including liver, muscle, and kidney for penicillin G both in swine and cattle well, including data not used in model calibration. For extralabel use (5× and 10× label dose) of penicillin G, Monte Carlo sampling technique was applied to predict times needed for tissue concentrations to fall below established tolerances for the 99th percentile of the population. This model provides a useful tool to predict tissue residues of penicillin G in swine and cattle to aid food safety assessment, and also provide a framework for extrapolation to other food animal species.

The optimal operation planning of a Kanban system with variable lead times

Abstract In the majority of the previous research on Kanban systems delivery lead time is treated as a fixed value. In many practical situations, however, the lead time is variable. In this paper, optimal operation planning of a fixed interval withdrawal Kanban with variable lead times is proposed. A cost is incurred for inventory level less than the safety inventory level, since the risk of shortage of inventory must be considered. Behaviour of the optimal number of Kanbans and the withdrawal interval of Kanbans are investigated in terms of various parameters such as standard deviation and mean lead time.

Cocaine use increases [ 3HWIN 35428 binding sites in human striatum

Animal studies suggest that chronic cocaine exposure may increase the function and/or synthesis of the dopamine transporter (DAT) under certain conditions, but the literature is complex. In order to test the hypothesis that cocaine exposure alters the DAT in humans, preliminary studies were done characterizing [ 3HWIN 35428 binding in human striatum from normal controls. Following these experiments, the effects of chronic cocaine were examined in post mortem striatal specimens from 7 cocaine users and 7 controls matched for age and post mortem interval, employing quantitative autoradiography. Initial saturation experiments indicated that a one-site model was preferred with a K d of11±4nM. [ 3HWIN 35420 binding was then examined in cocaine users and controls at 0.5, 5, 10, and 50 nM radioligand concentrations. At each concentration of [ 3HWIN 35420, optical densities for cocaine-exposed subjects were increased in caudate, putamen, and accumbens. The results suggest that total numbers of binding sites were increased in cocaine users. Based on the present and previous results, it appears that the regulation of the DAT is fairly plastic, and is highly sensitive to cocaine dosing regimes and withdrawal intervals. Chronic adaptations induced by cocaine in the DAT could contribute to the symptoms of binging, withdrawal depression, and/or craving.

Repeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens

Behavioral and brain regional dopamine responses to cocaine (10 mg/kg) were concurrently monitored using in vivo microdialysis in freely-moving rats pretreated with 4 daily injections of saline or cocaine (10 mg/kg). Repeated cocaine produced a behavioral sensitization characterized by a downward oriented locomotor activation profile. In contrast, both caudate and nucleus accumbens dopamine responses were significantly diminished in the drug-pretreated group. These results, obtained following two days of drug withdrawal, differ from previous reports of an enhanced dopamine response after longer withdrawal intervals. While the duration of withdrawal may play an important role in the quantitative features of the dopamine response to subsequent stimulant administration, these results suggest that an enhanced dopamine response may not be required for the expression of behavioral sensitization. A compensatory increase in the dopamine uptake carrier, resulting from chronic cocaine-induced uptake blockade, is discussed as a possible mechanism underlying the reduced dopamine response.

Occurrence of the alcoholic tolerance phenomenon and its relation to the daily frequency of ethanol doses and with the presence of a withdrawal interval, in an experimental model of alcoholism in rats

In this paper we present the effects of the number of daily toxic doses of alcohol and of the duration of withdrawal period on alcohol tolerance in rats submitted to cycles of 21 doses each. It was observed that alcohol tolerance was increased in animals which received less number of alcohol doses by day and that some degree of tolerance can be detected even after a withdrawal interval of 15 days.

Lack of tolerance or withdrawal effects in mice after chronic administration of the non-sedating anxiolytic, CGS 9896

CGS 9896, a non-sedating anxiolytic, was compared to diazepam with respect to the development of tolerance and withdrawal. Both compounds were administered daily to mice at various doses (3, 10 or 30 mg/kg) for periods of up to 4 weeks. Measures of sedation/muscle relaxation, motor activity and anticonvulsant effects were then assessed. When administered acutely, CGS 9896 increased motor activity, had no effect on traction reflex, and elevated the threshold for PTZ-induced convulsions. After chronic administration of CGS 9896, no changes in these paraneters were observed compared to the effects seen after acute treatment. Acute administration of diazepam reduced motor activity, impaired traction reflex and increased PTZ-induced convulsion threshold. Tolerance developed to the effects of diazepam in all three measures. Following a four week dosing period with 30 mg/kg of either CGS 9896 or diazepam, the drugs were withdrawn and similar behavioral measures obtained at various withdrawal intervals up to 15 days. In separate groups of mice, precipitated withdrawal was also assessed by the administration of the benzodiazepine inverse agonist, CGS 8216. No effects were observed after any period of withdrawal from CGS 9896. By contrast, withdrawal from diazepam resulted in significant alterations of motor activity and convulsion threshold. These results indicate that CGS 9896 is likely to be free of underirable tolerance and withdrawal effects typically associated with the benzodiazepines.

Delayed emergence of antidepressant efficacy following withdrawal in olfactory bulbectomized rats

Repeated antidepressant treatment attenuates the step-down passive avoidance deficit which is induced by olfactory bulbectomy in rats. Using a shuttlebox passive avoidance procedure, the effects of antidepressants were investigated after various drug withdrawal intervals. Imipramine, amitriptyline, doxepin, bupropion and mianserin were effective at 48 and usually 72 hours after withdrawal, but no significant attenuation of the deficit was seen 4 hours after withdrawal from any antidepressant tested. At least 4 to 7 days of imipramine treatment were required for efficacy. A high dose of d-amphetamine (5 mg/kg) produced similar results while tranylcypromine and haloperidol were inactive at all withdrawal intervals tested. The olfactory bulbectomy syndrome may reflect functional derotonin deficiency, which would be ameliorated through antidepressant-induced alterations in serotonin receptor sensitivity.

Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 6. A comparison of pindolol and propranolol in treatment of patients with angina pectoris. The role of intrinsic sympathomimetic activity

Pindolol, a new beta-adrenergic blocking drug with intrinsic sympathomimetic activity, and propranolol were given in increasing equipotent doses (pindolol: 2.5 to 10 mg. every 6 hours; propranolol: 10 to 40 mg. every 6 hours) over 12 weeks in a double-blind randomized trial to 41 patients with angina pectoris. The drugs were then gradually withdrawn over a two week period. With maximum doses, both pindolol and propranolol increased exercise capacity, compared to control, on multistage treadmill testing (pindolol: 8.0 ± 0.4 to 9.7 ± 0.3 mets, p < 0.01; propranolol: 8.0 ± 0.4 to 9.6 ± 0.3 mets, p < 0.05). At each exercise level both pindolol and propranolol decreased the heart rate, systolic blood pressure, and rate-pressure product (HR × BP). At the 9 met exercise level, the HR × BP decreased from 17,420 ± 850 to 13,205 ± 510 mm. Hg min.−1 with pindolol (p < 0.002); with propranolol; 18,106 ± 440 to 13,205 ± 480 mm. Hg min.−1 (p < 0.01). At the same level the magnitude of exercise-induced ECG ST depression decreased from 1.3 ± 0.3 to 0.4 ± 0.15 mm. with pindolol (p < 0.05), and from 1.3 ± 0.3 to 0.8 ± 0.2 mm. with propranolol (p < 0.05). Both drugs reduced the number of spontaneous attacks of angina pectoris per week. Pindolol did not appreciably decrease the resting heart rate (66.8 ± 1.9 vs 64.6 ± 1.2) or HR × BP (8,254 ± 418 vs 7,651 ± 210 mm. Hg min.−1 in contrast to propranolol, which reduced both (heart rate: 70.5 ± 2.2 to 62.2 ± 2.4, p < 0.01; HR × BP: 8,677 ± 423 to 7,338 ± 455 mm. Hg min.−1, p < 0.005). In addition, pindolol slightly increased the echocardiographically estimated ejection fraction at rest (0.59 ± 0.02 to 0.62 ± 0.02, p < 0.02), while propranolol depressed it (0.57 ± 0.02 to 0.51 ± 0.01, p < 0.04). Both pindolol and propranolol could be safely withdrawn over a gradual two week withdrawal interval.

Use of Two-Dimensional Methods for Calculating Well Coning Behavior

Abstract A published calculation method for predicting incompressible, multidimensional fluid displacement has been adapted to the problems of water and gas coning in oil wells. Since depth and radial distance from the wellbore are the two key dimensions affecting the shape of a gas or water cone, coning calculations are well suited to the use of two-dimensional methods. The alternating direction implicit procedure (ADIP) was used for relaxation calculations of two-phase potentials in a two-dimensional grid. From the potentials and the capillary pressure relationship, saturation and pressure distributions were calculated which trace cone growth with time. Predictions have been made for well producing histories both before and after core breakthrough. To check validity of the method, two-dimensional calculations have matched the coning behavior and produced water-oil ratio history of a laboratory sand-packed model. They have also matched the coning behavior of several producing wells, for which the calculations were compared with produced water or gas cuts and logs showing water or gas cone movements. Introduction The application of two-phase, two-dimensional calculations using ADIP to various reservoir flow problems has been described in the literature. When adapted for computer solution, this method has proved to be a powerful tool for simulating well and reservoir behavior. This paper discusses the method as applied to well coning calculations. Single-well and coning calculations comprise an especially difficult class of two-dimensional problems which require special techniques for computer calculation and determination of reservoir characteristics. Refs. 4 through 8 describe previous approaches to the coning problem. Several examples of water and gas coning calculations, including studies on both laboratory models and producing wells, are presented here. The two-dimensional method accounts realistically for the most critical parameters affecting coning behavior, including production rate, formation stratification, horizontal and vertical permeabilities, depth of well penetration, gravity and capillary forces. The method considers the different densities and viscosities of the two phases and the relative permeability and capillary pressure characteristics of the rock and fluids. In addition to tracing cone growth in the vicinity of the wellbore, the method calculates the overall movement of the fluid interface throughout the well's drainage volume. Incompressible fluid flow is assumed to occur between the producing interval and the well' s limit of drainage. Calculations can be made for the producing history both before and after cone breakthroughA typical two-dimensional grid or array of blocks used to solve a coning problem contains about 400 blocks. The well's cylindrical drainage volume can be represented by about 20 radial subdivisions and the formation thickness by 20 vertical subdivisions. The grid spacing is normally smaller near the withdrawal interval to define the cone shape accurately. For this work we used an IBM 7074 digital computer having a core memory of 10,000 ten-digit words. A typical study, covering 5 to 10 years of well producing history, required from three to six hours of computing time. MATHEMATICAL SIMULATION OF CONING BEHAVIOR BASIC METHOD In coning calculations, the reservoir volume drained by the producing well is represented by a two-dimensional system of blocks as shown in Fig. 1 for water coning studies. The horizontal dimensions of the blocks increase with radial distance from the well axis in geometric progression, i.e., the block size is small near the wellbore and large near the well's drainage radius (re). SPEJ P. 345ˆ