摘要:

In order to achieve the greatest chance for maximum benefit from theophylline in the management of chronic asthma, the serum concentration should be maintained in the therapeutic range of 10 to 20 &mgr;g/ml. Conventional rapid release formulations produce excessive fluctuations in serum concentrations that can result in variability in clinical response between doses. In contrast, slow release formulations have the potential to achieve relatively constant serum concentrations with 12-hour dosing intervals, thus providing around-the-clock stabilisation of the hyper-reactive airways that characterise chronic asthma. Furthermore, the decreased frequency of dosing with these formulations can improve patient compliance. However, significant differences in rate and extent of absorption exist between the available formulations. Single-dose bioavailability studies comparing a slow release product with an oral solution or plain uncoated tablet in a crossover design permit examination of the rate and extent of absorption. Comparison of a slow release product with an oral reference following multiple doses at steady-state permits examination of the extent but generally not rate of absorption.The mean fraction absorbed-time profile, calculated from a modification of the Wagner-Nelson equation, is a process-independent method of comparing rates of absorption of different products after single doses. A prospective study in 14 children with chronic asthma has demonstrated that this modified equation, when rearranged to iteratively solve for serum concentrations, can accurately predict steady-state serum concentrations for different dosing intervals in patient populations with different rates of elimination. When slow release products are compared in this manner at 8- or 12-hour dosing intervals for patients with slow elimination, clinically relevant differences between brands are not apparent. However, in patients with rapid elimination, i.e. children, cigarette smokers, and 25% of non-smoking adults, application of this method shows that only some formulations (i.e. ‘Slo-Bid Gyrocaps’ and ‘Theo-Dur’, which is also marketed under different brand names such as ‘Sustaire’, ‘Pulmi-Dur’ and ‘Theolin Retard’) can maintain serum concentrations within the therapeutic range for an entire 12-hour dosing interval. More rapidly absorbed slow release products must be administered at 8-hour dosing intervals in patients with rapid elimination, despite promotional claims to the contrary. Current products promoted for once-a-day administration are clinically inadequate because of incomplete and erratic absorption, and/or excessive serum concentration fluctuations. With one of these formulations, ‘Theo-24’ (also marketed under the name ‘Pulmo-Timelets’), there is evidence that food induces dose dumping of potentially toxic amounts of the drug.The primary goal for a slow release product should be to maintain a constant serum concentration which is a function of the rate of absorption (a product variable), the rate of elimination (a patient variable), and the dosing interval (a prescribing variable). The dose of all slow release theophylline products must be slowly titrated to age-specific mean weight-adjusted levels before serum concentrations are obtained to guide final dosage adjustment.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic activity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily characterised. Specific and sensitive high-pressure liquid chromatographic methods have become available only recently and this partly explains the scarcity of pharmacokinetic data on the drug.Available evidence suggests that absorption of amiodarone following oral administration is erratic and unpredictable; oral bioavailability ranges from 22 to 86%. The drug is eliminated largely by metabolism; less than 1% of the dose is excreted unchanged in the urine. Biliary excretion may have a role in the overall elimination of the drug. Desethylamiodarone is the only metabolite positively identified in the plasma of patients receiving treatment with amiodarone; no data are available on its possible pharmacological activity.Since it is a highly lipophilic drug, amiodarone is extensively distributed into tissues. Adipose tissue and skeletal muscle accumulate large amounts of the drug during long term treatment. Myocardium/plasma ratios of amiodarone are high both in man and in animals; peak concentrations in the myocardium are reached within half an hour after administration of an intravenous bolus to dogs. Placental transfer of amiodarone has been demonstrated in humans, while its blood profile is not modified by dialysis treatment.In vitroprotein binding of amiodarone has been reported to be 96.3 ± 0.6%.The plasma half-life of amiodarone after single-dose administration has been reported to be in the range of 3.2 to 79.7 hours. However, after withdrawal of long term amiodarone treatment the half-life is as long as 100 days. Total body clearance ranges from 0.10 to 0.77 L/min after single-dose intravenous administration, and the apparent volume of distribution ranges between 0.9 and 148 L/kg.Amiodarone disposition kinetics in patients with cardiac arrhythmias are not different from those in healthy volunteers. However, the possible effects of liver and cardiac failure on the drug's kinetics have not been studied.Amiodarone potentiates the anticoagulant effect of warfarin, probably by inhibition of its metabolism. Increases of steady-state concentrations of digoxin, together with the appearance of signs of digitalis toxicity, have been reported when amiodarone was given to patients receiving long term treatment with digoxin. Amiodarone has also been shown to interact with other antiarrhythmic agents such as quinidine and procainamide.The time of onset of action of amiodarone after a single intravenous dose ranges between 1 and 30 minutes and its duration of effect between 1 and 3 hours. During long term oral treatment, the therapeutic effect is observed after a delay of 2 to 21 days and can last more than 1 month after withdrawal of therapy. The time course of amiodarone electrophysiological effects after intravenous bolus administration to dogs follows its myocardial concentrations.The plasma steady-state concentration of amiodarone found to be effective in man ranges from 0.4 to 11.99 &mgr;g/ml; however, even if no therapeutic range has yet been defined, there is good agreement on keeping steady-state levels between 1.0 and 2.5 &mgr;g/ml in patients treated for arrhythmias.Clinically relevant extracardiac side effects have been reported, such as corneal deposits, thyroid dysfunction, peripheral neuropathy, pulmonary fibrosis and, less importantly, liver toxicity. Many of these side effects seem related to the dose and duration of amiodarone therapy, but information on their relationship to drug plasma concentrations is not available.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

Labetalol was the first of a new class of antihypertensive drugs with both &agr;- and &bgr;-adrenoceptor blocking properties present in the same molecule. Its efficacy has been confirmed by double-blind studies in the treatment of all grades of hypertension and in angina pectoris. The drug's major dose-related side effect is postural hypotension.The clinical formulation of labetalol consists of equal proportions of 4 optical isomers. One of these (the RR isomer) is probably responsible for the drug's &bgr;-adrenoceptor blockade and another (the SR isomer) produces most of the &agr;-blockade. Most of the presently available pharmacokinetic information concerning labetalol is from studies utilising a fluorimetric assay but this has recently been superceded by more specific high-pressure liquid chromatographic (HPLC) procedures.Labetalol is absorbed rapidly after oral administration with peak plasma concentrations generally being achieved within 2 hours. The bioavailability varies from 10% to over 80% in different subjects. Average bioavailability has been reported to correlate with age, with values of approximately 30% in the 30- to 40-year age group and approximately 65% at 80 years. There is also evidence that the bioavailability increases moderately when the drug is taken with food. About 50% of the drug is bound to protein in the plasma.The apparent volume of distribution at equilibrium varies from approximately 200 to over 800L, suggesting that concentration of labetalol occurs in extravascular sites. Radiochemical analysis in animals has shown high levels of accumulation in the lung, liver and kidney with little present in brain tissue. This is in keeping with the relatively low lipid solubility of labetalol.The half-life of labetalol in plasma is 3 to 3.5 hours. The drug is eliminated mainly by hepatic metabolism with the production of several biologically inactive glucuronides which in turn are excreted in the urine and bile. Approximately 85% of labetalol in the blood is removed during a single passage through the liver; thus, like propranolol, labetalol's clearance is probably flow dependent (i.e. it is sensitive to alterations in hepatic blood flow). Small doses of the drug (i.e. 300mg daily) have been shown to reduce antipyrine clearance by approximately 15%, and further studies are necessary to determine whether high doses produce a greater, possibly clinically significant, inhibition of mixed-function oxidase activity.After both single doses and during long term treatment the plasma concentration-time profile of labetalol shows marked variation between different individuals. A broad relationship exists between the plasma concentration and the fall in blood pressure, particularly in the upright position. However, individual sensitivity to the drug's hypotensive action also plays a major role in determining the response.There is only limited information available concerning the handling of labetalol in pregnancy and in disease states. In newborn infants, plasma labetalol concentrations are 30 to 50% of those of the mother and concentrations in breast milk have been reported to be 22 to 45% of the maternal plasma concentration. In chronic liver disease, bioavailability of the drug is reported to be doubled and plasma concentrations are substantially higher than in normal controls. In chronic renal disease the pharmacokinetic handling is reported to be virtually unaltered.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The pharmacokinetics of ampicillin and propylthiouracil were studied in 6 and 9 patients, respectively, before and several times up to a year after a shunt operation for extreme obesity. The drugs were given intravenously and orally making it possible to estimate the absolute bioavailability. The bioavailability of propylthiouracil (about 80%) was unchanged by the surgical procedure but the fraction of ampicillin (given as pivampicillin) absorbed decreased from a preoperative value of 109 ± 44% to 44 ± 30% 12 months after the bypass operation. Volumes of distribution transiently decreased in the postoperative period for ampicillin. Clearance was initially reduced for both ampicillin and propylthiouracil after operation but returned to normal values a year later. Half-lives of both drugs were unchanged.These results are compared with previous data on pharmacokinetics in intestinal shunt patients and a tabular review is presented. Although no general rules presently emerge from the data available, it seems prudent to closely monitor intestinal shunt patients on drug therapy by both laboratory and clinical methods.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

12 obese patients, pair-matched with 12 normal subjects, received a single 1mg oral dose of alprazolam. Nine similar subject pairs received a single 0.5mg oral dose of triazolam. Oral volume of distribution (Vd) was much greater in obese than control subjects for alprazolam (mean 114vs73L, p < 0.001), but there was no difference between the 2 groups for triazolam (117vs116L). Apparent oral clearance (not corrected for body weight) of alprazolam was lower, although not significantly so, in obesity (66vs88 ml/min), but for triazolam it was much lower in the obese (340vs531 ml/min, p < 0.005). Elimination half-life, which is dependent on both Vd and clearance, was prolonged in obesity for alprazolam (22vs11h, p < 0.001) due to the increase in Vd, and also for triazolam (4.1vs2.6h, p < 0.025) because of the decreased clearance. Plasma protein binding was unchanged in obese compared with control subjects for both alprazolam and triazolam.During long term administration alprazolam should therefore take longer to reach steady-state concentrations in obese patients but the final levels achieved should be no different than for patients of normal bodyweight, provided dosage is adjusted for ideal rather than total bodyweight. In contrast, triazolam has impaired clearance in obesity. However, if given once-daily it still would not accumulate with long term dosing due to its short half-life relative to the interval between doses.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS

摘要:

The effects of diurnal variation on bioavailability assessments were examined using computer-simulated data based on the changes observed in theophylline kinetics. During one 12-hour dosage interval (noon to midnight), clearance was assumed to be larger than during the other dosage interval (midnight to noon). Oral data was simulated until steadystate occurred. Intravenous bolus data, which represented a stable-isotope pulse dose, was also simulated for both the high and low clearance dosage intervals. When the respective areas under the serum concentration-time curves were compared, the systemic availability (F = AUCpo/AUCiv) during the dosage interval with the larger clearance was greater than 1.0, but during the dosage interval with the smaller clearance it was less than 1.0. When computing the bioavailability of a drug, diurnal variations should be assessed as a potential cause of variation.

ISSN:0312-5963    

出版商:ADIS    

年代:1984

数据来源: ADIS