Pharmacokinetics of chlormezanone in elderly patients

Summary There is little information about the factors which influence drug protein binding between species. We have therefore investigatived the role of pH on the binding of gallopamil, a calcium channel antagonist known to exhibit pH-sensitive binding, among four species, human, baboon, bovine, and canine. We used pure protein solutions of ₁ acid glycoprotein (AAG) (60 mg·l^–1), albumin (45 gm·l^–1), and their combination and three values of pH, 7.0, 7.4, and 8.0. Gallopamil protein binding was determined over a concentration range of 2.0×10^–7mol·l^–1 to 2.1×10^–3mol·l^–1 using equilibrium dialysis.Gallopamil binding in all solutions was best described using a two binding site model in the combination solution and a one binding site model in the pure solutions. pH did not affect the number of identical binding sites. However, the influence of pH on gallopamil binding was species specific. Increasing the pH from 7.0 to 8.0 influenced binding affinity differently between species.There were directionally similar changes in unbound fraction at a gallopamil concentration of 2×10^–7mol·l^–1 as pH increased, although there were species differences in the degree of change. In protein solutions containing both AAG and albumin a reduction in pH from 7.4 to 7.0 resulted in species-specific increases in the unbound fraction. Increasing the pH from 7.4 to 8.0 again resulted in species-specific reductions in the unbound fraction of gallopamil. Similar changes were seen when pure AAG or albumin solutions were used, indicating species variance in both gallopamil protein binding and the effect of pH on binding.     

Pharmacokinetics of ciprofloxacin in elderly patients

For perioperative prophylaxis 200 mg ciprofloxacin were administered as a short intravenous infusion to 17 patients aged 57-84 years before transurethral resection (TUR-P) or transvesicular enucleation (TVP) of the prostate. 13 patients were injected simultaneously with 2.5 g ioxitalamic acid i.v. to determine the kidney function. In 11 patients the plasma concentrations were assayed and the pharmacokinetic parameters calculated. At the end of infusion the concentrations of ciprofloxacin in plasma reached 4.2 +/- 0.8 microgram/ml and decreased after a fast distribution period (plasma half-life 0.20 +/- 0.09 h) with a terminal half-life of 4.2 +/- 1.3 h to 0.2 +/- 0.09 microgram/ml after 10 h. The apparent volume of distribution in steady state was 183 +/- 45% of body weight, the plasma clearance 457 +/- 146 ml/min/70 kg. The average concentrations in prostatic adenoma tissue were at all sampling times higher (2fold) than in plasma. The mean concentrations in prostatic secretion were about half of the respective plasma concentrations. High concentrations of the concomitantly administered ioxitalamic acid in prostatic secretion are considered as an indicator of urinary contamination. In those patients high ciprofloxacin concentrations in prostatic secretion are not reliable.     

Pharmacokinetics of naproxen in elderly patients

Summary The pharmacokinetics of naproxen have been examined in 13 elderly patients (mean age 84.2 years) and in 9 younger patients (mean age 53.9 years) at the end of a 21 day course of therapy with naproxen 500 mg b.d. The mean pre-dose concentration on days 19, 20 and 21 was significantly higher in the elderly patients than in the controls (60.1 vs. 43.3 µ g · ml^–1). The AUC (0–24) was significantly higher in the elderly subjects only when normalized for body weight (9.1 vs. 5.4 µg·ml^–1·h kg^–1 p0.02). The AUC was significantly higher in the elderly group compared to the control group also in the normalized form. The apparent clearance of naproxen was reduced in the elderly compared to the control patients (315 vs. 628 ml·h^–1). The percentage protein binding of naproxen was the same in both groups (99.8%) but the free concentration of naproxen was significantly higher in the elderly patients than in the control patients (141 vs. 89.8 ng·ml^–1). Although there was no excess of side effects in the elderly patients it is suggested that when naproxen is given to elderly patients, therapy should be started at the lower end of the dosage range.     

Pharmacokinetics of reboxetine in elderly patients with depressive disorders

OBJECTIVES: To examine the pharmacokinetic characteristics of the selective norepinephrine reuptake inhibitor, reboxetine, in elderly patients with depression. PATIENTS: Twelve female inpatients (mean age 80 +/- 4 years) with major depressive or dysthymic disorder were enrolled in a 4-week uncontrolled study of oral reboxetine 2-8 mg/day. METHODS: After a one-week washout period, patients were randomized into two groups (groups A and B, n = 6/group). Reboxetine was given twice daily, starting with 2 mg/day during week 1 and increasing by 2 mg/day each week to 8 mg/day in week 4. Pharmacokinetic evaluations were carried out at two dosage levels in each group: at the end of weeks 1 and 3 in group A (2 and 6 mg/day), and at the end of weeks 2 and 4 in group B (4 and 8 mg/day). Blood and urine samples were taken for determination of reboxetine pharmacokinetics. RESULTS: Reboxetine displayed linear pharmacokinetics, with dose-proportional changes, in elderly depressed patients. Mean total urinary recovery ranged from 4.06 to 6.17%. The mean area under the plasma concentration-time curve (AUCtau) and the maximum plasma drug concentration (Cmax) showed considerable variation between patients; at a dosage of 4 mg/day, AUCtau was 1,466-6,866 ngxh/ml and Cmax ranged from 169 to 663 ng/ml. CONCLUSIONS: The pharmacokinetics of reboxetine are linear across the dosage range of 2-8 mg/day in elderly depressed patients, although Cmax and AUCtau values are higher (and more variable) than in young adults. These results support the use of a lower starting dose (4 mg/day) of reboxetine in the elderly.     

Pharmacokinetics of garenoxacin in elderly patients with respiratory tract infections

The pharmacokinetics of the new oral des-fluoroquinolone antimicrobial garenoxacin (GRNX) was investigated in elderly patients with respiratory tract infections. Patients were treated with GRNX (200 mg or 400 mg) once daily for 7 days. Plasma GRNX concentrations were determined and pharmacokinetic parameters were estimated by Bayesian predictions using reported population pharmacokinetic parameters. At each dose, the maximum plasma concentration (C_max) and the area under the concentration–time curve (AUC) were comparable with those reported in young subjects, except that the estimated C_max and AUC values in one patient receiving the 200 mg dose whose body weight and creatinine clearance rate (CL_Cr) were 38 kg and 17 mL/min, respectively, were higher than those of the other patients given 200 mg GRNX and were comparable with those of patients who received the 400 mg dose. These results suggest that the recommended dose of GRNX should be 400 mg for most elderly and young patients, but only 200 mg in patients whose body weight and CL_Cr are <40 kg and <30 mL/min, respectively.     

Pharmacokinetics of theophylline in ten elderly patients

The two-compartment pharmacokinetics of theophylline in ten hospitalized elderly patients with apparently normal renal, hepatic and cardiopulmonary functions was investigated after intravenous administration of the drug. Nine patients suffered from slight hemiparesis and one from Parkinson's disease. Biological theophylline half-lives of 5.4--9.0 hours and plasma clearence values of 28--42 ml kg-1hr-1 were found. The apparent volumes of distribution during the beta-phase, Vdbeta, were 0.33--0.43 1 kg-1. It is concluded that a therapeutic concentration of about 10 microgram theophylline per ml serum could be established in the investigated group of elderly patients following an intravenous initial loading dose of 3.7 mg theophylline per kg followed by a continuous infusion of 0.35 mg per kg body weight per hour. In the therapeutic use of theophylline monitoring of the serum theophylline concentration is generally advised because of the elsewhere reported variability in the biological half-life of the compound.     

The relative effects of digoxin and diltiazem upon ventricular ectopic activity in patients with chronic atrial fibrillation.

In eight patients with chronic atrial fibrillation, treatment with digoxin (plasma drug concentration 1.3 to 2.0 nmol l-1) was associated with a significantly higher incidence of ventricular premature beats (VPBs) (mean 22.8 h-1) than diltiazem 120 mg three times daily (mean 6.8 h-1) (P less than 0.05). Seven out of the eight patients showed an increase in numbers of VPBs recorded over 24 h during treatment with digoxin when compared with diltiazem. The clinical importance of these results is unclear, but atrial fibrillation and ischaemic heart disease frequently co-exist, and increases in ventricular ectopy may predispose to serious ventricular arrhythmias following myocardial infarction.     

Pharmacokinetics of flosequinan in elderly patients with chronic congestive heart failure

Summary We have investigated the pharmacokinetics of the direct vasodilator flosequinan in elderly patients with congestive heart failure. Eight patients received a single dose of 50 mg, and 8 patients received once-daily treatment with 25 mg for two weeks.In the single dose study, the t_max of flosequinan was 2.5 h, C_max was 1.17 g · ml^–1 and t_1/2 was 5.63 h. The t_max of the metabolite BTS 53554 was 20.3 h, C_max was 1.44 g · ml^–1 and t_1/2 was 62.0 h.BTS 53554 accumulated gradually in the 14-day repeated dose study and steady-state was reached after approximately 2 weeks. Flosequinan was not found to accumulate.Adverse reactions were not observed in either the single or repeated dose study.It is advisable to consider renal function and body weight when flosequinan is to be administered to elderly patients with congestive heart failure. The initial dose should be 25 mg.     

老年慢阻肺患者的茶碱药物动力学及临床应用

对４０例慢性阻塞性肺病（ＣＯＰＤ）患者进行氨茶碱药物动力学测定。结果显示：慢性喘息支气管炎（喘支）消除速率常数Ｋ０．０９３４±０．０１４（ｈ－１），消除半衰期Ｔ１／２７．６±１．３；肺心病伴肺部感染或呼吸衰竭Ｋ０．０６５±０．０２（ｈ－１），Ｔ１／２１２．０±３．９（ｈ）；肺心病伴心、肝功能异常者Ｋ０．０３８±０．０１６（ｈ－１），Ｔ１／２２１．５±９．５（ｈ）。本文比较了３种给药方法的血药浓度并探讨适合我国老年ＣＯＰＤ患者的氨茶碱剂量     

慢性阻塞性肺病者人茶碱药物动力学研究

本实验用萤光偏振免疫分析仪(TDX)测定茶碱血药浓度。对8名老年慢性阻塞性肺病(COPD)患者进行了氨茶碱口服多剂量给药的药物动力学研究。血药浓度数据在IBM—PC计算机上用PKBP-Ni程序处理,得到老年COPD患者的茶碱药物动力学参数,房室模型以一拟合。消除速率常数(Ke)为0.0555±0.0111h~(-1),消除半衰期(T1/2)为13.01±2.98h,表观分布容积(Vd)为29.42±6.80L,清除率(CL)为1.61±0.37L/h,曲线下面积(AUC)为131.3±33.8hmg/L。本实验得到的COPD老人茶碱的T1/2比文献报道的健康老人的T1/2有明显延长,CL有所下降。     

Pharmacokinetics of pirprofen in young volunteers and elderly patients

Summary Plasma concentrations of pirprofen were measured in 11 elderly arthritic patients and 6 healthy young volunteers at the beginning and end of 8 days treatment with 400 mg doses twice daily. The mean ages of the two groups were 74.5 and 21.8 years, respectively. There were no statistically significant differences in peak concentrations, times to peak, areas under the curve or terminal elimination half-lives between the groups after single dosing. Repeated dosing increased plasma drug concentrations in both groups but the extent was as predicted from the single dose data. Again there were no statistically significant differences between the groups, although pre-dosing plasma concentrations were higher in the elderly compared with the young individuals. The results of this relatively small study suggest that advancing age and arthritic disease appear to have little influence on the pharmacokinetics of pirprofen and no modification in the dosage recommendation in elderly patients without overt renal or hepatic impairment is indicated.     

Efficacy of oral mexiletine in the prevention of exercise-induced ventricular ectopic activity

Summary The anti-arrhythmic effect of oral mexiletine on exercise-induced ventricular arrhythmia was studied in a double blind trial of 10 patients suffering from ventricular ectopic beats of different origins. There was a good reproducibility of the amount of ectopic ventricular activity between consecutive exercise tests when no active drug was given. Treatment for 1 week with mexiletine 600 mg daily resulted in a statistically significant reduction in ventricular ectopic beats, particularly during and after exercise; there were virtually no side-effects. The results suggest that mexiletine has considerable potential in the treatment of ventricular arrhythmias.     

Pharmacokinetics and the antiarrhythmic effect of mexiletine in patients with chronic ventricular arrhythmias

A new antiarrhythmic agent, 1-(2,6- dimethylphenoxy )-2-aminopropane (mexiletine), was investigated in 10 patients with chronic premature ventricular contractions (PVCs) to evaluate the antiarrhythmic efficacy and the pharmacokinetics after single intravenous, single oral and repeated oral dosings of mexiletine 150 mg. Mexiletine was well absorbed from the intestinal tract. The relative bioavailability was 83.2 +/- 8.9% (mean +/- S.E.). The time-concentration curve of mexiletine fitted in well with two-compartment open model. Elimination half-life, volume of distribution and plasma clearance were 10.54 +/- 0.26 h, 2.10 +/- 0.49 l/kg, 6.01 +/- 0.63 ml/min/kg, respectively. The computer-simulated time-concentration curves of multiple oral dosings , which were based on the kinetic parameters from single oral dosing, conformed well with measured concentrations. This might be applied to predict the plasma level of mexiletine. The steady state of plasma mexiletine level was reached 4-5 days after 450 mg/day dosings and ranged 0.75-2.18 micrograms/ml. In 6 of 10 patients, the frequency of PVCs was suppressed more than 75% as compared with the pre-medication value. Mexiletine was well tolerated at a dose of 450 mg/day. However, of 4 patients with the dose increased to 600 mg/day, the administration was ceased in three patients due to gastrointestinal symptoms and tremor. All of these adverse reactions disappeared when the administration was stopped. These results suggest that mexiletine is effective against ventricular arrhythmias and the dosage should be carefully adjusted. The prediction of plasma level would be applied to the dosage regimen of mexiletine.     

Pharmacokinetics and biological activity of atacicept in patients with rheumatoid arthritis

Atacicept is a recombinant fusion protein containing the extracellular ligand-binding portion of the transmembrane activator and CAML interactor (TACI, CD267) receptor and inhibits B lymphocyte stimulator (BLyS, CD257) and a proliferation-inducing ligand (APRIL, CD256), both potent stimulators of B cell maturation, proliferation, and survival. Atacicept pharmacokinetics and pharmacodynamics were assessed in a double-blind, placebo-controlled, phase I study in patients with active, moderate to severe rheumatoid arthritis receiving atacicept either as a single subcutaneous or repeated, every other week dose. Pharmacokinetic profiles were determined by measuring serum concentrations of free atacicept and its complex with BLyS. Nonspecific immunoglobulin (Ig)M, IgG, and IgA; IgM-RF (rheumatoid factor), IgG-RF, and IgA-RF antibody levels; and B cell profiles provided markers of biological activity. Pharmacokinetic, biological activity, and relationships between atacicept dose and Ig antibody response were evaluated. Pharmacokinetic profiles of atacicept were nonlinear, influenced by saturable binding with its ligands, but were consistent and predictable. Atacicept treatment reduced Ig and RF serum concentration. IgM antibody levels were most sensitive to atacicept, followed by IgA and IgG, underlining the biological activity of atacicept in patients with rheumatoid arthritis. These findings can be used to explore dosing regimen design scenarios in future studies.     

舒芬太尼在老年胃肠手术患者的药代动力学

目的观察舒芬太尼(麻醉性镇痛药)在老年胃肠手术患者的药代动力学特征。方法随机选择老年胃肠手术患者12例,ASAⅠ～Ⅱ级,年龄61～68岁,体质量62～70 kg;全身麻醉后,经前臂静脉一次性注射舒芬太尼2μg.kg-1,于注药后1,3,5,10,20,30,60,120,240和360 min采集桡动脉抗凝血浆1mL,注入真空试管,-80℃低温保存待测;用液相色谱-质谱联用法测定血浆舒芬太尼浓度,3P97药理学程序判断房室模型,并计算药代动力学参数。结果舒芬太尼在老年胃肠手术患者的血药浓度-时间曲线可用三指数函数方程表示,主要药代动力学参数t1/2π,t1/2α和t1/2β分别为(0.02±001),(0.20±0.05),(2.51±0.81)h;Vc和Vd分别为(0.55±0.10)和(9.01±0.75)L.kg-1;CL和AUC分别为(2.64±0.66)L.kg.h-1和(2.85±0.71)mg.h.L-1。结论舒芬太尼在老年胃肠手术患者的药代动力学符合三室开放模型,腹内压的变化可影响舒芬太尼的药代动力学特征,在临床用药时应根据患者的具体情况增减剂量以达最佳疗效。     

Pharmacokinetics of indoprofen in elderly patients following repeated oral administration

Twenty patients suffering from osteoarthritis or rheumatoid arthritis, aged between 60 and 85 years, received 200 mg indoprofen tablets thrice daily for 4-7 days. Following the last dose, plasma samples were drawn and analysed for indoprofen. The mean peak plasma concentration of 25.5 +/- 7.06 micrograms/ml indoprofen was reached after 1.25 +/- 0.71 h. The total area under the curve was calculated as 207.2 +/- 108.7 micrograms X h/ml. Indoprofen was eliminated with a mean elimination half-life of t1/2 beta = 8.29 +/- 2.93 h compared with 5.5 +/- 0.64 h in young subjects. In elderly patients receiving indoprofen, terminal plasma half-lives and area under the plasma level time curves corrected for body weight were moderately increased compared with young subjects whereas no significant differences were found for Vd beta. During the dosage interval indoprofen levels were appreciably higher in elderly patients than in healthy volunteers due to higher nadir values and slower elimination half-lives, whereas only minor differences could be detected for peak plasma levels. The differences observed between young healthy volunteers and elderly patients may be explained by the reduction of renal function with increasing age, since creatinine clearance was 30-40% lower than normal values. The dose schedule for elderly patients over 60 years of age should therefore be adjusted to 200 mg indoprofen twice daily. A further reduction of the total daily dose should be considered for patients suffering from renal diseases associated with reduced creatinine clearance.     

Pharmacokinetics of pirprofen and its pyrrol metabolite in elderly patients

Summary Plasma concentrations of pirprofen and of its pyrrol metabolite were assessed in 9 elderly patients (3 males, 6 females; mean age 76 years) suffering from chronic degenerative disease. Pirprofen 400 mg in 4 ml was administered i.m. and the pharmacokinetic profile of the drug and the metabolite was calculated.The AUC, C_max and t_1/2 of pirprofen were similar to those found in previous studies, and, as expected, those parameters for the pyrrol metabolite were lower (C_max=2.8 µg/ml^–1; t_max=6.4 h; AUC(0–32)=56.5 µg · h · ml^–1). One patient (n=8) showed different pharmacokinetic behaviour, which is discussed.The data suggest that age has little influence on the pharmacokinetic of pirprofen, although unpredictable responses should always be considered in clinical practice.