Comparison of two different loading doses of digoxin in severe renal impairment

Summary The correct loading dose of digoxin in patients with advanced renal failure is still a matter of discussion. The effect has been studied of loading doses of digoxin 0.625 mg or 1.25 mg given over 48 h according to randomized crossover design to healthy volunteers and to two different groups of patients with renal impairment and the same mean endogenous creatinine clearance of about 15 ml/min. The subsequent maintenance dose for 4 days was digoxin 0.25 mg in the volunteers and 0.125 mg in both groups of patients. The minimum plasma digoxin concentrations before each dose was measured by radioimmunoassay and the plasma levels in the different groups have been compared. In the healthy volunteers no significant difference was found during the study, despite wide variation in the plasma digoxin concentration. In contrast, in patients with renal failure, the group with the higher loading dose showed significantly higher plasma concentrations 24, 36 and 48 h after drug administration, reaching the highest mean value of 2.2 ng/ml at 48 h. However, after 120 h of maintenance therapy a mean digoxin concentration of 1.3 mg/ml was found in both groups. Thus, despite different loading doses identical plasma concentrations were reached during administration of the same maintenance therapy. The higher plasma digoxin concentration obtained during administration of a higher loading dose might be the cause of arrythmias in individual patients.     

Simulation of the effect of patient nonadherence on plasma concentrations of carbamazepine from twice-daily extended-release capsules

OBJECTIVE: Carbamazepine (CBZ) effectively treats simple, complex, and secondarily generalized partial seizures. Computer simulations were carried out to investigate the effect of missing or delaying doses of carbamazepine extended-release capsules (CBZ-ERC) on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to therapeutic levels. PATIENTS AND METHODS: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400-mg fasting dose of CBZ-ERC. The model was used to simulate plasma CBZ concentrations following multiple doses given every 12 h to hypothetical long-term CBZ-treated patients, with the CBZ elimination half-life set to 13.7 h to account for enzymatic autoinduction. The model was then used to simulate plasma CBZ concentrations when a dose is taken 3, 6, or 9 h late, or when two doses are taken at one time. RESULTS: Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4 microg/ml only to 4 microg/ml after 24 h without medication, and only to 2.5 microg/ml after 36 h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9 microg/ml, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3 h before taking the next scheduled dose, will not lead to harmful spikes in plasma concentrations of CBZ. CONCLUSIONS: The simulations suggest that taking a missed dose of CBZ-ERC as soon as remembered, up to two doses at one time, may be the best strategy to return plasma CBZ concentrations to steady-state levels. Since the model used in this study is a simplified model of a highly complex situation, caution should be used when relating these results to clinical practice until trials are conducted in patients.     

Simulation of the effect of patient nonadherence on plasma concentrations of carbamazepine from twice-daily extended-release capsules

SUMMARY

Objective: Carbamazepine (CBZ) effectively treats simple, complex, and secondarily generalized partial seizures. Computer simulations were carried out to investigate the effect of missing or delaying doses of carbamazepine extended-release capsules (CBZ-ERC) on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to therapeutic levels.

Patients and methods: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400-mg fasting dose of CBZ-ERC. The model was used to simulate plasma CBZ concentrations following multiple doses given every 12?h to hypothetical long-term CBZ-treated patients, with the CBZ elimination half-life set to 13.7?h to account for enzymatic autoinduction. The model was then used to simulate plasma CBZ concentrations when a dose is taken 3,6, or 9?h late, or when two doses

are taken at one time.

Results: Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4μg/ml only to 4?μg/ml after 24?h without medication, and only to 2.5μg/ml after 36h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9|ig/ml, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3h before taking the next scheduled dose, will not lead to harmful spikes in plasma concentrations of CBZ.

Conclusions: The simulations suggest that taking a missed dose of CBZ-ERC as soon as remembered, up to two doses at one time, may be the best strategy to return plasma CBZ concentrations to steady-state levels. Since the model used in this study is a simplified model of a highly complex situation, caution should be used when relating these results to clinical practice until trials are conducted in patients.     

Carbamazepine-phenytoin interaction: elevation of plasma phenytoin concentrations due to carbamazepine comedication

By intrapatient comparison at constant phenytoin (PHT) dose, the effect of carbamazepine (CBZ) comedication on PHT was studied in a group of 24 epileptic outpatients. In half of the patients with steady-state PHT plasma concentration, a significant increase of this concentration was noted after CBZ was added to their regimen. Twenty percent showed clinical manifestations of acute drug toxicity initially thought to be CBZ related. The mean PHT plasma concentration for the 12 patients (22.7 +/- 5.64 micrograms/ml) as well as concentration/dose ratio for PHT (4.61 +/- 1.65 micrograms/ml plasma per mg/kg/day dose) was significantly higher (p less than 0.001) with concomitant administration of CBZ than when PHT was given alone: PHT concentration, 12.54 +/- 3.93 micrograms/ml and PHT concentration/dose ratio, 2.52 +/- 0.78 micrograms/ml plasma per mg/kg/day dose. Those patients with higher PHT plasma concentrations seem to be at higher risk of PHT toxicity due to CBZ comedication.     

Saliva carbamazepine levels in children before and during multiple dosing.

1 Saliva carbamazepine (CBZ) pharmacokinetics were determined in six children aged 7-11 years at the start and after 5 weeks of CBZ therapy. 2 A single oral dose of CBZ, 14.7 +/- 2.3 mg kg -1, was administered and mixed saliva was collected at intervals during the next 36 h. CBZ therapy was then continued using the same total daily dose divided into two equal doses. After 5 weeks of therapy saliva samples were collected once more as on day 1. 3 The mean (+/- s.d.) saliva CBZ clearance increased over the study period from 142 +/- 28 to 402 +/- 79 ml h -1 kg -1 (P less than 0.001) and the mean half-life decreased from 23.6 +/- 5.3 to 8.0 +/- 2.3 h (P less than 0.005). The mean apparent volume of distribution after the first dose, 4.72 +/- 0.84 1 kg -1, was similar to that after 5 weeks treatment, 4.66 +/- 1.68 1 kg -1. 4 The mean saliva steady-state CBZ concentrations after 5 weeks therapy were less than 40% of those predicted from the single dose kinetic parameters.     

Pharmacokinetics of carbamazepine in psychiatric patients

Plasma levels of carbamazepine (CBZ) were studied in 10 patients with psychiatric illnesses who were given the drug every 12 hours for 28 days. No correlation has been found between the daily dose of carbamazepine (calculated for body weight) and the steady-state level of the drug. In most patients taking CBZ as the only drug, a 10-20% fall in plasma drug level occurred between the first and second week of treatment, suggesting autoinduction process. A significant correlation was obtained between the plasma level of CBZ measured after the first dose of the drug and the subsequent steady state concentration. This makes possible to predict the steady-state CBZ concentration early in the treatment.     

Autoinduction and steady-state pharmacokinetics of carbamazepine and its major metabolites.

1. The effect of carbamazepine (CBZ) dose change on mean plasma concentrations of CBZ, its two metabolites and apparent steady-state clearance was studied in 77 affectively ill patients receiving CBZ at doses of 100-1200 mg day-1. 2. Autoinduction of CBZ metabolism appeared to be complete within 1 week of starting CBZ therapy or dose change, and its degree was linearly related to CBZ daily dose. 3. Curvilinear plots were obtained for steady-state concentrations of CBZ and its -10,11-epoxide metabolite, and for the ratio of CBZ-10,11-epoxide to CBZ level, versus daily dose of CBZ. 4. On the contrary, steady-state concentration of CBZ-10,11-diol increased proportionately with the dose. This indicates that there is no dose dependency in absorption of CBZ, and that dose-dependent autoinduction of CBZ metabolism is the main cause of the curvilinear relationship between dose and steady-state concentration of CBZ and its intermediary metabolite, CBZ-10,11-epoxide.     

Effect of clarithromycin on the pharmacokinetics of carbamazepine in rhesus monkeys

Clarithromycin, an advanced-generation macrolide antimicrobial, is less prone to drug interactions as compared to erythromycin. Based on two case reports in which increased carbamazepine (CBZ) plasma concentrations were observed in patients receiving clarithromycin, a crossover multiple dose study was designed to find out the pharmacokinetic interaction between CBZ and clarithromycin in rhesus monkeys. CBZ (46 mg/kg/d) was administered to the monkeys alone and along with clarithromycin (20 mg/kg/d). Blood samples were collected from 0-24 h. Plasma concentrations of CBZ were measured by HPLC technique. Pharmacokinetic data revealed an increase in plasma concentrations, AUC(0-24) and t1/2e of CBZ when coadministered with clarithromycin, but the increase was not statistically significant. These findings suggest careful administration and plasma monitoring of CBZ concentrations when coadministered with clarithromycin.     

Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy

Zonisamide (CI-912) is an experimental antiepileptic drug. Since this drug is to be evaluated initially as an add-on medication, an investigation was conducted to study its kinetics in the presence of two standard antiepileptic drugs. Patients in two groups, one on maintenance phenytoin (PHT) monotherapy and the other on maintenance carbamazepine (CBZ) monotherapy, each received a single dose of four 100-mg capsules of zonisamide; and blood samples were obtained at periodic intervals. Plasma and red blood cell (RBC) concentrations of zonisamide were measured by high performance liquid chromatography. Plasma and RBC areas under the curve produced by single doses of zonisamide in patients receiving CBZ were significantly higher than those receiving PHT (p less than 0.05). Clearance values, although not statistically significantly different, were lower for the CBZ group; and consistent with this, plasma and RBC concentrations decreased more rapidly in the PHT group. The approximate values for t1/2 were 36.4 h in plasma and 54.2 h in RBC for patients treated with CBZ, and 27.1 h in plasma and 35.8 h in RBC for patients treated with PHT. The RBC/plasma ratio varied eightfold within a given curve. These findings suggest that the dosage of zonisamide in epileptic patients might need to be varied depending on the comedication.     

Pharmacokinetics: time-dependent changes--autoinduction of carbamazepine epoxidation

Drugs labeled with stable isotopes have been useful to study time-dependent changes in kinetics. Early studies suggested that carbamazepine (CBZ) may induce its own metabolism, but this could not be proved until tetradeuterium-labeled CBZ (CBZ-D4) was synthesized and then given to patients. CBZ-D4 was administered to three children during long-term treatment of epilepsy with CBZ. After 17 to 32 days of treatment, the plasma clearance of CBZ-D4 was doubled, but during the next four months, there was no further increase, indicating that autoinduction was complete within one month. Two patients with chronic alcoholism were treated with CBZ for five days. Half of the first dose of 600 mg was comprised of CBZ-D4. The half-life of this CBZ-D4 dose in the two patients (20 and 26 hr, respectively) was similar to the post-steady-state half-life of CBZ (23 hr in both patients) measured later. A single dose of CBZ given one week after the last maintenance dose had a longer half-life (46 and 45 hr, respectively), which probably is close to the disposition of the drug before starting the treatment with CBZ. This shows that autoinduction of CBZ metabolism was completed during the very first doses of CBZ. Autoinduction also disappeared rapidly after stopping the treatment. We have shown that it is mainly the epoxide-diol pathway that is induced, both during autoinduction and after induction with other antiepileptic agents.     

急性冠状动脉综合征患者脑钠肽水平变化的临床观察

目的 探讨急性冠状动脉综合征(ACS)患者经保守或介入治疗后血浆脑钠肽水平的变化.方法 ACS患者95例,介入治疗37例为介入组,保守治疗58例为保守组,健康体检者41例为对照组.酶联免疫吸附法(ELISA)测定入院即刻、第3天、第5天、第10天4个时间点的血浆脑钠肽水平.结果 保守组的血浆脑钠肽水平在入院即刻、第3天、第5天均高于对照组(P＜0.05),但3个时点动态变化不大(P=0.427);介入组在入院即刻、第3天、第5天的血浆脑钠肽水平也均高于对照组(P＜0.05),但3个时点动态变化不大(P=0.544).在第10天保守组和介入组的血浆脑钠肽水平都显著回降,但仍高于对照组且有统计学意义(P=0.025,P=0.012).入院即刻、第3天、第5天及第10天介入组和保守组血浆脑钠肽水平比较无统计学意义.结论 急性冠状动脉综合征患者血浆脑钠肽水平第1周内保持较高水平,第10天显著回降,但仍高于正常水平.急性冠状动脉综合征患者经保守或介入治疗后10 d内血浆脑钠肽水平的变化情况相近.     

Plasma levels of disopyramide after administration of conventional capsules and sustained-release tablets

A study was carried out in 33 patients with myocardial infarction and complicating arrhythmias to compare plasma levels of disopyramide attained after administration of conventional capsules or sustained-release tablets. On Day 1, 29 patients started treatment wtih 600 mg disopyramide in 3 divided doses of conventional capsules. In 18, disopyramide plasma concentrations of 3 mg/l or more were achieved within 300 minutes after the first dose. On the second day, patients were allocated at random to receive treatment double-blind for 11 days with 500 mg disopyramide daily given either as conventional capsules (17 patients) or as sustained-release tablets (16 patients). Plasma concentrations were measured just before and 3 hours after the morning dose. Mean maximum and minimum concentrations in the conventional capsule group were 4.4 mg/l and 2.8 mg/l, respectively, compared to 4.3 mg/l and 3.0 mg/l, respectively, in the sustained-release tablet group. For the next 30 days all patients continued treatment with sustained-release tablets. Mean disopyramide plasma concentration measured 15 to 18 hours after the last dose was 2.8 mg/l. Myocardial function was estimated during and 1 week after discontinuing disopyramide treatment. The mean fractional fibre shortening (echocardiography) during treatment was 23% less than that 1 week after discontinuation. The mean PEP/LVET (systolic time interval recording) was 7% higher during treatment compared with 1 week after discontinuation. In 4 cases, mean ejection fraction, measured by scintigraphic methods, during treatment was 10% less than 1 week after discontinuation. Anti-arrhythmic effect was investigated by continuous monitoring in the first 12 days and by Holter monitoring during the 30-day ambulant period and 1 week after discontinuing disopyramide. A significant reappearance of warning arrhythmias could be detected after discontinuing disopyramide sustained-release tablets. No anti-arrhythmic effect was detected in 4 patients. Six patients had to be withdrawn because of side-effects. It is concluded that disopyramide sustained-release tablets 500 mg per day in 2 divided doses gives therapeutic plasma concentrations of 3 mg/l comparable with conventional capsules. A myocardial depressive effect is noted of about 10%.     

Carbamazepine 10,11-epoxide in children.

Concentrations of carbamazepine (CBZ) and its 10,11-epoxide metabolite (CBZ-E) were measured in simultaneously collected plasma and mixed saliva samples from 15 children (aged 1-13 years). Saliva concentrations of CBZ and CBZ-E were measured in hourly samples taken from six of these children during dose intervals whilst on different dose or dose-frequency regimens. Saliva and plasma CBZ (r = 0.91; P less than 0.001) and CBZ-E (r = 0.91; P less than 0.001) concentrations were significantly correlated. The mean +/- s.d. steady state CBZ-E/CBZ concentration ratio in the six children was 0.40 +/- 0.21 and was similar at all times within the 12 h dose interval. The mean +/- s.d. percentage fluctuation of the combined CBZ + CBZ-E (103.0 +/-28.9) was significantly less than that of CBZ-E (145.5 +/- 52.8) but not CBZ (109.6 +/- 31.1). If CBZ and CBZ-E have equipotent anticonvulsant activity in man, the contribution of CBZ-E approximates to 30% of total anticonvulsant effect in children taking CBZ alone.     

Single dose and steady state pharmacokinetics of valproic acid in adult epileptic patients.

The pharmacokinetics of valproic acid was studied in ten adult epileptic patients (five f + five m, 19-48 years; 28 +/- 12, mean +/- SD, and body mass 45 to 70 kg; 61 +/- 7, mean +/- SD) both after single dose and at the steady state. Sodium valproate was given in a 900 mg single oral dose on the first day of therapy, followed by 3 x 300 mg/day during the three subsequent days (at the intervals of 7, 8 and 9 h). During the first day, plasma was obtained just before the drug was given, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10 and 12 h after drug administration. On the fourth day of therapy (at steady state), plasma was obtained just before the next dose and 3 h after the drug administration. The plasma concentrations of valproic acid were measured by gas chromatography with flame ionization detection, after extraction with chloroform. The pharmacokinetic parameters, necessary to define the pharmacokinetics of valproic acid, were calculated both after single dose: Cmax, tmax, kel, t1/2, Vd, AUC and Cl, and at steady state: Cminss Cmaxss and Fl%. These parameters, as well as plasma levels of the drug, were used to describe the pharmacokinetic behaviour of valproic acid under these clinical conditions, and mainly were in agreement with the values published in the literature.     

Quinidine dosage, with special reference to an oral loading dose schedule.

1 Plasma concentrations of quinidine were analyzed in 52 cardiac patients after different oral loading doses and during different maintenance dosage intervals using both conventional and sustained release preparations of quinidine. 2 The majority of patients reached therapeutic plasma concentrations in the order of 2--4 microgram/ml within 3 h after the loading dose of 600--800 mg of rapidly absorbed ordinary quinidine sulphate tablets and institution of maintenance therapy with sustained release tablets 1 h after the loading dose. 3 The dosage interval of 12 h during maintenance therapy with sustained release tablets gave as acceptable plasma drug fluctuations as an 8 h interval. 4 A large individual variation in plasma concentrations was noticed. Thus monitoring of therapy by plasma concentration analyses is desirable.     

Activity of citalopram on adenosine and serotonin circulating levels in depressed patients

Citalopram is a selective serotonin reuptake inhibitor used in the treatment of depression. Recent investigations have shown that it reduces in rat brain the release of excitatory amino neurotransmitters acid glutamate and aspartate by the involvement of the inhibitory neuromodulator adenosine. In this study, we described citalopram and serotonin levels in plasma and platelets, as well as plasma adenosine levels, in depressive patients during acute and chronic administration of citalopram. Twelve patients affected by Major Depression (DSM-IV) received a single oral dose of citalopram in the morning, 5 mg in the first 5 days, 10 mg from the 6th to the 10th day, and 20 mg from the 11th to the 40th day. Blood samples for citalopram, serotonin, and adenosine were collected at Time 0 and 4, 12 and 24 hours after drug administration on the first day of citalopram 5 mg, and on the first and the last day of citalopram 20 mg. Citalopram, serotonin, and adenosine concentrations in plasma increased after citalopram administration, and the highest levels were observed on the last day of treatment. Citalopram was detectable in platelets with concentrations showing a time variation similar to plasma values. Serotonin levels in platelets decreased after drug administration, reaching the lowest values on the last day of treatment.     

Systemic availability of ergotamine tartrate after three successive doses and during continuous medication

Summary Plasma ergotamine concentrations were determined by radioimmunoassay in 10 healthy subjects after a 2 mg oral dose of ergotamine, administered at 24 h intervals on three consecutive days. After the first dose the mean peak plasma level of 0.35±0.05 (SEM) ng/ml was found 1–2 h after administration. In the samples obtained 2 h after the second and third doses, plasma ergotamine levels did not exceed the first peak value. On the other hand, after the third and last dose the plasma ergotamine began to rise slowly, reaching maximum of 0.70± 0.10 ng/ml on the 6th day after administration. This supports the concept of accumulation of the drug or of immunoreactive metabolites. CSF ergotamine was determined in 4 patients, who underwent lumbar puncture for other diagnostic purposes, 1 to 2 h after the 2 mg oral dose. A concentration of 0.40± 0.03 ng/ml was observed. In seven out of 18 migraine patients who were taking ergotamine preparations daily (mean 11.7 mg/week), ergotamine could not be detected in plasma 1 h after administration of the dose. In the remaining migraine patients, the pattern of plasma ergotamine after both the daily and the test doses was similar to that of the 10 healthy subjects. The results in volunteers and migraine patients suggest notable variation in bioavailability of the drug. It seems that in most subjects there is accumulation or tissue redistribution of ergotamine or its immunoreactive metabolites, although in a significant number of migraine patients who use the drug daily, ergotamine does not appear to be biologically available.     

体重与伏立康唑稳态血药谷浓度的相关性分析

目的分析临床患者体重与伏立康唑稳态血药谷浓度的相关性。方法采用HPLC 法对57 例使用伏立康唑静脉滴注治疗的患者进行稳态血药谷浓度测定, 分析其与体重的相关性。结果在使用200 mg、q12 h 维持剂量的伏立康唑时,随体重增加,伏立康唑稳态血药谷浓度呈降低趋势;70 －80 kg 体重患者中采用300 mg、q12 h 的维持剂量患者的稳态谷浓度明显高于采用200 mg、q12 h 维持剂量的患者（P 〈0. 01）。结论体重与伏立康唑稳态血药谷浓度有一定相关性。     

Controlled evaluation of a supplementary dose of carbamazepine on psychomotor function in epileptic patients

Summary The effect of an additional dose of 400 mg carbamazepine (CBZ) on a series of simple psychomotor tests was investigated in 8 patients with epilepsy receiving chronic CBZ monotherapy in a balanced randomised double-blind placebo controlled cross-over study. Psychomotor testing and blood sampling for total and free CBZ and CBZ 10,11 epoxide (CBZ-E) concentrations were performed at 10, 12, 14, 16 and 18 h after the extra dose which was administered at 23.00 h on the previous evening. The CBZ increment produced significant impairment of (i) choice reaction recognition time from 10–16 h after the dose (ii) total choice reaction time at 12 h (iii) card sorting at 12 h (iv) sedation scoring at 12 h. No significant effect on critical flicker fusion threshold, finger tapping or simple memory testing was noted. No patient reported increased side-effects in the placebo phase while 5 noted new symptoms likely to be attributable to the additional CBZ. Areas under the concentration-time curves from 10–18 h were higher following CBZ than placebo for total and free CBZ and CBZ-E concentrations. This study has demonstrated decrements in performance of a series of simple psychomotor tests in epileptic patients receiving a supplemental CBZ dose. Patients with epilepsy who require high CBZ concentrations for optimal control of seizures may be at risk of concurrent impairment of psychomotor function. Simple objective measures of performance may help in assessing the benefit-risk ratio.     

非线性混合效应模型法估算癫痫患者卡马西平的群体药动学参数

目的:建立癫痫患者卡马西平(CBZ)的群体药动学(PPK)模型。方法:采集我院服用CBZ的270例门诊癫痫患者的稳态血药浓度数据(共316个样本)以及患者相关资料数据。应用非线性混合效应模型(NONMEM)法估算癫痫患者CBZ的PPK参数值,建立PPK模型。并运用自举法(Bootstrap)验证模型的可靠性。结果:年龄(AGE)、每日服药剂量(DKG)、体质量(BW)均为CBZ清除率(CL)的影响因素。最终模型:当AGE≤14岁时,CL(L/h)=[2.55+0.013×(AGE-15)]×(DKG/0.011)0.443×(BW/40)0.392;AGE>14岁时,CL(L/h)=2.55×(DKG/0.011)0.443×(BW/40)0.392。表观分布容积(Vd)=85L。经Bootstrap法验证,本模型稳定、可靠。结论:用NONMEM软件成功建立我院癫痫患者服用CBZ的PPK模型。根据本院癫痫患者的PPK模型,结合患者DKG、BW和合并用药可估算其CL,优化临床个体化用药方案。