The pharmacodynamics of the new anti-arrhythmia preparation bonnecor in patients with extrasystoles]

The pharmacodynamics, antiarrhythmic activity and tolerance of bonnecor were studied in 25 patients with acute myocardial infarction (AMI) and 23 patients with chronic ischemic heart disease (IHD) complicated by cardiac rhythm disorders in the form of extrasystoles. Extrasystoles were revealed in 92% of AMI patients at a single administration of bonnecor and in 82.5% of IHD patients at long-term oral administration of the drug. Bonnecor exerted no influence on arterial blood pressure and heart rate, did not change the parameters of the intracardiac hemodynamics. Bonnecor is well tolerated by patients, its main side effect is the prolongation of PQ interval of the ECG.     

Bonnecor--a new anti-arrhythmia preparation

The antiarrhythmic properties of a new drug bonnecor being a derivative of dibenzazepine were studied on different models of arrhythmias. Bonnecor proved to be effective in the treatment of both atrial and ventricular arrhythmias of various genesis except rhythm disorders induced by ouabain intoxication. The drug was shown to exert a pronounced antifibrillatory effect and to increase the electrical stability of the intact and ischemic myocardium.     

The anti-arrhythmia activity and effect on the heart conduction system of the new anti-arrhythmia preparation bonnecor

In 10 patients with frequent ventricular extrasystoles there were studied the antiarrhythmic effectiveness and side effects of a new drug bonnecor at a single intravenous administration in doses from 15 to 60 mg (0.17-0.91 mg/kg). It was found that the drug exerted the antiarrhythmic effect at dosages of over 0.4 mg/kg and side effects and toxic effects occurred at dosages of over 0.7 mg/kg. The optimal dose for a single intravenous administration was regarded to be the dose of 0.6 mg/kg. The mechanisms of action of bonnecor were studied during intracardiac electrophysiological investigation. The drug was shown to suppress the conduction of excitation along the atrioventricular node, the His-Purkinje system, the ventricular myocardium and the abnormal pathways of conduction. Thus, bonnecor may be referred to as an agent of class I according to the classification of Vaughan Williams. When administered intravenously (0.6 mg/kg) bonnecor was found to interrupt and prevent the recurrent development of atrioventricular tachycardia and also supraventricular tachycardias at the presence of the abnormal pathways of conduction.     

三七总皂苷鼻腔给药的药代动力学与药效学

目的研究三七总皂苷鼻腔用粉雾剂以混悬液形式给药后在大鼠体内的药代动力学过程及对心脑血管疾病的保护作用。方法HPLC测定三七总皂苷混悬液大鼠鼻腔给药后血样中人参皂苷Rg1的浓度，考察药物在体内的动力学过程，并计算其绝对生物利用度；结扎SD大鼠的左冠状动脉建立急性缺血性心肌梗死模型，夹闭沙鼠的双侧颈总动脉建立脑缺血再灌注模型，考察三七总皂苷混悬液对心脑血管疾病的保护作用。结果三七总皂苷混悬液鼻腔给药后，Rg1在大鼠体内的过程符合二室模型，其绝对生物利用度为103.56％；对大鼠急性缺血性心肌梗死及沙鼠脑缺血再灌注所引起的脑水肿和脑卒中症状均具有明显的缓解作用，且呈剂量依赖性，剂量越高，保护作用越强。结论药代动力学和药效学结果证明，三七总皂苷鼻腔给药制剂具有很好的开发前景。     

Antibody pharmacokinetics and pharmacodynamics

The U.S. Food and Drug administration (FDA) has approved several polyclonal antibody preparations and at least 18 monoclonal antibody preparations (antibodies, antibody fragments, antibody fusion proteins, etc.). These drugs, which may be considered as a diverse group of therapeutic proteins, are associated with several interesting pharmacokinetic characteristics. Saturable binding with target antigen may influence antibody disposition, potentially leading to nonlinear distribution and elimination. Independent of antigen interaction, concentration-dependent elimination may be expected for IgG antibodies, due to the influence of the Brambell receptor, FcRn, which protects IgG from catabolism. Antibody administration may induce the development of an endogenous antibody response, which may alter the pharmacokinetics of the therapeutic antibody. Additionally, the pharmacodynamics of antibodies are also complex; these drugs may be used for a wide array of therapeutic applications, and effects may be achieved by a variety of mechanisms. This article provides an overview of many of the complexities associated with antibody pharmacokinetics and pharmacodynamics.     

Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine.

The combination of artemether and lumefantrine (benflumetol) is a new and very well tolerated oral antimalarial drug effective even against multidrug-resistant falciparum malaria. The artemether component is absorbed rapidly and biotransformed to dihydroartemisinin, and both are eliminated with terminal half-lives of around 1 hour. These are very active antimalarials which give a rapid reduction in parasite biomass and consequent rapid resolution of symptoms. The lumefantrine component is absorbed variably in malaria, and is eliminated more slowly (half-life of 3 to 6 days). Absorption is very dependent on coadministration with fat, and so improves markedly with recovery from malaria. Thus artemether clears most of the infection, and the lumefantrine concentrations that remain at the end of the 3- to 5-day treatment course are responsible for eliminating the residual 100 to 10 000 parasites. The area under the curve of plasma lumefantrine concentrations versus time, or its correlate the plasma concentration on day 7. has proved an important determinant of therapeutic response. Characterisation of these pharmacokinetic-pharmacodynamic relationships provided the basis for dosage optimisation, an approach that could be applied to other antimalarial drugs.     

The pharmacokinetics and pharmacodynamics of newer inotropic agents

In the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or 'refractory' despite its inotropic effects. This review focuses on the pharmacokinetics and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation. Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of milrinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure, that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose, however, undergoes hepatic metabolism to many metabolites, including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers, resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory function. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations, although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma. Enoximone and its sulphoxide metabolite, piroximone, are two compounds currently undergoing investigation for the treatment of chronic cardiac failure.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effect of dosing time on the pharmacokinetics and pharmacodynamics of a 'once-a-day' sustained release theophylline preparation.

1. The pharmacokinetics and the bronchodilating effect of theophylline were studied during 1 week of morning dosing and 1 week of evening dosing in a randomized cross-over design in thirteen patients with reversible airways obstruction, treated with a new 'once-a-day' theophylline capsule formulation. 2. There were no differences between the mean pre-dose trough plasma concentration, maximal plasma concentration, trough-to-peak variation, tmax, area under the plasma drug concentration time-curve after morning or evening dosage. There was only a slightly but significantly higher plasma theophylline concentration between 16 and 20 h after evening dosing. 3. The mean plasma drug concentration time-curves were relatively flat with a mean trough to peak variation of 73.9% after morning dosing and 66.7% after evening dosing. Both sets of mean data were within the 10-20 mg l-1 therapeutic range. 4. The variations in FEV1 and PEFR throughout the 24 h after either morning or evening dosing were similar and followed the normal pattern of diurnal variation. 5. Adverse effects were mild and occurred in three patients without causing discontinuation of the study. 6. The theophylline preparation used appears suitable for once a day administration either in the morning or in the evening.     

Correlations of pharmacokinetics and pharmacodynamics of a combined preparation containing pyrrolidone and pyroglutamic acid

Experiments showed that a new drug composition containing pyrrolidone and pyroglutamic acid exhibits a significant cerebrovascular effect upon peroral administration in rats. The pharmacokinetics of pyrrolidone monitored upon its combined administration with pyroglutamic acid shows that this drug, as a component of the composition, is characterized by a high absolute bioavailability and permeability trough the blood-brain barrier. The presence of pyroglutamic acid slows down the absorption and elimination of pyrrolidone and enhances its distribution in the organs and tissues. There is a correlation between the concentration of pyrrolidone in the brain, on the one hand, and the levels of cerebral microcirculation and arterial pressure on the other hand. An increase in the concentration of pyrrolidone in the brain is accompanied by more intensive cerebral blood flow and by a decrease in the arterial pressure.     

Macrolides: pharmacokinetics and pharmacodynamics

Three pharmacokinetic/pharmacodynamic parameters--(i) the peak concentration to the minimum inhibitory concentration ratio (C(max)/MIC); (ii) the area under the concentration-time curve to MIC ratio (AUC(24h)/MIC); and (iii) the time the concentration exceeds the MIC (T>MIC)--are important predictors of the clinical efficacy of antibiotics. For antibiotics with pronounced concentration-dependent killing, such as the fluoroquinolones or the aminoglycosides, C(max)/MIC and AUC(24)/MIC are the main factors that establish efficacy. Antibiotics with a weak, or no, concentration dependency generally have their efficacy linked to T>MIC, and these include the beta-lactams and the conventional macrolides. Antibiotics with weak concentration-dependent effects, but with prolonged persistent effects, such as tetracyclines and azithromycin, have their activity mostly related to the AUC(24)/MIC. By applying these concepts to current antibiotics, and also to the development of novel agents, it is possible to optimise their dosages and administration schedules. This will maximise therapeutic efficacy, may prevent or delay the emergence of bacterial resistance to antibiotics, and can certainly minimise side-effects.     

Modelling the pharmacokinetics and pharmacodynamics of trimazosin

The pharmacokinetics and pharmacodynamics of trimazosin are described following both intravenous and oral administration to 6 normotensive, male volunteers. The IV and oral drug and metabolite (1-hydroxytrimazosin) concentration data are fitted simultaneously to the same pharmacokinetic model. The pharmacodynamic response, change in systolic blood pressure following 5 min in the erect posture, is described using several possible models. The most efficient is one which attributes the response to both the parent drug and its principal metabolite. The response following oral administration is also consistent with this model. It appears that the reduction in blood pressure following administration of trimazosin at steady state may be governed by the concentration of metabolite.     

Heparin pharmacokinetics and pharmacodynamics.

Heparin was discovered approximately 75 years ago and has been used extensively for the last 50 years to treat thromboembolic disorders. An endogenous glycosaminoglycan, heparin is found largely in the liver, lung and intestine. It is available for exogenous administration both as unfractionated and low molecular weight heparin. Unfractionated heparin is a heterogenous mixture of polysaccharide chains of varying length resulting in a range of molecular weights from 3000 to 30,000D while low molecular weight heparin ranges from 3000 to 6000D. Heparin produces its antithrombotic effect by binding to antithrombin III and this complex then binds to thrombin. In order to accomplish this a total of 18 to 22 monosaccharide units is necessary including a specific pentasaccharide binding site for antithrombin III. After either subcutaneous or intravenous injection heparin is distributed primarily within the intravascular space. A short distribution phase is seen which is thought to correspond to endothelial cell binding and internalisation. The disposition curve for unfractionated heparin has a unique concave-convex shape which is the result of combined saturable and nonsaturable elimination mechanisms. The nonsaturable elimination mechanism is renal and is the primary route of elimination for low molecular weight heparins. For this reason, the concave-convex pattern is not seen with low molecular weight preparations. Both forms of heparin are useful antithrombotic agents; however, the correlation between the antithrombotic effect and an in vitro laboratory test for either type still needs further clarification.     

The pharmacodynamics and pharmacokinetics of a new calcium antagonist nisoldipine in normotensive and hypertensive subjects

Summary The pharmacodynamic and pharmacokinetic profiles of nifedipine and nisoldipine were compared in a double blind, placebo-controlled study. Nisoldipine, 10 mg significantly reduced systolic blood pressure but nifedipine 20 mg retard did not, although both drugs had significant pharmacodynamic effects as evidenced by increased heart rates. The terminal elimination half-life in plasma was similar for both drugs with a mean of 2 h. The pharmacodynamics of nisoldipine were studied in 8 hypertensives following both acute and chronic administration. Antihypertensive efficacy was demonstrated after acute dosing and was maintained over 4 weeks of twice daily treatment as monotherapy.     

The pharmacodynamics and pharmacokinetics of the combination of nifedipine and doxazosin

Summary In a single-blind study 12 normotensive men took nifedipine 20 mg (Group 1, n=6) or doxazosin 2 mg (Group 2, n=6), followed by the combination. Each subject attended on four 9-h study days for evaluation of the effects of single and multiple doses of the monotherapy and the effects of adding single and multiple doses of the second drug. Measurements of BP, HR, plasma drug concentrations, and apparent liver blood flow were recorded. The combination was generally well tolerated.BP was consistently lower with the combination than with either monotherapy: for example, average erect BP was 108/61 (Group 1) and 112/62 mmHg (Group 2) compared with 122/66 and 116/68 during steady-state monotherapy.The introduction of nifedipine in Group 2 was associated with a significant increase in liver blood flow at 1.5 h: 1560 vs 1050 ml · min^–1 during monotherapy with doxazosin.There was no significant kinetic interaction. In particular, the steady-state AUC of doxazosin was unaffected by the addition of nifedipine: 257, 307, 301, and 256 ng · ml^–1 · h for the 4 study days (Group 2).     

新型棕榈酰谷氨酸-顺铂纳米粒的制备及其体外药效研究

目的以棕榈酰谷氨酸为载体材料制备新型高载药顺铂纳米粒(palmoyl glutamic acid-cisplatin-nanoparticles,PG-CDDP-NPs),并对其体外抗肿瘤活性进行研究。方法采用肖顿-鲍曼缩合法合成棕榈酰谷氨酸两亲性材料,以所合成的材料为载体,利用其与顺铂的配位作用制备高载药新型顺铂纳米粒,并对所制备的PG-CDDP-NPs性质进行考察;以市售顺铂注射剂为对照,采用MTT法考察了PG-CDDP-NPs对人肝癌细胞HEPG2的体外抗肿瘤活性。结果合成了棕榈酰谷氨酸,并成功制备了高载药量的PG-CDDP-NPs,PG-CDDP-NPs粒径为(106.33±4.45)nm,粒度分布较均匀,包封率为(84.20±0.81)%,载药量质量分数高达(27.03±0.12)%。体外释放研究表明,PG-CDDP-NPs具有缓慢释药性质,24 h累积释放量质量分数仅为(28.74±1.37)%。体外药效学实验结果显示PG-CDDP-NPs和CDDP-S对高表达的人肝癌细胞HEPG2细胞的IC50值分别为3.54μmol·L-1和4.55μmol·L-1。结论以棕榈酰谷氨酸为载体材料可制备高载药量的顺铂纳米粒;PG-CDDP-NPs在体外对HEPG2细胞有杀伤作用,与顺铂注射剂相比,显示出较强的抑瘤效果,PG-CDDP-NPs是一种具有潜在应用价值的顺铂纳米制剂。     

The pharmacokinetics and pharmacodynamics of a new sustained-release leuprolide acetate depot compared to market references

OBJECTIVE: The aim of this study was to compare the efficacy of Lutrate 3.75 and 7.5 mg depot to marketed references Lucrin 3.75 mg and Procrin 7.5 mg depot. METHODS: 20 healthy male volunteers were randomly assigned to receive 1 of 4 active single dose treatments in this double-blind, parallel-group pilot study. Leuprolide acetate and testosterone levels were quantified by radioimmunoassays. RESULTS: The pharmacokinetic profile of leuprolide could be well-described by a 4-step release curve. Leuprolide levels were detectable 14 days longer after injection of the test formulations as compared to the reference products. The total AUC observed with 3.75 and 7.5 mg of the test product were approximately 1.5- and 2.2-fold higher, compared to the reference products, respectively. After the expected testosterone "flare-up" effect, castration was achieved in 4 of 4 subjects with the test formulations, 4 of 5 subjects with Procrin and 2 of 5 subjects with Lucrin. On average, castration lasted more than 1 month with both test formulations compared to 2 weeks with the reference products. CONCLUSION: Sustained release of leuprolide from this new depot formulation suppressed testosterone levels at least as effectively and for a longer period of time than the reference products.     

The pharmacokinetics and pharmacodynamics of bumetanide in normal subjects

The pharmacokinetics and pharmacodynamics of bumetanide (1 mg) administered either orally or intravenously were studied in a group of normal subjects using high-pressure liquid chromatography. A two-compartment model adequately fitted the intravenous data. Renal clearance (85 ml min^–1 contributed 65% to the total elimination of bumetanide irrespective of whether a model-dependent or model-independent method was used. Oral administration of bumetanide elicited a greater and a more prolonged pharmacological response than did intravenous bumetanide. An attempt is made to relate the pharmacokinetics of the drug to its pharmacodynamics.     

Clinical pharmacokinetics and pharmacodynamics of isepamicin

Isepamicin is an aminoglycoside antibacterial with properties similar to those of amikacin, but with better activity against strains producing type I 6'-acetyltransferase. The antibacterial spectrum includes Enterobacteriaceae and staphylococci. Anaerobes, Neisseriaceae and streptococci are resistant. The lower and upper break-points are 8 and 16 mg/L. Like other aminoglycosides, isepamicin exhibits a strong concentration-dependent bactericidal effect, a long post-antibiotic effect (several hours) and induces adaptive resistance. Isepamicin is administered intravenously or intramuscularly at a dosage of 15 mg/kg once daily or 7.5 mg/kg twice daily. Isepamicin is not bound to plasma proteins, and it distributes in extracellular fluids and into some cells (outer hair cells, kidney cortex) by active transport. Isepamicin is not metabolised and is eliminated solely via the renal route with an elimination half-life (t 1/2 beta) of 2 to 3 hours in adults with normal renal function. The clearance of isepamicin is reduced in neonates, and 7.5 mg/kg once daily is recommended in children <16 days old. Clearance is also reduced in the elderly, but no dosage adjustment is required. In patients with chronic renal impairment, isepamicin clearance is proportional to creatinine clearance (CLCR); the recommended regimen is 8 mg/kg with an administration interval of 24 hours in moderate impairment, 48 hours in severe impairment, 72 hours for CL(CR) 0.6 to 1.14 L/h (10 to 19 ml/min) and 96 hours for CL(CR) 0.36 to 0.54 L/h (6 to 9 ml/min). In end-stage renal failure, isepamicin is eliminated by haemodialysis, but the administration interval should be determined by monitoring the plasma concentration. Compared with healthy volunteers, patients in the intensive care unit or with neutropenic cancer have an increased volume of distribution and a lower clearance, but the 15 mg/kg once daily regimen remains adequate. Isepamicin kinetics are linear in the range 7.5 to 25 mg/kg, so that dosage adjustments, if necessary, are straightforward. Isepamicin can induce nephro-, vestibulo- and oto-toxicity. However, animal and clinical studies show that isepamicin is one of the less toxic aminoglycosides. The usefulness of maintaining serum aminoglycoside concentrations within a therapeutic range remains controversial. With isepamicin, it is proposed to achieve a 1-hour concentration (30 minutes after a 30-minute infusion) >40 mg/L to maximise bactericidal efficacy, and a 'trough' concentration (at the end of the administration interval) <5 mg/L to minimise toxicity. These thresholds should be modified on an individual basis, considering covariates such as concomitant treatment, underlying disease, nature of bacterial strain and site of infection.     

Population pharmacokinetics and pharmacodynamics of ciclesonide

Ciclesonide is a novel glucocorticoid that is converted into ciclesonide--active principle (CIC-AP) in the lung. The study objectives were to identify a structural model for population pharmacokinetic (PK) analysis of CIC-AP using nonlinear mixed-effects modeling, assess the influence of select covariates on PK and/or pharmacodynamic (PD) parameters, and investigate the effects of CIC-AP on endogenous cortisol. Pooled concentration data from nine phase I studies (dose: 400-3600 micrograms) involving healthy and asthmatic patients were included in the PK analysis. There were 151 subjects (3300 observations) for the CIC-AP population PK analysis. Various models examined inter- and intrasubject variability for the PK parameters. Population estimates of the PK parameters of clearance and volume of distribution were 396 L/h (64.8% co-efficient of variation [CV]) and 1190 L (41.2% CV), respectively. Pharmacodynamic population estimates included maximum cortisol release rate, 3140 ng/h (5.4% CV). The EC50 of CIC-AP was 0.88 ng/mL. Ciclesonide is a safe corticosteroid that causes negligible cortisol suppression. The disposition and effect of CIC-AP can be described using mixed-effect modeling. The estimated EC50 is similar to mean Cmax from an 800-micrograms dose, further suggesting CIC-AP has little effect on cortisol suppression.     

The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD), its major active metabolite, were compared in 39 healthy male volunteers (13 Asian, 12 Caucasian and 14 African-American). In a four-way, double-blind crossover design, subjects were administered (1) 30 mg oral adinazolam mesylate SR tablets, (2) 10 mg parenteral (IV) adinazolam mesylate, (3) 30 mg IV NDMAD and (4) placebo. Venous blood samples were collected at specific time intervals after drug administration and assayed for adinazolam and NDMAD concentrations. Sedation was rated at the time of each blood draw according to the Nurse-Rated Sedation Scale, and the digit-symbol substitution test was administered to evaluate psychomotor performance. After IV administration of adinazolam, Asians manifested significantly higher C_max, larger AUC and lower CL of both adinazolam and NDMAD than their Caucasian and African-American counterparts. Likewise, after IV NDMAD Asians had significantly higher NDMAD C_max and AUC than Caucasians and African-Americans. Most of these differences remained statistically significant after controlling for body surface area. With PO adinazolam, Asians also manifested substantially higher C_max, larger AUC and lower CL for both adinazolam and NDMAD; however, with the exception of C_max, these differences did not reach statistical significance. These results are in accordance with previous observations for ethnic-related differences in drug pharmacokinetics. In contrast, pharmacodynamic differences were not noted among the three study groups. Received: 19 June 1996/Final version: 17 September 1996