达非那新

达非那新是一种选择性M3受体阻滞剂，临床主要用于治疗膀胱过度活动综合征。它能明显减少尿失禁和排尿次数，降低尿急的程度，有良好的耐受性。常见的不良反应为口干和便秘，对中枢神经系统和认知功能的影响与安慰剂相似。     

The clinical pharmacokinetics of escitalopram

Escitalopram is the (S)-enantiomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram. Clinical studies have shown that escitalopram is effective and well tolerated in the treatment of depression and anxiety disorders. Following oral administration, escitalopram is rapidly absorbed and reaches maximum plasma concentrations in approximately 3-4 hours after either single- or multiple-dose administration. The absorption of escitalopram is not affected by food. The elimination half-life of escitalopram is about 27-33 hours and is consistent with once-daily administration. Steady-state concentrations are achieved within 7-10 days of administration. Escitalopram has low protein binding (56%) and is not likely to cause interactions with highly protein-bound drugs. It is widely distributed throughout tissues, with an apparent volume of distribution during the terminal phase after oral administration (V(z)/F) of about 1100L. Unmetabolised escitalopram is the major compound in plasma. S-demethylcitalopram (S-DCT), the principal metabolite, is present at approximately one-third the level of escitalopram; however, S-DCT is a weak inhibitor of serotonin reuptake and does not contribute appreciably to the therapeutic activity of escitalopram. The didemethyl metabolite of escitalopram (S-DDCT) is typically present at or below quantifiable concentrations. Escitalopram and S-DCT exhibit linear and dose-proportional pharmacokinetics following single or multiple doses in the 10-30 mg/day dose range. Adolescents, elderly individuals and patients with hepatic impairment do not have clinically relevant differences in pharmacokinetics compared with healthy young adults, implying that adjustment of the dosage is not necessary in these patient groups. Escitalopram is metabolised by the cytochrome P450 (CYP) isoenzymes CYP2C19, CYP2D6 and CYP3A4. However, ritonavir, a potent inhibitor of CYP3A4, does not affect the pharmacokinetics of escitalopram. Coadministration of escitalopram 20mg following steady-state administration of cimetidine or omeprazole led to a 72% and 51% increase, respectively, in escitalopram exposure compared with administration alone. These changes were not considered clinically relevant. In vitro studies have shown that escitalopram has negligible inhibitory effects on CYP isoenzymes and P-glycoprotein, suggesting that escitalopram is unlikely to cause clinically significant drug-drug interactions. The favourable pharmacokinetic profile of escitalopram suggests clinical utility in a broad range of patients.     

The clinical pharmacokinetics of phenytoin

Procedures for estimating the variability in dosage requirements of phenytoin to achieve steadystate plasma concentrations of 10–20 mg/liter and for estimating the plasma concentrations produced on a fixed dose are given. Further, a method is proposed for estimating the dosage required to achieve a desired steady-state plasma phenytoin concentration when a steady-state value on a known daily dose has been measured, A method is also described for estimating dosage requirements when two or more plasma concentrations have been measured. These methods are derived from data obtained on administering phenytoin in four to five different dosage regimens until steady state was achieved in each of nine volunteers. The drug was administered orally as a suspension every 8 hr, starting with about 100mg/day. The daily dose was increased in steps, and maintained at each daily dose rate for 6–14 days, or longer. Blood samples were drawn 4 and 8 hr after the last dose on 2 successive days at the end of each step and analyzed for phenytoin concentration. The average of these values was used to estimate the steady-state plasma concentration, C_pss. For each subject the C_pss values were fitted to a rearranged Michaelis-Menten equation C_pss =K_mR/(V_m-R). In this equation R is the dosing rate, V_m is the maximum rate of metabolism, and K_m is a constant equal to the plasma concentration at which the metabolism rate is one-half maximum. The average values found for V_m and K_m were 10.3 mg/kg/day and 11.54 mg/liter, respectively. The individual values of V_m and K_m appear to be constant over time, but there is considerable interindividual variability: coefficients of variation are 25% and 50%, respectively.Supported in part by grants (GM-16496, GM-01791, and GM-00001) from the National Institutes of Health. Dr. Martin was a recipient of a grant from the Swiss National Research Foundation.     

氢溴酸达非那新合成路线图解

氢溴酸达非那新 (darifenacin hydrobromide, 1) 化学名称为 2-{1-[2-(2,3-二氢苯并呋喃-5-基)-乙基] -3-吡咯烷基}-2,2-二苯基乙酰胺氢溴酸盐，英文化学名称为 2-{1-[2-(2,3-dihydrobenzofuran -5-yl)-ethyl]-pyrrolidin-3-yl} -2,2-diphenyl-acetamide hydrobromide，是由瑞士 Novartis 公司研制的新药。该药于2005年 1 月首次在德国上市，同年 2 月在美国上市。达非那新与人体毒蕈碱受体各亚型的结合亲和力比较显示，对 M3 与 M1、M3 与 M2、M3 与 M4 以及 M3 与 M5 的 Ki 值之比分别是 9.3、59.2、59.2 以及12.2，从而可以看出达非那新对 M3 受体具有较强的选择性。 研究发现，达非那新对膀胱的作用尤为显著，可以增加膀胱容积，增加无尿急迫时间，提高生活质量。目前，达非那新正成为治疗膀胱过度活动症(over active bladder, OAB)的首选药物。本文作者按不同的起始原料及反应路线，对氢溴酸达非那新的制备方法进行综述。     

苯酰甲硝唑胶囊人体生物等效性研究

目的　研究苯酰甲硝唑胶囊人体生物等效性。方法　 10名健康男性志愿受试者 ,随机分为 2组 ,分别于早晨空腹 1次口服对照品或供试品 96 0mg。 1wk后再交叉服药。受试者分别于服药前和服药后 0 5、1、2、3、4、6、8、12、2 4、30、36和 48h抽取静脉血 3ml,以高效液相法测定甲硝唑血药浓度。结果　两药均符合口服一级吸收一房室开放模型。主要参数 :Tmax为 (3 12± 0 90 )h和 (5 10± 1 6 0 )h ,Cmax为 (6 5 1± 1 2 5 )mg·L-1和 (5 32± 0 87)mg·L-1,AUC为(113 5 9± 19 84)mg·h-1·L-1和 (10 6 96± 19 6 2 )mg·h-1·L-1。各参数间除Tmax和Cmax差异有显著性外 (P <0 0 5 )其它差异均无显著性。供试品相对生物利用度为 (95 0 7±14 70 ) % ,RSD 15 46 %。结论　生物等效性检验后认为两药AUC体内生物等效性相同 ,Cmax和Tmax生物等效有差异。     

The effect of age on clinical pharmacokinetics of piracetam

In this study the pharmacokinetics of 2-oxopyrrolidine-1-acetamide (piracetam, Nootrop), were studied in 10 geriatric patients with multiple diseases aged between 69 and 87 years. After intravenous administration of 6 g piracetam, the concentration of the drug in plasma was measured after 5, 10, 15 and 30 min as well as after 1, 2, 4, 6, 8, 10, 12 and 24 h. An analysis of laboratory diagnostic findings was carried out in parallel. The kinetic parameters were correlated with the laboratory diagnostic data and discussed together with the currently available results in the literature. The finding which seems to be of particular significance is that multimorbidity is a more important factor influencing the pharmacokinetics than age.     

Felodipine clinical pharmacokinetics.

Absorption of felodipine is rapid and complete. A pronounced first-pass metabolism results in a bioavailability of 15%, irrespective of the oral formulation used. The peak plasma concentrations and area under the plasma concentration-time curve are linearly related to the dose. The variability in plasma concentrations is wide, and individualization of the dosage is recommended. Plasma felodipine concentrations are increased in the elderly, and in patients with congestive heart failure or liver cirrhosis; in these patients felodipine should be started at a low dosage. Food intake has no clinically significant effect on felodipine absorption. Serum digoxin concentrations are increased by felodipine in plain tablet form, but not when it is administered as extended release tablets. Activators, inducers and inhibitors of the cytochrome P450 system affect the plasma concentrations of felodipine. No displacement reactions with high affinity protein binding drugs have been observed. There is a significant correlation between plasma concentration and haemodynamic effect. The mean elimination half-life of 24h together with the extended release formulation of felodipine favours once-daily dosage in patients with hypertension.     

Fleroxacin clinical pharmacokinetics.

Fleroxacin is a new member of the class of fluoroquinolones. The drug has good activity (i.e. minimum inhibitory concentrations at less than 2 mg/L against 90% of strains) against a wide range of Gram-positive and Gram-negative bacteria. High performance liquid chromatography is used to determine concentrations of fleroxacin and its metabolites in biological fluids. Absorption of orally ingested drug is rapid as the peak plasma concentration of approximately 5 mg/L is reached in 1 to 2h after a single dose of 400mg. The systemic availability is close to 100%. Fleroxacin is poorly bound to plasma proteins (23%) and exhibits excellent tissue distribution. Renal clearance accounts for 60 to 70% of elimination. The drug is metabolised to form antimicrobially active N-demethyl-fleroxacin and inactive N-oxide-fleroxacin. In multiple dose studies the accumulation ratio of a once-daily dosage regimen is about 1.3, as predicted from the elimination half-life of 10 to 12h. Compared with ciprofloxacin, fleroxacin has a greater systemic availability and a longer half-life. Fleroxacin concentrations are higher in elderly patients, but further studies are needed to establish whether a dosage reduction should be recommended for this age group. In patients with renal disease dosage adjustment is recommended since a decreased renal clearance of fleroxacin leads to a significant prolongation of the elimination half-life. Fleroxacin is only poorly eliminated by peritoneal dialysis or haemodialysis. The most important drug-drug interaction is a decrease in systemic availability of fleroxacin after ingestion of aluminium- or magnesium-containing antacids. There is no evidence of a significant interaction between fleroxacin and theophylline. Only limited data are available on adverse reactions of fleroxacin. The most important adverse effects appear to be photosensitivity and a dose-dependent incidence of central nervous system reactions including sleep disorders.     

Primer on clinical pharmacokinetics

Basic concepts of clinical pharmacokinetics and principles of therapeutic drug monitoring are discussed. Pharmacokinetic variables such as volume of distribution, clearance, and half-life describe drug disposition in the body; in individual patients, these values may vary substantially. Serum concentrations of drugs may be influenced by numerous factors, such as route of administration, bioavailability, tissue distribution, and clearance. Therapeutic drug monitoring is designed to individualize drug dosages to achieve steady-state concentrations within a range of values that correlates well with patient response. An understanding of clinical pharmacokinetics and drug monitoring facilitates interpretation of serum concentrations in individual patients.     

Ofloxacin clinical pharmacokinetics.

Ofloxacin is a new fluoroquinolone with a spectrum of activity similar to other fluoroquinolones with activity which includes Chlamydia trachomatis, Mycobacterium spp., Mycoplasma spp. and Legionella pneumophila. Through its additional mechanisms of action, ofloxacin may be less susceptible to the development of resistance from Staphylococcus aureus commonly seen with currently available fluoroquinolones. The impact of these findings cannot be evaluated without further clinical experience. The pharmacokinetics of ofloxacin are characterised by almost complete bioavailability (95 to 100%), peak serum concentrations in the range of 2 to 3 mg/L after a 400mg oral dose and an average half-life of 5 to 8h. In comparison with other available quinolones, elimination is more highly dependent on renal clearance, which may lead to more frequent dosage adjustments in patients with impaired renal function. Ofloxacin appears less likely to affect the pharmacokinetics of drugs (e.g. theophylline) which commonly interact with fluoroquinolones such as ciprofloxacin and enoxacin. The properties of ofloxacin make it a therapeutic alternative to currently available fluoroquinolones.     

The influence of renal function on clinical pharmacokinetics of moxonidine

Investigations were carried out on 24 hypertensive or borderline hypertensive patients with different degrees of renal function. Eight had normal renal function [glomerular filtration rate (GFR) greater than 90 ml/min], 8 moderate (GFR 30 to 60 ml/min) and 8 severe renal impairment (GFR less than 30 ml/min). All patients were given moxonidine 0.3mg once daily for 7 days and both pharmacokinetic and pharmacodynamic data were determined. During moxonidine treatment plasma elimination half-life, area under the plasma concentration-time curve (AUC) and apparent total clearance (CLT) showed statistically significant differences among patients in the 3 groups. Elimination half-life was 2.6 +/- 0.9 hours in patients with a GFR greater than 90 ml/min and increased to 6.9 +/- 3.7 hours in those with a GFR less than 30 ml/min (mean +/- SD; p = 0.012). Correspondingly, AUC0-24 h rose from 5.4 +/- 2.7 to 17.2 +/- 7.9 micrograms/L . h (p = 0.001), and CLT decreased from 1150 +/- 602.l ml/min to 369 +/- 227.6 ml/min (p = 0.001). These data suggest that once-daily administration of 0.3mg moxonidine may be appropriate in patients with impaired renal function. Independent of renal function, moxonidine was well tolerated in 22 of 24 patients. No deterioration in renal function as a consequence of the use of moxonidine was found. Thus, in patients with renal failure, dosage of moxonidine should be individually titrated according to the desired clinical response, as is recommended for hypertensive patients without renal impairment.     

氢溴酸达非那新合成方法研究

目的合成氢溴酸达非那新。方法以R-(+)-3-羟基吡咯烷盐酸盐为原料,经氯代、氨基保护、缩合、脱N-保护基、氰基水解,与L-(+)-酒石酸成盐,再经皂化游离等反应,制得3-(S)-(-)-(1-氨甲酰基-1,1-二苯基甲基)四氢吡咯,与5-(2-溴乙基)-2,3-二氢苯并呋喃缩合、成盐,制得氢溴酸达非那新。结果与结论氢溴酸达非那新的总收率为23%,产物结构经1H-NMR和MS进行了确认。     

The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction

Differences in the clinical pharmacology of the 3 currently available oral phosphodiesterase-5 (PDE5) inhibitors, sildenafil, vardenafil, and tadalafil, are largely determined by their clinical pharmacokinetics as well as their PDE inhibitory activity profile. This review comparatively discusses the major characteristics of the pharmacokinetic profile of all 3 PDE5 inhibitors, including bioavailability and rate of absorption, Biopharmaceutical Classification System categorization, elimination mechanisms, and metabolic profile including active metabolites, as well as the drug-drug interaction potential and modification of pharmacokinetic properties under selected physiologic and pathophysiologic conditions. The review is aimed at providing comparative clinical pharmacology data to allow for scientifically rational, evidence-based prescribing and dosing decisions regarding the clinical use of these medications for the treatment of erectile dysfunction.     

头孢美唑的药动药效学与临床

头孢美唑（ＣＭＺ）为一种半合成头霉素类抗生素，本品在日本和欧美已较广泛应用，国内从１９８８年起进行了临床观察及验证。结果表明ＣＭＺ有抗菌谱广，耐酶稳定，体内分布好，不良反应低等特点。具有良好的临床应用价值。本文概述了近年国内外有关ＣＭＺ的药动药效学及临床应用研究情况，以其供临床应用本品时参考。     

Nonlinear pharmacokinetics: clinical Implications

Nonlinear pharmacokinetics (in other words, time or dose dependences in pharmacokinetic parameters) can arise from factors associated with absorption, first-pass metabolism, binding, excretion and biotransformation. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. One of the more important sources of nonlinearity is the partial saturation of presystemic metabolism exhibited by such drugs as verapamil, propranolol and hydralazine. In such cases, circulating drug concentrations are sensitive not only to dose size but also to rate of absorption: slower absorption may decrease the overall systemic availability. The binding of drugs to plasma constituents, blood cells and extravascular tissue may exhibit concentration dependence. This can cause pharmacokinetic parameters based on total blood or serum drug concentrations to be concentration-dependent. Often, in these cases, parameters based on free drug concentration appear linear. An important consideration in regard to concentration-dependent serum binding is the difficulty in relating total concentration to a usual therapeutic range if free concentration is a better indicator of drug effect. Measurement of free concentration is needed in these cases, particularly if the intersubject variability in binding is high. An example of this behaviour is valproic acid. Partial saturation of elimination pathways can result in the well known behaviour typical of Michaelis-Menten pharmacokinetics. Small changes in dosing rate can make much larger differences in steady-state concentration. The time to achieve a given fraction of steady-state becomes longer as the dosing rate approaches the maximum elimination rate. Alcohol and phenytoin are examples of drugs that exhibit such behaviour. The sensitivity of steady-state concentration and cumulation rate to changes in dosing rate are both influenced by the magnitude of parallel first-order elimination pathways: even a first-order pathway that is only 1 to 2% of maximum clearance (which occurs at very low concentration) can be an important determinant of steady-state concentration and cumulation rate when concentrations are high. Theophylline and salicylate have significant parallel first-order elimination pathways as well as saturable pathways. Autoinduction causes an increase in clearance with long term administration. In some cases, dosage adjustment must be made to compensate for the increase, and the possibility that the degree of induction may be dose- or concentration-dependent must be kept in mind. Carbamazepine is a major example of autoinduction. It is fortunate that only a few of the many hundreds of drugs in use exhibit nonlinear behaviour that leads to clinical implications.(ABSTRACT TRUNCATED AT 400 WORDS)     

Translation of pharmacokinetics to clinical medicine

The translation of pharmacokinetics to clinical medicine involves answering the following question: “When the pharmacodynamic or chemotherapeutic activity of a drug is known, how must its dosage regimen be adapted to its pharmacokinetic characteristics so that the desired therapeutic effect may be achieved and maintained?” This presentation discusses examples of pharmacokinetic analyses which influence the practice or principles of practical therapeutics. Physicians have intuitively appreciated the basic importance of pharmacodynamics because they are primarily interested in the action of a drug on the patient. However, in pharmacokinetics we consider the fact that there is not only a unidirectional action but also a mutual interaction between drug and organism. The action of the organism on the drug may be summarized in terms of the pharmacokinetic parameters: absorption, distribution, metabolism, and excretion. These parameters are examined with respect to drug accumulation, relation of pharmacokinetic data to therapeutic effects, saturation phenomena, the effect of kidney disease, the variation of pharmacokinetic parameters in individual patients due to age, pH of body fluids, and the states of wakefulness.     

头孢匹胺临床药物动力学研究

为研究头孢匹胺在中国健康志愿者中的体内过程特点 ,对 8名男性受试者接受单剂静脉滴注头孢匹胺 1g后的药物动力学进行了研究 ,并以头孢哌酮为对照药 ,亦予以单剂静滴 1g。同时以高效液相色谱法和微生物法测定两药血、尿药物浓度。结果表明 ,头孢匹胺消除半减期较头孢哌酮者为长 ,两者分别为 (4 .6 6±0 .94)和 (1.97± 0 .35 ) h;头孢匹胺的 AUC较头孢哌酮为大 ,分别为 (841.39± 2 0 8.0 9)和 (2 89.10± 5 9.12 ) (h·mg) / L。两者均以非肾消除途径为主 ,头孢匹胺自尿中排出给药量的 (18.45± 2 .72 ) % ,头孢哌酮为 (2 3.2 3± 4.30 ) %。     

The pharmacokinetics of some psychoactive drugs and relationships to clinical response

Over the past decade a variety of studies have been carried out in the Department of Psychiatry and Human Behavior at the University of California, Irvine, investigating the pharmacokinetics of some psychoactive pharmacological agents and the relationships of these pharmacokinetics to certain clinical responses. This report summarizes and provides an overview of these studies.     

Overview of the clinical pharmacokinetics of oxcarbazepine

Oxcarbazepine (GP 47680, 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine- 5-carboxamide) is an antiepileptic drug registered worldwide by Novartis under the trade name Trileptal((R)). Trileptal((R))is approved as adjunctive therapy or monotherapy for the treatment of partial seizures in adults and in children. In the US, Trileptal((R)) is approved as adjunctive therapy in adults and in children >/=4 years of age and as monotherapy in adults and in children.Trileptal((R))is currently marketed as 150, 300 and 600mg film-coated tablets for oral administration. A 60 mg/mL (6%) oral suspension formulation has also been registered worldwide.Oxcarbazepine and its pharmacologically active metabolite, 10-monohydroxy derivative (MHD; 10,11-dihydro-10-hydro-carbamazepine; GP 47779) show potent antiepileptic activity in animal models comparable to that of carbamazepine (Tegretol((R))) and phenytoin. Oxcarbazepine and MHD have been shown to exert antiepileptic activity by blockade of voltage-dependent sodium channels in the brain.Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is responsible for the pharmacological effect of the drug. This step is mediated by cytosolic arylketone reductases. MHD is eliminated by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidised to the pharmacologically inactive dihydroxy derivative (DHD). The absorption of oxcarbazepine is complete. In plasma after a single oral administration of oxcarbazepine the mean apparent elimination half-life (t((1/2))) of MHD in adults was 8-9h. Food has no effect on the bioavailability of the highest strength of the final market image tablet (600mg). At steady state MHD displays predictable linear pharmacokinetics at doses ranging from 300 to 2400mg. In children with normal renal function, renal clearance of MHD is higher than in adults, with a corresponding reduction in the terminal t((1/2)) of MHD. Consequently, although no special dose recommendation is needed, an increase in the dose of oxcarbazepine may be necessary to achieve similar plasma levels to those in adults. In patients with moderate to severe renal impairment (creatinine clearance <30 mL/min), the elimination t((1/2)) of MHD is prolonged with a corresponding 2-fold increase in area under the concentration-time curve. Therefore, a dose reduction of at least 50% and a prolongation of the titration period is necessary in these patients. Mild-to-moderate hepatic impairment does not affect the pharmacokinetics of MHD. Based on in vitro and in vivo findings and compared with antiepileptic drugs such as carbamazepine, phenytoin and phenobarbital, oxcarbazepine has a low propensity for drug-drug interactions. In vitro, MHD inhibits the cytochrome P450 (CYP) 2C19 (ki [inhibition constant] = 88 micromol/L). At oxcarbazepine doses above 1.2g, a 40% increase in the concentration of phenytoin and a 15% increase in phenobarbital levels were observed. Oxcarbazepine/MHD at high doses may slightly increase phenobarbital and phenytoin plasma concentrations. Therefore, when using high doses of oxcarbazepine an adjustment in the dose of phenytoin may be required. In vitro, MHD is only a weak inducer of uridine diphospate (UDP)-glucuronyltransferase (UDPGT) and therefore is unlikely to have an effect on drugs that are mainly eliminated by conjugation through the UDPGT enzymes (e.g. valproic acid and lamotrigine). Weak interactions between MHD and antiepileptic drugs that are strong inducers of CYP enzymes have been identified. Carbamazepine, phenobarbital and phenytoin have been shown to reduce MHD levels by 30-40% when coadministered with oxcarbazepine, with no decrease in efficacy. Oxcarbazepine decreases the plasma hormone levels (ethinylestradiol and levonorgestrel) of oral contraceptives and may therefore have the potential to cause oral contraception failure.