儿童丙戊酸群体药动学

目的:研究仅有临床稀疏数据的儿童丙戊酸群体药动学.方法:收集667例儿童癫痫患者的常规治疗药物监测资料,将794对血药浓度-时间数据利用群体药动学理论经CPKDP程序处理,提取儿童群体药动学参数,再经Bayesian反馈法及二步迭代计算出儿童个体药动学参数.结果:儿童丙戊酸群体药动学主要参数Ke、Vm、CL在单用丙戊酸组分别为(4.5±2.2)h-1、(1.4±0.5)L·kg-1和(14.5±4.3)mL·h-1·kg-1;在合并其他抗癫痫药物时分别为(7.3±3.4)h-1、(1.4±0.6)L·kg-1、(24.8±9.3)mL·h-1·kg-1.预测浓度和实测浓度显著相关;合并PB、PTH、CBZ、CNP对丙戊酸的药动学有显著影响.结论:本研究对儿童丙戊酸给药方案个体化提供有价值的参考依据.     

Physiologically based pharmacokinetics of valproic acid in rabbits

Protein-binding parameters of valproic acid (VPA) in rabbit serum were determined. Due to the non-linear binding, the binding percentage decreased from 91 to 41% when the serum concentration of VPA rose from 10 to 1000 μg/ml. The hepatic clearance of VPA as unbound drug followed Michaelis-Menten kinetics. A physiologically based pharmacokinetics model was adopted to interpret the overall disposition of VPA in rabbits which incorporated the non-linear plasma protein binding and non-linear intrinsic hepatic clearance. The predicted plasma and tissue concentrations were found to be in good agreement with the observed concentrations. The reason why the plasma concentration versus time curves appear to be apparently parallel in spite of remarkable changes in the unbound concentration among three different doses could be explained by the association effects in which an increase in the total plasma concentration may produce a decrease in intrinsic hepatic clearance consistent with Michaelis-Menten kinetics resulting in an increase in the unbound fraction of VPA in plasma.     

Anticholinergic burden and risk of cognitive impairment in elderly nursing home residents with depression

BackgroundAlthough the adverse cognitive effects of anticholinergic medications in the elderly are well-documented, little is known regarding the cognitive impact of anticholinergics among nursing home residents with depression.ObjectiveThis study examined the risk of mild-to-moderate cognitive impairment due to anticholinergic burden among elderly nursing home residents with depression.MethodsA population-based nested case-control study was conducted using Minimum Data Set (MDS)-linked Medicare data where the base cohort included patients ≥ 65 years with depression who had intact cognition (MDS Cognition score of 0 or 1) and no dementia. Cases were identified as those who had mild-to-moderate cognition (MDS Cognition score of 2–4). Each case was matched on age and sex to one control using incidence density sampling. The study evaluated cumulative anticholinergic burden (defined as score of 3 or more) within 30, 60 and 90 days preceding the event date based on the Anticholinergic Drug Scale (ADS). Conditional logistic regression model stratified on matched case-control sets was performed to evalaute cognitive impairment due to cumulative anticholinergic burden after controlling for other risk factors.ResultsThe study sample included 3707 cases with mild-to-moderate cognition and 3707 matched controls with intact cognition. Bivariate analysis showed significant association between cumulative anticholinergic exposure and cognitive impairment (Odds Ratio [OR], 1.15; 95% Confidence Interval [CI],1.04–1.30); after controlling for potential risk factors, cumulative anticholinergic exposure 30 days preceding the event was no longer associated with cognitive impairment, (aOR, 1.07; 95% CI, 0.95–1.21). However, the odds of cognitive impairment increased with cumulative anticholinergic exposure 60 days (aOR 1.16; 1.04–1.30) and 90 days (aOR 1.28; 1.14–1.44) before the event date.ConclusionCumulative anticholinergic use for prolonged exposure periods was associated with modestly increased risk of cognitive impairment in elderly residents with depression who had intact cognition. The findings suggest the need to be cautious when prescribing multiple anticholinergic drugs in residents, including those with intact cognition.     

Pharmacokinetics of valproic acid in the elderly

The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68-89 years) and six young control subjects (age 24-26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half-lives (15.3 +/- 0.7 s.e. mean in the elderly vs 13.0 +/- 1.0 h in the young), volumes of distribution (0.16 +/- 0.01 l/kg in the elderly vs 0.14 +/- 0.01 l/kg in the young) and clearance (7.5 +/- 0.9 ml h-1 kg-1 in the elderly vs 7.7 +/- 0.6 ml h-1 kg-1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/- 12 ml h-1 kg-1 (control value in the young) to 77.7 +/- 5.5 ml h-1 kg-1 (P less than 0.02). Free VPA fraction was 9.5 +/- 0.6% in the elderly and 6.6 +/- 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.     

Population pharmacokinetics of lamotrigine in elderly patients

Lamotrigine is being used more frequently in elderly patients. Dosing of lamotrigine in elderly patients is based largely on studies from younger adults and not evidence-based data from elderly patients. The goal of this study is to determine the pharmacokinetic parameters, such as clearance, and the factors that have a significant effect on these parameters to provide evidence-based information that can be used to dose elderly patients taking lamotrigine. Lamotrigine plasma concentrations from 148 elderly patients (aged 59-92 years) were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check. The results showed that the blood urea nitrogen/serum creatinine ratio, weight, and phenytoin use significantly affect apparent clearance of lamotrigine. These results show that clinicians may need to take into account these covariates when dosing lamotrigine in this population.     

丙戊酸清除率的群体药动学模型的建立

目的:建立中国癫痫病患者丙戊酸清除率的群体药动学模型.方法:前瞻性收集上海、北京两地4所医院服用丙戊酸的350名患者的稳态血药浓度(n=435).数据分析采用非线性混合效应模型.结果:最终模型为:CL(L·h-1)=0.0422·Dose·BSA0.269·1.41(如果合用卡马西平,否则为1)·1.37(如果合用苯妥因,否则为1)·(0.00735·PBS 0.807)(如果合用苯巴比妥,否则为1)·(Dose/950)(如果Dose大于950 mg·m-2·d-1,否则为1)·1.21(如果BSA大于1.7 m2,否则为1)·1.24(如果年龄小于6,否则为1).上式中Dose为日剂量(mg·m-2·d-1);BSA为体表面积(m2);PBS为苯巴比妥的日剂量(mg·m-2·d-1).结论:根据患者的生理用药资料,结合上述模型,可估算其清除率,为制定给药方案提供依据.     

Use of hexadeuterated valproic acid and gas chromatography-mass spectrometry to determine the pharmacokinetics of valproic acid

Di-[( 3,3,3-2H3]propyl)acetic acid, a hexadeuterated analogue of valproic acid, was synthesized and its pharmacokinetic properties compared with valproic acid. Concentrations of valproic acid and [2H]valproic acid in serum and saliva were determined by GC-MS using selected-ion monitoring. Saliva drug levels were measured with good precision down to 0.1 microgram/mL. Kinetic equivalence of valproic acid and [2H]valproic acid was demonstrated in a single-dose study in a human volunteer. An isotope effect was observed for omega-oxidation, but the difference in metabolism was not sufficient to make [2H]valproic acid biologically nonequivalent. The application of [2H]valproic acid to determine the kinetics of valproic acid under steady-state concentrations was evaluated in the same volunteer. The kinetic data obtained with [2H]valproic acid was consistent with previously reported values for valproic acid including kinetic differences observed between single-dose and steady-state experiments. Saliva levels of valproic acid were found to give a good correlation (r = 0.953) with total serum valproic acid under multiple-dose conditions. A concentration dependence was found for the ratio of saliva valproic acid to free valproic acid in serum, low ratios being observed at high serum concentrations of valproic acid.     

Pain in nursing home residents: management strategies

Pain is prevalent and undertreated in nursing home residents, despite the existing wide array of effective pharmacological and nonpharmacological treatment modalities. In order to improve the quality of life of these vulnerable individuals, practitioners require education about the correct approach to assessment and management. Assessment should be comprehensive, taking into account the basic underlying pathology (e.g. osteoarthritis, osteoporosis, peripheral neuropathy, fibromyalgia, cancer) as well as other contributory pathology (e.g. muscle spasm, myofascial pain) and modifying comorbidities (e.g. depression, anxiety, fear, sleep disturbance). Pharmacological management should be guided by a stepped-care approach, modelled after that recommended by the World Health Organization for treatment of cancer pain. Nonopioid and opioid analgesics are the cornerstone of pharmacological pain management. Tricyclic antidepressants and anticonvulsants can be very effective for the treatment of certain types of neuropathic pain. In addition to treating the pain per se, attention should be given to prevention of disease progression and exacerbation, as maintaining function is of prime importance. Nursing home residents with severe dementia challenge the practitioner's pain assessment skills; an empirical approach to treatment may sometimes be warranted. The success of treatment should be measured by improvement in pain intensity as well as physical, psychosocial and cognitive function. Effective pain management may impact any or all of these functional domains and, therefore, substantially improve the nursing home resident's quality of life.     

The relationship of an anticholinergic rating scale with serum anticholinergic activity in elderly nursing home residents

ndings support the validity of the CR-ACh-mod. However, unexplained variance in SAA suggests that the CR-ACh-mod could benefit from improvements. Future research will evaluate the effect of including factors such as dose and the relative anticholinergic burden from drugs at each of the rating levels. An alternative explanation for the variance which is supported by recent research is that nondrug factors contribute to SAA.     

Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients

BACKGROUND: Therapeutic drug monitoring of mycophenolic acid (MPA) may minimise the risk of acute rejection after transplantation. Area under the curve (AUC) rather than trough concentration-based monitoring is recommended and models for AUC estimation are needed. OBJECTIVES: To develop a population pharmacokinetic model suitable for Bayesian estimation of individual AUC in stable renal transplant patients. PATIENTS AND METHODS: The population pharmacokinetics of MPA were studied using nonlinear mixed effects modelling (NONMEM) in 60 patients (index group) receiving MPA on a twice-daily basis. Ten blood samples were collected at fixed timepoints from ten patients and four blood samples were collected at sparse timepoints from 50 patients. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements and covariates. The predictive performances of the Bayesian procedure were evaluated in an independent group of patients (test group) comprising ten subjects in whom ten blood samples were collected at fixed timepoints. RESULTS: A two-compartment model with zero-order absorption best fitted the data. Covariate analysis showed that bodyweight was positively correlated with oral clearance. However, the weak magnitude of the reduction in variability (from 34.8 to 28.2%) indicates that administration on a per kilogram basis would be of limited value in decreasing interindividual variability in MPA exposure. Bayesian estimation of pharmacokinetic parameters using samples drawn at 20 minutes and 1 and 3 hours enabled estimation of individual AUC with satisfactory accuracy (bias 7.7%, range of prediction errors 0.43-15.1%) and precision (root mean squared error 12.4%) as compared with the reference value obtained using the trapezoidal method. CONCLUSION: This paper reports for the first time population pharmacokinetic data for MPA in stable renal transplant patients, and shows that Bayesian estimation can allow accurate prediction of AUC with only three samples. This method provides a tool for therapeutic drug monitoring of MPA or for concentration-effect studies. Its application to MPA monitoring in the early period post-transplantation needs to be evaluated.     

HPLC法测定丙戊酸的血药浓度

目的：建立快速柱前衍生-高效液相色谱法测定丙戊酸（VPA）血药浓度的方法。方法：选择ω-溴苯乙酮为衍生试剂,环己烷羧酸为内标,Hypersil ODS-C18柱（250mm×4．6mm,5μm）为分析柱;流动相为甲醇-水（75：25,V／V）,检测波长为248nm,流速为1．0ml／min。血样经酸化后以二氯甲烷提取。结果：内标环己烷羧酸和VPA的保留时间分别为8．0min和12．8min,线性范围为25～200μg／ml,平均回收率为100．61％,日内、日间RSD均小于4．19％。结论：本法快速、简便、准确,适合临床常规监测需要。     

Occurrence of potential drug-drug interactions in nursing home residents

Objective — It has been suggested that elderly people are at increased risk of drug-related problems such as drug-induced adverse effects, drug-drug interactions and drug-disease interactions. This is particularly the case for nursing home residents because of the often complicated and multiple co-morbidity that occurs in these people. The aim of this study was to develop prescribing indicators to assess systematically the occurrence and nature of potential drug-drug interactions (DDIs) in a cohort of Dutch nursing home residents. Method — The study was conducted in residents aged 65 years and over in six nursing homes (n=2,355, two-year study period). Computerised medication data for the residents were evaluated with respect to co-prescribing of potentially interacting drugs. All DDIs that were classified as clinically relevant according to the Dutch National Drug Interaction Database were studied. DDIs were classified into three categories according to their pharmacological mechanism: 1 — pharmacokinetic interactions at the level of gastrointestinal (GI) absorption; 2 — pharmacokinetic interactions at the level of metabolism and excretion; and 3 — pharmacodynamic interactions. Key findings — Thirty-two per cent (n=748) of all residents were exposed to one or more combinations of drugs that could lead to clinically adverse outcomes. The numbers of residents who received drug combinations with a mechanism of interaction from category 1, 2 or 3 were 73 (3 per cent), 164 (7 per cent) and 612 (26 per cent) respectively. The number of medications prescribed was significantly associated with the occurrence of a potential DDI (P<0.05). Drugs most frequently involved were oral anticoagulants, antibiotics and theophylline. Conclusion — During the two-year study period, about one-third of the residents were exposed to at least one drug interaction considered clinically relevant. Adequate surveillance systems are needed to enable better identification of these interactions with a view to preventing potential clinical problems. Using the prescribing indicators developed in this study, such surveillance could focus on detection and clinical aspects of potential DDIs and possible alternative treatments.     

Use of psychotropic drugs in elderly nursing home residents with and without dementia in Helsinki, Finland

OBJECTIVE: Use of psychotropic medication is very common in nursing home residents. Our objective was to describe the use of psychotropic drugs in all long-term nursing home residents > or =65 years of age with and without dementia in Helsinki, Finland. METHOD: The study was a cross-sectional assessment of the nursing home population. The residents' health status was assessed and data on their demographic factors, health and medication use were collected from medical charts in February 2003. RESULTS: Of all nursing home residents in Helsinki, 82% (n = 1987) participated in the study. The nursing home residents' mean age was 83.7 (SD 7.7) years, 80.7% were female, and 69.5% were diagnosed with dementia. The mean number of drugs [corrected] given regularly was 7.9 (SD 3.6) per day per resident[corrected] Of the participants, 79.7% were regularly taking psychotropic medication. Conventional antipsychotics were administered to 18.9% of residents and atypical antipsychotics to 27.0%. Of the residents, 26.7% were on selective serotonin reuptake inhibitors (SSRIs), 3.1% on tricyclic antidepressants and 17.6% on other antidepressants. Altogether, 44.6% of residents were taking one or more antidepressant. More than a quarter (26.3%) were taking at least one anxiolytic drug. Hypnotics were used by 27.5%. However, only moderate dosages of psychotropic drugs were being taken. Only 10.4% of individuals with dementia were regularly taking cholinesterase inhibitors and four residents were taking memantine. CONCLUSIONS: Use of psychotropic drugs is very common in nursing homes in Helsinki, Finland, with four of five nursing home residents regularly receiving psychotropic drugs. Only one in ten residents were receiving cholinesterase inhibitors. Physicians caring for nursing home residents require further education on the benefits and adverse effects of psychotropic drugs in frail elderly people.     

Quality of psychopharmacological medication use in nursing home residents

BackgroundDespite well-documented evidence regarding antipsychotic use in older adults residing in nursing homes (NHs), there is a lack of evidence-based use and quality benchmarks for other psychopharmacological medications (PPMs), including antidepressants, anxiolytics, and sedative-hypnotics.ObjectiveTo estimate the prevalence and patterns of use of PPMs and to measure the quality of PPM use.MethodsUsing a 5% random sample of 2007 Medicare claims data linked to the Minimum Data Set 2.0, this cross-sectional study identified a nationally representative sample of 69,832 NH residents with ≥3 months of institutionalization. This study measured 1-year prevalence and quality of PPM use, as assessed by indication, dose, and duration of use defined and operationalized according to the current Centers for Medicare and Medicaid Services Unnecessary Medication Guidance for Surveyors and relevant practice guidelines.ResultsOver two-thirds of residents (72.1%, n=50,349) used ≥1 PPM in 2007, with the highest prevalence seen in antidepressants (59.4%), and the lowest in anxiolytics (8.9%). Almost two-thirds (61.0%) of PPM users used ≥2 PPM classes. Compared to other PPM therapeutic classes, antipsychotic users had greatest evidence of guideline adequate use by indication (95.8%) and dose (78.7%). In addition, longer duration of adequate treatment was observed among antipsychotic users (mean = 208 days, standard deviation [SD] = 118) as compared to anxiolytic (mean = 159 days, SD = 118) and sedative-hypnotic users (mean = 183 days, SD = 117).ConclusionsThis study found that PPM use remains highly prevalent among long-stay Medicare NH residents. While antipsychotic use remained high (31.5%), little antipsychotic use was deemed inadequate by indication. However, the 1-year prevalence of use, dose, and duration of use of other PPMs remain high and potentially inadequate. Practitioners and policy-makers should heed both the high use and lower prescribing quality of antidepressants, anxiolytics, and sedative-hypnotics in NH residents.     

Analysis of drug-drug interactions among nursing home residents

The extent of clinically important drug-drug interactions in the patient population of a nursing home was studied. The administration of medications to all 138 residents of two wards of the hospital-affiliated facility was monitored for 15 days through a review of nurses' medication-administration records and patients' charts. Information on the nature and timing of administered drug combinations was compared with published information to identify potential drug interactions. If a serious drug interaction was suspected, the recorded information was verified through the nurse in charge of that patient. Few of the drug interactions commonly reported to occur in nursing homes were observed at the facility, where drug therapy is monitored by a team of geriatric practitioners that includes two pharmacists. Of the 24 suspected interactions that were identified, 11 had potential clinical importance, and all 11 involved drug combinations that could alter the metabolism or action of one of the drugs. However, only two patients were exposed to any substantial degree of risk, and dosages of the drugs involved were adjusted. An additional 13 patients were taking a combination of drugs that could have altered the intestinal absorption of one of the drugs. Careful timing of drug administration avoided this potential problem. With proper education of the nursing staff, immediate clarification of medication orders, and optimal timing of drug administration, many clinically important drug-drug and drug-food interactions can be avoided in nursing home patients.     

First-dose and steady-state pharmacokinetics of valproic acid in children with seizures

The serum concentration-time curve of valproic acid was followed in 25 children after single oral doses of the drug and at steady-state. Total body clearance (CL), half-life (t 1/2), and apparent volume of distribution (Vd) were calculated from the terminal portion of the curve and from the area under the serum concentration-time curve (AUC). The CL and Vd were significantly greater at steady-state (0.42 +/- 0.20 ml/min/kg and 0.231 +/- 0.067 L/kg, respectively) than after a single dose (0.32 +/- 0.13 ml/min/kg and 0.191 +/- 0.055 L/kg, respectively). This difference was most pronounced in patients with valproic acid dosage increases in excess of 20% and no change in their concurrent anticonvulsant therapy between the single-dose and steady-state study periods. The t 1/2 was not significantly different between the 2 study periods. There was a significant correlation between age and both CL and Vd after single doses and at steady-state. The t 1/2 did not appear to be age related. These results suggest that the adequacy of the dosage regimen must be determined during maintenance therapy rather than extrapolated from data obtained after a single dose. Re-evaluation of therapy as the child grows older may also be necessary in view of the age-related differences in valproic acid pharmacokinetics which this study has demonstrated.