Sweat testing for the detection of atomoxetine from paediatric patients with attention deficit/ hyperactivity disorder: application to clinical practice

Atomoxetine (ATX) is a selective norepinephrine reuptake inhibitor approved since 2002 for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents, and adults as an alternative treatment to methylphenidate. Within the framework of a project evaluating the use of alternative biological matrices for therapeutic monitoring of psychoactive drugs in paediatric and non‐paediatric individuals, the excretion of ATX and its principal metabolites has been recently studied in oral fluid and hair. The aim of this study was to describe the excretion profile of ATX and its metabolites 4‐hydroxyatomoxetine (4‐OH‐ATX) and N‐desmethylatomoxetine (N‐des‐ATX) in sweat following the administration of different dosage regimens (60, 40, 35, and 18 mg/day) of ATX to six paediatric patients. Sweat patches were applied to the back of each participant and removed at timed intervals. ATX and its metabolites were measured in patches using a previously validated liquid chromatography‐tandem mass spectrometric (LC‐MS/MS) method. Independently from the administered dose, ATX appeared in the sweat patches 1 h post administration and reached its maximum concentration generally at 24 h. Peak ATX concentrations ranged between 2.31 and 40.4 ng/patch and did not correlate with the administered drug dose, or with body surface area. Total ATX excreted in sweat ranged between 0.008 and 0.121 mg, corresponding to 0.02 and 0.3% of the administered drug. Neither 4‐OH‐ATX, nor N‐des‐ATX was detected in either of the collected sweat patches. Measuring ATX in sweat patches can provide information on cumulative drug use from patch application until removal. Copyright © 2012 John Wiley & Sons, Ltd.     

In Situ Monitoring and Modeling of the Solution-Mediated Polymorphic Transformation of Rifampicin: From Form II to Form I

In this article, the solution-mediated polymorphic transformation of rifampicin was investigated and simulated in 3 solvents at 30°C. The solid-state form I and form II of rifampicin was characterized by powder X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, Raman spectroscopy, and Fourier transform infrared spectroscopy (FTIR). To explore the relative stability, solubility data of form I and form II of rifampicin in butan-1-ol were determined using a dynamical method. In addition, Raman spectroscopy and focused beam reflectance measurement were used to in situ monitor the transformation of rifampicin from form II to form I. The liquid state concentration of rifampicin was measured by UV spectroscopic method. To investigate the effect of solvent on transformation, the transformation experiments were carried out in 3 solvents. Furthermore, a mathematical model was built to describe the kinetics of dissolution, nucleation, and growth processes during transformation by using experimental data. By combination of experimental and simulation results, it was found that the transformation process of rifampicin is controlled by dissolution of form II in heptane, whereas the transformation in hexane and octane was firstly controlled by dissolution of solid-state form and then controlled by growth of form I.     

Population Pharmacokinetic/Pharmacodynamic Modeling of Systemic Corticosteroid Inhibition of Whole Blood Lymphocytes: Modeling Interoccasion Pharmacodynamic Variability

Purpose To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness. Materials and Methods Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five - way crossover, placebo - controlled study. Measurements included plasma drug and cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP). Population data analysis was performed using a Monte Carlo-Parametric Expectation Maximization algorithm. Results The final indirect, multi-component, mechanism-based model well captured the circadian rhythm exhibited in cortisol production and suppression, lymphocyte trafficking, and WBLP temporal profiles. In contrast to PK parameters, variability of drug concentrations producing 50% maximal immunosuppression (IC₅₀) were larger between subjects (73–118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC₅₀ for ex vivo WBLP were highly correlated with those determined in vitro for the four drugs (r ²  = 0.928). Conclusions The immunosuppressive dynamics of the four corticosteroids was well described by the population PK/PD model with the incorporation of inter-occasion variability for several model components. This study provides improvements in modeling systemic corticosteroid effects and demonstrates greater variability of system and dynamic parameters compared to pharmacokinetics. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

低血糖昏迷临床分析

目的 探讨低血糖昏迷的临床分析。方法 对1999年～2002年收治的各种原因所致的低血糖昏迷20例进行回顾性分析。结果 20例患者中有18例经有效治疗后意识转清醒，二例误诊。结论 详细询问病史，分析发病原因早期治疗是抢救成功的关键。     

数学建模思想在普通医学院校数理统计教学中渗透的探索

探讨在医药数理统计教学中渗透数学建模思想的重要性及意义,通过实例阐述如何把数学建模思想渗透到数理统计教学中,激发学生学习兴趣,培养学生应用能力和创新意识。     

In Vivo Reversibility of the Jejunal Glucose and Cation Transport Alteration Caused by Intraluminal Surfactants in the Rat

Abstract Tied jejunal loops in anaesthetized rats were under standardized conditions pre-exposed for 30 min. with Tyrode solution containing surfactants. 5, 20 or 150 min. after wash out of bulk surfactant, the loops were re-instilled with Tyrode containing glucose at 5–15 mmol/l. Net glucose, sodium and potassium transport were studied for 15 min. by changes in intraluminal amounts, and compared with results obtained in control rats. The surfactants (mmol/l) tested were the anionics dioctylsulphosuccinate (5.6) and dodecylsulphate (8.5–17), the cationics cetrimonium bromide (2.1–4.1) and benzalkonium chloride (2.1), the nonionics Triton X100 (0.25%) and Lubrol WX (0.25–0.5%) plus cholic acid (4.9) and desoxycholic acid (1.3–2.5). In most cases, the glucose transport was normal or fairly normal after 150 min., most of the restoration taking place shortly after surfactant removal. However, Lubrol in particular caused more irreversible effects. Generally, the changes in net cation transport tended to be less easily reversible than the alteration in glucose transport. In so far as a normal or near to normal glucose transport is unlikely to occur unless both functional and structural integrity of the epithelium is preserved, the results indicate that in most cases there is but insignificant epithelial damage under the experimental conditions. Since, furthermore, these surfactants can interact with glucose transport in the same technique even at lower concentration and shorter incubation time than used here, it is concluded that the interaction of surfactants with intestinal transport is not neccessarily linked to gross histo-pathological changes.     

瑞格列奈对糖耐量减低患者的干预治疗

目的:本文探讨胰岛素早期分泌改善治疗对糖耐量减低的干预疗效.方法:对60例糖耐量减低患者随机分组,进行饮食、运动或瑞格列奈干预治疗.结果:对照组(饮食、运动组)血糖、胰岛素轻度下降,无统计学差异(P＞0.05);治疗组(小剂量瑞格列奈组)血糖、胰岛素显著下降(P＜0.05),有统计学意义.结论:小剂量瑞格列奈能改善糖耐量减低患者的糖耐量,使其恢复正常糖耐量状态.     

Intestinal Absorptive Transport of the Hydrophilic Cation Ranitidine: A Kinetic Modeling Approach to Elucidate the Role of Uptake and Efflux Transporters and Paracellular vs. Transcellular Transport in Caco-2 Cells

Purpose The mechanism of intestinal drug transport for hydrophilic cations such as ranitidine is complex, and evidence suggests a role for carrier-mediated apical (AP) uptake and saturable paracellular mechanisms in their overall absorptive transport. The purpose of this study was to develop a model capable of describing the kinetics of cellular accumulation and transport of ranitidine in Caco-2 cells, and to assess the relative contribution of the transcellular and paracellular routes toward overall ranitidine transport. Methods Cellular accumulation and absorptive transport of ranitidine were determined in the absence or presence of uptake and efflux inhibitors and as a function of concentration over 60 min in Caco-2 cells. A three-compartment model was developed, and parameter estimates were utilized to assess the expected relative contribution from transcellular and paracellular transport. Results Under all conditions, ranitidine absorptive transport consisted of significant transcellular and paracellular components. Inhibition of P-glycoprotein decreased the AP efflux rate constant (k₂₁) and increased the relative contribution of the transcellular transport pathway. In the presence of quinidine, both the AP uptake rate constant (k₁₂) and k₂₁ decreased, resulting in a predominantly paracellular contribution to ranitidine transport. Increasing the ranitidine donor concentration decreased k₁₂ and the paracellular rate constant (k₁₃). No significant changes were observed in the relative contribution of the paracellular and transcellular routes as a function of ranitidine concentration. Conclusions These results suggest the importance of uptake and efflux transporters as determinants of the relative contribution of transcellular and paracellular transport for ranitidine, and provide evidence supporting a concentration-dependent paracellular transport mechanism. The modeling approach developed here may also be useful in estimating the relative contribution of paracellular and transcellular transport for a wide array of drugs expected to utilize both pathways.     

Effects of Hangover on Psychomotor Skills Related to Driving: Modification by Fructose and Glucose

Abstract Thirty healthy male volunteers drank ethyl alcohol (1.75 g/kg) from 6 p. m. to 9 p. m., which resulted in hangover the next morning, and 10 subjects served as controls. The twenty subjects, who drank alcohol, received glucose or fructose during the same evening (1.0 g/kg) or on the following morning (0.5 g/kg). In the hangover phase psychomotor performance was recorded by a choice reaction test, two coordination tests and an attention test. The intensity of the hangover was graded subjectively and objectively. Blood ethanol, acetaldehyde and glucose concentrations were analysed. The testing procedure was repeated at 8, 10 and 12 a. m. Ethanol, administered alone, increased significantly the number of mistakes on the choice reaction test in hangover phase, but this effect was abolished by the simultaneous administration of sugar. On the other hand, after the combined administration of ethanol and sugars the number of mistakes and mistake percentage on one coordination test were increased. The etiology on the impaired psychomotor skill during the hangover period is probably not directly related to the pathophysiology of the hangover, as there was no correlation between the impairment of the psychomotor performance and the intensity of the hangover of the subjects.     

Dissolution of lonizable Drugs into Unbuffered Solution: A Comprehensive Model for Mass Transport and Reaction in the Rotating Disk Geometry

A model has been developed to describe the mass transport and reaction of ionizable compounds where mass transfer is caused by convection and diffusion from a rotating disk. Dissolution rates of benzoic acid, 2-naphthoic acid, and indomethacin in aqueous solutions of high ionic strength (I = 0.5 with potassium chloride) at 25°C were investigated. The model includes the effects of diffusion, convection, and simultaneous acid/base reaction at all points in the region adjacent to the dissolving solid. The solution of the transport equations is obtained numerically with an iterative algorithm which uses (a) closure of all material balances and (b) equilibria at the solid/liquid surface as constraints. The model solution yields both the flux of the dissolving acid and the concentration profile of each component. Reduced values of all reaction rate constants are used in the region adjacent to the dissolving surface to allow convergence of the computation. Although nonequilibrium concentration values are calculated, it is shown that the theoretical dissolution rate determined as the solution of the model is insensitive to the magnitude of the rate constants as their maximum useable values are approached. Comparisons of the model results with experimentally determined fluxes show close agreement and confirm that the transport mechanisms in the model formulation are consistent with the measured values. Further, the inclusion of convection allows accurate calculations without utilization of an arbitrary boundary layer thickness. Accurate dissolution rates can be determined using this technique under a wide range of conditions, except at low pH.     

Modeling Circadian Rhythms of Glucocorticoid Receptor and Glutamine Synthetase Expression in Rat Skeletal Muscle

Purpose The circadian rhythm of endogenous corticosterone (CS) may produce fluctuations of downstream gene expression in normal rats. This study examined changes in glucocorticoid receptor (GR) and glutamine synthetase (GS) expression in rat skeletal muscle in relation to plasma CS over a 24-h period. Methods Fifty-four normal male Wistar rats were sacrificed at 18 time points (n = 3) over 24 h. Plasma CS concentrations and gastrocnemius muscle GR and GS mRNA and GS activity were measured. Results The circadian rhythm of plasma CS was captured by a two-harmonic function. The expression of GR and GS mRNA and GS activity follow a circadian rhythm in normal rat skeletal muscle. GR mRNA reaches a trough at 4 h after the peak of plasma CS and it fluctuates between 0.55 and 0.9 fmol g tissue⁻¹. GS mRNA and activity reach peaks at 6 and 12 h after the endogenous CS peak. GS mRNA oscillates between 3 and 6 fmol g tissue⁻¹, whereas GS activity fluctuates between 17 and 23 μmol min⁻¹ g protein⁻¹. Mechanistic receptor/gene-mediated pharmacodynamic models were applied to describe the temporal patterns of GR mRNA, GS mRNA, and GS activity within the circadian cycle. Conclusions The integrated models were able to capture the circadian expression patterns of plasma CS, and GR and GS in normal rat skeletal muscle showing a dependence of tissue gene expression on plasma CS.     

Determining Dermal Absorption Parameters in Vivo From Tape Strip Data

Purpose: Tape stripping the outermost skin layer, the stratum corneum (sc), is a popular method for assessing the rate and extent of dermal absorption in vivo. Results from tape strip (TS) experiments can be affected significantly by chemical diffusion into the sc during the time required to apply and remove all of the TSs, t_TS. Here, we examine the effects of this problem on the interpretation of TS experimental results. Methods: Dermal absorption of 4-cyanophenol (4CP) in humans was studied using TS experiments to assess conditions in which diffusion alters TS results. Mathematical models were developed to assess the effects of diffusion on parameter estimation. Results: For an experiment with t_TS > t_lag (i.e., the lag time for a chemical to cross the sc), the permeability coefficient for 4CP, P_sc,v, calculated including t_TS, was consistent with values from the literature (i.e., 0.0019 cm/h). When diffusion during stripping was not included in the model, P_sc,v was 70% smaller. Conclusions: Calculations show that chemical concentrations in TSs can be affected by diffusion during tape stripping, but if t_TS < 0.2 t_lag and the exposure time is > 0.3 t_lag, TS concentrations are not significantly affected by t_TS.     

Systemic molecular and cellular changes induced in rats upon inhalation of JP-8 petroleum fuel vapor

Limited information is available regarding systemic changes in mammals associated with exposures to petroleum/hydrocarbon fuels. In this study, systemic toxicity of JP-8 jet fuel was observed in a rat inhalation model at different JP-8 fuel vapor concentrations (250, 500, or 1000?mg/m³, for 91 days). Gel electrophoresis and mass spectrometry sequencing identified the α-2 microglobulin protein to be elevated in rat kidney in a JP-8 dose-dependent manner. Western blot analysis of kidney and lung tissue extracts revealed JP-8 dependent elevation of inducible heat shock protein 70 (HSP70). Tissue changes were observed histologically (hematoxylin and eosin staining) in liver, kidney, lung, bone marrow, and heart, and more prevalently at medium or high JP-8 vapor phase exposures (500–1000?mg/m³) than at low vapor phase exposure (250?mg/m³) or non-JP-8 controls. JP-8 fuel-induced liver alterations included dilated sinusoids, cytoplasmic clumping, and fat cell deposition. Changes to the kidneys included reduced numbers of nuclei, and cytoplasmic dumping in the lumen of proximal convoluted tubules. JP-8 dependent lung alterations were edema and dilated alveolar capillaries, which allowed clumping of red blood cells (RBCs). Changes in the bone marrow in response to JP-8 included reduction of fat cells and fat globules, and cellular proliferation (RBCs, white blood cells-WBCs, and megakaryocytes). Heart tissue from JP-8 exposed animals contained increased numbers of inflammatory and fibroblast cells, as well as myofibril scarring. cDNA array analysis of heart tissue revealed a JP-8 dependent increase in atrial natriuretic peptide precursor mRNA and a decrease in voltage-gated potassium (K+) ion channel mRNA.     

Comparative toxicity and biochemical responses of certain pesticides to the mature earthworm Aporrectodea caliginosa under laboratory conditions

This study was conducted to investigate the toxicity of aldicarb, cypermethrin, profenofos, chlorfluazuron, atrazine, and metalaxyl toward mature Aporrectodea caliginosa earthworms. The effects of the LC(25) values of these pesticides on the growth rate in relation to glucose, soluble protein, and activities of glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), acid phosphatase (AcP), and alkaline phosphatase (AIP) were also studied. The results showed that aldicarb was the most toxic of the tested pesticides, followed in order by cypermethrin, profenofos, chlorfluazuron, atrazine, and metalaxyl. A reduction in growth rate was observed in all pesticide-treated worms, which was accompanied by a decrease in soluble protein and an increase in transaminases and phosphatases. Relationships between growth rate, protein content, transaminases, and phosphatases provided strong evidence for the involvement of pesticidal contamination in the biochemical changes in earthworms, which can be used as a bioindicator of soil contamination by pesticides.     

Glucose and Cation Transport in Rat Jejunum,Ileum and Colon in vivo: Effects of Anionic and Nonionic Surfactants,and of Desoxycholate

Abstract Osmotically balanced solutions of glucose (0.5–300 mM) and sodium chloride, containing surfactants, were instilled into the small or large intestine of anaesthetized rats. Net absorption or secretion of glucose, sodium and potassium was studied. The surfactants tested were dodecylsulphate (3.4–17 mM), dioctyl-sulphosuccinate (1.8–11 m/M), Lubrol WX (0.1–0.5%), Triton × 100 (0.25%) and desoxycholate (2.5 mM). Qualitatively, the results were similar to those obtained previously with cationic compounds, suggesting a common mode of action for all surfactants studied. 17 mM dodecylsulphate seemed to abolish completely physiological glucose transport in the jejunum and ileum. At a lower concentration, and with the other surfactants, normal glucose transport was affected to an intermediate extent.     

Skin Mini-Erosion Sampling Technique: Feasibility Study with Regard to Serial Glucose Measurement

Purpose. To describe a dermally non-invasive serial sampling technique and to test its clinical feasibility with regard to glucose measurement. Methods. A standardized skin mini-erosion devoid of the epidermal barrier, and covered by an artificial one, was formed by a suctioning technique. Interstitial fluid (IF) was extracted serially by brief application of negative pressure, and its glucose content compared with that in capillary or venous blood samples. Results. The procedure caused no discomfort. The epidermis regenerated rapidly after experimentation. There were no complications. In non-diabetic subjects (n = 13) the mean of all IF values measured daily for 6 days was 6.2 ± 0.1 mmol/1 (±SE). The corresponding capillary blood glucose value was 5.6 ± 0.1 mmol/1, and the venous glucose value was 5.4 ± 0.1 mmol/1. The differences between IF glucose values and invasive control values remained within narrow limits throughout. The 2SD limits of agreement for the differences were 1.44 mmol/1 (IF vs. capillary blood samples) and 1.76 mmol/1 (IF vs venous samples) respectively. The OGTT curves suggested glucose kinetics to be similar in IF and in capillary blood. In diabetic subjects, the mean of IF values determined serially during one day was 15.3 ± 1.0 mmol/1 (range, 6.7–21.8 mmol/1), and the corresponding mean capillary value was 12.0 ± 0.9 mmol/1 (range, 3.3–17.2 mmol/1). The ICC for all paired photometric observations was 0.948. Conclusions. The results suggest the new sampling technique to be a feasible approach for clinical and experimental purposes. A functionally integrated sampling patch is entering the clinical testing stage.     

Atmospheric Spray Freeze-Drying: Numerical Modeling and Comparison With Experimental Measurements

Atmospheric spray freeze-drying (ASFD) represents a novel approach to dry thermosensitive solutions via sublimation. Tests conducted with a second-generation ASFD equipment, developed for pharmaceutical applications, have focused initially on producing a light, fine, high-grade powder consistently and reliably. To better understand the heat and mass transfer physics and drying dynamics taking place within the ASFD chamber, 3 analytical models describing the key processes are developed and validated. First, by coupling the dynamics and heat transfer of single droplets sprayed into the chamber, the velocity, temperature, and phase change evolutions of these droplets are estimated for actual operational conditions. This model reveals that, under typical operational conditions, the sprayed droplets require less than 100 ms to freeze. Second, because understanding the heat transfer throughout the entire freeze-drying process is so important, a theoretical model is proposed to predict the time evolution of the chamber gas temperature. Finally, a drying model, calibrated with hygrometer measurements, is used to estimate the total time required to achieve a predefined final moisture content. Results from these models are compared with experimental data.     

Mathematical Modeling to Reduce Waste of Compounded Sterile Products in Hospital Pharmacies

In recent years, many US hospitals embarked on “lean” projects to reduce waste. One advantage of the lean operational improvement methodology is that it relies on process observation by those engaged in the work and requires relatively little data. However, the thoughtful analysis of the data captured by operational systems allows the modeling of many potential process options. Such models permit the evaluation of likely waste reductions and financial savings before actual process changes are made. Thus the most promising options can be identified prospectively, change efforts targeted accordingly, and realistic targets set. This article provides one example of such a datadriven process redesign project focusing on waste reduction in an in-hospital pharmacy. A mathematical model of the medication prepared and delivered by the pharmacy is used to estimate the savings from several potential redesign options (rescheduling the start of production, scheduling multiple batches, or reordering production within a batch) as well as the impact of information system enhancements. The key finding is that mathematical modeling can indeed be a useful tool. In one hospital setting, it estimated that waste could be realistically reduced by around 50% by using several process changes and that the greatest benefit would be gained by rescheduling the start of production (for a single batch) away from the period when most order cancellations are made.     

急进与久居高原者血糖、血脂和电解质变化对复方甲基异噁唑片药动学影响

目的 研究急进与久居高原者血糖、血脂和电解质含量变化对复方甲基异噁唑片药动学影响。方法 采用高效液相色谱法测定平原、急进高原和久居高原3组2个群体健康汉族男性青年志愿者口服单剂量复方甲基异噁唑片前后15个时间点血浆药物浓度。应用全自动生化仪测定3组血糖、血脂和电解质含量。采用DAS 2.0和SPSS 13.0统计软件计算3组受试者口服复方甲基异噁唑片后磺胺甲噁唑的药动学和血糖、血脂和电解质参数。结果 急进高原组和久居高原组受试者的药动学参数Ke、MRT、t_1/2、Cl与平原组相比有显著性差异,急进高原组t_1/2、V与久居高原组相比有显著性差异。久居高原组血糖和血脂含量高于平原组和急进高原组,载脂蛋白含量A则显著减少(P均<0.01)。急进高原组K含量增加,与平原组相比有统计学意义(P<0.05)。久居高原组Cl和Ca与急进高原组相比差异显著(P分别<0.05和0.01),急进高原组与久居高原组P均低于平原组(P<0.01)。葡萄糖(GLU)和胆固醇(TCH)与t_1/2正相关,APOA与t_1/2和V/F负相关(P<0.01)。K和Ca与AUC正相关(P分别小于0.05和0.01),与Cl/F和V/F负相关(P分别小于0.05和0.01)。Cl与V/F负相关(P<0.05)。结论 急进与久居高原者血糖、血脂和电解质含量变化对复方甲基异噁唑片药动学有显著影响。