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The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence.

ABSTRACTObjective:To determine the association between incident proton pump inhibitor (PPI) use and Clostridium difficileinfections across multiple countriesMethod:National data covering the total population in Australia and Korea, the Canadian population over 65 years and a 3 million person random sample data set from Taiwan were assessed, as were data from a worker insurance population and a hospital inpatient/outpatient population in Japan. Sequence symmetry analysis was used to assess the association with oral vancomycin dispensing as the outcome of interest.Results:54,957 patients were included. Positive associations were observed in Australia; adjusted sequence ratio (ASR) 2.48 (95% CI 1.90, 3.12), Korea ASR 2.15 (95%CI 2.11, 2.19), Canada ASR 1.45 (95% CI 1.16, 1.79), Japan hospital dataset ASR 3.21 (95%CI 2.12, 4.55) and Japan worker insurance dataset ASR 5.40 (95% CI 2.73, 8.75). The pooled result was ASR 2.40 (95%CI 1.88, 3.05) and 3.16 (95%CI 1.95, 5.10) when limited to Japan, Korean and Taiwan. Results did not vary by individual PPI. The temporal analysis showed effects within the first two weeks of PPI initiation.Conclusion:Our study confirms the association between PPI initiation and C. difficileinfections across countries in the Asia-Pacific region.

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To present a design for Prescription-Event Monitoring in Japan (J-PEM). In J-PEM, pharmacists are asked to register patients who are prescribed the ‘test drug' or a ‘control drug' for the first time ever, the drug, and prescribing physician. Although J-PEM does not identify all users of a drug, this method provides concurrent controls. In J-PEM, a questionnaire for the pharmacist and one for the prescribing physician are mailed 6 months after the drug to be monitored is first prescribed to a patient. Doctors and pharmacists are asked to report events that occurred in the patient after the drug was prescribed. The questionnaire for the physician includes questions that are specific to the class of drug that was prescribed, to obtain information on possible confounding variables. Pharmacists are requested to give information on all concomitant drugs used by the patient during or for a part of the period that the patient was taking the drug to be monitored. Compared with the UK PEM, the weakness of J-PEM is its inability to identify all users of a drug, and its strengths are the availability of concurrent controls and a relatively large amount of information per patient. Copyright © 1999 John Wiley & Sons, Ltd.

The finite dose in vitro percutaneous absorption kinetics of timolol, a β-blocker, was studied. The flux of timolol across excised human abdominal cadaver skin was measured over a period of 72h following application of a 40-μm thickness patch containing 5,10, or 20% (w/v) timolol free base. Amounts of timolol in the patch and skin were also determined at 6,12,24,48, and 72h after the application of the 20% (w/v) patch. The mean diffusion and partition parameters were estimated to be 0.018h-1and 125.9 μm, respectively, using a newly developed theory. Diffusion and partition parameters were estimated using the values for amounts of a drug eventually partitioning into the perfusing water, as well as two newly proposed conceptual parameter values, AUCAvand AUCAs, which are the AUCs of drug amounts in vehicle and skin, respectively. The dose-dependent skin–timolol interaction is also discussed.

A random walk method for a diffusion equation is applied to the model for a suspension with a finite dissolution rate developed by Ayres and Lindstrom in 1977. In the method, the diffusion of dissolved drug and dissolution of crystal are calculated separately using a simple BASIC program. The random walk method strictly meets the principle of the conservation of mass as the drug amount in each sublayer rather than the concentration at each subinterval is concerned in the ointment. The model is used to analyze the release of betamethasone 17‐valerate from a pressure‐sensitive silicone adhesive into a sink. The drug release from the 1.50 mg/mL patch shows no substantial discrepancy from that predicted by the classic suspension model assuming an infinite dissolution rate. However, the classic model overestimates the release from the 3.08 and 5.88 mg/mL patches. The disagreement is lessened when the dissolution rate is assumed to be finite. However, the model does not give a perfect explanation because the drug release from the 3.08 and 5.88 mg/mL patches in the early phase is faster than the model predicts.

Summary: Routinely collected clinical data on 104 critically ill patients who had received an aminoglycoside (gentamicin or tobramycin) were evaluated using a proposed approach to forecast aminoglycoside-related nephrotoxicity. Observed steady-state peak and trough concentrations were greater than the respective predicted values when one-compartment model was assumed. This difference was particularly eminent for trough concentrations. The bias (difference between predicted and observed values) for trough concentrations was analyzed assuming tissue accumulation by an extended least-squares method to estimate population pharmacokinetics. The mean values for terminal half-life of gentamicin and tobramycin in patients who did not develop nephrotoxicity were estimated to be approximately 50 and 116 h, respectively. By using these values, the bias of trough concentration was found to be greater in patients who developed nephrotoxicity during or within 60 days after the therapy than in those who did not. Our results suggest that assessing the bias of steady-state trough concentrations of aminoglycosides can provide a useful index to forecast an aminoglycoside-induced nephrotoxicity.

The percutaneous permeation and sorption isotherm (equilibrium) profiles of betamethasone and betamethasone 17-valerate were estimated in an in vitro study with excised human skin. Corticosteroids were measured by HPLC. The stratum corneum (dry weight)/water partition coefficient of betamethasone 17-valerate was 20 times greater than that of betamethasone. Nevertheless, when aqueous saturation was maintained in the donor solution, the mean steady-state flux of betamethasone 17-valerate through split-thickness skin was 57.6 ng/cm2/h, whereas that of betamethasone was 15.2 ng/cm2/h. This was presumably because the aqueous saturation concentration of beta-methasone (60 μg/mL) was 11 times greater than that of betamethasone 17-valerate (5.4 μg/mL), so that the calculated saturation concentrations of the two corticosteroids in stratum corneum were within a factor of 2. However, the drug amounts or concentrations of the more lipophilic corticosteroid (betamethasone 17-valerate) attained in viable layers (viable epidermis and dermis) at steady state were predicted to be greater than those of the less lipophilic corticosteroid (betamethasone) when the results in the permeation and equilibrium studies were interpreted by a mathematical model. The drug distribution pattern predicted (i.e., that a more lipophilic corticosteroid preferentially partitions into viable layers) was reasonable when compared with that observed in the permeation study. The mean drug amount of betametha-sone 17-valerate in dermis was four times greater than that of betametha-sone, whereas the drug amounts of both corticosteroids in epidermis were similar to each other.

A novel method to differentiate basic vehicle models for topically applied drugs is proposed. In this method, the rate of drug release as a function of time, obtained by using a flow-through cell, is plotted on both semilogarithmic and logarithmic scales. In the Solution Case, where all of the drug is dissolved in the vehicle, the profiles become linear on the semilogarithmic scale. However, in the Suspension Case, where the initial drug amount per vehicle volume is greater than the solubility of the drug and the vehicle contains finely dispersed drug, the profiles are linear on the logarithmic scale with a slope of −0.5. They abruptly depart from this pattern upon depletion of the suspended phase. The different attributes of the profiles for the drug release rate–time curves in these two cases can be visualized more clearly when vehicle thickness and drug concentration are varied. The theoretical principles are illustrated in profiles for the drug release–rate time plots of therapeutic patches containing the beta blocker timolol. This was formulated at different concentrations in an acryl copolymer with varied thickness. The release profiles were best fitted to the Solution Case treatment of the data.

Conclusion: The histologic grades of multiple neoplastic lesions in the large intestines of 41 patients were studied. Of the 41 patients, 16 had multiple polyps, 12 each had a carcinoma as well as one or more polyps, and the remaining 13 each had two or more carcinomas. Differences in the grades of histologic atypia among multiple neoplastic lesions were minimal. Therefore, the multiple neoplastic lesions present were considered to have airsen simultaneously or successively within a relatively short period of a given patient's life, rather than randomly in different periods. Of 25 patients who had carcinomain situ or infiltrating carcinoma, 17 had accompanying precancerous conditions or carcinoma elsewhere in the large intestine, and the remaining eight had accompanying nonmalignant polyps.

n vitro percutaneous permeation of betamethasone 17- valerate through excised human skin was studied. Pressure-sensitive silicone adhesive containing betamethasone 17-valerate in suspension was used as a vehicle. Steady-state flux through the split-thickness skin was similar to that through the isolated epidermis. However, the lag-time and half-life after removal of the vehicle were longer for the splitthickness skin than from epidermis. At steady state, 37% of the drug in the split-thickness skin was partitioned in dermis. When the kinetic parameters of a simple single-layer model are defined to specify the permeability coefficient and the drug amount in skin at steady state, this model can predict the longer half-life observed for the split-thickness skin sample compared with that for epidermis. The difference between the observed and theoretical values of the half-life after removal of the vehicle was within 23%. On the other hand, the lag-time had a large variation and the simple diffusion model failed to be predictive. A single-layer model described by two or three kinetic parameters may be able to describe percutaneous permeation kinetics even when the processes after the compound permeation through stratum corneum are not negHgibte. However, it is stressed that none of the kinetic parameters inherent in this simple model directly represents one of the single physicochemical parameters, such as diffusion and partition coefficients and path length of each skin layer.

The role of viable skin layers (viable epidermis and dermis) is examined by the three-layer model using parameter values for betamethasone 17-valerate. The mathematical three-layer diffusion model indicates that the lag time and half-life after vehicle removal in epidermis and split-thickness skin are longer than those in stratum corneum without viable layers, even if drug flux at steady-state is minimally altered. The theoretical values of the lag time and half-life predicted for epidermis and split-thickness-skin samples are compatible with the values observed in another in vitro study. The results predicted by the three-layer model indicate that the simplified model (single-layer or compartment model), which regards the whole skin as one diffusion layer or one compartment, may be warranted because all three skin layers have the same half-life after vehicle removal. The parameters used in the simplified model are estimated from some of the following values directly obtainable in the experiment: flux from skin and amount in the whole skin at steady-state, lag time, and drug concentration or amount maintained to be unchanged in the donor site. However, the simplified model often cannot resolve some discrepancy between the data and model (e.g., the ratio of the half-life to lag time) even if the data may be explained by the three-layer model.

A random walk method for predicting percutaneous drug absorption pharmacokinetics was proposed. The profiles predicted by this method were compatible with those predicted by the analytical method. The random walk method is particularly useful for predicting complex processes such as repeated topical application of a drug. The amount of a drug released into skin from four therapeutic timolol patches was measured when the patches were serially applied for 2.5h each on the same site of six healthy male volunteers. On the average, 33.2, 23.4, 15.1, and 16.5% of the applied dose was released into skin from the first, second, third, and fourth patches, respectively. This pattern was comparable with the predicted profiles (43.9, 30.2, 24.4, and 21.1%) of amounts of drug which were expected to be released from the first to fourth patches into skin, respectively. The estimation method for the normalized skin–capillary boundary clearance is also described and applied in examining the percutaneous absorption of timolol. The estimated value for this parameter was much greater than the diffusion parameter, indicating that the removal process of timolol by the local circulation is much faster than the diffusion process through skin.

The possible effects of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril, a prodrug requiring hepatic de-esterification to an active angiotensin-converting enzyme (ACE) inhibitor enalaprilat, were assessed in a randomized, crossover study. Cimetidine (400 mg) or placebo was administered orally every 12 h for 3 days and on the day of a single oral administration of enalapril maleate (10 mg) to seven healthy male subjects. Serum ACE, plasma renin activity (PRA). plasma aldosterone concentration (PAC), and α-human atrial natriuretic peptide (α-hANP) were measured before and 4 h after the enalapril dosing. There were no significant differences in any serum- and urine-derived kinetic parameters of enalapril and enalaprilat, nor in hemodynamics. PAC. or α-hANP between the two treatment trials. ACE decreased and PRA increased to a similar extent in the two trials. Serum enalaprilat concentration correlated significantly (p < 0.001) with percentage of inhibition of ACE activity. The results suggest that the pharmacokinetics and pharmacodynamics of enalapril are unaffected by preadministration of cimetidine. Thus, cimetidine does not appear to alter hepatic esterase activity toward enalapril.

Kinetics and resting and exercise-induced hemodynamic and ECG effects of nicainoprol, a new antiarrhythmic structurally resembling propafenone or propranolol, were investigated in eight healthy male subjects receiving a 1-hour infusion (100 mg) and oral dose (200 mg) in a randomized-crossover fashion. Nicainoprol in plasma and urine was determined by a specific HPLC assay. Plasma concentration-time data were fitted to a triexponential equation. Mean postinfusion kinetic data were: α-phase half-life = 3.1 minutes, β-phase half-life = 106.6 minutes, and γ-phase half-life = 12.4 hours; volume of central compartment = 0.114 L/kg; steady-state volume of distribution = 0.67 L/kg; total clearance = 3.6 ml/min/kg; and renal clearance = 0.56 ml/min/kg. Absolute bioavailability was approximately 70% and peak plasma drug concentration occurred 2.3 hours after oral administration. Interindividual variability in AUC was 1.6- and 2.4-fold after intravenous and oral administration, respectively. Cumulative fraction excreted unchanged in urine was approximately 15% and 9% of the dose after intravenous and oral administration, respectively. Resting heart rates were increased, whereas exerciseinduced heart rates were unchanged after both doses. QRS durations were widened after both doses. PR and QTCintervals were prolonged during intravenous study. The results suggest that nicainoprol is an enzyme-limited or poorly extracted drug suitable for both intravenous and oral administration and devoid of β-blocking action in humans, at least with doses tested in this study. Its ECG properties appear to be similar to those of class I antiarrhythmics.

The pharmacokinetics and pharmacodynamics (blood pressure, heart rate, serum angiotensin-converting enzyme, and plasma renin activity) of enalapril and enalaprilat were studied after oral administration of enalapril maleate (10 mg) to seven biopsy-proven cirrhotic patients and to seven healthy subjects. The mean Cmax, AUC, and urinary excretion of enalapril and enalaprilat were greater and less (p < 0.01), respectively, and mean oral clearance of enalapril was less (p < 0.01) in the cirrhotic group than in the healthy group. However, there was no significant difference in the mean total drug (enalapril plus enalaprilat) excretion between the two groups. Blood pressure fell (p < 0.05) only at 3 or 4 hours postdose, with no change in heart rate in the two groups. Serum angiotensin-convering enzyme (ACE) decreased (p < 0.001) and plasma renin activity (PRA) increased (p < 0.05) in the two groups. The magnitude of the percentage of inhibition of ACE activity was comparable between the two groups. Serum enalaprilat concentration correlated (p < 0.001) with the percentage of inhibition of ACE activity. The results suggest that the bioactivation of enalapril to enalaprilat is considerably impaired in patients with cirrhosis but that the pharmacodynamic effects do not appear to be blunted in those patients. The mechanism and clinical implications remained unclear.Clinical Pharmacology and Therapeutics (1989) 45, 657–665; doi:10.1038/clpt.1989.87

Several theories describing percutaneous drug absorption have been proposed, incorporating the mathematical solutions of differential equations describing percutaneous drug absorption processes where the vehicle and skin are regarded as simple diffusion membranes. By a solution derived from Laplace transforms, the mean residence time MRTand the variance of the residence time VRTin the vehicle are expressed as simple elementary functions of the following five pharmacokinetic parameters characterizing the percutaneous drug absorption: (1) kd, which is defined as the normalized diffusion coefficient of the skin, (2) kc, which is defined as the normalized skin-capillary boundary clearance, (3) the apparent length of diffusion of the skin ld, (4) the effective length of the vehicle lv, and (5) the diffusion coefficient of the vehicle Dv. All five parameters can be obtained by the methods proposed here. Results of numerical computation indicate that: (1) concentrationdistance curves in the vehicle and skin approximate two curves which are simply expressed using trigonometric functions when sufficient time elapses after an ointment application; (2) the most suitable condition for the assumption that the concentration of a drug in the uppermost epidermis can be considered unchanged is the case where the partition coefficient between vehicle and skin is small, and the constancy of drug concentration is even more valid when the effective length of the vehicle is large; and (3) the amount of a drug in the vehicle or skin and the flow rate of the drug from vehicle into skin or from skin into blood becomes linear on a semilogarithmic scale, and the slopes of those lines are small when Dv is small, when the partition coefficient between vehicle and skin is small, when lv is large, or when kc is small. A simple simulation method is also proposed using a biexponential for the concentration-time curve for the skin near the skin-capillary boundary, that is, the flow rate-time curve for drug passing from skin into blood.

The percutaneous drug absorption process and its clinical significance are not fully known. In this article we propose a theoretical method to obtain two parameters (kdand kc) of percutaneous drug absorption from in vivodata. These parameters are related to diffusion of a drug through the skin and removal process at the skin-capillary boundary, respectively, characterizing several pharmacokinetic aspects of the drug applied to the skin. Moreover, by employing these two kinetic constants, a simulation of percutaneous drug absorption can be theoretically generated. On the basis of our theoretical considerations on the percutaneous drug absorption process described herein, we conclude that the percutaneous drug absorption process is better understood by employing two kinetic constants in a mathematical model and that its clinical application would be highly possible.

In recent years, compartment models have been advocated for percutaneous drug absorption.- However, in vitro percutaneous permeation processes where steady-state is eventually attained have long been described using Fick's Law of Diffusion. Fick's Law is also sometimes applied to in vitro and in vivo percutaneous absorption pharmacokinetics where a finite dose is given. Although both compartment and diffusion models are currently employed to describe percutaneous absorption pharmacokinetics, it is not well known whether a compartment model can substitute for a diffusion model. This communication indicates that a compartment model is roughly interchangeable with a diffusion model so that finite dose percutaneous absorption processes, including those after the removal of vehicle and repeated dosing, can be approximated by a compartment model.

The lag times and steady-state flux predicted by a specific case of the compartment model, which was recently proposed to generate finite-dose percutaneous permeation pharmacokinetics, are compared with those predicted by the diffusion model. When the intercompartmental transfer rate constants are defined so that the three statistical moments of the compartmental model (the mean residence times of a drug in the vehicle and that in the skin and the variance of residence time in the vehicle) are identical to those in the diffusion model, the lag times and steady-state flux values predicted by the two models are the same.

Ascorbate oxidase activity rapidly increased during callus formation from pumpkin fruit tissue. The activity reached a maximum at 5 days after transfer and then declined. In callus which had been subcultured at about 4-week intervals for more than one year, the activity also increased after transfer to fresh medium and reached a maximum in the early logarithmic phase of growth. Light had little effect on the appearance of ascorbate oxidase activity in pumpkin callus. In the callus grown in the presence of 10μM CuSO4, the activity was about 10 times that in the presence of 0.1 μM CuSO4, suggesting that the formaton of ascorbate oxidase in pumpkin callus is stimulated by copper, a prosthetic metal of the enzyme. From 45 to 75% of the total ascorbate oxidase activity in pumpkin cell suspension cultures was found in the medium. Ascorbate oxidase activity in the medium, as well as that in the cells, increased soon after transfer to fresh medium, and reached a maximum at about 5 days.