Collaboration across the pond: the multi-school progress testing project.

This collaborative project between the National Board of Medical Examiners and four schools in the UK is investigating the feasibility and utility of a cross-school progress testing program drawing on test material recently retired from the United States Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge (CK) examination. This article describes the design of the progress test; the process used to build, translate (localize), review, and finalize test forms; the approach taken to (web-based) test administration; and the procedure used to calculate and report scores. Results to date have demonstrated that it is feasible to use test items written for the US licensing examination as a base for developing progress test forms for use in the UK. Some content areas can be localized more readily than others, and care is clearly needed in review and revision of test materials to ensure that it is clinically appropriate and suitably phrased for use in the UK. Involvement of content experts in review and vetting of the test material is essential, and it is clearly desirable to supplement expert review with the use of quality control procedures based on the item statistics as a final check on the appropriateness of individual test items.

Corticosteroid resistance in eosinophilic gastritis--relation to in vitro eosinophil survival and interleukin 5.

Eosinophilic gastritis is usually responsive to corticosteroid therapy. In some cases, large doses and protracted treatment are required. This report describes a case of eosinophilic gastritis that was partially corticosteroid resistant. To determine mechanisms that explain this patient's incomplete response to corticosteroid therapy, peripheral blood eosinophils and serum were isolated from the patient. We found the in vitro survival of the patient's eosinophils was prolonged. In addition, his serum both promoted in vitro eosinophil survival and nullified the survival inhibiting of effect of hydrocortisone (10 microM). Furthermore, antibody against interleukin 5 (IL5) partially inhibited the enhanced eosinophil survival produced by the patient's serum and completely blocked the decrease in survival resulting from hydrocortisone. These observations indicate that elevated circulating levels of IL5 may contribute to the peripheral eosinophilia and corticosteroid resistance in some patients with eosinophilic gastritis.

Effect of age on ibuprofen pharmacokinetics and antipyretic response.

The effect of age on ibuprofen pharmacokinetics and antipyretic effect was studied in 49 infants and children aged 3 months to 10.4 years. The relationship of plasma concentration to antipyretic effect was examined in 38 of the children by using an iterative least squares technique that allows estimation of drug concentration with time in a theoretical effect compartment and rate constant for elimination of drug from the effect compartment. There was a delay of 1 to 3 hours between peak ibuprofen plasma concentration and peak temperature decrement. The mean elimination rate constant from the effect compartment was 0.6 hour-1, corresponding to a half-life of drug in the effect compartment of 1.1 hours. The mean slope of the effect compartment concentration versus temperature regression line was -0.242 degrees C/mg per liter. Age did not significantly influence the rate of absorption of ibuprofen, its plasma concentration, its rate of elimination, or the time course of ibuprofen concentration in the effect compartment. However, in younger children the onset of antipyresis was earlier, maximum antipyretic effect was greater, and the area under the curve of the percentage of change in temperature from baseline versus time was greater than in older children. We conclude that the greater relative body surface area in younger children may allow more efficient dissipation of heat in response to antipyretic-induced lowering of the temperature "set point" in the hypothalamus.

Interspecies differences in the effect of pH on gallopamil protein binding to albumin and alpha 1-acid glycoprotein.

There is little information about the factors which influence drug protein binding between species. We have therefore investigated the role of pH on the binding of gallopamil, a calcium channel antagonist known to exhibit pH-sensitive binding, among four species, human, baboon, bovine, and canine. We used pure protein solutions of alpha 1 acid glycoprotein (AAG) (60 mg.l-1), albumin (45 gm.l-1), and their combination and three values of pH, 7.0, 7.4, and 8.0. Gallopamil protein binding was determined over a concentration range of 2.0 x 10(-7) mol.l-1 to 2.1 x 10(-3) mol.l-1 using equilibrium dialysis. Gallopamil binding in all solutions was best described using a two binding site model in the combination solution and a one binding site model in the pure solutions. pH did not affect the number of identical binding sites. However, the influence of pH on gallopamil binding was species specific. Increasing the pH from 7.0 to 8.0 influenced binding affinity differently between species. There were directionally similar changes in unbound fraction at a gallopamil concentration of 2 x 10(-7) mol.l-1 as pH increased, although there were species differences in the degree of change. In protein solutions containing both AAG and albumin a reduction in pH from 7.4 to 7.0 resulted in species-specific increases in the unbound fraction. Increasing the pH from 7.4 to 8.0 again resulted in species-specific reductions in the unbound fraction of gallopamil. Similar changes were seen when pure AAG or albumin solutions were used, indicating species variance in both gallopamil protein binding and the effect of pH on binding.

Evaluation of the interaction of lithium and alprazolam.

A potential pharmacokinetic interaction between lithium and alprazolam was studied in 10 normal subjects. Pharmacokinetic parameters were determined from the following regimens: single-dose alprazolam, multiple-dose lithium, and multiple-dose alprazolam with lithium. Steady-state alprazolam clearance during multiple dosing with lithium was not different from that with the single dose of alprazolam. Lithium renal clearance decreased when it was coadministered with alprazolam (31.2 vs. 22.4 ml/minute, p less than 0.05). There was a small but significant increase in the steady-state area under the curve for lithium in the presence of alprazolam (10.3 vs. 11.1 mEq/hour/liter). The small increase in the serum lithium concentrations and decrease in lithium renal clearance was probably the result of lower urine flow rates (1.46 vs. 0.98 ml/minute, p less than 0.05) with the combination of the drugs. This is supported by a weak but significant linear relationship between urine flow rates and lithium renal clearance (N = 57, r = 0.353, p = 0.007). The percent of daily lithium dose recovered at steady-state from the 24-hour urine collection decreased significantly from 93.6% to 78.2% in the presence of alprazolam. This suggests that alprazolam may decrease lithium absorption. The results of this study do not support a definitive interaction of lithium and alprazolam and there is little clinical significance to the small rise in serum lithium concentrations.

Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine.

A study was performed to determine if the pharmacokinetics of bromocriptine is altered by factors that have been shown to interact with other ergot compounds. The effects on bromocriptine plasma concentrations by bromocriptine coadministration with caffeine and erythromycin were evaluated in five male volunteers. Serial blood samples were obtained during a 12-hour period after a single 5 mg oral dose of bromocriptine (alone and after 4-day treatments of either erythromycin estolate, 250 mg four times/day, or caffeine, 200 mg four times/day). There were no significant alterations of bromocriptine pharmacokinetic parameters after caffeine, although statistical power was very low. With the use of erythromycin, the bromocriptine area under the concentration-time curve standardized to body weight increased significantly by 268%, whereas peak bromocriptine plasma concentration (Cmax) increased to 4.6 times the Cmax from bromocriptine alone. Time to achieve Cmax was not altered by erythromycin. We conclude that erythromycin can markedly increase the systemic bioavailability of bromocriptine, which can lead to increased therapeutic or adverse effects, whereas the effects of caffeine require further study.

A survey of pharmacists recommendations for food supplements in the U.S.A. and U.K.

A survey was sent to 1,000 pharmacists in metropolitan Detroit U.S.A. (19.7% responded) and 750 pharmacists in the U.K. (57.9% responded) to assess the frequency of recommendations for health food stores, minerals, multivitamins, natural vitamins, protein supplements, Stresstabs, and weight-reduction products. Pharmacists were also asked about their five most common reasons for recommending vitamins and minerals from a list of 16 items, which included alcoholism, anaemia, arthritis, athletically active, children, colds, dieting, fatigue, feeling nervous, headaches, old age, pain, pregnancy, prophylaxis, skin problems, stress or other. About 40% of the U.S.A. community pharmacists recommended multivitamins more than five times a week compared to 28.6% of U.K. community pharmacists. Anaemia (48.6%), dieting (44.8%), alcoholism (42.3%), pregnancy (40.0%), and fatigue (36.8%) were the five most common reasons for pharmacists to recommend vitamins and minerals, this was consistent, for the most part, with the American Medical Association's Council on Scientific Affairs report, however, a large number of pharmacists placed the non-specific symptoms of fatigue and stress in the five most common reasons for which they recommend vitamins or minerals.

Pharmacists' perceptions of alternative health approaches--a comparison between U.S. and British pharmacists.

A survey was sent to 1,000 United States (U.S.) pharmacists (19.7% responded) and 750 British pharmacists (63.0% responded) to assess their perceived knowledge, perceived usefulness, referrals, and utilization of alternative health approaches (AHA). More than 50% of U.S. and British citizens had 'never heard of' or 'only heard of' about half of the 21 AHA assessed. Acupuncture was the AHA felt to be most useful by the majority of pharmacists, both in the U.S. (83.8%) and in Britain (91.0%). Osteopathy (38.6%) and chiropractic (33.5%) were most often referrals by U.S. pharmacists, whereas homeopathy (14.7%) and osteopathy (14.5%) were most often referrals by British pharmacists. The most utilized AHAs were osteopathy (21.8%) and chiropractic (19.3%) by U.S. pharmacists and homeopathy (10.1%) and herbal medicine (6.0%) by British pharmacists. Differences exist in the perceived knowledge, perception of usefulness, referrals, and utilization of AHAs between U.S. and British pharmacists. It is quite likely that the low-response rates, particularly among the U.S. pharmacists, may mask even greater ignorance about AHAs. It may also underestimate the proportion of pharmacists who are of the view that AHAs are useless and not worthy of answering questions about.

Pharmacodynamic modeling of concentration-effect relationships after controlled-release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease.

Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 micrograms/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 micrograms/ml. LD plasma concentrations fluctuating around 0.9 micrograms/ml may result in the "on/off" effects seen in Parkinson's disease.

Controlled-release carbidopa/levodopa (Sinemet 50/200 CR4): clinical and pharmacokinetic studies.

Several controlled-release carbidopa/levodopa preparations have been formulated to achieve a more stable and extended antiparkinsonian action. The most effective is Sinemet CR (Sinemet CR4), with an erodible polymer matrix that retards release of levodopa. In 19 parkinsonians with prominent dose-by-dose fluctuations, double-blind crossover trials comparing 8-week regimens of standard carbidopa/levodopa (25/100) to Sinemet CR (50/200) showed comparable clinical outcomes, with mean daily dosing for optimal control reduced from 10.2 to 5.4 (although mean daily levodopa dosage increased from 1,340 to 1,781 mg/day). Most patients improved on the Sinemet CR regimen in hours "on" and in ratings of clinical state and disability. With pharmacokinetic studies correlated to clinical ratings, plasma levodopa was less variable during Sinemet CR treatment, and clinical responses showed greater uniformity. Compared to standard Sinemet 25/100, time to peak levodopa concentration (2.3 versus 1.1 hrs), onset of maximal clinical improvement (2.2 versus 1.1 hrs), and other indices were significantly delayed with Sinemet CR. Levodopa bioavailability and clearance were similar between formulations. Although onset of clinical response is slower, the Sinemet CR formulation lessens peak-dose and "wearing-off" responses occurring with conventional carbidopa/levodopa and offers substantial improvement for some parkinsonians.

Pharmacokinetic and pharmacodynamic modeling of L-dopa plasma concentrations and clinical effects in Parkinson's disease after Sinemet.

Eleven parkinsonian patients participated in a pharmacokinetic/pharmacodynamic study in an attempt to model levodopa (L-DOPA) plasma concentrations to clinical effect. Carbidopa 25 mg/L-DOPA 100 mg (Sinemet 25/100) was given orally, and blood samples were obtained before and serially for 4 hours after the dose. Effect measurements were obtained with each blood sample and included tapping score, timed walking, and global assessment of motor function. Mean L-DOPA plasma concentrations were fitted to a one-compartment pharmacokinetic model. A time-wise plot of modeled plasma L-DOPA concentrations versus mean effect measurements revealed a counter-clockwise hysteresis. Effect compartment concentrations were determined by a least squares approach, which determined elimination rate constants by minimizing hysteresis. Half-times for the equilibration between plasma and the effect compartment were 0.39 h for tapping, 0.36 h for walking, and 0.34 h for the global score. Pharmacodynamic data were fit best with an Emax model with baseline effect for tapping (Emax = 53.2 taps/60 s, EC50 = 0.58 microgram/ml) and global score (Emax set at 5.0 by limits of scale, EC50 = 2.53 micrograms/ml). A linear model best described the relationship between predicted effect site concentration and timed walking. L-DOPA plasma concentrations after oral Sinemet did not correlate well with clinical response because clinical response lags behind plasma concentrations. Half-times for equilibration between plasma and the effect site were similar for all of the effects measured.

Elevations in thyroid-stimulating hormone in normal subjects after receiving short-term lithium carbonate.

Nine normal, healthy male subjects had significantly elevated thyroid-stimulating hormone (TSH) concentrations while receiving oral lithium carbonate for two weeks. The mean minimum lithium serum concentration was 0.765 mEq/L. The TSH concentrations after 15 days on lithium were significantly correlated to the TSH concentration at baseline. No correlation was found between mean minimum lithium steady-state concentration and TSH concentration after 15 days on lithium. Further research is necessary to determine if a high baseline TSH concentration or an early rise in TSH will predict those patients who will eventually develop hypothyroidism after long-term lithium therapy.

Comparison of three lithium dosing methods in 950 "subjects" by computer simulation.

This study compared the accuracy of the one-point method (OPM) of Cooper et al., the repeated one-point method (ROPM) using a 12 h initial dosage interval (ROPM-12), and the ROPM using a 24 h initial dosage interval (ROPM-24) for predicting lithium steady-state concentrations after lithium carbonate 600 mg every 12 h. Pharmacokinetic values for elimination rate constant (k), volume of distribution (V), and absorption rate constant (ka) were generated randomly for 950 subjects to produce normally distributed values of the parameters with target means and standard deviations in accordance with values reported in the literature. Errors with a mean of zero and a standard deviation of +/- 5% (SD5%) and +/- 10% (SD10%) were added to the calculated lithium concentrations used in the prediction methods to simulate assay and timing errors. The mean (+/- SD) values generated for k, ka, and V were 0.035 +/- 0.008 (h-1), 0.897 +/- 0.059 (h-1), and 40.97 +/- 5.27 (L), respectively. Prediction errors were smallest with the OPM (SD5%, SD10%) and ROPM-24 (SD5%). There was a significant correlation between k and the prediction error for the OPM (SD5%, SD10%) and the ROPM-24 (SD5%). The OPM was the most accurate of the methods studied; however, it tended to underpredict actual concentrations in subjects with long half-lives.

Unusual treatment response of a severe dystonia to diphenhydramine.

A 27-year-old man was admitted to the emergency department with a fluphenazine decanoate-induced dystonia. He was treated with 125 mg diphenhydramine IV in four doses and 2 mg benztropine IM. A fluctuating response was observed before continued remission of the dystonia. Possible reasons for variable patient responses to diphenhydramine are discussed.