Driving ability after acute and sub-chronic administration of levocetirizine and diphenhydramine: a randomized,double-blind,placebo-controlled trial

Rationale Sedation following antihistamine use poses a danger to ambulant patients involved in daily activities such as driving. Objective To investigate effects of levocetirizine (5 mg), diphenhydramine (50 mg), and placebo on driving ability during normal traffic. Methods Forty-eight healthy volunteers participated in a double-blind, placebo-controlled, randomized clinical trial. Treatments were administrated on days 1, 2, 3 and 4, exactly 1.5 h before the start of the standardized driving test (performed on day 1 and day 4). In the standardized driving test, subjects were instructed to drive with a steady lateral position, while maintaining a constant speed (95 km/h). Primary parameter was the standard deviation of lateral position (SDLP; cm). Statistical analyses were performed separately for day 1 and day 4, using analysis of variance and an equivalence test. Equivalence to placebo was evidenced if the 95% confidence interval lay between −2.6 cm and +2.6 cm. Results SDLP after levocetirizine was equivalent to placebo on both day 1 (−0.66 cm; +1.12 cm) and day 4 (−0.37 cm; +1.28 cm). In contrast, SDLP after diphenhydramine differed significantly from placebo on both day 1 (P<0.0001) and day 4 (P<0.0003). On day 1, the 95% confidence interval of diphenhydramine (+1.85 cm; +3.63 cm) was partially above the upper equivalence limit (+2.6 cm), indicating clinically relevant driving impairment. On day 4, however, the 95% confidence interval of diphenhydramine (+0.74 cm; +2.38 cm) was contained within the acceptance range. Conclusion In contrast to diphenhydramine, driving performance was not significantly affected while using 5 mg levocetirizine once daily.     

Acute pharmacological effects of temazepam,diphenhydramine, and valerian in healthy elderly subjects

Elderly insomniacs are often treated pharmacologically with benzodiazepines, antihistamines, or natural products. A double-blind, randomized, crossover, placebo-controlled study was performed to assess the comparative pharmacodynamics of single doses of temazepam (15 and 30 mg), diphenhydramine (50 and 75 mg), and valerian (400 and 800 mg) in 14 healthy elderly volunteers (mean age, 71.6 years; range, 65-89). Assessments were made at 0, 0.5, 1, 2, 3, 4, 6, and 8 hours postdosing with use of validated measures of subjective sedation and mood (visual analogue scales, Tufts University Benzodiazepine scale) and psychomotor performance (manual tracking and digit symbol substitution tests). Temazepam had dose-dependent effects on sedation and psychomotor ability with a distinct time course. Temazepam 30 mg had the most detrimental effect on psychomotor ability (p < 0.001 compared with all other treatments). Temazepam 30 mg and both doses of diphenhydramine elicited significantly greater sedation than placebo (p < 0.05, all), and temazepam had the greatest effect. There was no difference in sedation scores between 50 and 75 mg diphenhydramine. Sedative effects were slightly lesser with 15 mg temazepam and were not significant in comparison with placebo. Psychomotor impairment was evident after administration of 75 mg diphenhydramine in comparison with placebo on the manual tracking test (p < 0.05); this was less than the impairment with 30 mg temazepam (p < 0.001) but similar to that with 15 mg temazepam (NS). No psychomotor impairment was detected with 50 mg diphenhydramine. Valerian was not different from placebo on any measure of psychomotor performance or sedation.     

Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring

Rationale Most studies that investigated the next-day residual effects of hypnotic drugs on daytime driving performances were performed on healthy subjects and after a single drug administration. Objectives In the present study, we further examine whether the results of these studies could be generalised to insomniac patients and after repeated drug administration. Method Single and repeated (7 day) doses of zolpidem (10 mg), zopiclone (7.5 mg), lormetazepam (1 mg) or placebo were administered at bedtime in a crossover design to 23 patients (9 men and 14 women aged 38.8±2.0 years) with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) primary insomnia. Driving tests were performed 9–11 h post-dose. Results Results showed that treatment effects were evidenced for subjective sleep, for driving abilities, and for electroencephalogram (EEG) recorded before (resting EEG) and during the driving simulation test (driving EEG). Compared to placebo, zopiclone increased the number of collisions and lormetazepam increased deviation from speed limit and deviation from absolute speed, whereas zolpidem did not differentiate from placebo on these analyses. EEG recordings showed that in contrast to zolpidem, lormetazepam and zopiclone induced typical benzodiazepine-like alterations, suggesting that next-day poor driving performance could relate to a prolonged central nervous system effect of these two hypnotics. Conclusion The present results corroborate studies on healthy volunteers showing that residual effects of hypnotics increase with their half-lives. The results further suggest that drugs preserving physiological EEG rhythms before and during the driving simulation test 9–11 h post-dose, such as zolpidem, do not influence next-day driving abilities.     

Lack of interaction between orlistat and oral contraceptives

Objectives: Orlistat, a potent and selective inhibitor of gastrointestinal lipases, is designed for the treatment of obesity. A double-blind, randomised, placebo-controlled, 2-way crossover study investigated the possible influence of orlistat on the ovulation-suppressing action of combination oral contraceptives (OC). Methods: After an 8-day run-in prior to the first of two consecutive menstrual cycles (Day 1 was the first day of menstruation), two groups of 10 healthy women, 20–27 years of age and on a stable regimen with OCs, received either 120 mg orlistat t.i.d. or placebo t.i.d. on Days 1–23 of the first cycle, and, separated by a placebo washout period on Days 24–28, the alternative treatment on Days 1–23 of the second cycle. In both cycles, serum luteinizing hormone (LH) was measured on Days 12–16 and progesterone on Days 12, 16, 19–23. Results: The geometric means of time-averaged concentrations (Days 12–16 for LH and Days 19–23 for progesterone) in the cycles with orlistat and placebo, respectively, and the one-sided 95% confidence region for the mean in the cycle with orlistat were 1.92, 2.03 and < 2.23 IU l⁻¹ for LH and 0.147, 0.145 and < 0.176 μg l⁻¹ for progesterone. The one-sided 95% confidence region for the ratio (orlistat/placebo) of geometric means was < 1.06 for LH and < 1.11 for progesterone. Conclusion: During normal ovulation the peak serum concentration of LH is above 30 IU l⁻¹ around Day 14 of the cycle, and that of progesterone exceeds 3 μg l⁻¹ around day 21. The 95% confidence regions for the means, as well as all individual concentrations, were below these limits. It was concluded that orlistat did not influence the ovulation suppressing action of oral contraceptives. Received: 18 April 1995/Accepted in received form: 6 November 1995     

Clinical decision support systems and antibiotic use

Aim To review and appraise randomised controlled trials (RCT) and ‘before and after' studies published on clinical decision support systems (CDSS) used to support the use of antibiotics. Methods A literature search was carried out in October 2006 using MEDLINE including Medical Subject Heading (MeSH) terms (1966–2006), EMBASE (Excerpta Medica, 1980–2006) and International Pharmaceutical Abstracts (IPA, 1970–2006) using the combinations of the following terms: (Decision support systems) or (CDSS) AND (antibiotics) or (anti-infectives) or (antibacterials) or (antimicrobials). Only English language papers were selected. Editorials, letters and case reports/series were excluded. The reference sections of all retrieved articles were also searched for any further relevant articles. Results Forty articles were identified. Five RCT and six ‘before and after' studies were retrieved. In the RCTs, three studies used computer-based CDSS, one paper-based CDSS and one a combination of both. Two studies were conducted in primary care and three within secondary care. The primary outcomes for each study were different and only three studies were significant in the favour of the use of CDSS. ‘Before and after' studies were used where RCT were not feasible. One ‘before and after' study was excluded because it did not include any control group. The remaining five included historical control groups and evaluated the use of computer-based CDSS within secondary care. Their primary outcomes also varied but all concluded significant benefits of CDSS. Only three of ten studies were conducted outside the USA; one in Switzerland and two in Australia. Conclusion CDSS could be a powerful tool to improve clinical care and patient outcomes. It presents a promising future for optimising antibiotic use. However, it is difficult to generalise as most studies were conducted in the United States. Although RCT are the ‘gold standard' in research, they may not be feasible to conduct. Realising that different study designs answer different questions would allow researchers to choose the most appropriate study design to evaluate CDSS in a specified setting.     

Effect of benazepril amlodipine combination on fibrinolysis in hypertensive diabetic patients

Objective The aim of this study was to compare the effects of benazepril and amlodipine in monotherapy versus in combination with plasma t-PA and PAI-1 activity in hypertensive type-2 diabetic patients.Methods After an initial 6-week wash-out, single-blind placebo period, 38 patients, 17 men and 21 females, were randomly assigned to receive benazepril 10 mg o.d. or amlodipine 5 mg o.d. or their combination o.d. at the same dosage for 6 weeks in three crossover periods each separated by a 2-week placebo wash-out period (3×3 latin square). At the end of the placebo run-in period and of each treatment period, BP, plasma PAI-1 and tPA activity were evaluated.Results Both benazepril and amlodipine were similarly effective in reducing systolic blood pressure (SBP) (–17.6 mmHg with benazepril and –19.8 mmHg with amlodipine; P<0.001 versus placebo), and diastolic blood pressure (DBP) (–11.1 mmHg, –13.2 mmHg, respectively). Combination therapy produced greater reduction in SBP/DBP values (–28.3/–20.5 mmHg; P<0.001 versus placebo, P<0.01 versus benazepril and amlodipine). Benazepril monotherapy significantly decreased plasma PAI-1 activity (–8.4 IU/ml, P<0.05) while it did not influence t-PA activity (+0.02 IU/ml). Amlodipine monotherapy produced a significant increase in t-PA activity (+0.27 IU/ml, P<0.05) while it did not influence PAI-1 activity (+0.8 IU/ml). The amlodipine/benazepril combination produced both a significant decrease in plasma PAI-1 activity (–8.7 IU, P<0.05) and a significant increase in t-PA activity (+0.26 IU/ml, P<0.05).Conclusions These data suggest that in hypertensive type-2 diabetic patients, a population with an impaired fibrinolysis, the benazepril/amlodipine combination, may improve the fibrinolytic balance more than the single drugs.     

Meta-analysis of the diagnostic efficiency of frequency-doubling technology for primary glaucoma

The overall diagnostic capabilities and utility of frequency-doubling technology (FDT) in patients with primary glaucoma, which was diagnosed by standard automated perimetry (SAP) and/or optic disc appearance as the gold standard, were assessed. A comprehensive electric retrieval in MEDLINE, EMBASE, Cochrane Library, BIOSIS, Previews, HMIC, IPA, OVID, CNKI, CBMdisc, VIP information, CMCC, CCPD, SSreader, 21dmedia and manual retrieval in related textbooks, journals, congress articles and their references at home and abroad were performed to identify relevant articles in English or Chinese. The corresponding references were retrieved by means of electric retrieval and manual retrieval from different databases or materials. Criteria for inclusion or exclusion were established according to validity criteria for diagnostic studies published by the Cochrane Methods Group on Screening and Diagnostic Tests. The quality of the included articles was then assessed and characteristics were extracted. Statistical analysis was performed with Meta Test version 0.6 software to test the heterogeneity of the included articles. The appropriate effects model was selected to calculate pooled weighted sensitivity and specificity. Summary receiver operating characteristic (SROC) curve was drawn and the area under the curve (AUC) was calculated. Finally, sensitivity analysis was performed. Twenty-one studies out of 206 retrieved articles were included, with a total of 3172 patients. The reported sensitivity of FDT ranged from 0.51 to 1.00, and specificity from 0.58 to 1.00. The pooled weighted sensitivity and specificity of FDT with 95% confidence intervals (95% CI) after correction for standard error were 0.86 (0.80–0.90) and 0.87 (0.81–0.91), respectively. The AUC of SROC was 93.01%. Sensitivity analysis demonstrated no disproportionate influences of individual studies. The included articles are of good quality and FDT can be a highly efficient diagnostic test for primary glaucom a based on Meta-analysis. Translated from Chin J Ophthalmol, 2006, 42(5): 403–408 [译自: 中华眼科杂志]     

Efficacy and safety of non-benzodiazepine and non-Z-drug hypnotic medication for insomnia in older people: a systematic literature review

Insomnia is highly prevalent in older persons and significantly impacts quality of life, functional abilities, and health status. It is frequently treated with benzodiazepines or Z-drugs. Due to adverse events, an increased use of alternative sedative medications has been observed in older adults. We aimed to study the efficacy and safety of alternative sedative medications for treating insomnia in older people, excluding benzodiazepines and Z-drugs. We conducted a systematic search of MEDLINE (PubMed), EMBASE, and the Cochrane Central register of Controlled Trials databases. We included randomized controlled trials and prospective and retrospective quasi-experimental studies, conducted in patients older than 65 years, without psychiatric or neurological comorbidities. The systematic search yielded 9483 articles, of which 24 were included in this review, describing nine different sleep medications in total. No clear beneficial impact on sleep could be demonstrated in studies investigating the impact of melatonin (n = 10), paroxetine (n = 1), diphenhydramine (n = 1), tiagabine (n = 2), and valerian (n = 1). Ramelteon slightly improved sleep latency (n = 4), while doxepin was found to provide a sustained sleep improvement with a safety profile that was comparable to placebo (n = 3). Suvorexant showed an improved sleep maintenance with only mild side effects (n = 1). One study detected increased adverse effects of trazodone after 3 months but did not evaluate the effect on sleep. The overall level of evidence was limited, making it difficult to draw robust conclusions. Preliminary evidence points towards suvorexant, doxepin, and possibly ramelteon as effective and safe pharmacological alternatives for treating insomnia in older adults.     

Effects of desloratadine,diphenhydramine, and placebo on driving performance and psychomotor performance measurements

Introduction First-generation antihistamines taken for relief of allergic rhinitis are sedating and pose potential risks for those driving a car or operating machinery. Desloratadine is a potent, selective, histamine H₁-receptor antagonist that does not easily cross the blood–brain barrier. It is nonsedating at therapeutic doses and should not affect driving or psychomotor performance.Objective This study compared the acute effects of desloratadine with diphenhydramine (active control) and placebo on the performance of healthy subjects evaluated with standard over-the-road driving tests (primary objective). The subjects performances were also evaluated (secondary objective) with the use of conventional performance tests.Methods Eighteen men and women received a single dose of desloratadine 5 mg, diphenhydramine 50 mg, or placebo during each period of this randomized, double-blind, three-way, crossover study. Two hours post-dosing, subjects operated a specially instrumented vehicle in a 90-min test designed to measure their ability (1) to maintain constant speed and lateral position while following another vehicle at a constant distance and (2) to respond to brake signals. Additionally, a full battery of performance tests was administered.Results No significant differences were noted between desloratadine and placebo in standard deviation of lateral position (SDLP), whereas diphenhydramine treatment significantly increased SDLP (P<0.001 for both comparisons). Brake reaction time was significantly faster following treatment with desloratadine than diphenhydramine (473.72 ms vs 541.22 ms; P<0.001) or placebo (512.06 ms; P=0.033). No differences were seen among treatments in deviation of speed or distance to the lead car. The majority of performance tests showed no significant differences among groups.Conclusion Desloratadine at a therapeutic dose does not impair driving performance.     

Next-day residual sedative effect after nighttime administration of an over-the-counter antihistamine sleep aid, diphenhydramine, measured by positron emission tomography

Antihistamines often are self-administered at night as over-the-counter (OTC) sleep aids, but their next-day residual sedative effect has never been evaluated using a reliable quantitative method such as positron emission tomography (PET). We performed a double-blind, placebo-controlled, crossover study in which we evaluated the residual effect the next day after nighttime administration of diphenhydramine, a commonly used OTC sleep aid, in terms of brain H? receptor occupancy (H?RO) measured using 11C-doxepin-PET. We also compared the results of diphenhydramine with those of bepotastine, a second-generation antihistamine. Eight healthy adult male subjects underwent PET measurement the morning (11:00) after random oral administration of diphenhydramine (50 mg), bepotastine (10 mg), or placebo the night before (23:00). Binding potential ratios and H?ROs were calculated in different brain regions of interest such as the cingulate gyrus, frontotemporal cortex, and cerebellum. Subjective sleepiness and plasma drug concentration also were measured. Calculation of binding potential ratios revealed significantly lower values for diphenhydramine than for bepotastine or placebo in all regions of interest (P < 0.01). Cortical mean H?RO after diphenhydramine treatment was 44.7% compared with 16.6% for bepotastine treatment (P < 0.01). Subjective sleepiness was not significantly different among the subjects treated with each test drug or the placebo. In conclusion, the next-day residual sedative effect after nighttime administration of the OTC sleep aid diphenhydramine was verified for the first time by direct PET measurement of H?RO. Taking into account the possible hangover effect of OTC antihistamine sleep aids, care needs to be taken during their administration.     

Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study

Objective To conduct a thorough QT study of levocetirizine, a non-sedating antihistamine, in accordance with International Conference on Harmonisation (ICH) E14 guidance. Methods The study was designed as a single-dose, placebo and positive-controlled, four-way crossover, randomised trial in which 52 healthy male and female subjects participated. Levocetirizine (5 and 30 mg) and placebo were administered double-blind, and the positive control, moxifloxacin (400 mg), was open-label. Electrocardiograms (ECGs) were obtained by continuous Holter monitoring at various time points (three per time point) during a 24-h period at baseline and after each treatment. The ECGs were read centrally in a blinded manner. QT intervals were corrected for heart rate using a gender- and study-specific correction (QT_cSS) and Fridericia’s correction (QT_cF). The largest QTc time-matched and baseline-subtracted difference between each active drug and the placebo (largest ΔΔQT_cSS) was derived from a mixed-effect analysis of variance. Results The one-sided 95% upper limits of the largest ΔΔQT_cSS for levocetirizine were 5.7 ms (5 mg) and 3.9 ms (30 mg), with mean estimates of 2.9 and 1.1 ms, respectively. Similar results were obtained for the ΔΔQT_cF data. Statistically, moxifloxacin significantly lengthened the QT_cSS, with a one-sided 95% lower limit of the largest ΔΔQT_cSS of 10.5 ms and a mean estimate of 13.4 ms. There was no relationship between the measured ΔQT_cSS and the plasma concentration of levocetirizine, whereas a statistically significant linear relationship was observed with the plasma concentration of moxifloxacin [slope estimate 0.004 ms/(ng/mL); 95% confidence interval: 0.003–0.005]. Conclusions Overall, the results of this thorough QT study indicate that the methodology of the trial was valid and sensitive enough to demonstrate the absence of effect of levocetirizine at both therapeutic (5 mg) and supra-therapeutic (30 mg) doses on cardiac repolarisation.     

Differentiating the effects of centrally acting drugs on arousal and memory: an event-related potential study of scopolamine, lorazepam and diphenhydramine

The degree to which apparent amnesic effects of various centrally acting drugs are secondary to their effects on arousal remains a contentious issue. The present study uses two methods to dissociate memory and arousal effects of the cholinergic antagonist, scopolamine (SP), and the GABA-A/benzodiazepine receptor agonist, lorazepam (LZ). First, it compared their effects to those of an antihistamine, diphenhydramine (DPh), to provide an active control for arousal reduction. Second, it used the same measure – event-related potentials (ERPs) – as as a parallel index of both the arousal and cognitive effects of the drugs. Fifty participants were allocated to one of five parallel treatment groups (0.6 mg SP; 2 mg LZ; 25, 50 mg DPh; placebo). ERPs were recorded during a continuous word recognition task as well as during an “oddball” task. SP, LZ and 50 mg DPh produced a similar profile of effects on certain indices of arousal and on early components of ERPs. However, SP and LZ (but not DPh) produced marked impairments of episodic memory, and this pattern was similar to that on later components of ERPs. Memory impairments by SP and LZ were highly significant on retention in the continuous recognition task and further, no drug effects were found on response bias. Subsequent free recall was similarly very impaired by SP and LOR but not by the antihistamine. We conclude that benzodiazepines and anticholinergic drugs both reduce arousal and induce amnesia, but these effects are not interdependent. Our findings provide strong evidence for a dissociation between the effects on episodic memory and on arousal of these centrally acting compounds. Received: 27 November 1996/Final version: 19 June 1997     

Control in the middle (CIM) for three-period crossover studies

Three-period crossover studies can be efficient and convenient methods of conducting Phase II clinical trials. Non-randomly placing control in the middle (CIM) has not been practiced but may be extremely useful in studies testing herbal products for which placebos are not available, or for distinguishing between behavioral and biological effects. Furthermore, this design can serve as a valuable addition to classical studies of either (a) two competing treatments or (b) treatment versus placebo versus an open label "nothing" as the control. Therefore, we propose rigorous designs that will help practitioners efficiently answer research questions where (1) two active treatments need to be compared against each other with treatment vs. placebo comparisons being of secondary importance; (2) a single active treatment needs to be tested where no placebo is available; or (3) the placebo effect is of interest in a treatment vs. placebo trial. For studies where no placebo is available, deception will be required, with participants told that in one randomly selected period (#1 or #3) they will receive the active treatment, and that they will receive a new experimental inert placebo in the other period. Assuming this design is approved by an ethics committee, it can be very useful in biomedical research.     

Effect of sulindac on the cough reflex of healthy subjects.

The effects of a single dose of sulindac 200 mg and placebo on the capsaicin-induced cough reflex were studied in a two-phase double-blind crossover study in 18 healthy subjects. Sulindac increased the threshold for capsaicin cough response significantly, but did not alter D5, peak response, or the total cough response when compared with placebo values.     

Effects of 2-week treatment with temazepam and diphenhydramine in elderly insomniacs: a randomized, placebo-controlled trial

A randomized, controlled, crossover clinical study compared 14-night treatment with 15 mg temazepam, 50 mg diphenhydramine, and placebo in elderly individuals with insomnia (mean age, 73.9 years; range, 70-89 years). Primary outcome measures were subjective assessments of sleep recorded on sleep diaries. Secondary measures were the morning-after psychomotor impairment, using the digit symbol substitution task and the manual tracking task, and the morning-after memory impairment, using a free-recall procedure. Results showed sleep improvements with 15 mg temazepam compared with placebo-sleep quality (mean score, 3.3 +/- 0.9 vs 2.9 +/- 0.8; P = 0.03), total sleep time (6.9 +/- 1.0 hours vs 6.3 +/-1.3 hours; P = 0.02), number of awakenings (1.5 +/- 1.3 vs 2.0 +/- 1.2; P < 0.001), and sleep-onset latency (25 +/- 22 minutes vs 37 +/- 25 minutes; P = 0.03). Improvements were seen with diphenhydramine treatment compared with placebo on the number of awakenings only (mean, 1.7 +/- 1.1 vs 2.0 +/- 1.2; P < 0.05). Numbers of adverse events reported were similar after all treatments, although there was 1 fall during temazepam treatment. Findings indicate that temazepam is more effective than diphenhydramine when compared with placebo at the doses tested, although this advantage is mitigated by the risk of falls associated with temazepam use. The choice of agent to use in the elderly must consider these relative benefits and risks.     

Application of Clinical Trial Simulation to Compare Proof-of-Concept Study Designs for Drugs with a Slow Onset of Effect; An Example in Alzheimer's Disease

Objective Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200–400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials.Materials and Methods A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A ‘positive trial’ reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025).Results A 4 × 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability.Conclusion CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US$4M in direct costs and a firm decision 8–12 months earlier than a 12-week parallel group trial.     

Effects of central and peripheral nicotinic blockade on human nicotine discrimination

Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg PO), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10–40 μg/kg per min IV), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 μg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 μg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects. Received: 15 April 1998/Final version: 23 July 1998     

A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol

Purpose To examine the effect of common excipients such as sugars (sorbitol versus sucrose) on bioequivalence between pharmaceutical formulations, using ranitidine and metoprolol as model drugs.Methods Two single-dose, replicated, crossover studies were first conducted in healthy volunteers (N = 20 each) to compare the effect of 5 Gm of sorbitol and sucrose on bioequivalence of 150 mg ranitidine or 50 mg metoprolol in aqueous solution, followed by a single-dose, nonreplicated, crossover study (N = 24) to determine the threshold of sorbitol effect on bioequivalence of 150 mg ranitidine in solution.Results Ranitidine Cmax and AUC(0–∞) were decreased by ∼50% and 45%, respectively, in the presence of sorbitol versus sucrose. Similarly, sorbitol reduced metoprolol Cmax by 23% but had no significant effect on AUC(0–∞). An appreciable subject-by-formulation interaction was found for ranitidine Cmax and AUC(0–∞), as well as metoprolol Cmax. Sorbitol decreased the systemic exposure of ranitidine in a dose-dependent manner and affected bioequivalence at a level of 1.25 Gm or greater.Conclusions As exemplified by sorbitol, some common excipients have unexpected effect on bioavailability/bioequivalence, depending on the pharmacokinetic characteristics of the drug, as well as the type and amount of the excipient present in the formulation. More research is warranted to examine other ‘common’ excipients that may have unintended influence on bioavailability/bioequivalence.The opinions expressed in this article are those of the authors and do not necessarily represent the views or policies of the Food and Drug Administration.     

Informative dropout modeling of longitudinal ordered categorical data and model validation: application to exposure–response modeling of physician’s global assessment score for ustekinumab in patients with psoriasis

The physician’s global assessment (PGA) score is a 6-point measure of psoriasis severity that is widely used in clinical trials to assess response to psoriasis treatment. The objective of this study was to perform exposure–response modeling using the PGA score as a pharmacodynamic endpoint following treatment with ustekinumab in patients with moderate-to-severe psoriasis who participated in two Phase 3 studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 or 90 mg or placebo, followed by active treatment or placebo crossover to ustekinumab, dose intensification or randomized withdrawal and long-term extension periods. A novel joint longitudinal-dropout model was developed from serum ustekinumab concentrations, PGA scores, and patient dropout information. The exposure–response component employed a semi-mechanistic drug model, integrated with disease progression and placebo effect under the mixed-effect logistic regression framework. This allowed potential tolerance to be investigated with a mechanistic approach. The dropout component of the joint model allowed the examination of its potential influence on the exposure–response relationship. The flexible Weibull dropout hazard function was used. Visual predictive check of the joint longitudinal-dropout model required special handling, and a conditional approach was proposed. The conditional approach was extended to external model validation. Finally, appropriate interpretation of model validation is discussed. This longitudinal-dropout model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate-to-severe plaque psoriasis.     

Effect of pertussis toxin on baclofen- and diphenhydramine-induced amnesia

The effect of pretreatment with pertussis toxin at the doses of 0.25 and 0.50 μg per mouse ICV on the amnesic effect produced by baclofen (0.1–4 mg kg⁻¹ IP), diphenhydramine (15–30 mg kg⁻¹ IP) and scopolamine (0.5–5 mg kg⁻¹ IP) was investigated in the mouse passive avoidance test. Ten days after a single injection of pertussis toxin, baclofen (2–4 mg kg⁻¹ IP) amnesia was prevented. By contrast, pertussis toxin had no effect on diphenhydramine- and scopolamine-induced amnesia. Pretreatment with pertussis toxin at both doses used did not impair motor coordination of the mice, as revealed by the rota-rod test. The present results indicate that the activation of pertussis toxin-sensitive G-proteins represents an important transduction step in memory impairment induced by GABA_B (γ-aminobutyric acid B) agonists, but not by antihistaminic and antimuscarinic drugs. Received: 3 June 1997/Final version: 16 October 1997