The pharmacology and clinical outcomes of amphetamines to treat ADHD: does composition matter?

Attention-deficit hyperactivity disorder (ADHD) treatment options include pharmacological and nonpharmacological approaches. In North America, psychostimulants (amphetamine and methylphenidate) are considered first-line pharmacological treatments for patients (children, adolescents and adults) with ADHD. However, in the UK, National Institute for Health and Clinical Excellence (NICE) guidelines have placed short-acting d-amphetamine as a third-line treatment option due to a lack of contemporary, published clinical trials on its efficacy and the concerns from clinical and patient experts regarding the potential for increased abuse and/or misuse compared with methylphenidate. These guidelines do not account for some of the more recent amphetamine products that have been developed to alleviate some of these concerns, but that are not currently approved in the UK or other European countries. The purpose of this review is to describe the pharmacology and clinical efficacy of various amphetamine compositions, as well as to explore the apparent differences in these compositions and their associated risks and benefits. A PubMed literature search was conducted to investigate amphetamine pharmacology, clinical efficacy and safety and ADHD outcomes in the published literature from 1980 through March 2011. Search terms included the keywords 'ADHD' or 'ADD' or 'hyperkinetic disorder' and any of the following keywords combined with 'or': 'amphetamine', 'dexamphetamine', 'mixed amphetamine salts', 'lisdexamfetamine' and 'methamphetamine'. The search included English-language primary research articles and review articles but excluded editorial articles and commentaries. The literature search resulted in 330 articles. Pertinent articles relating to amphetamine pharmacology, compositions, clinical efficacy and safety, effectiveness and tolerability, ADHD outcomes and abuse liability were included in this review. The different delivery profiles of amphetamine compositions result in pharmacological and pharmacokinetic differences that contribute to varying effects in the clinical treatment of ADHD, ADHD outcomes and abuse liability. The efficacy and safety of amphetamine compositions for the treatment of ADHD have been demonstrated in clinical trials and meta-analyses, and the long-acting amphetamine compositions have been widely studied and found efficacious without increased adverse effects. Long-acting amphetamine compositions offer the obvious advantage of enhanced duration of action over short-acting amphetamine compositions, and lisdexamfetamine has been shown to have reduced abuse liability compared with short-acting amphetamine.     

Price elasticity of demand for cannabis: does potency matter?

Using high-quality data collected in France in 2005 from more than 250 regular cannabis users, we estimate both quantity discount and price elasticity of cannabis net of the effect of perceived quality and real potency. We find evidence of substantial price discount and obtain a short-term price consumption elasticity ranging from ?1.7 to ?2.1, meaning that the demand for cannabis is elastic. Controlling for potency, either real or perceived, has little effect on the magnitude of the discount effect – even if customers are ready to pay more when their perception of the product quality is high – and no impact on price elasticity.     

Price responsiveness of demand for cigarettes: does rationality matter?

Meta-analysis is applied to aggregate-level studies that model the demand for cigarettes using static, myopic, or rational addiction frameworks in an attempt to synthesize key findings in the literature and to identify determinants of the variation in reported price elasticity estimates across studies. The results suggest that the rational addiction framework produces statistically similar estimates to the static framework but that studies that use the myopic framework tend to report more elastic price effects. Studies that applied panel data techniques or controlled for cross-border smuggling reported more elastic price elasticity estimates, whereas the use of instrumental variable techniques and time trends or time dummy variables produced less elastic estimates. The finding that myopic models produce different estimates than either of the other two model frameworks underscores that careful attention must be given to time series properties of the data.     

Statistical analysis of environmental monitoring data: does a worst case time for monitoring clean rooms exist?

To determine the relationship between the sampling time of the environmental monitoring, i.e., viable counts, in aseptic filling areas and the microbial count and frequency of alerts for air, surface and personnel microbial monitoring, statistical analyses were conducted on 1) the frequency of alerts versus the time of day for routine environmental sampling conducted in calendar year 1994, and 2) environmental monitoring data collected at 30-minute intervals during routine aseptic filling operations over two separate days in four different clean rooms with multiple shifts and equipment set-ups at a parenteral manufacturing facility. Statistical analyses showed, except for one floor location that had significantly higher number of counts but no alert or action level samplings in the first two hours of operation, there was no relationship between the number of counts and the time of sampling. Further studies over a 30-day period at the floor location showed no relationship between time of sampling and microbial counts. The conclusion reached in the study was that there is no worst case time for environmental monitoring at that facility and that sampling any time during the aseptic filling operation will give a satisfactory measure of the microbial cleanliness in the clean room during the set-up and aseptic filling operation.     

Plasma concentration monitoring of busulfan: does it improve clinical outcome?

High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/L improves graft retention. Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.     

Cocrystal or salt: does it really matter?

A structural analysis of over 80 salts and cocrystals synthesized from equimolar amounts of carboxylic acids and N-heterocycles demonstrates that salt formation as a result of proton transfer from the acid to the base frequently (11/24; 45%) results in a lattice with an unpredictable chemical (solvate) or stoichiometric composition. However, if no proton transfer takes place and the result is a molecular cocrystal, a crystal lattice with an unexpected chemical content or stoichiometry is much less likely (3/61; 5%). These results indicate that the process of converting a neutral carboxylic acid into a carboxylate anion can have important structural consequences that make structure prediction and targeted supramolecular synthesis of salts much more difficult than of cocrystals. Consequently, cocrystals may offer new opportunities for producing a greater diversity of solid forms of drug substances that exhibit the appropriate balance of critical properties for development into a viable and effective drug product.     

Measuring the stability of illicit drug markets: why does it matter?

Contemporary drug policy in the United States favors a balanced approach including a supply side dimension. The supply side dimension is grounded in the assumption that the disruption of illicit drug markets will result in diminished capacity of the markets to provide for consumer demand and thereby a reduction in the use of illicit drugs and a related increase in demand for treatment. In this paper we consider the disruption of methamphetamine markets in 10 cities in terms of the relative stability of those markets. We use data from the Arrestee Drug Abuse Monitoring (ADAM) program for the years 2000-2003. We conduct a comparative analysis of those markets and look at patterns of methamphetamine use and participation in treatment in those cities. Our findings demonstrate how it is possible to construct measures of market stability, and how to use those measures to assess the stability of illicit drug markets in terms of both relative value and in fluctuation over time. We also demonstrate that markets with different patterns of stability will exhibit different patterns of drug using and treatment participation. We conclude that understanding patterns of market stability will help us to understand and respond to patterns of drug using and treatment participation.     

Is selective reporting of clinical research unethical as well as unscientific?

BACKGROUND: Studies that do not confirm their prior hypotheses, otherwise called "negative" studies, receive less interest from different parties including authors, editors and sponsors, and so, not to publish such studies is a common phenomenon. Opinions differ on whether or not this phenomenon introduces imprecision into the assessment of health research and care. OBJECTIVE: The current paper gives arguments against and in favor of publishing "negative" trials, and tries to give suggestions for a more balanced approach to this problem. RESULTS: Arguments against publishing "negative" trials include: we need not publish erroneously "negative" trials; we need not publish a "negative" study out of worry that the favored treatment is inferior; full-length reports of "negative" trials devaluate the quality of literature, because the data are usually not so important, and generally receive little interest from readers, and so, not to publish them is a more or less "natural" matter of course. Arguments in favor of publishing "negative" trials include: no report reduces the flow of information because "negative" trials provide at least some evidence and balance against the overwhelming power of positive data readily accepted for publication; no report violates the promise to patient participants; studies that do not confirm prior hypotheses are especially important; not-publishing leads to unnecessary repetition of research. Initially, trials were frequently "negative" not only due to lack of power but also due to inappropriate hypotheses and poor designs. Currently, this is less so, and the issue of selective reporting, therefore, needs to be reassessed. Suggestions for a more balanced approach to the problem of selective reporting might include: careful planning before the trial begins, reduces the chance of biased and erroneously "negative" trials; any trial, "positive" or "negative", provides probabilities rather than truths; this notion does not explain away publication bias but does make it less of a problem; "negative" trials may not be appropriate for general journals but very relevant to specialist journals as well as other organs of specialist groups; ethical committees and trial review boards should address the issue of publishing as part of their function. CONCLUSION: Data from properly executed trials should routinely be made available. However, we should not forget that the empirical observations provided by clinical trials, are statistically tested, and that statistics are based merely on probabilities. It means that we must consider a more philosophical attitude to clinical trial evidence in terms of acceptance that scientific truths are rarely absolute.     

Who's left? Symptoms of schizophrenia that predict clinical trial dropout

A significant proportion of subjects drop out of medium to long‐term clinical studies prior to trial completion. This may bias reported study outcomes and reduce the statistical power of analyses. There is therefore a need for researchers to better understand the characteristics of dropout populations to increase completion rates. Data from a set of participants recruited as part of a 24‐week placebo‐controlled trial were used to determine the relationship between the five Lindenmayer factors of positive, negative, cognitive, anxiety/depression and excitement symptoms and dropout at trial completion. Results indicated that the rate of trial dropout was significantly predicted by scores on the negative Lindenmayer factor (X²(6, N = 126) = 15.60, p < .05). By trial completion, participants with ‘high’ negative Lindenmayer scores dropped out at a rate of 64%, whereas ‘medium’ and ‘low’ groups dropped out at 43% and 30%, respectively. No other relationship between symptom severity scores and dropout across the remaining Lindenmayer factors was found. These findings reflect important considerations for the future design of clinical trials involving people with schizophrenia and may also provide clues into treatment compliance issues more generally. Copyright © 2011 John Wiley & Sons, Ltd.     

Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?

Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure–response (E–R) analysis may be more sensitive than simple changes in QT_c interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT studyfrom one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E–R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn.     

Productivity costs in health-state valuations : does explicit instruction matter?

BACKGROUND: There has been considerable debate on whether productivity costs should be captured in the numerator or the denominator of the cost-effectiveness ratio. That debate cannot be resolved on the basis of theoretical arguments alone because the final choice also depends on what is incorporated in health-state valuations by respondents and how this influences outcomes. At the moment, little is known about whether the effects of ill health on income are included in health-state valuations, and how instructions on including or excluding the effects on income influence health-state valuations. AIM: To conduct an empirical study of health-state valuations to test: (i) whether or not respondents spontaneously include the effect of ill health on income and leisure time; (ii) the impact on the valuation of inclusion (or exclusion) of such effects; and (iii) the influence of explicit instructions on this matter. METHODS: Three questionnaires were developed and administered to the general public. Health-state valuations were conducted by visual analogue scale scoring of three health states of differing severity taken from the EQ-5D. Version 1 had no directions regarding inclusion/exclusion of effects of ill health on income. Those respondents who spontaneously included effects on income were subsequently asked to value the same three health states again, excluding these effects. Version 2 had explicit instructions to incorporate the effects on income. Version 3 stated that income was assumed to not change as a result of ill health. Respondents for versions 2 and 3 were also questioned about inclusion of effects on leisure time. RESULTS: Giving explicit instructions on the incorporation or exclusion of effects of ill health on income did not lead to significant differences in subsequent health-state valuations. In the absence of instruction, 36% of respondents included and 64% excluded effects on income, but the health-state valuations of the two groups were not significantly different. Eighty-four percent of respondents included the effects of ill health on leisure activities, and again this had no significant impact on the resulting health-state valuations. CONCLUSIONS: It appears that neither spontaneous differences in incorporation of effects on income, nor explicit instructions will yield significantly different health-state valuations. This may suggest that QALY measures are insensitive to concerns regarding effects on income even when these are (explicitly) incorporated, and these effects may therefore be best placed on the cost side of the cost-effectiveness ratio.     

Substance abuse intensive outpatient treatment: does program graduation matter?

Program graduation, even after controlling for length of stay, may predict for improved outcomes in some substance abuse treatment settings. We investigated the role of program graduation by comparing social outcomes and inpatient utilization the years before and after treatment among graduates and dropouts of a Veterans Administration substance abuse intensive outpatient program. At enrollment, graduates and dropouts were similar in all spheres measured. Patients who completed the treatment program used significantly fewer psychiatric inpatient bed days of care the year after they completed the program, both in comparison to their own prior use and in comparison to program dropouts. Graduates were more likely to be abstinent and less likely to fully relapse or be incarcerated at 6-month followup. Further research is needed to discern optimal treatment length-that which maximizes both length of stay and completion rates, while optimizing use of limited treatment resources.     

Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome?

We report a case of neonatal symptoms of irritability, increased tonus and convulsions after in-utero exposure to paroxetine 30 mg/day. The infant's symptoms commenced on the first day after birth and persisted for 10 days. Paroxetine levels were undetectable on day 6. Extensive investigations excluded infective and metabolic causes. Serotonin toxicity due to paroxetine seems the most likely mechanism, though an important differential diagnosis is a paroxetine discontinuation (withdrawal) syndrome. Differentiating between these two syndromes in the neonate presents a dilemma for clinicians. Irrespective of the mechanism, we recommend that all neonates exposed to antidepressants, particularly serotonin reuptake inhibitors (SSRIs), during the last trimester should be followed-up closely for adverse symptoms commencing in the first 10 days after birth. The possibility of such symptoms needs to be discussed with women who are considering starting or continuing antidepressant treatment in pregnancy. All neonatal adverse drug events should be reported to a pharmacovigilance centre. Further research is warranted.