How persistent is the effect of smoking urges on cognitive performance?

Several studies have provided empirical support for S. T. Tiffany's (1990) hypothesis that drug urges interfere with cognitive performance. The authors examined the persistence of this effect. Results from an experiment involving 48 smokers and 46 nonsmokers, using a paradigm developed by R. A. Zwaan and T. P. Truitt (1998), suggest that the effect of smoking urges in cognitive performance dissipates over time. The implications of this finding for cognitive theories of drug urges and for future research on the effects of smoking urges are discussed.     

Is the rodent maternal separation model a valid and effective model for studies on the early-life impact on ethanol consumption?

Rationale

Early-life events can cause long-term neurobiological and behavioural changes with a resultant effect upon reward and addiction processes that enhance risk to develop alcohol use disorders. Maternal separation (MS) is used to study the mediating mechanisms of early-life influences in rodents. In MS studies, the pups are exposed to maternal absence during the first postnatal weeks. The outcome of MS experiments exhibits considerable variation and questions have been raised about the validity of MS models.

Objectives

This short review aims to provide information about experimental conditions that are important to consider when assessing the impact of early-life environment on voluntary ethanol consumption.

Results

The results from currently used MS protocols are not uniform. However, studies consistently show that longer separations of intact litters predispose for higher ethanol consumption and/or preference in adult male rats as compared to shorter periods of MS. Studies using individual pup MS paradigms, other controls, low ethanol concentrations, adult females or examining adolescent consumption reported no differences or inconsistent results.

Conclusions

There is no “a rodent MS model”, there are several models and they generate different results. The compiled literature shows that MS is a model of choice for analysis of early-life effects on voluntary ethanol consumption but there are examples of MS paradigms that are not suitable. These studies emphasize the importance to carefully designed MS experiments to supply the optimal conditions to definitely test the research hypothesis and to be particulate in the interpretation of the outcome.     

Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain?

During the four decades that research has been carried out on antipsychotic drugs, a variety of methods have been used to study the effects of these compounds on dopamine neurotransmission. An important issue in this research was to find an explanation for the difference between "typical" and "atypical" antipsychotic drugs. The hypothesis that the beneficial properties and the motor side effects of antipsychotic drugs result from their effects on different groups of dopamine neurons has received considerable attention. Numerous researchers have tried to discover regiospecific actions of antipsychotic drugs in mesolimbic and in mesocortical dopamine neurons. An overview of these research attempts is presented here. Electrophysiological studies showed a selective action of atypical antipsychotic drugs on A10 dopamine neurons. It was found that chronic treatment with these compounds induced a preferential depolarisation block of the A10 neurons that project to the mesolimbic areas. The model represents certain clinical features of antipsychotic drug use and offers a possible explanation for the lack of extrapyramidal side effects of atypical antipsychotic drugs. Dopamine neurons projecting from A10 to the frontal cortex are also considered as a possible site of action of atypical antipsychotic drugs. Microdialysis studies have shown that certain atypical antipsychotic drugs selectively enhance the release of dopamine in the prefrontal cortex when compared with typical antipsychotic drugs. The finding that repeated treatment with antipsychotic drugs increased dopamine D(2) receptor binding in the frontal cortex confirms the significance of this brain area. These properties might indeed explain certain beneficial effects of atypical antipsychotic drugs such as improvement of cognitive dysfunction. However the effects of typical and atypical antipsychotic drugs in the frontal cortex could not be fully differentiated, which illustrates the difficulty of localising clinical effects of antipsychotic drugs in terms of regional dopamine neurons. Recently new insights into the mechanism of action of typical and atypical antipsychotic drugs have been published. Clinical positron emission tomography (PET) studies have indicated that a moderate dopamine D(2) receptor occupancy, probably combined with a high dissociation rate, might provide the optimal clinical conditions for an antipsychotic drug, without inducing extrapyramidal side effects. Moreover the efficacy of benzamides as atypical antipsychotic drugs suggests that low to moderate dopamine D(2) blockade is probably the most important-if not the only-criterion that determines "atypicality". Interestingly these new insights are based on PET studies of the human basal ganglia and not on the comparison of different brain areas. Apparently, according to this concept an ideal antipsychotic drug need not to act on a particular type of dopamine neurons, as it is the moderate dopamine D(2) receptor occupancy that determines the desirable clinical effects. It is concluded that both beneficial actions and side effects, of antipsychotic drugs might be dose dependently localised in A9 as well as A10 dopamine neurons.     

Prescribing antiepileptic drugs: should patients be switched on the basis of cost?

To assess the costs of switching from one antiepileptic drug (AED) to another, all associated direct and indirect costs, not only drug acquisition costs, must be considered. The perspective of the healthcare system evaluated in cost-effectiveness analysis is of crucial importance. Multiple clinical factors can influence clinical decisions regarding switching AEDs. The economic cost of poorly controlled epilepsy is enormous and the most cost-effective intervention is an AED that provides total seizure control. Cost-minimisation studies have evaluated costs associated with various medications. If only efficacy and adverse events were considered, then the 'older' AEDs were generally more cost effective than the 'newer' AEDs. Most studies only examine very specific clinical situations and are not suitable for establishing general clinical recommendations. The pharmacoeconomics of AED choice is highly country specific. While switching to generic formulations is, in general, cost effective, some changes may be detrimental and more costly than remaining on the trade name preparation. For example, as a result of differences in bioavailability and possible loss of seizure control, changing patients to generic phenytoin and carbamazepine can be problematic. Fosphenytoin may only be cost effective in certain clinical situations compared with intravenous phenytoin. Seizure control should not be sacrificed on the basis of costs alone, as the major endpoint in treating epilepsy with AEDs is seizure control without adverse effects. Switching AEDs in clinical practice still depends on the individual clinical situation and choosing AED therapy solely on the basis of initial acquisition costs is unlikely to be cost effective in the long-term care of patients with epilepsy.     

Are constipation drugs effective and safe to be used in children? A review of the literature

INTRODUCTION: Functional constipation is a common and often enduring problem in childhood. Although functional constipation is well defined by the Rome III criteria, these criteria have not always been integrated in general practice. Early diagnosis and treatment are key factors with respect to successful long-term outcome, as chronic constipation has a negative effect on the quality of life and is a burden for the public healthcare system. The safety of laxatives used for paediatric-functional constipation is based on well-designed trials carried out mostly in adults. Therefore, we conducted a review of the literature outlining the evidence for the efficacy and safety of laxatives used in chronic paediatric-functional constipation. AREAS COVERED: This review clearly shows a lack of large well-designed placebo-controlled trials in children with constipation. Therefore, any interpretation with regards to the evidence for the effectiveness or safety of laxatives used in children is difficult and we extended the search for side effects to the adult literature. EXPERT OPINION: In adults, new promising drugs are on the virtue of breaking through in the treatment of chronic constipation. Carrying out well-defined placebo-controlled trials in children should be the next step before using these drugs.     

Pharmacodynamic activity of drugs and ecotoxicology--can the two be connected?

Therapeutic agents, active substances as well as metabolites, have been detected in the environment, notably in the aquatic compartment. Such contamination may induce adverse environmental effects, and the question is, whether respective hazards could be deduced from their pharmacodynamic properties and activities, and whether there could indeed be relevant risks at the (very low) environmental concentrations observed. While it would seem that, in many cases, the concentrations of drugs needed to elicit pharmacodynamic responses will exceed the environmental concentrations by factors in the range of 10(4)-10(6), and while, furthermore, pharmacodynamically-mediated influences by drug residues on eco-organisms are possible only if the pharmacodynamic target (enzyme, receptor) is expressed and functionally active in some way in the respective eco-organism, such considerations should not, however, deflect from the fact that the specificities of drug substances are defined in terms of the human target structures, and that other organisms may exhibit different specificity profiles. Examples of such species specificities are discussed in this paper and lead to the conclusion that, on the one hand, pharmacodynamic effects, classified as secondary and considered irrelevant for the therapeutic activity in humans, might potentially play a major role in other (non-mammalian) eco-organisms, and that, on the other hand, the--"anthropocentrically" defined--primary pharmacodynamic activities of drugs could induce effects in (non-mammalian) eco-organisms totally different from the therapeutic effects. It is further argued that even slight, non-significant influences on single components within regulatory cascades, like cellular division or signal transduction, that would not result in any acutely discernible effect, might ultimately, through sequential propagation or through interaction with additional, unrelated factors, affect a whole population by its negative consequences on fitness: disturbances in hormonal homeostasis ("endocrine disruption"), in immunological status, in signal transduction or gene activation may serve as examples. From these considerations it is concluded that a more "mechanism-based" approach to the experimental investigation of potential environmental hazards through the contamination of, especially, the aquatic compartment by drug residues should therefore yield more meaningful results and insights than the indiscriminate use of a standard battery of ecotoxicology assays.     

Can genetics inform the management of cognitive deficits in schizophrenia?

There is no doubt that schizophrenia has a significant genetic component and a number of candidate genes have been identified for this debilitating disorder. Of note, several of these are implicated in cognition. Cognitive deficits constitute core symptoms of schizophrenia, and while current antipsychotic treatment strategies aim to help psychosis-related symptomatology, the cognitive symptom domain is largely inadequately treated. A number of other pharmacological approaches (e.g. using drugs that target specific neurotransmitter systems) have also been attempted for the amelioration of cognitive deficits in this population; however, these too have had limited success so far. Psychological interventions appear promising, though there has been speculation regarding whether or not these produce long-term functional improvements. Pharmacogenetic studies of the cognitive effects of currently available antipsychotics, although in relatively early stages, suggest that the treatment of cognitive deficits in schizophrenia may be advanced by focusing on genetic variants associated with specific cognitive dysfunctions in the general population and using this to match the most relevant pharmacological and/or psychological interventions with the genetic and cognitive profiles of the target population. Such a strategy would encourage bottom-up advances in drug development and provide a platform for individualised treatment of cognitive deficits in schizophrenia.     

Therapeutics and prion disease: can immunisation or drugs be effective?

Prion diseases are of considerable importance because of the threat of a variant form of Creutzfeldt Jakob disease that has emerged in recent years. Pre-clinical diagnosis of prion diseases still remains poor and effective therapies also do not exist at present. This review examines research on possible therapeutic strategies that might have potential benefits if applied before neurodegeneration has occurred.     

Can antiarrhythmic agents be selected based on mechanism of action?

When selecting an antiarrhythmic agent the clinician needs to be able to accurately predict the probability that a particular drug will serve its intended purpose in a given patient. This is difficult because of the complexity of variables which govern the relationship between drug administration and clinical outcome. The efficacy of a drug may potentially be predicted from its mechanism of action. At least two classifications of antiarrhythmic agents based on mechanism of action have been proposed. The Vaughan Williams classification is based on the predominant electrophysiological effects of a drug on the action potential. In the Sicilian Gambit approach, a number of potential targets ('vulnerable parameters') for drug action are identified and antiarrhythmic drugs or substances that affect cardiac electrophysiology are characterised by their actions on each of these. The usefulness of these classification systems in predicting antiarrhythmic drug efficacy are limited. Furthermore, in the Vaughan Williams classification not all drugs in the same class have identical effects, whereas some drugs in different classes have overlapping actions. The Sicilian Gambit requires in-depth knowledge regarding cellular and molecular targets of antiarrhythmic agents which may make it intimidating or simply impractical for regular clinical use. Surrogate measures such as 24-hour Holter monitoring and programmed electrical stimulation have been used to predict anti-arrhythmic drug efficacy. However, studies such the Cardiac Arrhythmia Suppression Trial (CAST) have shown that suppression of ventricular ectopy on Holter monitoring does not necessarily correlate with improved survival and may in fact be dangerous. Conversely, studies using programmed electrical stimulation to assess drug effect on variables such as tachycardia inducibility, refractory period and ventricular tachycardia cycle length show that suppression of tachycardia inducibility, prolongation of refractory period and prolongation of ventricular tachycardia cycle length, are all associated with reduced recurrence of tachycardia and possibly improved survival. The most practical use of the current classification systems applied to antiarrhythmic agents may be in their ability to predict with reasonable accuracy, the risk and type of proarrhythmia based on the mechanism of action of an agent.     

Can we develop neurally acting drugs for the treatment of migraine?

Serotonin (5-HT)(1B/1D) receptor agonists, which are also known as triptans, represent the most important advance in migraine therapeutics in the four millennia that the condition has been recognized. The vasoconstrictive activity of triptans produced a small clinical penalty in terms of coronary vasoconstriction but also raised an enormous intellectual question: to what extent is migraine a vascular problem? Functional neuroimaging and neurophysiological studies have consistently developed the theme of migraine as a brain disorder and, therefore, demanded that the search for neurally acting antimigraine drugs should be undertaken. The prospect of non-vasoconstrictor acute migraine therapies, potential targets for which are discussed here, offers a real opportunity to patients and provides a therapeutic rationale that places migraine firmly in the brain as a neurological problem, where it undoubtedly belongs.     

What is the impact of ethics on clinical trials?

Ethics has often been ignored or evaded in clinical trials, and the conditions under which global clinical trials are conducted make this problem likely to persist. Ethics can, however, have an impact at any of several stages of a trial when the individuals involved are committed. This editorial provides historical examples of ignoring, evading or, alternatively, using ethical help to improve clinical trials, and suggests that the actual role of ethics depends on the individuals involved.     

Can pharmacogenetics help rescue drugs withdrawn from the market?

Observations over the later half of the last century have suggested that genetic factors may be the prime determinant of drug response, at least for some drugs. Retrospectively gathered data have provided further support to the notion that genotype-based prescribing will improve the overall efficacy rates and minimize adverse drug reactions (ADRs), making personalized medicine a reality. During the last 16 years, 38 drugs have been withdrawn from major markets due to safety concerns. Inevitably, a question arises as to whether it might be possible to 'rescue' some of these drugs by promoting genotype-based prescribing. However, ironically pharmacogenetics has not perceptibly improved the risk/benefit of a large number of genetically susceptible drugs that are already in wide clinical use and are associated with serious ADRs. Drug-induced hepatotoxicity and QT interval prolongation (with or without torsade de pointes) account for 24 (63%) of these 38 drug withdrawals. In terms of the number of drugs implicated, both these toxicities are on the increase. Many others have had to be withdrawn due to their inappropriate use. This paper discusses the criteria that a drug would need to fulfill, and summarizes the likely regulatory requirements, before its pharmacogenetic rescue can be considered to be realistic. One drug that fulfils these criteria is perhexiline (withdrawn worldwide in 1988) and is discussed in some detail. For the majority of these 38 drugs there are, at present, no candidates for genetic traits to which the toxicity that led to their withdrawal may be linked. For a few other drugs where a potential candidate for a genetic trait might explain the toxicity of concern, the majority of patients who experienced the index toxicity had easily managed nongenetic risk factors. It may be possible to rescue these drugs simply by careful attention to their dose, interaction potential and prescribing patterns, but without the need for any pharmacogenetic test. In addition, the pharmacogenetic rescue of drugs might not be as effective as anticipated as hardly any pharmacogenetic test is known to have the required test efficiency to promote individualized therapy. Multiple pathways of drug elimination, contribution to toxicity by metabolites as well as the parent drug, gene-gene interactions, multiple mechanisms of toxicity and inadequate characterization of phenotype account for this lack of highly predictive tests. The clinical use of tests that lack the required efficiency carries the risks of over- or under-dosing some patients, denying the drug to others and decreasing physician vigilance of patients. Above all, at present, prescribing physicians lack an adequate understanding of pharmacogenetics and its limitations. It is also questionable whether their prescribing will comply with the requirements for pretreatment pharmacogenetic tests to make pharmacogenetic rescue a realistic goal.     

Evaluation of acute effects of melatonin on ethanol drinking in ethanol na?ve rats

Objective:

The objective was to evaluate the acute effect of melatonin on ethanol drinking in ethanol naïve rats and to determine the specificity of the effect of melatonin on ethanol intake as compared to an intake of plain tap water or sugar water.

Materials and Methods:

A total of three experiments (2 weeks duration each) using different drinking solutions (ethanol, plain tap water, sugar water) was conducted in individually housed male wistar rats of 5 weeks age. Each animal had access to bottles containing drinking solutions for 2 h a day. In each experiment, on day 1, day 2, day 4, day 5, day 8, day 9, day 11, day 12 rats received drinking solutions. Each individual rat received single doses of saline, melatonin (50 mg and 100 mg/kg), and naltrexone on day 2, 5, 9, and 12, 1-h before receiving drinking solution. The order of drug administration is permuted such a way that each animal received the drugs in a different order in different experiments.

Results:

Melatonin has significantly decreased ethanol consumption by the rats and effect is dose-dependent. Naltrexone also has caused a significant reduction in the ethanol consumption. The maximum reduction in ethanol consumption was seen with melatonin 100 mg/kg dose compared to melatonin 50 mg/kg and naltrexone. There was no statistically significant effect of melatonin on plain water and sugar solution intake.

Conclusions:

Melatonin decreases ethanol consumption in ethanol naïve rats. The effect of melatonin is similar to naltrexone affecting selectively ethanol consumption, but not plain water and sugar water consumption.KEY WORDS: Dependence, ethanol, melatonin, naltrexone     

Vaccines against drugs of abuse: a viable treatment option?

Drug addiction is a chronically relapsing brain disorder. There is an urgent need for new treatment options for this disease because the relapse rate among drug abusers seeking treatment is quite high. During the past decade, many groups have explored the feasibility of using vaccines directed against drugs of abuse as a means of eliminating illicit drug use as well as drug overdose and neurotoxicity. Vaccines work by inducing drug-specific antibodies in the bloodstream that bind to the drug of abuse and prevent its entry into the brain. The majority of work in this area has been conducted with vaccines and antibodies directed against cocaine and nicotine. On the basis of preclinical work, vaccines for cocaine and nicotine are now in clinical trials because they can offer long-term protection with minimal treatment compliance. In addition, vaccines and antibodies for phencyclidine, methamphetamine and heroin abuse are currently under development. An underlying theme in this research is the need for high concentrations of circulating drug-specific antibodies to reduce drug-seeking and drug-taking behaviour when the drug is repeatedly available, especially in high doses. Although vaccines against drugs of abuse may become a viable treatment option, there are several drawbacks that need to be considered. These include: a lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice;a lack of an effect on drug craving that predisposes an addict to relapse; and tremendous individual variability in antibody formation. Forced or coerced vaccination is not likely to work from a scientific perspective, and also carries serious legal and ethical concerns. All things considered, vaccination against a drug of abuse is likely to work best with individuals who are highly motivated to quit using drugs altogether and as part of a comprehensive treatment programme. As such, the medical treatment of drug abuse will not be radically different from treatment of other chronic diseases.     

Can the renin-angiotensin system protect against stroke? A focus on angiotensin II receptor blockers

From a patient's perspective, stroke is the most devastating form of cardiovascular disease, representing the number one cause of permanent disability in the United States. Treatment of hypertension significantly reduces the risk of stroke; however, it is unclear whether all antihypertensive agents are equivalent in this regard. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of cardiovascular events, including stroke. Although attenuation of the renin-angiotensin system (RAS) is often credited with the blood pressure-independent effects of this class of agents, this hypothesis has not been confirmed with regard to the end point of stroke. In fact, drugs that activate the RAS, such as diuretics and dihydropyridine calcium channel blockers, are as effective or superior to ACE inhibitors for stroke prevention. Angiotensin II receptor blockers (ARBs) selectively block the angiotensin II subtype I receptor, which results in a reflexive increase in levels of angiotensin II and unopposed activation of angiotensin II subtype 2 receptors. Clinical trials comparing ARBs with active controls have reported significant reductions in stroke in ARB-treated patients. Data on ARBs and other drugs that activate the RAS (diuretics and dihydropyridine calcium channel blockers) support a potential role for the RAS in protecting against stroke. Ongoing trials with ARBs are evaluating stroke as a primary end point, and results should help to further elucidate the role of ARBs in this disease. Until then, it is prudent to treat hypertension with an agent or combination of agents that are likely to result in a rapid and sustained reduction in blood pressure, taking into consideration patient characteristics, comorbidities, tolerability, and cost.