Conditioned place preference: what does it add to our preclinical understanding of drug reward?

Rationale: Benzodiazepines are effective in the treatment of anxiety disorders over a prolonged period of time. This results in relatively stable plasma concentrations over the course of a day. However, due to differences in drug clearance in rats, which generally metabolize and clear drugs much more rapidly than humans, it is difficult to model this steady level in rats. Objectives: Several methods of chronic alprazolam administration were compared to determine which would best result in reproducible, therapeutically relevant levels of the drug. Methods: Male Sprague-Dawley rats were administered alprazolam via two subcutaneous routes, Alzet 2ML2 osmotic minipumps and commercially produced slow-release pellets, for 1 week and 2 weeks, respectively. Additionally, alprazolam was orally administered for 2 weeks by mixing the compound into a commercially available liquid, fat emulsion-based diet. The use of silastic implants to deliver several different benzodiazepines was also evaluated in vitro. Results: Following 7 days of alprazolam administration at 2 mg/kg per day via osmotic minipump, plasma concentrations in ten identically treated rats ranged from <1 ng/ml to 97 ng/ml. Slow-release pellets produced more consistent plasma concentrations, but were only minimally effective at raising plasma concentrations. In vitro studies utilizing silastic implants containing 90 mg drug in 6 cm of tubing revealed stable release of only 45–55 μg/day alprazolam versus 625–650 μg/day diazepam. In contrast to these methodologies, incorporation of alprazolam into a commercially available liquid diet (~25–150 mg/kg per day) provided consistent, dose-dependent increases in plasma concentrations of alprazolam and its metabolites in a range appropriate for mimicking clinical exposure. Conclusions: These findings indicate that the most effective technique to produce plasma concentrations of alprazolam that are reproducible, clinically pertinent, and consistent between rats is to incorporate the drug into a liquid diet. These findings may also be of value in determining dosing routes for other benzodiazepines or psychotropic drugs. Electronic Publication     

Sudden death and ventricular preexcitation: is it necessary to treat the asymptomatic patients?

Currently, asymptomatic ventricular preexcitation, which has been put at rest for many decades, remains a clinical challenge as there are no predictors of sudden death, which can be the first clinical presentation of the syndrome. Identification of risk factors for sudden death is important, considering the availability of a definitive treatment. Now, as radiofrequency catheter ablation of accessory pathways has reported success rates approaching 100 percent without major complications in many centers worldwide, it becomes unacceptable that even one asymptomatic individual with WPW will die or will experience life-threatening arrhythmic events. In our extensive experience a short anterograde refractory period of accessory pathways, inducibility of sustained tachyarrhythmias and the presence of multiple accessory pathways are the strongest predictors of life-threatening arrhythmias and sudden death. Therefore, it is not yet justified that, after an incidental diagnosis of WPW syndrome has been made, no risk stratification by invasive testing is done. Subjects at high risk, particularly if young or adolescent, should be identified and then ablated in the same session as they can develop lethal arrhythmic events within a few years and this is our current practice. Recently, we sent a questionnaire to investigate clinical practices over a large number of centers around the world about asymptomatic ventricular preexcitation. A total of 100 replies were received and the results demonstrate that there is worldwide agreement in performing invasive electrophysiologic testing and prophylactic ablation in selected subjects. These findings provide strong evidence to revisit current guidelines, which appropriately in the absence of evidence had been conservative.     

Blood pressure variability in risk stratification: What does it add?

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Biopharmaceutical characterisation of herbal medicinal products: are in vivo studies necessary?

Herbal medicinal products have to meet comparable standards concerning the assessment of efficacy, safety and (bio)pharmaceutical quality as chemically defined synthetic drugs. However, these requirements are not fulfilled for many herbal products so far, particularly regarding in vitro dissolution and in vivo bioavailability. The necessity of in vivo studies for a biopharmaceutical characterisation of the products depends on the solubility/permeability properties of the active drug ingredient as well as dissolution behaviour of the dosage form. Also, in the case of herbal medicinal products, a waiver of in vivo BA/BE studies is recommended as long as the active ingredient is highly soluble according to the Biopharmaceutics Classification System and dissolution of the dosage form takes place rapidly (>85%/20 min) in physiological buffer systems (pH 1-8).     

Was Louis-Joseph Proust (1754-1826) a pharmacist?

Proust's first formulation of the law of definite proportions was published in a paper on iron oxides (1794). He spent the major part of his professional life in Spain, where he contracted to take a teaching and searching position. He was apprenticed to his father to study pharmacy, and he studied chemistry with Hilaire-Marin Rouelle. His early interrupted education is shown through his abilities as an analyst, the persons with whom he was in communication, his share in manufacturers' assays and his researches towards health and food chemistry. More fundamental was his belief in natural principles of order as representative of the thought of the ideologues.     

What does it mean to want to quit?

INTRODUCTION AND AIMS: To report on the prevalence of attitudes and beliefs about the importance of wanting to quit and need for use of cessation assistance, that may act as barriers to quitting smoking and adopting cessation assistance. DESIGN AND METHODS: National telephone survey of 802 randomly selected adults (685 smokers, 117 recent quitters). RESULTS: Seventy per cent of smokers believed that 'wanting to quit' was both a necessary and sufficient condition for being able to quit. While only one-third of smokers believed that they were too addicted to be able to quit, only a quarter believed they could quit any time they want to. Belief that use of cessation assistance is a sign of weakness was endorsed by 35% of participants, and related to stage of change. DISCUSSION AND CONCLUSIONS: Beliefs about the importance of wanting to quit are commonly held. Many smokers appear to believe that a rational, unambivalent desire to quit is needed before it is worthwhile trying. Short-term impulses to act are not perceived as sufficient. The role of cessation assistance in helping smokers form a rational desire to quit appears to be poorly understood by the majority of smokers. There is a need to engender greater understanding of the potential value of cessation aids to smokers experiencing ambivalence about wanting to quit.     

The classification of antiseptic products to be administered to wounds--another borderline case between medicinal products and medical devices?

The importance of a correct demarcation between a Medicinal Product (MP) and a Medical Device (MD) is undisputedly one of the major topics related to the development and launch of a new healthcare product. However, for some products the correct demarcation between MPs and MDs can turn out to be somewhat complicated. This article aims to provide an overview on the existing legislation and its adequate application based on a suitable example at hand. Article 2 (2) of the European Directive 2001/83/EC as amended by Directive 2004/27/EC on the Community code relating to medicinal products for human use stipulates that the respective Medicinal Products Legislation must be applied whenever a product can be covered by both the definitions for MPs and for products regulated by other legal provisions enacted by the European Community, e.g. Cosmetic Products (CPs) or MDs. This basic principle implies that the decision to base the risk-benefit assessment of the product in question on the Medical Device Directive (MDD) would contradict the aforementioned constitutional principle, pursuant to which the stricter of the regulatory procedures theoretically possible is to apply in cases of doubt. In contrast to the approval procedure established for MPs, the MDD requires a Conformity Assessment Procedure to be performed by the manufacturer himself and a "Notified Body". Thus, in the majority of cases the responsibility for the risk assessment of MDs lies solely with the manufacturer and is prior to launch not subject to further scrutiny by regulators. Only in specific cases, i.e. for the Conformity Assessment Procedure of Class III MDs which contain an Active Pharmaceutical Ingredient one of the Member States competent authorities designated in accordance with Directive 65/ 65/EEC has to be involved before taking a decision. It is therefore important that the classification of the product is carried out carefully in full compliance with existing legal provisions, also taking into account the related guidance documents issued by the European Commission. The adequate application of these rules is explained using the example of the antiseptic compound polihexanide, which is used both in approved medicinal products (wound antiseptics) and wound irrigation solutions labelled as medical devices.     

Lessons learned from nerve agent attacks in Iran and Japan: Is it really necessary to stockpile oximes?

Nerve agents have only ever been used in Iran and Japan: in the Iran-Iraq war and the Matsumoto and Tokyo subway sarin attacks. When discussing responses to nerve agent attacks in peace-time, it is important to maximize the lessons learned from these two incidents. The golden standard for the treatment of nerve agents has conventionally been the combination of atropine sulfate, oxime, and diazepam as recommended. While this recommendation also applies to civil defense for terrorism in peace-time, there is nonetheless a need to re-evaluate the golden standard. In addition, factors such as cost-effectiveness must be considered.     

Apparent marked reduction in early antivenom reactions compared to historical controls: Was it prophylaxis or method of administration?

Objective

Serious morbidity and mortality following snakebite injuries are common in tropical regions of the world. Although antivenom administration is clinically effective, it carries an important risk of early anaphylactic reactions, ranging from relatively benign nausea, vomiting, and urticaria to life-threatening angioedema, bronchospasm and hypotension. Currently, no adequately powered study has demonstrated significant benefit from the use of any prophylactic drug. A high rate of anaphylactic reactions observed during a trial of three different antivenoms in Ecuador prompted adoption of premedication with intravenous (IV) hydrocortisone and diphenhydramine together with dilution and slower administration of antivenom.

Design

In a rural mission hospital in Eastern Ecuador, 53 consecutive snakebite victims received a new antivenom regimen in 2004-2006, comprising prophylactic drugs and IV infusion of diluted antivenom over 60 min. They were compared to an historical control cohort of 76 patients treated in 1997-2002 without prophylactic drugs and with IV “push” injection of undiluted antivenom over 10 min. All these patients had incoagulable blood on admission and all were treated with Brazilian Instituto Butantan polyspecific antivenom.

Results

Baseline characteristics of the historical control and premedicated groups were broadly similar. In the historical group, early reaction rates were as follows: 51% of patients had no reaction; 35% had mild reactions; 6% moderate; and 6% severe. In the premedicated/slow IV group, 98% of patients had no reaction; 0 mild; 0 moderate; and 2% severe. The difference in reaction rates was statistically significant (p < 0.001).

Conclusions

Premedication with intravenous hydrocortisone and diphenhydramine together with dilution of antivenom and its administration by IV infusion over 60 min appeared to reduce both the frequency and severity of anaphylactic reactions. A randomized blinded controlled trial is needed to confirm these encouraging preliminary findings.     

Are placebo controls necessary to test new antidepressants and anxiolytics?

One measure of a treatment's effectiveness is the regularity with which it proves superior to placebo. That measure also tells us about the consequences of using a treatment as a standard against which to test a new agent. To assess the frequency with which approved and presumably effective antidepressants and anxiolytics show statistical superiority over placebo, we reviewed placebo-controlled clinical trials of antidepressants and anxiolytics in a singularly large database free of publication bias. We evaluated clinical-trial data from the nine antidepressants approved by the FDA between 1985 and 2000. These trials comprised 10030 depressed patients who participated in 52 antidepressant clinical trials evaluating 93 treatment arms of a new or established antidepressant. Similarly, we examined clinical trials data from the 13 anxiolytics approved by the FDA between 1985 and 2000. These trials comprised 8,340 anxious patients, 40 anxiolytic clinical trials and 75 treatment arms of a new or established anxiolytic. Fewer than half (48%, 45/93) of the antidepressant treatment arms showed superiority to placebo. Among anxiolytics, 48% (36/75) of anxiolytic treatment arms showed superiority over placebo. These data suggest that conventional psychopharmacologic treatments for depression and anxiety are superior to placebo less than half the time and call into serious question the widely propagated notion that placebo controls can be dispensed with in clinical trials of these agents. Exclusion of placebo controls in favour of non-inferiority trials would result in a high likelihood that ineffective antidepressants and anxiolytics would be foisted on the public and, less dangerous but also problematic, that potentially effective agents would be missed.     

Human exposure to insecticide products containing pyrethrins and piperonyl butoxide (2001–2003)

Pyrethrum, used as an insecticide for centuries, is derived from dried and ground flowers of Chrysanthemum cinerariaefolium. Its current major use is in insecticide products to the control insects in the home and food handling establishments. We investigated human incidents reported through the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS^©) associated with regulated insecticides containing pyrethrins and piperonyl butoxide (PY/PBO) from 2001 to 2003. Special attention was paid to dermal and respiratory effects. Although there are limitations associated with TESS data, we observed that

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Despite extensive use, incidents with reports of moderate or major adverse effects were relatively rare (717 moderate and 23 major outcomes out of 17,873 calls).     

Therapeutic monitoring of mycophenolate mofetil in organ transplant recipients: is it necessary?

Adequate immunosuppression minimising the risk of organ rejection with acceptable tolerability of the used drugs is a crucial step in organ transplantation. The primary goal is to maintain a consistent time-dependent target concentration by tailoring individual dosage leading to the best efficacy and tolerability combination. The use of therapeutic drug monitoring (TDM) to optimise immunosuppressive therapy is routinely employed for maintenance drugs such as cyclosporin and tacrolimus. The question whether therapeutic monitoring of mycophenolic acid (MPA) in organ transplant recipients treated with mycophenolate mofetil is necessary is not definitely answered. The correlation of mycophenolic acid pharmacokinetic parameters with efficacy and toxicity makes the therapeutic monitoring of this drug promising. However, further studies are mandatory to draw the best guidelines in order to achieve higher levels of evidence that MPA-TDM may improve patient outcome.