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1.
对作用于中枢神经系统的药物,包括物质依赖戒断药物,在其研发中,新药滥用可能性的评估非常重要.本文就相关法规的要求进行了梳理,并对新药滥用可能性临床评估的范围、方法、注意事项等进行了归纳和讨论.  相似文献   

2.
This paper represents a comprehensive review of laboratory studies investigating the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective effects of these drugs, most of which are either barbiturates or benzodiazepines, have been measured using various self-report questionnaires and their reinforcing effects have been studied using self-administration and choice procedures. Studies using both subjective and reinforcing effects reveal orderly relations between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates are associated with higher abuse liability than benzodiazepines), between different doses of the drugs (e.g. higher doses are usually associated with higher abuse liability) and among different compounds within a class. The subjective and reinforcing effects of barbiturates and benzodiazepines depend critically upon the subject populations that are tested and it is argued that individuals with histories of drug abuse provide a more sensitive indicator of abuse liability than healthy volunteers. Several principles of abuse liability testing are discussed, including the selection of an appropriate subject population, the use of blind drug administration procedures, the comparison of a test compound to an appropriate standard, the inclusion of a placebo and a wide range of doses of the test drug and the use of multiple measures of likelihood of abuse.  相似文献   

3.
Subjective effects of the nicotine lozenge: assessment of abuse liability   总被引:1,自引:1,他引:0  
Rationale. A nicotine lozenge was developed as a novel smoking cessation aid. Abuse liability, which in this context refers to use by novices not addicted to tobacco, may be expected to be low for the lozenge due to the relatively slow route of nicotine absorption. However, its resemblance to commercially marketed lozenges and its palatability, intended to increase medication compliance, may increase its abuse liability, especially among younger individuals. Objectives. The present study evaluated the abuse liability of the nicotine lozenge. Effects of the lozenge on cigarette craving were also measured. Methods. Subjective and physiological effects of the nicotine lozenge were tested in healthy adult smokers (n=12, 22–55 years old); a group of younger subjects (n=12, 18–21 years) was also included to allow for assessment of abuse liability of the lozenge in young adults specifically. Amphetamine and a confectionery lozenge were included in the study conditions as positive controls for abuse liability and palatability, respectively, and nicotine gum was included to allow for comparison with a marketed oral nicotine replacement product with low abuse liability. Results. The nicotine lozenge did not increase ratings of traditional abuse liability predictors (good effect, like effect, MBG scale of the ARCI), while amphetamine significantly increased ratings on these measures. The lozenge dose dependently decreased craving for cigarettes after 70 min of abstinence, but only in the older group. Palatability of the lozenge was rated lower than a confectionery lozenge, but not lower than nicotine mint gum. Conclusions. Results suggest that the nicotine lozenge has low abuse liability, both in adults and young adults. The lozenge reduces craving to smoke, although craving reduction may not apply to young adults (18–21 years). Subjective effects of the lozenge are consistent with utility as a smoking cessation aid and are comparable to those of nicotine gum. Electronic Publication  相似文献   

4.
Acute subjective and physiological effects were examined to provide information relevant to abuse liability of new nicotine delivery systems. Subjects (n = 12) were overnight-deprived smokers who received 0, 4, 8 and 16 active puffs from nicotine-containing cigarettes (0.1 mg per puff), 0, 1, 2 or 4 nasal sprays (0.5 mg nicotine per spray) and 0, 30, 60 and 120 vapor inhalations (estimated 0.013 mg nicotine per inhalation) in a within-subject single blinded design. While smokers clearly liked cigarette puffs, there was much less evidence of liking produced by either nasal spray or vapor inhaler; only modest elevations on a measure of good drug effects were observed. The novel delivery products engendered unpleasant effects of burning throat and nose, watery eyes, runny nose, coughing and sneezing that might be expected to limit abuse liability. Nicotine plasma level and heart rate increase was dose-related for cigarettes and nasal spray but not for vapor inhaler, indicating limited nicotine delivery with the latter device. Overall, results are consistent with the conclusion that the nicotine nasal spray and vapor inhaler are of substantially lower abuse liability than cigarettes in experienced cigarette smokers receiving initial exposure to these products. Received: 28 May 1996 / Final version: 25 October 1996  相似文献   

5.
A structured approach to assess the risk to allergic individuals from food allergens requires as a first step the experimental measurement of minimum eliciting doses in a population that is as representative as possible of the relevant allergic population, using a standardised protocol. These doses are established in controlled challenge studies, but logistical and statistical constraints mean that a proportion of the allergic population may still be at risk of reacting at doses below those which have been or could feasibly be tested. However, statistical modelling of the dose distribution resulting from such challenges permits inferences to be drawn about the proportion of allergic individuals that are likely to react to specified (low) amounts of residual allergen in food. However, different statistical models, which all provide good fits to the experimental data yield different values outside the experimental range. Consequently, the outputs from these models require a form of validation, which demonstrates how close the predictions are to reality. In addition to characterisation of the hazard, for each allergenic food this validation requires information about exposure to undeclared allergen, the actual number of reactions taking place in the wider allergic population, and the prevalence of allergy to that food.  相似文献   

6.
ABSTRACT

Introduction

Methylphenidate remains a first-line medication for treating ADHD in children and adults. However, its behavioral pharmacological similarities to methamphetamine and cocaine have historically created concern for its potential as a drug of abuse. In September 2019, the FDA published a docket requesting comments for the development of abuse deterrent formulations for CNS stimulants, emphasizing the abuse of methylphenidate as a public health concern.  相似文献   

7.
8.
Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS.  相似文献   

9.
Therapeutic uses and risks associated with the opioids, cannabis, cocaine, and phencyclidine are discussed as well as limitations of the developmental animal and clinical pediatric literature, especially with respect to problems of quantitative risk assessment. Human and animal developmental findings for methadone and cannabis are compared with respect to long-term behavioral effects with special emphasis on pharmacological and interpretive issues. It is suggested that neonatal withdrawal is the most serious neurobehavioral sequela associated with maternal use of opioid and other sedative-hypnotic compounds. Withdrawal phenomena are described and attempts to develop animal models are discussed. Methodological considerations including surrogate fostering, pair-feeding, and problems associated with the administration of compounds to lactating dams are discussed in the context of the adequacy of the EPA developmental neurotoxicity battery to characterize risk for abuse substances as well as the new NIDA medication compounds.  相似文献   

10.
Rats were trained to escape from aversive electrical brain stimulation delivered to the midbrain reticular formation (MRF) or to obtain rewarding intracranial stimulation delivered to the medial forebrain bundle (MFB). The threshold for escape behavior was determined by a modification of the psychophysical method of limits. Likewise, reward thresholds were determined by a rate-free psychophysical method. Acute administration of ethylketocyclazocine (EKC) (0.06-1.0 mg/kg s.c.) raised escape threshold in a dose-dependent manner while having no effect on non-specific measures of sedation or motor impairment. This suggests that opioids with kappa receptor activity specifically modulate pain at a supraspinal level. Administration of EKC had no effect on the threshold for rewarding intracranial stimulation to the MFB suggesting that EKC has low potential for abuse.  相似文献   

11.
Two inbred strains of Tryon rats were tested for consumption of morphine (0.5 mg/ml) and alcohol (10% w/v) solutions in both free and forced situations. Statistically significant differences in intake by strain were found both for morphine and alcohol. The Tryon S3 strain consumed significantly more morphine than the S1 strain in two of the four phases of the experiment. The Tryon S1 strain consumed significantly more alcohol than the S3 in two of the four phases. Factors affecting consumption of drug solutions including sex and activity level were assessed using analysis of covariance. Strain differences were apparent even when these factors were removed from the analyses. These results are discussed in relation to previous reports suggesting a common addiction liability for both morphine and alcohol in inbred strains of animals.  相似文献   

12.
13.
Context: Diplazium esculentum, a commonly consumed seasonal vegetable, has been reported to have some pathological effects in some animals. But, its effect on the male reproductive function has not yet been studied. Objective: To investigate the effects of boiled D. esculentum (BDE), the form which human consumes, on male reproductive functions of Swiss albino mice. Materials and methods: Male (120 in no.) and female (80 in no.) Swiss albino mice (6–8 weeks of age) were fed orally with 80, 160 and 320?mg/kg bw of BDE within a span of 180 d. After the treatment, body weight, absolute- and relative-testis weight, relative-weight of other organs, their biochemical parameters, hypo-osmotic swelling test (HOST) of spermatozoa, testis histology and fertility and fecundity tests were performed to justify the toxic effects of D. esculentum on male reproductive functions. Results: Significant dose- and time-dependent decreases were observed in body weight, absolute- and relative-testis weight, relative-weights of other organs and their biochemical parameters, percentage of live spermatozoa and percentage of fertility and fecundity in BDE fed mice. Significant decreases were observed in diameter, perimeter and area of the seminiferous tubules of mice treated for 180 d. The percentage of empty seminiferous tubules was increased significantly in BDE treated mice when compared to the controls. Discussion and conclusion: These results suggest that the intake of D. esculentum, even after cooking, may induce infertility by altering the male reproductive function, and therefore, should be evaluated further as a potential antifertility agent.  相似文献   

14.
Drug-induced seizures are a serious adverse effect and assessment of seizure risk usually takes place at the late stage of drug discovery process, which does not allow sufficient time to reduce the risk by chemical modification. Thus early identification of chemicals with seizure liability using rapid and cheaper approaches would be preferable. In this study, an optimal support vector machine (SVM) modeling method has been employed to develop a prediction model of seizure liability of chemicals. A set of 680 compounds were used to train the SVM model. The established SVM model was then validated by an independent test set comprising 175 compounds, which gave a prediction accuracy of 86.9%. Further, the SVM-based prediction model of seizure liability was compared with various preclinical seizure assays, including in vitro rat hippocampal brain slice, in vivo zebrafish larvae assay, mouse spontaneous seizure model, and mouse EEG model. In terms of predictability, the SVM model was ranked just behind the mouse EEG model, but better than the rat brain slice and zebrafish models. Nevertheless, the SVM model has considerable advantages compared with the preclinical seizure assays in speed and cost. In summary, the SVM-based prediction model of seizure liability established here offers potential as a cheaper, rapid and accurate assessment of seizure liability of drugs, which could be used in the seizure risk assessment at the early stage of drug discovery. The prediction model is freely available online at http://www.sklb.scu.edu.cn/lab/yangsy/download/ADMET/seizure_pred.tar.  相似文献   

15.
Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3–10 mg/kg) did not produce alcohol-like stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 μg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 μg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 μg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.  相似文献   

16.
Keratinous matrices – hair and nails – accumulate substances over time and allow retrospective investigation of past consumption. Analysis of these matrices can provide information complementary to blood and urine analysis or can be used as standalone. So far, research has primarily focused on the detection of substances in hair, while studies in nails are scarce. In this study, we assessed concentrations of drugs of abuse and their metabolites in hair, fingernails, and toenails collected from the same individuals to evaluate differences and correlations between matrices. A total of 26 hair, 24 fingernail, and 18 toenail samples were collected. Samples were analysed by a validated liquid chromatography–tandem mass spectrometry method able to simultaneously detect the following compounds: amphetamine (AMP), methamphetamine, 3,4‐methylenedioxymethamphetamine (MDMA), 3,4‐methylenedioxyethylamphetamine, morphine (MOR), codeine (COD), 6‐monoacetylmorphine (6‐MAM), methadone (MTD), 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP), cocaine (COC), benzoylecgonine (BE), and ecgonine methyl ester (EME). Strong positive correlations between hair, fingernails, and toenails were present for COC, BE, EME, AMP and MDMA. MOR, COD, 6‐MAM, MTD and EDDP showed positive trends. Concentrations were generally higher in nails compared to hair. Ratios between parent compounds and their metabolites were assessed for 6‐MAM/MOR, EDDP/MTD, BE/COC and EME/COC. Preliminary cut‐off concentrations for COC, BE, EME and AMP in fingernails and toenails were proposed. In light of these results, nails can be considered as a useful alternative to hair for monitoring of long‐term drug consumption. However, care should be taken regarding the variability in the accumulation of compounds between the matrices.  相似文献   

17.
The effects of centrally acting drugs on body weight changes during 8-h periods in the daytime were studied in the rat in attempts to relate those effects with morphine-type physical liability. Repeated administration of drugs which have morphine-type physical dependence liability altered the prevailing pattern of continuous body weight decrease during the observation period in control animals to an initial increase and subsequent decrease. Withdrawal of these drugs following chronic drug treatment caused a precipitous loss of body weight. Such a body weight loss was further enhanced by the administration of naloxone. In chronically morphine-treated animals, substitution for morphine with a single dose of a test drug caused an increase in body weight or attenuated the loss of body weight due to morphine withdrawal when the test drug has physical dependence liability. Drugs may be classified according to their effects on body weight changes into several groups, each with different physical dependence liability. It is concluded that physical dependence liability of centrally acting drugs can be predicted simply, inexpensively and objectively, by their effects on the pattern of daily body weight changes.  相似文献   

18.
19.
This article presents a model of case management with rural clients entering drug and alcohol treatment. As part of a larger treatment protocol called Structured Behavioral Outpatient Rural Therapy, behavioral contracting is combined with strengths perspective case management to help rural clients motivate themselves to engage and complete drug and alcohol treatment. This combined approach is designed to continually communicate and teach an “A-B-C” cognitive-behavioral approach to problem-solving and change. While not a panacea for addressing the myriad problems facing clients with drug use problems, such an approach promises to improve “treatment as usual” formats, which often ignore the formidable obstacles to human change experienced by rural clients and clinicians.  相似文献   

20.
目的观察复方蛇脂凝胶对皮肤刺激性和过敏反应。方法用复方蛇脂凝胶多次局部涂抹家兔的皮肤进行刺激,观察皮肤刺激性;对豚鼠皮肤多次局部涂抹致敏,观察过敏反应。结果复方蛇脂凝胶对家兔皮肤无刺激性,对豚鼠皮肤的多次刺激过敏致敏试验均无出现皮肤明显红斑、水肿等皮肤过敏反应和全身性过敏反应。结论复方蛇脂凝胶对皮肤无刺激性和过敏性作用。  相似文献   

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