利培酮治疗以阴性症状为主的精神分裂症38例

目的 :观察利培酮治疗以阴性症状为主的精神分裂症的疗效及安全性。方法 :对 3 8例以阴性症状为主的住院精神分裂症患者 ,男 2 8例 ,女 10例 ,年龄 ( 2 9.5± 12 .6)岁 ,给予利培酮 2～ 8mg d ,po ,疗程 10周 ,采用阴性症状评定量表和临床疗效总评进行评定。结果 :显效率 5 0 .0 % ,有效率 78.9% ,阴性症状评定量表总分显著下降 ,不良反应以锥体外系症状为主。结论 :利培酮是治疗以阴性症状为主的精神分裂症较理想的药物     

Drug discrimination studies

Opioid agonists and agonist/antagonists comprise a heterogeneous body of compounds that can be partitioned into at least three groups on the basis of their discriminative stimulus properties in several animal species: (1) stimulus effects similar to those of morphine or fentanyl and blocked completely by low doses of antagonists, such as naloxone and naltrexone; (2) stimulus effects similar to those of ethylketocyclazocine or nalorphine and blocked by higher doses of antagonists; (3) stimulus effects similar to those N-allylnormetazocine or phencyclidine and not blocked by antagonists. This diversity of stimulus properties is consistent with other evidence that multiple populations of receptors mediate the actions of opioids. In man, drugs in group 1 produce subjective effects that are entirely morphine-like and highly reinforcing whereas drugs in groups 2 and 3 produce dysphoric and psychotomimetic subjective effects. Thus, discriminative stimulus properties of opioids appear to reflect drug actions at the neuronal level that are directly relevant to potential for abuse in man.     

Apomorphine increases ethanol discrimination

Rats were trained to discriminate between the stimulus properties of 600 mg/kg ethanol and saline in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower ethanol doses and analysis of the dose-response curve indicated an ED50 of 372 mg/kg. Pretreatment with 0.16 mg/kg apomorphine produced increased discriminative performance at each ethanol dose and the combination generated a dose-response curve parallel to ethanol administered alone with an ED50 of 232 mg/kg. This significant shift to the left of the ethanol dose-response curve after apomorphine administration is discussed in relation to dopaminergic neuronal systems and the clinical use of apomorphine alcoholics.     

Four-choice drug discrimination in pigeons

(+)Amphetamine was added as a training stimulus for pigeons previously trained to discriminate among pentobarbital, morphine and saline using a three-choice procedure. Pigeons quickly learned the four-choice drug discrimination. Generalization from the training drugs was similar to that established with simpler drug discriminations; pentobarbital generalized to chlordiazepoxide, morphine generalized to methadone, and (+)amphetamine generalized to cocaine and methamphetamine. Low doses of phencyclidine generalized to saline, while higher doses partially generalized to pentobarbital and (+)amphetamine. When dose-response curves were redetermined with a cumulative-dosing procedure, the same pattern of generalization occurred as under single-dose procedures. Dose-response curves were quantal under both the single-dose and the cumulative-dosing procedures. The four-choice procedure offers some important advantages for studying the discriminative stimulus effects of drugs that interact with multiple receptor subtypes and for studying drug mixtures.     

Drug discrimination in neurobiology.

Areas of neurobiological interest are identified towards which drug discrimination (DD) studies have made important contributions. DD allows ligand actions to be analyzed at the whole organism level, with a neurobiological specificity that is exquisite and often unrivalled. DD analyses have thus been made of a vast array of CNS agents acting on receptors, enzymes, or ion channels, including most drugs of abuse. DD uniquely offers access to the study of subjective drug effects in animals, using a methodology that also is transposable to humans and has generated unprecedented models of pathology (e.g., chronic pain, opiate addiction). Parametric studies of such independent variables as training dose and reinforcement provide refined insights into the dynamic psychophysiological mechanisms of both drug effects and behavior. Three different mechanisms have been identified by which discriminative, and perhaps other behaviors, can come about. DD also is superbly sensitive to small, partial activation of molecular substrates; this has enabled DD analyses to pioneer the unravelling of molecular mechanisms of drug action (attributing, f.ex., LSD's particular subjective effects to an unusual, partial activation of 5-HT, and perhaps other receptors). DD has both oriented and served as a tool to conduct drug discovery research (e.g., pirenperone-risperidone, loperamide). The DD response arguably constitutes a quantal, rather than graded, variable, and as such allows a comprehension of molecular, pharmacological, and behavioral mechanisms that would have been otherwise inaccessible. Perhaps most important are the following further contributions. One is the notion that particular, different levels of receptor activation are associated with qualities of neurobiological actions that also differ and are unique, this notion arguably constituting the most significant addition to affinity and intrinsic activity since the earliest theoretical conceptions of molecular pharmacology. Another contribution consists of studies that render redundant the notion of tolerance and identify fundamental mechanisms of signal transduction; these mechanisms account for apparent tolerance, dependence, addiction, and sensitization, and appear to operate ubiquitously in a bewildering array of biological systems.     

Nicotine-induced potentiation of ethanol discrimination

Rats were trained in a 2-lever, food-motivated operant task to discriminate intraperitoneal administration of ethanol (600 mg/kg) from vehicle. Dose-response curves for the ethanol cue were analyzed before and after pre-treatment of rats with intraperitoneal doses of 0.4 mg/kg or 0.2 mg/kg nicotine. Results demonstrate that nicotine potentiates ethanol-appropriate responding in test sessions. The results are discussed in light of the recognized correlation between smoking and alcohol intake.     

Caffeine potentiation of apomorphine discrimination

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Apomorphine, at doses different than the training dose, produced a dose-response relationship, whereas, caffeine (7.5–30 mg/kg) produced saline-like responding. However, co-administered of 15 mg/kg caffeine with 0.01, 0.02 or 0.04 mg/kg apomorphine potentiated the discriminative stimulus properties of these low apomorphine doses. This potentiation was antagonized by pretreatment with 0.25 mg/kg haloperidol. The results are consistent with the idea that caffeine, by virtue of being a phosphodiesterase inhibitor, may increase post-synaptic cyclic-AMP and this, in turn, may supersensitize the dopamine receptors and result in the potentiation of the apomorphine-induced dopaminergic responses.     

Intravenous cocaine discrimination in humans

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20 mg/70 kg cocaine. During the first session, saline and cocaine injections were alternated twice, with each separated by 1 hr. The injections were identified by letter codes. During the next 3 sessions, 12 trials were conducted, with saline and cocaine administered 6 times each in pseudorandom order. Thirty minutes following each injection, participants were asked to identify the injection by letter code. Seven of the 10 learned the discrimination (at least 10 trials correct). To evaluate sensitivity, the investigators tested participants with different doses of cocaine in test sessions. In the next phase, methamphetamine (5 and 10 mg/70 kg) and pentobarbital (50 and 100 mg/70 kg) were given intravenously during test sessions to determine whether the discrimination exhibited pharmacological class selectivity. During the evaluation of sensitivity and selectivity, training sessions were interspersed. As dose of cocaine increased, the number of participants identifying the test dose as cocaine increased, demonstrating sensitivity. The higher doses of methamphetamine and pentobarbital substituted for cocaine. The physiological and subjective effects of cocaine and methamphetamine were stimulant-like and dose related. Pentobarbital produced no physiological changes but increased Visual Analog Scale ratings of Sedation, Good Drug Effect, and High. This failure to demonstrate pharmacological selectivity may be related to participants' learning a drug-vs.-no-drug discrimination, and thus it may be necessary to alter training procedures in future studies.     

充分发挥技术支撑作用 药品检测车运行初见成效

目的总结药品检测车运行以来的工作经验。方法介绍了以药品检测车为平台,充分发挥技术支撑的作用,大胆创新,积极探索新的药品快速检测方法。结果与结论通过实践证明,药品检测车已逐渐显现其在药品监督管理中的作用。     

Effects of prior saline-morphine discrimination by pigeons on three-way discrimination including two morphine doses

The discriminative stimulus properties of morphine sulfate (MS) and their alteration by naltrexone (NTX) and d-amphetamine (AMP) challenges were examined in a quantitative dose 1, dose 2, and saline (SAL) drug discrimination task utilizing 1.8 mg/kg MS, 10 mg/kg MS, and SAL as discriminative stimuli under a fixed-ratio 30 schedule of food-maintained behavior in two groups of White Carneaux pigeons. Group A (Gp A) (n=6) subjects (Ss) were initially experimentally-and drug-naive, whereas group B Ss (n=4) were originally trained in a two-choice MS versus SAL discrimination task, and had a long behavioral and drug history. Significant differences were found in (1) number of sessions to criterion (STC) (group B greater than group A); (2) group A Ss generalized both NTX and AMP to SAL, whereas group, B Ss generalized AMP to the low dose (1.8 mg/kg) MS stimulus; and (3) in drug interaction test sessions, the high dose MS stimulus (10 mg/kg) in group A was unmodified by a range of challenge AMP doses (0.32 to 3.2 mg/kg). In contrast, group B Ss exhibited a shift to the low dose or SAL-appropriate keys when the same high dose MS stimulus was challenged by moderate doses of AMP. Group A and group B were similar in their pattern and distribution of responses when tested with various doses of MS, and also when challenge tests of the high dose MS stimulus were made with NTX. Qualitative generalization tests with the opiate agonist methadone suggested that methadone was more potent than MS in producing the discriminative stimulus properties learned under the MS stimulus conditions. It is suggested that the three-choice dose 1, dose 2, SAL discrimination procedure is a viable model to test agonist and antagonist relationships.     

Effect of multiple discrimination reversals on acquisition of a drug discrimination task in rats

There are many similarities between exteroceptive stimuli and interoceptive stimuli. Nevertheless, it has been suggested that behavior maintained by drug stimuli might be more difficult to reverse than behavior controlled by exteroceptive stimuli. Once a discrimination is established with an exteroceptive stimulus, it can be reversed by switching the reinforcement contingencies, and repeated reversals result in progressively faster relearning of the discrimination. To determine whether faster relearning of successive discrimination reversals also occurs when the discrimination is controlled by an internal drug stimulus, we trained rats to discriminate 3.2mg/kg phencyclidine-(PCP) from saline, in a two-lever food-reinforced operant task. After this discrimination was acquired, the reinforcement contingencies were reversed. A number of such discrimination reversals were performed to determine whether fewer trials would be needed to reach criterion performance with each reversal. Each time the reinforcement contingencies were switched, fewer training sessions were required for the subjects to reach criterion. These results are similar to those observed when a discrimination has been established with exteroceptive stimuli. The present study provides further evidence of the similarity between interoceptive drug stimuli and exteroceptive sensory stimuli.     

Caffeine discrimination in the rat

Rats were trained to discriminate 32 mg/kg caffeine from saline in a two-lever appetitive task. Across a range of caffeine test doses (1-32 mg/kg) rats showed a dose related generalization to the training cue. At intermediate caffeine dose levels, caffeine appeared to produce a more potent cue on tests following saline-training days than after drug-training days. Several psychomotor stimulants (d-amphetamine, methylphenidate, nicotine and TRH) failed to generalize to the caffeine cue. In contrast, theophylline did generalize to caffeine at a dose roughly twice that of the caffeine training dose.     

A Novel Metabolite from Aspergillus ochraceus JGI 25 Showing Cytotoxicity to Hela Cells

This study aims at the isolation of filamentous fungi, extraction of metabolites, and evaluation of the cytotoxic properties on HeLa cells and normal human lymphocytes. We isolated fungi from the soil by serial dilution method. One of the isolates was chosen and identified as Aspergillus ochraceus Wilhelm (Trichocomaceae) by standard techniques. The metabolites were extracted using methanol. Different concentrations of the extract were evaluated for their potential anticancer activity on HeLa cells by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay and the safety of the extract was checked on normal human lymphocytes. The extract was purified by chromatographic techniques like thin-layer chromatography and high-performance liquid chromatography, and subjected to mass spectrometric analysis. The extract showed significant cytotoxic potential on HeLa cells at low concentrations with a half maximal inhibitory concentration value of <50 μg/ml. The extract gave 10 fractions by thin layer chromatography, and fraction B had higher toxicity than the rest. This fraction gave a single peak by high-performance liquid chromatography and had a mass-to-charge ratio of 905.65, which did not match any of the earlier known fungal metabolites or metabolites from other strains of A. ochraceus. The metabolite from A. ochraceus is alkaloid in nature, cytotoxic to HeLa cells, and appears to be a novel with anticancer potentials, which could be explored further for characterization of the active component.     

Effects of cholinergic and non-cholinergic drugs on visual discrimination and delayed visual discrimination performance in rats

The effects of several centrally active drugs were investigated using two visual discrimination tasks: a two-lever food-rewarded conditional brightness discrimination, and a similar conditional brightness discrimination where a delay was introduced between the disappearance of the stimulus and the opportunity to respond on the levers for food. The substances tested (amphetamine, scopolamine, methylscopolamine, physostigmine, diazepam and-carboline benzodiazepine receptor antagonist, ZK 93426), all produced differing profiles of action on the performance parameters recorded. In the simple conditional visual discrimination, amphetamine increased omissions without significant effects on accuracy or response latency. Physostigmine enhanced response latencies and failures to respond without significant effects on accuracy. ZK 93426 had no consistent effects on accuracy although at higher doses, some increase in response latency was seen in the delayed responding version of the visual discrimination task. Diazepam had negative effects on all parameters in both discrimination procedures. Scopolamine disrupted responding, but not accuracy in the simple discrimination, whereas accuracy was reduced in a dose, but not delay dependent manner in the delayed discrimination. A similar effect to that observed with scopolamine was observed following methylscopolamine in the delayed discrimination procedure. In the simple visual discrimination small increases in accuracy were recorded, accompanied by increased response latencies.     

N-methyl-D-aspartate antagonists and drug discrimination.

Excitatory amino acids (EAA), such as glutamate, are thought to be involved in various disorders (e.g., ischemic brain damage, epilepsy, Parkinson's disease), and EAA antagonists have been suggested as potential treatments for these disorders. Phencyclidine (PCP), with produces psychotomimetic effects in humans, has antagonist properties at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors that have been suggested to underlie some of its actions. This suggestion, and concern about possible psychotomimetic activity, has stimulated research aimed at examining to what extent the behavioral profile of other NMDA antagonists resembles that of PCP. Drug discrimination (DD) is prominent among the procedures used to carry out such comparisons. The results of clinical studies with NMDA antagonists provide feedback about the predictive validity of the DD procedures used to characterize their preclinical behavioral profile. Further, DD is used also to examine the ability of compounds to attenuate the discriminative stimulus (DS) effects of PCP-type drugs, and results of such studies have been suggested to provide evidence of antipsychotic potential. Finally, although many instances of intermediate responding in DD can be explained by low efficacy at the receptors that mediate the DS effects of the training drug, certain outcomes produced by PCP-type drugs do not offer valid measures of efficacy, and require more detailed behavioral analyzes.     

Drugs and the discrimination of duration

Behavioral effects of intraseptal administration of cholinergic agents were analysed in cats pretreated with morphine 15–20 min or 40 min earlier. Drug-induced changes were measured both quantitatively (onset, duration, and frequency of behavioral items) and qualitatively (presence or absence of stereotyped and ritualized behavior patterns). Carbachol and scopolamine given 15–20 min after morphine accelerated and retarded, respectively, the normal development of the morphine syndrome: Carbachol resulted in the display of stereotyped and ritualized patterns, i.e., symptoms characteristic of cats pretreated 30–40 min earlier with morphine, whereas scopolamine reduced the frequency of the behavioral items in comparison with controls, and retarded the onset of stereotyped and ritualized patterns. Carbachol given 40 min after morphine also affected the fully developed morphine syndrome: It increased the frequency of stereotyped and ritualized patterns displayed at that time. This dose-dependent effect, mimicked by arecoline and the combination of acetylcholine and physostigmine, could be antagonized by atropine and scopolamine, which per se had no influence on the stereotyped and ritualized patterns. It is concluded that the degree of cholinergic muscarinic activity within the septal nuclei at least partly determines the genesis of the morphine syndrome in cats. The data are discussed in view of the hypothesis that systemically administered morphine and intraseptally applied cholinergic agents affect the cholinergic septo-hippocampal system in a common way via distinct sites of action at the level of the septal nuclei.