Reply to Letter to the Editor

Journal of Neuroimmune Pharmacology -     

Sensitization to apomorphine in pigeons is due to conditioning, subject to generalization but resistant to extinction

Apomorphine (Apo) administration induces a persistent bout of pecking in pigeons and other birds. Repeated injections of Apo in pigeons lead to sensitization, i.e. the pecking response to a particular dose increases up to a dose-dependent asymptotic level. It is also known that Apo-induced pecking can be classically conditioned to the cage environment where the animals experience the effect of the drug. Here we address the question of whether, and to what extent, the sensitization effect arises as a consequence of a conditioning or of a pharmacological process. An extinction experiment demonstrated that an extinction procedure supposed to be effective in inhibiting the conditioned pecking response was not effective in suppressing the sensitization to Apo, thus casting provisional doubt on the conditioning hypothesis. However, a conditioning experiment demonstrated that the sensitization effect undoubtedly involved an important component of conditioning to an experimental cage environment, but also suggested that there was an additional component possibly not due to learning. A generalization experiment, however, showed that this second component was very probably due to a stimulus generalization effect deriving from conditioning to the home cage, suggesting that learning can account for most, if not all, of the increase in Apo-induced pecking and that an exclusively pharmacological sensitization process plays, at best, a minor role. The apparent contrast between the results of the first experiment, indicating that the sensitization is not affected by inhibitory conditioning, and the results of the last two experiments, suggesting that the sensitization is due to excitatory conditioning, can be resolved by assuming that Apo induces a drug-state-dependent conditioning. These results are related to findings and arguments concerning the sensitization to psychostimulant drugs in mammals.     

Assessing Similarity to Existing Drugs to Decide Whether to Continue Drug Development

Developing a drug requires large investments, over many years, with dramatic increases in development costs at later stages. Thus, one wants to make a No Go decision on a compound early, unless evidence continues to suggest that the project will ultimately be successful, so that resources can be focused on the most promising compounds to benefit patients. Instead of predicting the probability of success of a Phase III study, our approach to this decision uses the Phase II study results to assess similarity of the novel compound to existing drugs that are classified by different decision categories, such as a clear Go decision (e.g., a clearly effective drug), a (unfortunately common) Not Sure decision (e.g., a potentially useful but not outstanding drug), and a clear No Go decision (e.g., a clearly not effective drug). We describe how this modeling can be done using both individual and binary endpoints and how results can be combined for several different endpoints. Potential extensions of the method are also discussed.     

延缓细菌耐药的对策

细菌耐药性的增长已成为全世界医学界共同注视的热点。细菌耐药性的产生明显降低了抗菌药的疗效 ,使其感染难以控制 ,甚至播散流行 ,严重危害患者的生命与健康。针对日益增长的细菌耐药 ,我们可采取什么对策 ,使人类永远赶超在细菌的前头 ,保持主动 ?1　建立健全的细菌耐药性监测系统　　每年在各地区不同类别的医疗单位收集一定数量常见致病菌和条件致病菌的菌株 ,用统一的经典方法测定细菌对常用抗菌药的药敏试验 ,以观察耐药状况的变迁。对于某些重要的致病菌、或有耐药趋势的、或已产生耐药的细菌更应重点监测。细菌耐药资料对指导临床…