ISSN:0272-4391    

DOI:10.1002/ddr.430320402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430320403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractGeneral pharmacology and safety pharmacology studies are of considerable value in drug discovery and safety assessment. The knowledge gained from these studies adds mechanistic perspectives and functional dimensions to contemporary animal pharmacology and toxicology studies. If conducted prior to initiation of drug development activities, general pharmacology and safety pharmacology studies can assist in the selection of drug classes and specific candidates for drug development, and contribute to selection of rational high doses for chronic toxicity studies. If conducted prior to initiation of clinical safety studies, these studies can influence the design of clinical protocols so that appropriate strategies are put in place to ensure appropriate patient management and care. Finally, general pharmacology and safety pharmacology studies can provide an important communication pathway between the non‐clinical and clinical segments of a drug development progra

ISSN:0272-4391    

DOI:10.1002/ddr.430320404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractGeneral Pharmacology/Safety Pharmacology studies are being used increasingly to support registration of clinical drug candidates. The value of these studies and the possible impact on the drug discovery and development processes is being recognized as evidenced by the increasing number of companies implementing formal General Pharmacology/Safety Pharmacology groups. The interactions of other departments such as Discovery, Drug Metabolism, Toxicology, Clinical Medicine, and Regulatory Affairs with General Pharmacology are highly dependent on the positioning within the particular organization and the goals set for General Pharmacology studies. The nature of these interactions and how they can be used to the advantage of drug discovery and development programs are discussed.

ISSN:0272-4391    

DOI:10.1002/ddr.430320405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe performance of general pharmacology procedures on new drug candidates supports both drug discovery and safety assessment activities; however, the potential contribution of general pharmacology to safety assessment has had less attention than other aspects of non‐clinical testing. Pharmaceutical companies are divided as to whether or not general pharmacology is integrated with the rest of toxicology testing or carried out as part of the discovery program, and, recently, discussions have taken place within Europe as to whether or not these studies should be subject to Good Laboratory Practice (GLP) conditions. All three regions (the United States, Europe, and Japan) require data on the pharmacological properties of new drugs to be included in a marketing application. This should cover primary and secondary pharmacological effects, and should provide information concerning potential adverse reactions. In addition, Europe and the United States request non‐clinical data on potential drug interactions. However, the most detailed requirements are described in the Japanese guidelines. This paper reviews the current regulatory environment in the European Community (EC), Japan, and the United States, highlighting some general features of the three regulatory systems which are relevant to general pharmacology, and summarising the specific guidelines for these studies in the three regions. Although there are significant differences between the detailed Japanese general pharmacology requirements and the more flexible Western approach, it is not clear that it is appropriate to include general pharmacology within the international harmonization discussions. Rather, deregulation in this area is a desirable goal for the fut

ISSN:0272-4391    

DOI:10.1002/ddr.430320406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractIn contrast to the well‐defined regulatory requirements for the conduct of animal toxicology studies, FDA regulations and guidelines for nonclinical pharmacodynamic studies are relatively general and do not require that any specific studies be conducted. General pharmacology studies are conducted to identify actions of a new agent in addition to those associated with the primary therapeutic utility. General pharmacology studies aimed at determining drug effects on cardiovascular, central nervous system, gastrointestinal, respiratory and pulmonary, renal, endocrine and metabolism, autonomic nervous system, and drug‐receptor functions were among the types of general pharmacology studies included in a sample of recent investigational new drug application (IND) and new drug application (NDA) submissions. Assessment of drug effects on cardiovascular, autonomic nervous system, and drug‐receptor interactions were given the greatest individual importance in identifying drug effects relevant to the assessment of a product's safety at the initial IND stage. At the NDA stage, general pharmacology studies find their greatest value in predicting drug‐drug interactions, defining mechanisms of action, characterizing the pharmacological correlates of drug‐overdose, identifying dose‐limiting effects for the chronic toxicity studies, and associating animal toxicity findings with known pharmacotoxic effects. General pharmacology studies provide valuable information to complement animal toxicity studies for evaluating a drug's potential ris

ISSN:0272-4391    

DOI:10.1002/ddr.430320407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe known effects of drugs from a variety of pharmacologic/therapeutic classes on the respiratory system and worldwide regulatory requirements support the need for conducting respiratory evaluations in safety pharmacology. The objective of these studies is to evaluate the potential for drugs to cause secondary pharmacologic or toxicologic effects that influence respiratory function. Changes in respiratory function can result either from alterations in the pumping apparatus that controls the pattern of pulmonary ventilation or from changes in the mechanical properties of the lung that determine the transpulmonary pressures (work) required for lung inflation and deflation. Defects in the pumping apparatus are classified as hypo‐ or hyperventilation syndromes and are evaluated by examining ventilatory parameters in a conscious animal model. The ventilatory parameters include respiratory rate, tidal volume, minute volume, peak (or mean) inspiratory flow, peak (or mean) expiratory flow, and fractional inspiratory time. Defects in mechanical properties of the lung are classified as obstructive or restrictive disorders and can be evaluated in animal models by performing flow‐volume and pressure‐volume maneuvers, respectively. The parameters used to detect airway obstruction include peak expiratory flow, forced expiratory flow at 25 and 75% of forced vital capacity, and a timed forced expiratory volume, while the parameters used to detect lung restriction include total lung capacity, inspiratory capacity, functional residual capacity, and compliance. Measurement of dynamic lung resistance and compliance, obtained continuously during tidal breathing, is an alternative method for evaluating obstructive and restrictive disorders, respectively, and is used when the response to drug treatment is expected to be immediate (within minutes post‐dose). The species used in the safety pharmacology studies conducted in our laboratory are the same as those used in toxicology studies since pharmacokinetic and toxicologic/pathologic data are available in these species. These data can be used to help select test measurement intervals and doses and to aid in the interpretation of functional change. The techniques and procedures for measuring respiratory function parameters are well established in guinea pigs, rats, a

ISSN:0272-4391    

DOI:10.1002/ddr.430320408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe kidney as a primary excretory organ is a major route of elimination for numerous xenobiotic agents. In the process, it is liable to the hemodynamic and injurious actions of drugs due to their concentration in the kidney. In this brief review, a number of methods for assessing kidney function (e.g., serum creatinine, enzymuria, inulin, and PAH clearances, etc.), with their advantages and limitations, are described. Various acute and chronic animal models (rats and dogs) commonly used in performing safety evaluation of drugs are described; several antihypertensive drugs are cited as examples. These models can be modified with varying number of measurements, depending on the pharmacological activity of test drugs, animal species, specific issues (e.g., vascular vs. tubular effects), pathophysiological conditions, etc.

ISSN:0272-4391    

DOI:10.1002/ddr.430320409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractIn the drug developmental process, information obtained from General Pharmacology assays plays an integral part in determining the future direction of the development. The evaluation of a drug in models of cardiovascular function can provide crucial data on cardiovascular activity unrelated to the drug's principal pharmacological action. These data can guide decision‐making steps in safety assessment and clinical studies and address problematic issues from regulatory agencies. While in‐depth protocols are necessary at times, in most instances examination of basic cardiovascular parameters (e.g., blood pressure, heart rate, and electrocardiogram) as well as evaluation of cardiovascular responses to selected autonomic nervous system stimulants, will reveal unpredicted pharmacological activities altering cardiovascular function and provide insight into mechanism of action. Through careful design of an appropriate protocol and animal model, detection of undesired cardiovascular activity can be simply and efficiently achie

ISSN:0272-4391    

DOI:10.1002/ddr.430320410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractIn the drug discovery process, compounds that demonstrate therapeutic potential must be free of undesirable side effects in order to reach the clinic. Compounds that interact with more than one target, such as a receptor, have the potential to elicit side effects, in comparison to those compounds that are selective for a single target. One predictive measure of whether a compound demonstrates specificity is to profile a compound's activity through a series of receptor binding assays in what is termed a safety screen. If a compound demonstrates activity, further studies are subsequently performed in functional assays in order to determine whether the compound possesses agonist or antagonist activity at that receptor. This article discusses some of the basic tenets of receptor pharmacology and their application to safety assessment.

ISSN:0272-4391    

DOI:10.1002/ddr.430320411

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY