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Pharmacology has traditionally been excluded from the mandatory application of good laboratory practice (GLP) principles. Consensus has been reached through the process of the International Conference on Harmonisation (ICH, Topic S7A) with regard to the definitions of the different types of pharmacology studies (ICH S7A): primary pharmacodynamic, secondary pharmacodynamic and safety pharmacology studies, and guidance on the quality standards (expectations for GLP conformity) for these study types have been provided. Primary pharmacodynamic studies are the only study types that are fully exempt from GLP requirements. Secondary pharmacodynamic and safety pharmacology studies are expected to be conducted to GLP quality standards -- preferably to full, formal GLP compliance, when results are used for human safety assessment. At the present time, regulatory authorities will most likely be prepared to exercise flexibility in their requirement for GLP compliance, however, if non-clinical studies used in human safety assessment are not formally in compliance with the principles of GLP, regulatory acceptance may not be guaranteed. Historically, the application of formal GLP standards in safety pharmacology studies appears to vary between test facilities, and a number of study components in safety pharmacology studies, e.g. ECG monitoring, may not always conform to formal GLP standards. Apparently, however, formal GLP standards for these study components can be implemented for a relatively low additional cost. Based on the guidance given in the ICH S7A guideline, it thus appears logical to recommend that test facilities and sponsors consider their organisation of safety pharmacology studies in view of sound study management and formal implementation of GLP, where needed. Organisation of study management should facilitate collaboration across scientific disciplines because a plethora of data, originating from basic pharmacodynamics, toxicology, kinetics, and metabolism, as well as from clinical investigations, are involved in a safety pharmacology assessment. Applying formal GLP standards to safety pharmacology studies, and, when indicated, to secondary pharmacodynamic studies, does not influence the scientific standards of studies. However, applying formal GLP standards will ensure the quality, reliability and integrity of studies, which reflect sound study management. It is important to encourage a positive attitude among researchers and academics towards these lines, whenever possible. GLP principles applied to the management of non-clinical safety studies are appropriate quality standards when studies are used in the context of protecting public health, and these quality standards are therefore obviously pivotal for regulatory acceptance of non-clinical safety studies in general, and of safety pharmacology studies in particular.
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In spite of recent progress in the pharmacotherapy of depression major issues are still unresolved. These include the non-response rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants and the latency of several weeks until clinical improvement. The only non-pharmacological biological treatment options available so far which exert more rapid antidepressant efficacy are electroconvulsive therapy and, as an augmentation strategy, sleep deprivation. Current pharmacological treatments aim to enhance serotonergic and/or noradrenergic neurotransmission. In spite of emerging knowledge, the crucial mechanisms underlying both non-pharmacological treatments, which are responsible for antidepressant efficacy, are not yet clear so far. In the meantime several new pharmacological principles are under investigation with regard to their putative antidepressant potency. These include 5-HT1A receptor agonists, tachykinin receptor antagonists and various interventions within the hypothalamic-pituitary-adrenal system. While there is evidence for antidepressant properties of these new treatments in animal studies, in case series, in open studies and to some degree also in placebo controlled studies, no definite proof for the antidepressant efficacy of these new pharmacological strategies according to the requirements for evaluation of antidepressant drugs has been furnished so far. In contrast, for the established non-pharmacological treatment strategies including bright light therapy the clinical efficacy has been proven at least in subgroups of depression, but more knowledge of the main mechanisms underlying their antidepressant efficacy is still necessary. In addition new non-pharmacological treatments like repetitive transcranial magnetic stimulation, magnetic seizure therapy and Vagus nerve stimulation are currently under development. Nevertheless, a follow-up of both the new pharmacological strategies and non-pharmacological treatment options is of major importance to provide even better strategies for the clinical management of depression, which also is of great socio-economic impact.
A World Health Organisation (European Regional Office) working party has been established to review the progress of clinical pharmacology in European countries. As part of this review a questionnaire on the teaching of clinical pharmacology was sent to the Deans of all 350 medical schools in the region. Very few replies were received from U.S.S.R., Greece and Portugal and these countries' returns were not analysed further. The overall compliance rate (excluding these countries) was 82% with a figure of 84% from Western Europe and 74% from Eastern Europe. An average time of 96 h (range 0-320) was devoted to pharmacology teaching in the medical curriculum in Western Europe with 124 (0-240) h in Eastern Europe. In contrast 28 h (0-210) was devoted to clinical pharmacology teaching in Western Europe and 27 h (0-90) in Eastern Europe. On average in Western Europe each medical school had 2 individuals trained in clinical pharmacology with 1.3 posts in the subject and the figures for Eastern Europe were 2.3 and 1.1 respectively. However these figures hide a wide variance in the teaching of clinical pharmacology. Particularly in Western Europe there are a number of medical schools in Italy, Spain and the Federal Republic of Germany (FRG) where clinical pharmacology is not taught and there is a dearth of individuals trained in the subject. Every effort to encourage clinical pharmacology and its teaching should be made, particularly in these countries.
A central dogma of G protein-coupled receptor (GPCR) pharmacology has been the concept that unlike agonists, antagonist ligands display equivalent affinities for a given receptor, regardless of the cellular environment in which the affinity is assayed. Indeed, the widespread use of antagonist pharmacology in the classification of receptor expression profiles in vivo has relied upon this 'antagonist assumption'. However, emerging evidence suggests that the same gene-product may exhibit different antagonist pharmacological profiles, depending upon the cellular context in which it is expressed-so-called 'phenotypic' profiles. In this commentary, we review the evidence relating to some specific examples, focusing on adrenergic and muscarinic acetylcholine receptor systems, where GPCR antagonist/inverse agonist pharmacology has been demonstrated to be cell- or tissue-dependent, before going on to examine some of the ways in which the cellular environment might modulate receptor pharmacology. In the majority of cases, the cellular factors responsible for generating phenotypic profiles are unknown, but there is substantial evidence that factors, including post-transcriptional modifications, receptor oligomerization and constitutive receptor activity, can influence GPCR pharmacology and these concepts are discussed in relation to antagonist phenotypic profiles. A better molecular understanding of the impact of cell background on GPCR antagonist pharmacology is likely to provide previously unrealized opportunities to achieve greater specificity in new drug discovery candidates.
Social Pharmacology, a new field in Clinical Pharmacology, describes the relationships between Society and Drugs. Topics of Social Pharmacology are first, the social consequences of populations' exposure to drugs and, secondly, the social factors explaining drug use behind clinical or rational explanations. Social Pharmacology also investigates the reasons for prescription, delivery, consumption and self-medication of drugs (behind clinical or rational factors). The paper discusses the role of the different players of Social Pharmacology in the field of drug development, evaluation, prescription and consumption. For example, the pharmaceutical industry should play an important role in the discovery of new medically and socially "desirable" drugs. Drug companies are also involved in this field for drug information to doctors but also patients. Regulatory agencies are concerned by social factors involved in drug approval, regulation of the maximal level of drug use, application and transferability of clinical trials to daily clinical practice. Social Pharmacologists also investigate the factors (others than clinical or rational) regulating drug use. Drug consumption varies according to social characteristics of physicians (sub-speciality, medical education, cultural origin, etc) or patients (gender, age, education, country, kind of work, social status etc). Relationships between drugs and religion make up a large chapter of Social Pharmacology. Other topics in Social Pharmacology involving other health professionals (pharmacists), lawyers and the media are also discussed. Finally, drugs should be considered as important social markers of population behaviour. The role of the Social Pharmacologist is to identify these social and irrational factors governing drug use in order to adapt and rationalize drug utilization in daily clinical practice.
When the Arabic-Islamic medicine evolved partly as a consequence of the wave of translations from mainly Greek medical books to Arabic in the 9th century the pharmacological works, which were available, were also translated. The books of Dioscurides and Galen on pharmacological matters became the decisive books of pharmacological translated literature and they formed the basis of the pharmacological understanding in the subsequent extensive literature on pharmacognosy and pharmacology written in Arabic. Nevertheless the Arabs united these two disciplines in a regular pharmacy and they evolved it as an independent discipline, which although attached to medicine was regarded as having its own praxis. The physicians and scientists rationalized and systematized their knowledge of medicinal plants and drugs and extended their knowledge by using original observations and research. Many books on medicaments were written, both as materia medica, i.e. records on simple drugs, and dispensatories, i.e. books on compounded drugs. These two kinds of books were always written separately as they were seen by the Arabs themselves as pertaining to two different subdisciplines, which meant that they were separated too in independent chapters or books in general Arabic works on medicine. When the extensive translations of Arabic medical literature to Latin took place in Italy and Spain in the 11th and 12th centuries, the Arabic pharmacological literature was of course also translated, and its decisive influence on later medieval European medical writings is easy to demonstrate. In the 18th century Peter Forsskaal was one of the first Europeans in the modern scientific tradition to collect and make notes on drugs used in Cairo and in Yemen.
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The usefulness of Holter monitoring (HM) in selecting pharmacologic therapy for patients with sustained monomorphic ventricular tachycardia (VT) was evaluated in patients in whom no effective pharmacologic therapy could be determined in an electrophysiologic study (EPS). The study population consisted of 49 consecutive patients with sustained VT who were receiving long-term pharmacologic therapy despite the fact that no pharmacologic therapy had been found to be effective in the EPS. The efficacy of the pharmacologic therapies was assessed by HM. A reduction in frequent (10/h) premature ventricular contractions (PVCs) was used as an index of treatment efficacy, with therapies achieving substantial PVC suppression (>70% of all PVCs) being considered to be effective (HM effective group). When no therapy was found to be effective when assessed by HM, a drug with any other beneficial effect, eg, reduction in VT rate, was chosen (HM ineffective group). VT recurrence and survival were compared between groups. During the follow-up period of 31+/-28 months, VT recurrence was observed in a total of 25/49 patients: 3/17 patients in the HM effective group, in 18/25 in the HM ineffective group, and in 4/7 in the HM undetermined group (p=0.0487). Sudden cardiac death occurred in a total 7/49 patients: 2/17 patients in the HM effective group, 4/25 patients in the HM ineffective group, and 1/7 patient in the HM undetermined group (p=0.2828). Among patients in whom no effective therapy could be determined by EPS, the VT recurrence rate was significantly lower in the group in whom treatment was effective as assessed by HM than among those in whom treatment was assessed by HM to be ineffective. Sudden cardiac death rate was also lowest in the HM effective group, although the difference was not statistically significant. HM assessment was considered useful in selection of pharmacologic therapy for patients in whom no effective therapy could be determined in the EPS.
By the year 2000 the world's population will exceed 6 billion people, of whom one-half will be under the age of 15. Many of these children will die unnecessarily from diseases readily treatable with pharmaceutical agents. The discipline of pediatric clinical pharmacology has the potential to provide significant benefit to the world's children. Critical to the recognition of this potential is the blending of the expertise to be found in the disciplines of pediatrics, toxicology, clinical pharmacology, pharmacogenetics and clinical epidemiology. Through a marriage of these disciplines and an appropriate admixture of social sciences we may create a strong discipline focused on the encouragement of optimal drug therapy for children and for their protection from inappropriate drug exposure in utero. Such a development is the prime objective of the Pediatric Clinical Pharmacology Subcommittee: International Union of Pharmacology, Section of Clinical Pharmacology.
Safety Pharmacology is an integrated discipline that has evolved from the distinct fields of pharmacology, physiology and toxicology. Studies conducted under the guidance of 'Safety Pharmacology' are used to further the discovery, but more importantly, characterize the development of 'safe' biologically active new chemical entities (NCE). Safety Pharmacology studies identify, monitor and characterize potentially undesirable pharmacodynamic activities in non- or pre-clinical studies. This cursory review will highlight the history of Safety Pharmacology and overview the general recommendations of testing strategies used for preclinical core battery studies that are required according to the ICH regulatory S7A and S7B guidelines.
BACKGROUND: Different pharmacological approaches aimed at opioid detoxification are effective. Nevertheless a majority of patients relapse to heroin use, and relapses are a substantial problem in the rehabilitation of dependent heroin users. Some studies have suggested that the sorts of symptoms which are most distressing to addicts during detoxification are psychological symptoms rather than physiological symptoms associated with the withdrawal syndrome. OBJECTIVES: To evaluate the effectiveness of any psychosocial plus any pharmacological interventions versus any pharmacological alone for opioid detoxification, in helping patients to complete the treatment, reduce the use of substances and improve health and social status. SEARCH STRATEGY: We searched the Cochrane Central Register of Trials (CENTRAL) issue 3, 2003; MEDLINE 1966-2003; EMBASE 1980-2003; PsycINFO 1985-2003; relevant web sites; scan of reference list of relevant articles. There were no language or publication restrictions. SELECTION CRITERIA: Randomised controlled trials which focus on any psychosocial associated with any pharmacological intervention aimed at opioid detoxification. People less than 18 years of age and pregnant women were excluded. DATA COLLECTION AND ANALYSIS: The trials were independently assessed for inclusion and methodological quality by three reviewers. Data were extracted independently and double checked. MAIN RESULTS: The searching process resulted in the identification of 77 different studies: 8 studies met inclusion criteria. These studies considered 5 different psychosocial interventions and 2 substitution detoxification treatments: Methadone and Buprenorphine. The results show promising benefit from adding any psychosocial treatment to any substitution detoxification treatment in terms of completion of treatment RR 1.68 (95% CI 1.11-2.55), results at follow-up RR 2.43 (95% CI 1.61-3.66), and compliance RR 0.48 (95% CI 0.38-0.59). In respect of the use of heroin during the treatment, the differences were not statistically significant but favoured the combined treatments. REVIEWERS' CONCLUSIONS: Psychosocial treatments offered in addition to pharmacological detoxification treatments are effective in terms of completion of treatment, results at follow-up and compliance. Although a treatment, like detoxification, that exclusively attenuates the severity of opiate withdrawal symptoms can be at best partially effective for a chronic relapsing disorder like opiate dependence, this type of treatment is an essential step prior to longer-term drug-free treatment and it is desirable to develop adjunct psychosocial approaches that might make detoxification more effective. Limitations to this review are imposed by the heterogeneity of the assessment of outcomes. Because of lack of detailed information no meta analysis could be performed to analyse the results related to several outcomes.
Cigarette smokers (n = 387) completed a questionnaire measure of smoking motives, and subgroups of this sample provided external validation information. Seven factors emerged from a principal components' analysis: automatic, sedative, addictive, stimulation, psychosocial, indulgent and sensorimotor manipulation. A higher-order principal components analysis revealed the presence of two second-order factors. Inspection of the pattern of correlations between factor scores and criterion variables clearly indicated that the first four factors above and their underlying second-order factor are more closely related to nicotine pharmacology and mood-altering effects of nicotine than the latter three motives and their underlying second-order factor. Moreover, the positive correlations between these pharmacological motives and age, coupled with a negative relationship between age and the non-pharmacological motives, support the description of the smoking career as a progressive transfer of reward from non-pharmacological to pharmacological factors. These findings suggest that self-reported reasons for smoking represent more than bias in verbal report.
Disturbance of the normal mucociliary clearance due to hyperproduction of mucus and modification of its physicochemical characteristics is a common finding in airway diseases. Drugs that affect airway secretion have been developed and used to cleanse the respiratory tract for many centuries and in many countries. On the basis of the mechanism of their actions, the mucoactive drugs are classified into several groups. Some mucoactive drugs have direct effects on the production or composition of airway secretions, resulting in increased effectiveness of mucociliary clearance. Other mucoactive drugs do not have a specific action on mucus, but have beneficial effects on airway structure and function, which lead to correction of the pathophysiologic mechanisms that result in abnormal secretions. However, since many drugs have overlapping effects, it is difficult to classify these drugs into groups based on their major actions. Taken together with previous findings on mucoactive drugs, it appears that an antioxidant effect is a common property of mucoactive drugs and that it is a crucial action to exert their effects against airway diseases. In light of this idea, we must use specific experimental models to simulate pharmacologic events in airway inflammation. The development of new techniques has made it possible to identify and measure the mucus components, measure the rheologic parameters more accurately, and evaluate mucociliary clearance precisely in animals and humans. Therefore, with modifications of methods, we have investigated airway-cleansing drugs from various points of view to reflect actions in inflammatory states for more than two decades. Here, I introduce the methods we have used to study many of the parameters involved in airway clearance, including cough reflex, and describe some of the mucoactive-antitussive drugs that we have studied recently. There is an increasing usage of traditional Chinese herbal medicines in clinics and hospitals, because they tend to have moderate side effects and sometimes remarkable efficacy. To renormalize overall defects in airway disorders, Chinese medicines may be adequate, because they are composed of various herbs with weak but ubiquitous pharmacologic activities. We have been investigating Bakumondo-to. Bakumondo-to has been used for the treatment of bronchitis and pharyngitis accompanying severe dry cough. We found that unlike codeine Bakumondo-to had a notable antitussive activity against the cough associated with bronchitis and the cough increased by angiotensin-converting enzyme inhibitors. Recently, we have found that, in alveolar type II cells, Bakumondo-to attenuated phosphatidylcholine secretion increased by oxygen radicals from activated PMNLS. In addition, we found that Bakumondo-to itself stimulated phosphatidylcholine secretion and increased beta-adrenoceptor gene expression in rat alveolar type II cells. We studied the mechanism of action and clarified that Bakumondo-to increased glucocorticoid-sensitive promotor activity. The effect may contribute to its ubiquitous effectiveness in the treatment of airway diseases. Various parameters (chemical properties, physical properties, mucus production, surfactant phospholipid production, and mucociliary clearance) are considered to be important for the dynamics and mobilization of airway secretions. Pharmacologic investigation, with appropriate techniques, of the ability of an agent to modify these parameters can provide useful information about its mechanism of action. However, since these parameters are interconnected, it is very complicated to elucidate the precise mechanisms of action of mucoactive drugs. This means that the goal of treatment cannot always be achieved by the modification of a single parameter, but should, more realistically, be aimed at a renormalization of several parameters. On the basis of this idea, glucocorticoids are ideal mucoactive drugs because they exert various pharmacologic effects in the lung. From a polypharmacologic point of view, a traditional Chinese medicine can be classified as a glucocorticoid-like drug because Chinese medicines consist of many types of active components that have various pharmacologic effects. As one future course of research, we believe that efforts to seek compatible actions between glucocorticoids and Oriental medicines may lead to new opportunities for development of ideal airway-cleansing drugs with specific actions, i.e., suppression of gene expression.