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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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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.
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.
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.
The working group for reevaluation of the Guideline for General Pharmacology Studies has completed a draft guideline for Safety Pharmacology studies and plan to recommend replacing the existing guideline with the revised one. This proposed guideline is now subject to domestic and international consultation. The basic principle of the revision is to harmonize the guideline with the international concepts. The working group decided to change the title of "General pharmacology" to "Safety pharmacology", because the objective of this guideline is to assess the safety of a test substance in humans by examining the pharmacodynamic properties of the substance. The proposed guideline includes studies on vital functions as essential studies that should be performed prior to human exposure. Studies are also required to be conducted when predictable or unexpected observed effects are concerned. The working group recommends a case-by-case approach to select the necessary test items in consideration of the variable information available.
In order to generate information about the relative effectiveness of the most widely used pharmacological and non-pharmacological interventions for the prophylaxis of recurrent migraine (i.e., propranolol HCl and combined relaxation/thermal biofeedback training), meta-analysis was used to integrate results from 25 clinical trials evaluating the effectiveness of propranolol and 35 clinical trials evaluating the effectiveness of relaxation/biofeedback training (2445 patients, collectively). Meta-analysis revealed substantial, but very similar improvements have been obtained with propranolol and with relaxation/biofeedback training. When daily recordings have been used to assess treatment outcome, both propranolol and relaxation/biofeedback have yielded a 43% reduction in migraine headache activity in the average patient. When improvements have been assessed using other outcome measures (e.g., physician/therapist ratings), improvements observed with each treatment have been about 20% greater. In both cases, improvements observed with propranolol and relaxation/biofeedback have been significantly larger than improvement observed with placebo medication (14% reduction) or in untreated patients (no reduction). Meta-analysis thus revealed substantial empirical support for the effectiveness of both propranolol and relaxation/biofeedback training, but revealed no support for the contention that the two treatments differ in effectiveness. These results suggest that greater attention should be paid to determining the relative costs and benefits of widely used pharmacological and non-pharmacological treatments.
On the basis of extensive radioligand data and more limited functional data, three pharmacological subtypes of alpha 2-adrenergic receptors have been identified. More recently, three human genes or cDNAs for alpha 2-adrenergic receptors have been identified by molecular cloning. The relationship, however, among the pharmacologically defined subtypes and those identified by molecular cloning has not been clear. In order to resolve this issue, we have compared the pharmacological characteristics of the receptors identified by molecular cloning and expressed in COS-7 cells with the characteristics of the pharmacologically defined receptors in their respective prototypic tissue or cell line. The affinities (Ki values) of 12 subtype-selective alpha 2-adrenergic antagonists were determined for the alpha 2 receptor in the six preparations, by radioligand binding. Correlation analyses of the pKi values indicate that the alpha 2A subtype, as defined in the HT29 cell line, the alpha 2B receptor of the neonatal rat lung, and the alpha 2C subtype, as defined in an oppossum kidney cell line, correspond to the cloned human alpha 2-C10, alpha 2-C2, and alpha 2-C4 receptor subtypes, respectively.
At critical doses of PCP (10 mg/kg i.p. in the present studies), locomotor stimulation in mice is initially suppressed by short-lasting ataxia, albeit at higher levels of activity than controls. This provides a time-activity baseline of PCP-stimulated locomotion potentially sensitive to i) pharmacological antagonism indicated by a change in the time-activity relationship to that seen at lower PCP doses, ii) interaction with the ataxic phase resulting in further decreases in activity similar to that seen at higher PCP doses and iii) reductions in activity without a change in the time-activity relationship. This baseline was explored using three manipulations employed in the clinical management of PCP toxicity: treatment with a neuroleptic (haloperidol), a benzodiazepine (chlordiazepoxide) and modification in environmental stimulation (changing of lighting conditions). Both haloperidol (0.125-0.5 mg/ kg, i.p.) and chlordiazepoxide (5-20 mg/kg i.p.) further reduced activity during the ataxic phase of the PCP time-activity relationship qualitatively similar to the effects of pentobarbital (20-40 mg/kg i.p.). Changing of lighting conditions from red to white light resulted in significant reductions in levels of activity of PCP-treated animals but no change in the time-activity relationship. No manipulation resulted in true reversal of the PCP induced time-activity relationship. The results parallel the clinical findings that neuroleptic and benzodiazepine administration have no specific effects upon PCP-intoxication and that environmental manipulation may modify the degree of PCP stimulation. The time-activity baseline described may prove useful in the evaluation of the effects of pharmacological and non-pharmacological manipulations of PCP-induced activity in rodents.
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.