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PubMed1996

Clinical pharmacology and clinical trials in Japan.

Clinical pharmacology is the pursuit of rational therapeutics by following the scientific principles of medicine and pharmacology. In Japan the roles for clinical pharmacology and clinical pharmacologists have been evolving since the discipline appeared in the 1950s. Clinical pharmacology and clinical trials for drug development depend on each other, and clinical pharmacologists play an important role in drug development in Japan. As the discipline becomes more important and complicated, many issues regarding drug therapeutics and clinical trials in Japan have been raised, and several points of view have been expressed. The following suggestions have been made to improve clinical pharmacology in Japan: (a) Medical education in the field of clinical pharmacology must be improved by creating or improving clinical pharmacology programs in medical schools. (b) The appropriate infrastructure for clinical trials must be established so that the physicians' workload is reduced, and patients' participation in clinical trials becomes much easier. (c) Scientific and ethical standards of the pharmaceutical industry must be improved, and the effort should be made to produce drugs with new mechanisms of action or with significant expected benefits. (d) The regulatory agency must provide stronger support, encompassing all the various points of view of academic institutes and the pharmaceutical industry. In light of the enthusiasm demonstrated by the government, physicians, and pharmaceutical industry in Japan for continued progress in clinical pharmacology, it seems likely that all its challenges will be overcome in the near future. Hence, despite the various problems discussed here the future seems promising for the continued development of clinical pharmacology.

Clinical Trials as Topic↗

PubMed2002

Problem-based learning and teaching of medical pharmacology.

In the Faculty of Health Sciences at McMaster University, the traditional discipline-based boundaries dividing the teaching and learning of basic medical sciences, such as physiology and pharmacology, do not exist. For more than 3 decades, student-centered, self-directed problem-based learning (PBL) has been the main form of instruction for students learning pharmacology within the medical curriculum and the pharmacological issues are always embedded within a health-care problem, with consideration of many other relevant non-pharmacological issues. In PBL, pedagogic emphasis is placed on the process of learning via constructive inquiry rather than cumulative acquisition of factual knowledge. For the science students, typically in the Biology/Pharmacology cooperative courses, both student-centered learning and teacher-centered teaching approaches are being used. In this case, the PBL approach is adopted to complement the conventional lectures at the course level. For medical students, PBL continues to be the major form of instruction in a small-group tutorial setting at the curricular level. The PBL curriculum is integrated across organ systems (cardiovascular, renal, respiratory, gastrointestinal, neural, etc) and across the life cycle, spanning population- and behavior-related perspectives, rather than being recreated from discrete disciplinary areas (such as physiology, anatomy, biochemistry, pharmacology, and community medicine). Those students who lack a pharmacology background or wish to enhance their pharmacological knowledge can take a block elective or horizontal elective in pharmacology. Unlike science students, medical students need to sort out pharmacological principles from the overload of information, to integrate them into the clinically relevant situations, and to ultimately apply them to the management of patients' illness. This is most effectively achieved in a student-centered environment conducive to life-long learning.

Education, Medical, Undergraduate↗

PubMed2004

Nurses' perceptions of their pharmacology educational needs.

BACKGROUND: Pharmacology education in nursing has become increasingly important as nurses' roles in administering, prescribing and educating patients about their medications have grown. Some authors have expressed concern at the lack of science teaching in nurse education, and others have suggested that there is a theory-practice gap in this area of the curriculum. AIM: This paper reports a study to explore nurses' pharmacology education needs by identifying nursing roles that require pharmacology knowledge, and nurses' preparation for practice from preregistration pharmacology education. METHOD: A qualitative approach was used to collect data from a purposive sample of 10 qualified nurses from an emergency admissions unit in a city in the north of England. Semi-structured interviews were transcribed verbatim and categorized using Burnard's 14 stages. FINDINGS: This study revealed a limited understanding of the subject, and dissatisfaction with the teaching of pharmacology, with resulting anxiety on qualifying. Nursing roles identified as requiring pharmacology knowledge included drug administration, patient assessment, nurse prescribing, and patient medication education. CONCLUSION: The findings suggest that, although nurses have a limited understanding of pharmacology, they recognize the need for pharmacology knowledge in practice. Improved pharmacology teaching might increase nurses' confidence in performing drug administration, patient education, and nurse prescribing, and decrease anxieties related to these roles.

Attitude of Health Personnel↗

PubMed1995

Integration of pharmacology into a problem-based learning curriculum for medical students.

The purpose of this study is threefold: (1) to describe a method of integration of pharmacology subject matter with other disciplines, in a problem-based learning (PBL) curriculum employed at the Northwest Center for Medical Education (NWCME), Indiana University School of Medicine; (2) to present various evaluation methods employed to assess students' learning of pharmacology knowledge; and (3) to compare the academic performance of students who underwent a traditional curriculum versus the PBL curriculum in terms of class evaluations and the standard national board medical licensure examinations. The PBL curriculum is designed for the first 2 years of medical education and consists of six sequential steps: steps 1 and 2 deal with biochemistry and anatomy respectively; steps 3, 4 and 5 deal with physiology, neuroscience and general pathology/microbiology respectively; and step 6 is a multidisciplinary step, which integrates basic science subjects with clinical medicine, emphasizing the mechanism of disease in an organ-system approach. In the PBL curriculum students start learning pharmacology within 6 months of admission. The content and process of pharmacology are spread across the first and in the second year. The pharmacology content is divided into three segments, each of which is integrated with other basic science subjects that have maximum mutual relevance. The three segments are as follows: the general and systemic pharmacology (50%) was included in step 3; the neuropharmacology and toxicology (35%) part was included in step 4; the third segment consisted of antimicrobial agents, anticancer and antiinflammatory agents (15%) and was included in step 5. The class evaluation of student performance in the PBL curriculum consisted of two elements, the content examinations and the process evaluations, which include the tutorial and the triple-jump evaluations of problem-solving skills. In order to assess the overall academic performance of the PBL curriculum and traditional curriculum groups, three classes of students who took the PBLC were compared with three classes of students who underwent a TC for performance in terms of class grades and scores of National Board examinations (NBMEI and/or USMLE I). The PBL curriculum students performed as well as or better than the TC students as measured by the NMBEI and/or USMLE I. The gain in pharmacology knowledge of PBL students is accompanied by the presence of a positive experience that learning pharmacology is enjoyable. Our experience suggests that the segmental integration approach of instruction coupled with a system of content (internal and external examinations) and process (tutorial and triple-jump) evaluations, as outlined in this paper is a contextualized learning method that offers an effective way of imparting pharmacology knowledge to medical students.

Education, Medical, Undergraduate↗

PubMed2000

Lessons learned from the past: a guide for the future of clinical pharmacology in the 21st century.

This article is a documentary of the history of the American College of Clinical Pharmacology (ACCP) and the Journal of Clinical Pharmacology. The history of the college and of the journal is presented as summarized by a few of the many leaders who played key roles in the growth of the profession of Clinical Pharmacology. Together, the college, the journal, and all clinical pharmacologists working in academia, industry, CROs, or government in many different subspecialty areas of the discipline contribute to the advancement of clinical pharmacology, the development of new drugs, and to an improved quality of life for mankind. Achieving leadership in health care in an era of change requires actions to be dynamic and flexible. Leaders must be capable of self-development and self-education. Leaders must examine challenges from top to bottom and build on the leadership foundations of vision, courage, and knowledge. Strong leaders are needed for the future of clinical pharmacology to address the rapidly changing environment for health care givers and the challenges faced by those working in drug development or training new leaders. One lesson from the past, from the professional life of Harry Gold, is that it is very important to convey the excitement of the field of clinical pharmacology and to pass on this excitement and knowledge base to those currently leading the educational process necessary to keep clinical pharmacologists in the forefront of the medical arena of today and tomorrow. The college became an instrument for change in the field of clinical pharmacology. Forward thinking efforts of the college did not allow stagnation. All founding leaders of the college were possessed of a dream of "what could be and what should be." Two points should be emphasized: the importance of teaching teachers how to teach and the importance of forming national networks, such as the college, to concentrate on the role of teaching students. Today's students are the leaders of tomorrow. The training of any given student in the field of clinical pharmacology continues over many years and requires the effort of many qualified mentors. The ACCP continues to prepare for the changing demands of a new millennium. The college responded to three challenges: (1) utilization of new technologies consistent with contemporary trends; (2) identification of new member services; and (3) dissemination of a position paper defining the philosophical foundations of the college. The basic tenant of the college remains the same today as it has been over the years: provide a multidisciplinary educational environment to have a broad appeal to the membership interested in clinical pharmacology.

Forecasting↗

PubMed2000

[Proposals for innovative pharmacology education from the perspective of several fields--in response to rapidly changing times].

The Japanese Pharmacological Society has not given a symposium to discuss the topic of overall pharmacology education since 1994 (the 67th Annual Meeting). Thereafter, we have been witnessing great changes in the environment surrounding pharmacology, where scientific advances in life science have made boundaries between the various life sciences ambiguous and have brought the following questions before us: what is pharmacology and what should it be? Considering the situation, the Committee of Education of the Society organized a symposium on pharmacology education at the 73rd Annual Meeting in 2000, which will discuss current problems encountered in pharmacology education today and what pharmacology education should be hereafter. The symposists consisted of five people with backgrounds in basic medicine (biochemistry), clinical medicine (internal medicine), hospital pharmacy, pharmaceutical industry and administration (the Ministry of Health and Welfare). They unanimously emphasized that education of pharmacology should be reformed profoundly so as to contribute to a greater degree to professional medical services and new drug development as well as to basic science and meet the needs of the new era. We hope this symposium will trigger a further discussion on pharmacology education for the future.

Drug Industry↗

PubMed1994

[180 years of teaching and research in pharmcology in Oslo. The 100-year anniversary of the department of pharmacology].

The teaching of pharmacology and toxicology for medical students started in Norway 180 years ago, in 1814, when the first Norwegian medical school was founded in Kristiania (Oslo). The first professors, however, had to teach other medical disciplines in addition to pharmacology: Nils Berner Sørensen taught pathology and therapy, Fredrik Holst and Ernst Ferdinand Lochmann taught hygiene. 100 years ago, in 1894, Poul Edvard Poulsson was appointed professor in pharmacology and toxicology only. Poulsson became the founder of pharmacology in Norway and of the Department of Pharmacology. In particular, he became known for his textbook of pharmacology. The first edition appeared in 1905, and the textbook was later translated to several languages. The article reviews the early history of pharmacology in Norway, based on the biographies of the professors mentioned above and of their successors, Klaus Hansen and Jacob Molland. The Department of Pharmacology was reorganized in 1966. The most recent period is reviewed only briefly. The present status of the department and of pharmacology are emphasized.

History, 18th Century↗

PubMed2005

Predictors of non-pharmacological intervention in patients with paroxysmal atrial fibrillation: Value of neuroticism.

BACKGROUND: Non-pharmacological intervention is gaining increasing popularity in the treatment of patients with paroxysmal atrial fibrillation. We sought to investigate which factors play a role in the choice for non-pharmacological intervention with a particular focus on neuroticism. METHODS: The study group comprised 73 patients with paroxysmal atrial fibrillation (mean age 55+/-13 years, 50 males). On average, patients had a 3-year-history of one symptomatic paroxysm per week lasting 2 h. The degree of neuroticism was assessed using the short scale Eysenck Personality Questionnaire. RESULTS: During a mean follow-up period of 7.0+/-0.6 years, 20 patients (27%) underwent a non-pharmacological intervention for atrial fibrillation including His bundle ablation (n = 1), maze operation (n = 4), DDDR-pacemaker (n = 10), pulmonary vein ablation (n = 5). Multivariate regression analysis showed that age < 55 years (odds ratio 5.3, 95% CI 1.1-24.5), frequency of paroxysms of atrial fibrillation > 1 per week (odds ratio 5.9, 95% CI 1.2-28.5) and total number of anti-arrhythmic drugs (class I and III) used > 2 (odds ratio 3.4, 95% CI 1.6-6.9) were predictive of non-pharmacological intervention (all p < 0.05). In contrast, the degree of neuroticism was similar in patients who underwent non-pharmacological intervention as opposed to patients who did not undergo non-pharmacological intervention (4.5+/-3.3 vs. 4.0+/-2.9, p = NS). CONCLUSIONS: On the basis of this small study, neuroticism would not appear to play an important role in the decision to perform a non-pharmacological intervention. Instead, the data indicate that younger patients with pharmacologically refractory atrial fibrillation more often undergo non-pharmacological intervention.

Atrial Fibrillation↗

PubMed2001

Weight reduction and pharmacologic treatment in obese hypertensives.

This study was conducted to evaluate the mechanisms of weight loss-induced blood pressure (BP) reduction focusing, in particular, on the contributions of sympathetic nervous system activity, fasting plasma insulin, and leptin to BP levels, and to delineate the additional influence of antihypertensive drug therapy. Each of five groups of obese hypertensives were treated with the long-acting calcium channel blocker (CCB) amlodipine, the angiotensin converting enzyme (ACE) inhibitor enalapril with or without a weight reduction program, or a weight reduction program alone. The goal BP was less than 140/90 mm Hg for the pharmacologic treatment groups. The weight reduction program groups with or without pharmacologic treatment were divided into two groups; weight loss groups who succeeded in weight reduction (> or = 10%) and nonweight loss groups who failed in weight reduction (<10%) in the first 6 months. The final dose of CCB and ACE inhibitor were less in the combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups or in the pharmacologic and nonweight loss groups. In the weight reduction groups regardless of pharmacologic treatment, the percent reductions from baseline in plasma insulin, leptin, and norepinephrine (NE) were greater in the weight loss groups (> or = 10%) than in the nonweight loss groups (<10%). The reductions in plasma NE, insulin, and leptin were significantly greater and earlier in combined pharmacologic and weight loss groups than in the pharmacologic treatment alone groups. In ACE inhibitor groups, the reductions in plasma NE, in insulin, and especially in leptin were greater than the other groups. In the CCB alone group, reductions in insulin and leptin occurred, but there was no change in plasma NE. Reductions in insulin and leptin in CCB groups were less and occurred later than in the ACE inhibitor groups or the weight reduction alone group. These results show that weight loss associated with favorable metabolic improvements and these improvements are amplified when combined with pharmacologic treatment. Therefore, weight loss should be regarded as an essential component of any treatment program for obesity-related hypertension. A novel finding from this study is that ACE inhibition had a striking effect to lower plasma leptin. Suppression of sympathetic activity, insulinemia, and leptinemia appeared to play a role in the BP reduction accompanying weight loss.

Adult↗

PubMed1998

Teaching clinical pharmacology and therapeutics: selective for fourth-year medical students.

Teaching clinical pharmacology remains both a lifelong learning process and a lifelong challenge for clinical pharmacologists and other medical educators. In the current information age, with an explosion of drug-related data, the prime topic for discussion is how to teach clinical pharmacology. This article describes our response to the challenges in developing a selective course in clinical pharmacology, and our experience from the first 2 years of the course. Our emphasis is on how to provide in an efficient way knowledge, skills, and attitudes students will need as physicians in the coming decades. Faculty from the Center for Clinical Pharmacology at the University of Pittsburgh in conjunction with faculty from the University of Pittsburgh School of Medicine have developed a one-month intensive course in clinical pharmacology. The integrated course program consists of four overlapping components: 1) general clinical pharmacology (focused on individualization of drug therapy); 2) rational prescribing principles (general principles of drug selection, how to prepare a personal formulary); 3) disease-specific clinical topics (pharmacotherapy of diseases and medical conditions most commonly seen in routine medical practice); and 4) workshops for special attention topics (pharmacokinetics, pain treatment, toxicology, dialysis). In congruence with established educational goals, the course includes drug-, patient-, and disease-oriented concepts. A variety of learning formats (didactic and interactive lectures, one-day problem-based learning sessions, small group case discussions, self-directed and small group directed learning, quizzes, and computer-assisted learning) are used to teach students how to apply the general concepts of clinical pharmacology and rational pharmacotherapy to clinical medicine, and to prepare them to become independent lifelong learners in therapeutics. Student feedback from the first 2 years of this course indicates that this multi-modal teaching format is effective. The majority of students who took the course in clinical pharmacology in 1997 found it to be very beneficial.

Curriculum↗

PubMed2002

The educational preparation of undergraduate nursing students in pharmacology: a survey of lecturers' perceptions and experiences.

BACKGROUND: Nurses have key responsibilities in the administration and management of medication therapy and client education. It is of some concern therefore that the literature indicates that nurses are inadequately prepared in this area. AIMS: This paper explores the perceptions and expectations of lecturers about teaching and learning pharmacology in preregistration nursing courses. RESEARCH METHODS: Questionnaires were distributed to lecturers involved in teaching pharmacology to undergraduate nursing students during 2000. The questionnaire was distributed to all university campuses (n = 13) in Victoria, Australia, that are involved in undergraduate nursing education. The questionnaire was an adaptation of the survey instrument used in the Nursing and Medication Education [NAME] project and examined in this questionnaire: the integration of pharmacology teaching into nursing, range and depth of classroom-based pharmacology teaching, approaches to teaching and learning, nursing practice in a clinical context, related importance of patient education and communication skills, and the appropriate professional background of academics teaching pharmacology to preregistration nursing students. RESULTS: There was great variation between institutions as to the number of hours devoted to pharmacology and when it was offered. A number of respondents indicated that they were dissatisfied with the preparation of graduates and their knowledge base in pharmacology. LIMITATIONS: The study was limited by a low response rate of 34%. CONCLUSIONS: A review of nursing curricula is required to improve the knowledge base of nurses in pharmacology and to facilitate their skills in life-long learning.

Attitude of Health Personnel↗

PubMed2006

Pharmacology at the Jagiellonian University in Kracow, short review of contribution to global science and cardiovascular research through 400 years of history.

Pharmacology at the Jagiellonian University was taught since the foundation of the University in 1364 under then used names of medical botany and pharmacognosy. The first in Poland Division of Pharmacology and Pharmacognosy was created in 1857. Modern era in the history of pharmacology in Krakow starts in 1929 when Prof. Janusz Supniewski became the Head of the Department. He was the relentless researcher whose scientific interests were as diverse as ranging from anticancer chemotherapeutics, antibiotics, and oral hypoglycemic drugs to lipid-lowering agents. Skills of organic chemistry synthesis were of paramount importance for the scientific achievements. Prof. Supniewski died in 1964, leaving the Department well equipped in instruments. He raised in his laboratory many eminent scientists who later became heads of pharmacology departments throughout Poland. In 1964, the Head of the Department of Pharmacology became Prof. Ryszard Gryglewski. Under his leadership the Department focused scientific efforts on various aspects of cardiovascular pharmacology. Prof. Gryglewski established collaborations with many of the best pharmacology researchers in the world, including Sir John Vane, Nobel Prize laureate. Prof. Gryglewski's assistants had ample opportunity to train in these laboratories and to bring these skills back to Krakow. Prof. Gryglewski and his team published many articles in the most prestigious scientific journals. The most important themes included discovery of prostacyclin, role of nitric oxide and of free radicals for vascular biology. Since 2003, when Prof. Gryglewski retired, the Department of Pharmacology has been led by Prof. Ryszard Korbut.

Cardiovascular Physiological Phenomena↗

PubMedDate not supplied

Development and evaluation of a computer-assisted instruction package in clinical pharmacology for nursing students.

Recent reports commissioned by the Australian Government have highlighted the need to improve medication use in both community and hospital settings. Nurses are placed ideally to promote safe and effective drug use. The aim of this project was to develop and evaluate a computer-assisted instruction package, to help undergraduate nursing students improve their knowledge of clinical pharmacology, and to enhance their ability to contribute to the quality use of medications. In a collaborative project, staff of the Tasmanian Schools of Pharmacy and Nursing have produced the program PharmaCAL, using HyperCard 2.2 for the Apple Macintosh. A wide range of clinical pharmacology units are covered extensively, concentrating on drugs in common use and based on body systems: cardiovascular pharmacology (including hypertension, cardiac failure and angina); respiratory pharmacology; alimentary tract pharmacology (including peptic ulcer, diarrhea, and constipation); central nervous system pharmacology (analgesia, anxiety and insomnia, depression, psychoses, and epilepsy); antibiotic chemotherapy; and diabetes mellitus. Many color illustrations have been included. Each unit has a set of multiple choice questions to provide feedback to students. The package was evaluated in two ways. First, a questionnaire was used to assess users' opinions of the package. Second, a validated multiple choice test on clinical pharmacology and therapeutics was administered to 24 third-year nursing students before and after a set of sessions using the package and to a control group of 28 nursing students who were not exposed to the PharmaCAL package. The package generally was well received by the nursing students. Clinical pharmacology test scores significantly improved after using the package and were significantly higher than for the control group of students. The program is a useful adjunct to the existing nursing curriculum. It also could be used in postgraduate nursing education and other health sciences.

Analysis of Variance↗

PubMed1995

Structural, genetic and pharmacological identity of the rat alpha 2-adrenergic receptor subtype cA2-47 and its molecular characterization in rat adrenal, adrenocortical carcinoma and bovine retina.

Subsequent to the first alpha 2-adrenergic receptor (alpha 2-AR) gene cloning of alpha 2-C10 from human platelet, cloning of the first rodent alpha 2-AR cDNA, cA2-47, was reported. Based on the structural and limited pharmacological comparison, it was concluded that the rodent receptor is a molecular and pharmacological analog of the human receptor, which is pharmacologically classified as the alpha 2A-AR. A later study slightly revised the structure of the human receptor. Thus, the precise structural comparison of the rat receptor to the human platelet receptor is no longer valid. Another rat alpha 2-AR gene, RG20, was then cloned and was also found to be a structural analog of the human alpha 2-C10. It, however, varied slightly from the alpha 2A subtype pharmacology, but matched the newly defined alpha 2D subtype pharmacology. It was, therefore, concluded that RG20 encodes the alpha 2D subtype. The structural and pharmacological relationship of RG20 with cA2-47 is not known, although it has been tacitly assumed that both are the identical alpha 2D receptor subtypes. The present study addresses this and other issues relating to the precise structural, genetic and pharmacological relationship of cA2-47 with the human platelet alpha 2-C10 receptor, and also the localization of cA2-47 transcript in certain rat tissues. The results show that the cA2-47 receptor shows a high degree of sequence identity to the alpha 2-C10 receptor, yet important differences exist between them. The sequence identity of cA2-47 receptor to the RG20 receptor is almost, but not quite complete. The cA2-47 gene is not present in the human and the human gene is not present in the rat; that cA2-47 receptor subtype is pharmacologically similar to the RG20 receptor subtype, both being of the alpha 2D subtype. The cA2-47 receptor transcript in addition to being found in the rat brain is present in the rat adrenal gland, testes, adrenocortical carcinoma and the bovine retina.

Adrenal Cortex Neoplasms↗

PubMedDate not supplied

Comparison of risk stratification with pharmacologic and exercise stress myocardial perfusion imaging: a meta-analysis.

BACKGROUND: Although pharmacologic stress myocardial perfusion imaging (MPI) and exercise stress MPI have comparable diagnostic accuracy, their comparative value for risk stratification of patients with known or suspected coronary disease is not known. METHODS AND RESULTS: The data of 14,918 patients were combined from 24 studies evaluating prognosis in patients undergoing either pharmacologic stress or exercise stress MPI. Studies were included if a 2 x 2 table for hard cardiac events (cardiac death and myocardial infarction [MI]) could be constructed from the data available. Excluded were studies performed for post-MI, post-revascularization, or preoperative risk stratification. A weighted t test was used to compare the cardiac events, and a random effects model was used to calculate summary odds ratios. Summary odds ratios for hard cardiac events were similar for pharmacologic stress and exercise stress MPI. Summary receiver operating characteristic curves also showed no difference in discriminatory power between the stressors. The cardiac event rates were significantly higher with normal and abnormal test results with pharmacologic stress MPI than with exercise stress MPI (1.78% vs 0.65% [P < .001] for normal results and 9.98% vs 4.3% [P < .001] for abnormal results). Subgroup analysis revealed that both cardiac death and nonfatal MI were significantly higher with pharmacologic stress MPI. Patients undergoing pharmacologic stress MPI had a significantly higher prevalence of poor prognostic factors, and meta-regression revealed that exercise capacity was the single most important predictor of cardiac events. CONCLUSIONS: This meta-analysis shows that exercise stress MPI and pharmacologic stress MPI are comparable in their ability to risk-stratify patients. However, patients undergoing pharmacologic stress studies are at a higher risk for subsequent cardiac events. This is true even for those with normal perfusion imaging results.

Comorbidity↗

PubMedDate not supplied

Methodology used in safety pharmacology: appraisal of the state-of-the-art, the regulatory issues and new directions.

This is the second focused issue of the Journal of Pharmacological and Toxicological Methods that is devoted exclusively to methodology, opinions and regulatory issues related to Safety Pharmacology. This issue of the Journal highlights a record number of articles and abstracts from the 4th Annual Safety Pharmacology Society (SPS) meeting that was held in Covington, Kentucky September 27-29, 2004. The focus of this issue of the Journal is to present a description of currently used fundamental pharmacological methods as outlined in the regulatory guidance documents for pre-clinical safety testing of drugs (ICH S7A and S7B). This issue features articles that discuss methods related to in vivo and in vitro CNS, respiratory and cardiovascular core battery studies. Additionally, articles are included that discuss species differences and recording issues in EKG measurement; automated (HTS) electrophysiology methods for assessing drug-induced hERG blockade (i.e., PatchXpress 7000A and hERG-lite); methods that describe and validate the use of the guinea pig as a safety pharmacology screening model; methods used to predict QTc prolongation and mathematical models that describe beat-to-beat instability of QT duration; supplemental studies that assess and discuss emerging renal biomarkers and renal function and food effects on gastrointestinal transit time; pro-arrhythmia models, cardiac function assessment using 3-D echocardiography and a description of a novel open field motor activity system to assess the possible CNS effects of drugs. Thus, this issue of the Journal of Pharmacological and Toxicological Methods should be a primary resource aid to individuals in academia and industry that are interested in understanding Safety Pharmacology methods. It provides a comprehensive overview of current and advanced methods used in Safety Pharmacology studies today.

Animals↗

PubMed1999

Pharmacological stress testing.

Pharmacological stress in conjunction with radionuclide myocardial perfusion imaging has become a widely used noninvasive method of assessing patients with known or suspected coronary artery disease. In the United States, over one third of perfusion imaging studies are performed with pharmacological stress. Pharmacological stress agents fall into two categories: coronary vasodilating agents such as dipyridamole and adenosine, and cardiac positive inotropic agents such as dobutamine and arbutamine. For both, in the presence of coronary artery disease (CAD), perfusion image abnormalities result from heterogeneity of coronary blood flow reserve. Vasodilating agents work directly on the coronary vessels to increase blood flow, whereas inotropic agents work indirectly by increasing myocardial work load, which then leads to an increase in coronary blood flow. Both classes of agents have high accuracies for diagnosing coronary artery disease, and they have excellent safety records with acceptably low occurrences of side effects. For dipyridamole planar thallium imaging, pooled analysis yields a sensitivity of 85% and a specificity of 87% for diagnosis of coronary disease, but there is a large variation in reported values depending on various factors, such as the extent of postcatheterization referral bias, the type of imaging (planar versus single photon emission computed tomography [SPECT]), the types of patients being studied (single versus multivessel disease, men versus women), and the imaging agent used (thallium versus one of the technetium-based agents). Diagnostic accuracies for adenosine are similar to those of dipyridamole, with reported overall sensitivities ranging from 83% to 97%, and specificities ranging from 38% to 94%. For dobutamine, pooled analyses yield a sensitivity of 82% and a specificity of 75%. There is some concern that dobutamine may interfere with uptake of technetium-99m sestamibi, lowering the sensitivity for detection of disease, and thus the vasdodilating agents are generally preferred. Pharmacological stress testing has high clinical use for risk stratifying patients with known or suspected CAD, in patients after myocardial infarction, and in patients needing noncardiac surgery. Vasodilating agents are particularly advantageous in assessing post-myocardial infarction patients, allowing testing as soon as 2 days after the event. Like patients undergoing exercise stress testing, patients with normal perfusion images by pharmacological stress have a <1% annual incidence of cardiac events. The likelihood of an event increases with the extent and severity of perfusion abnormalities. However, it is important to consider clinical variables when using perfusion imaging for risk stratification, particularly in the presurgery patients. As with exercise testing, adjunct markers such as ST segment depression during testing, lung uptake of radiotracer (if thallium is used), and ventricular cavity dilatation add additional prognostic information to that available from the perfusion images alone. The aim of current research is to find better agents that are easier to use and that have fewer side effects. MRE-0470 is an experimental vasodilating agent that is more receptor selective than adenosine and promises a lower incidence of hypotension. Arbutamine more closely simulates exercise than dobutamine, and it can be administered by a closed-loop computerized delivery device. Work is also underway to look at novel uses of pharmacological stress agents, such as acquiring gated SPECT images during dobutamine infusion to enhance detection of myocardial viability. With increasing use of noninvasive testing in elderly patients and in patients with comorbidities that preclude adequate exercise, pharmacological stress testing has become an indispensable tool for radionuclide myocardial perfusion imaging studies. A good understanding of pharmacological stress testing is essential for performing high-quality nuclear cardiology

Cardiotonic Agents↗

PubMed2003

Integrated pharmacological preconditioning in combination with adenosine, a mitochondrial KATP channel opener and a nitric oxide donor.

BACKGROUND: Mitochondrial K(ATP) channel activation is an essential component of ischemic preconditioning. These channels are selectively opened by diazoxide and may be up-regulated by adenosine and nitric oxide. Therefore, pharmacological preconditioning with diazoxide in combination with adenosine and a nitric oxide donor (triple-combination pharmacological preconditioning) may enhance cardioprotection. METHODS AND RESULTS: Isolated and perfused rat hearts underwent ischemic preconditioning with 3 cycles of 5 minutes of ischemia and 5 minutes of reperfusion before 5 minutes of oxygenated potassium cardioplegia and 35 minutes of ischemia. Pharmacological preconditioning was performed by adding adenosine, diazoxide, and a nitric oxide donor S-nitroso-N-acetyl-penicillamine each alone or in combinations for 25 minutes followed by 10 minutes washout before cardioplegic arrest. Only triple-combination pharmacological preconditioning conferred significant cardioprotection as documented by highly improved left ventricular function and limited creatine kinase release during reperfusion that was comparable to that afforded by ischemic preconditioning. Mitochondrial K(ATP) channel activity assessed by flavoprotein oxidation was increased by diazoxide, but no further increase in flavoprotein oxidation was obtained by ischemic preconditioning and triple-combination pharmacological preconditioning. Significant activation of protein kinase C-epsilon was observed in only ischemic preconditioning and triple-combination pharmacological preconditioning. Pretreatment with the mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate or the protein kinase C inhibitor chelerythrine abrogated activation of protein kinase C-epsilon and cardioprotection afforded by ischemic preconditioning and triple-combination pharmacological preconditioning. CONCLUSIONS: Integrated pharmacological preconditioning is not simply mediated by enhanced mitochondrial K(ATP) channel activation, but is presumably mediated through amplified protein kinase C signaling promoted by coordinated interaction of adenosine, mitochondrial K(ATP) channel activation, and nitric oxide.

Adenosine↗