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PubMed1976

[Pharmacological studies of an antipschotic agent, penfluridol. (1). The central pharmacological actions].

Neuropharmacological properties of penfluridol (TLP-607) were investigated in experimental animals and were compared with those of haloperidol and chlorpromazine. Locomotor activity of mice significantly decreased at doses of 16-32 mg/kg p.o. Like haloperidol and chlorpromazine, TLP-607 (4-16 mg/kg p.o.) demonstrated catalepsy lasting for 48-72 hr in rats. TLP-607 strongly inhibited apomorphine-induced emesis in dogs and the ED50 was 0.016 mg/kg p.o. This effect lasted for 192 hr when administered 0.04 mg/kg p.o. TLP-607 antagnonized methamphetamine-induced stereotyped behavior in rats, and the ED50 was 1.83 ng/kg p.o. TLP-607 also inhibited conditioned avoidance responses in rats, and the ED50's in the pole climbing and Sidman avoidance methods were 6.73 and 3.4 mg/kg p.o., respectively. TLP-607 neither inhibited motor coordination nor enhanced hexobarbital-induced anesthesia in mice. These results suggest that TLP-607 is a potent and long-acting antipsychotic drug which has less neurotoxic side-effects.

Agonistic Behavior↗
PubMed2002

Development of innovative teaching materials: clinical pharmacology problem-solving (CPPS) units: comparison with patient-oriented problem-solving units and problem-based learning--a 10-year review.

The First Teaching Clinic in Clinical Pharmacology, sponsored by the American College of Clinical Pharmacology in September 1992, was designed for the preparation and development of new clinical pharmacology problem-solving (CPPS) units. CPPS units are case histories that illustrate pertinent principles in clinical pharmacology. Each unit consists of the following sections: introduction, learning objectives, pretest, four clinical pharmacology scenarios, posttest, answers to pre- and posttest questions, and selected references. The clinical pharmacology content of the CPPS units place greater emphasis on clinical information, drug selection, and risk/benefit analyses, and thus they complement the basic pharmacology presented in the patient-oriented problem-solving (POPS) units. In general, the CPPS units are intended for use by students more advanced in clinical pharmacology than first- and second-year medical students. The CPPS unit "Clinical Pharmacology of Antiepileptic Drug Use: Clinical Pearls about the Perils of Patty" was developed for use by third- and fourth-year medical students doing rotations in neurology or clinical pharmacology; advanced pharmacy students; residents in neurology, pediatrics, internal medicine, and family practice; fellows in clinical pharmacology, and those taking the board examination in clinical pharmacology. The CPPS unit titled "Geriatric Clinical Psychopharmacology" was written for third- and fourth-year medical students; residents in psychiatry, family practice, and internal medicine;fellows in clinical pharmacology; and those studying for boards in clinical pharmacology. The CPPS unit "Anisocoria and Glaucoma" was written for more advanced students of clinical pharmacology. The CPPS unit titled "Antiepileptic Drugs" was intended for second-year medical students. The second teaching clinic was held in November 1993 and focused on the development and editing of the CPPS units and their evaluations by faculty and students from academic centers. Evaluations by faculty and students have been overwhelmingly positive. Requests to use the CPPS units in various clinical pharmacology teaching programs were received from numerous schools within the United States and from abroad. The third teaching clinic in September 1995 included a follow-up focused on the uses of drug information databases in case problem exercises. These examples are presented to demonstrate the variety of educational activities the American College of Clinical Pharmacology is sponsoring to fulfill its strategic initiative dedicated to offer innovative teaching programs and to develop new teaching materials in clinical pharmacology. Collectively, all of the teaching clinics, symposia, and workshop efforts, sponsored by the various academic professional societies alone or together over the past decade, are necessary if new and innovative teaching materials in the field of basic science and in the fields of pharmacology and clinical pharmacology are to be continuously developed to keep pace with the new, rapidly changing developments in medicine to provide the best treatment for patients in the 21st century.

Anisocoria↗
PubMed2006

Safety pharmacology in focus: new methods developed in the light of the ICH S7B guidance document.

'Safety' continues to be a growth area in 'Pharmacology'. This issue of Journal of Pharmacological and Toxicological Methods is the third to be focused on methods development in the safety pharmacology area. The unusual nature of safety pharmacology mandates that methods development be done with, not only scientific validation, but also, adherence to the mandates of legislation to the forefront. This focused issue draws on a broad range of global safety pharmacology experts, many of whom operate in the industrial milieu. They have reviewed and updated current models, validated modifications, and have also introduced novel methodology important to the conduct of non-clinical safety pharmacology studies. The contributors were all active participants at the 5th Annual Safety Pharmacology Society (SPS) meeting held in Mannheim, Germany September 25-28, 2005. The publications presented here describe in vitro and in vivo pharmacological methods development that has been informed by the S7A regulatory guidance document for pre-clinical safety testing of drugs. While S7A describes the 'core battery' of methods used to characterize the safety pharmacology profile of a compound, the most recent news in Safety Pharmacology involves ratification of the related S7B safety guidance document. Unlike the past, S7B heralds a new era for the pharmaceutical industry since it now sets out how to address safety concerns of a new chemical entity (NCE) in relation to adverse actions on ventricular repolarization, a topic that has vexed industry and regulatory authorities for many years. Unsurprisingly there are many papers in the present issue that address this specific aspect of safety pharmacology. These include results from the Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) initiative, in which non-clinical in vitro (hERG and Purkinje fiber) and in vivo (QT dog study) assays were found to be useful in the determination of drug-induced QT prolongation risk, and thus provide better characterization of a biomarker for the potential risk in humans for development of the torsades de pointes syndrome. However, safety methods development does not begin and end with ventricular repolarization. This focused issue also describes the re-evaluation and validation of a primate CNS model for evaluating orthostatic hypotension, and outlines a simple and rapid rodent object recognition task model that can be used to assess the amnesic potential of an NCE. Reviews of respiratory safety studies as well as both in vitro and in vivo aspects of cardiovascular function are also described. There are also papers that describe the pharmacology of vehicles and solvents used to solubilize study drugs and the applicability of voltage-sensitive dyes to optically record cardiac action potentials from single myocytes. Thus, this issue of the Journal of Pharmacological and Toxicological Methods remains a primary resource for industrial and academic pharmacologists interested in better understanding non-clinical safety pharmacology methods.

Aged↗
PubMed2000

[The development of experimental pharmacology 1790-1850].

1. The use of drugs goes back to the origins of mankind. In historical times oral drug-lore became codified empiric drug theory (materia medica) and ultimately, in the 19th century, experimental pharmacology. The initiator of experimental pharmacology as an independent medical discipline is Rudolf Buchheim (1820-1879). This study traces the pathways leading to Buchheim and identifies his predecessors between 1790 and 1850. The history of empirical pharmacology and its major theories in Antiquity, the Middle Ages, and early modern times is summarized. For the 18th century an overview is given on early attempts at experimental testing of drug effects and on the new therapeutic systems and medical sects. 2. Many authors have dealt with the grievances of pharmacology and therapy between 1790 and 1850, among them chief representatives of contemporary medicine like the French Fourcroy, Bichat, Pinel, Alibert, Magendie, and the Germans Schönlein, Mitscherlich, Wunderlich, Henle, and Oesterlen. Their criticisms are a means for a better understanding of the situation. They cover the following aspects. Pharmacology is distorted by speculations on the causes of drug action and confusion with regard to terminology and indications. Drug actions are being tested with inadequate methods. An increase in the number of drugs is mistaken for an increase in knowledge. The statement is made that pharmacology is the least developed of all medical subjects. The critics point out that only a more developed chemistry, physiology, and etiology will allow a scientific pharmacology. The drug theories of the medical sects are likewise rejected. Polypharmacy, composite drugs, and absurd formulas are regarded with contempt. Aggressive drug therapy is repudiated, but this easily results in avoidance of drugs and in therapeutic nihilism. 3. In 1799 Johann Christian Reil elaborated his principles for a future pharmacology. Reil establishes the rules for clinical experiments on which a scientific pharmacology should be based. His goal is to explain the actions of drugs which are the results of biochemical alterations. Even though Reil's program is a theoretical conception, it anticipates a situation that was to take shape half a century later. Also in 1799 Adolph Friedrich Nolde published detailed rules for the critical examination of drug actions in patients, including aspects like placebo, compliance, statistics, and several ethical rules. Reil's and Nolde's programmatic messages vanished in the emerging German medicine of "Naturphilosophie". 4. In the decades after 1800 medicine was at its zenith in the Paris School. It became a hospital medicine, based on anatomy and pathology. François Magendie was one of its representatives. He started out as a physician in 1808 and became a physiologist who soon surpassed his teachers Bichat and Richerand. Magendie's sole interest were facts, which had to be unravelled by experiments, mainly on animals. He created modern physiology based on the laws of physics and chemistry. Nevertheless, he remained an outsider among the Paris School. Bichat and other predecessors of Magendie had considered an experimental pharmacology based on physiology, however, they did not provide knowledge resulting from experiments. Magendie published his first experimental study of a pharmacological problem in 1809. From then on he studied the mechanism and site of action of drugs and used them at the same time as tools for the investigation of physiological processes. After Sertürner's isolation of morphine from opium the preparation of pure alkaloids became a specialty of French pharmacists and chemists. Magendie sought their collaboration from 1817 on, convinced that pharmacology and therapy must be based on both physiology and chemistry. In 1821 he published his Formulaire pour la préparation et l'emploi de plusieurs nouveaux médicamens which marks the beginning of modern pharmacology. It grew throughout eight editions up to 1835. (ABST

Animals↗
PubMed1974

Second report on the organization of pharmacology in Great Britain.

1 A questionnaire was sent to 150 departments employing pharmacologists including all those academic departments teaching pharmacology, in Great Britain and Northern Ireland, and all industrial firms and research institutes engaged in pharmacological (27) and toxicological (38) work. All questionnaires were completed. The returns refer to the situation on 1st January 1972.2 There were 1,104 pharmacologists, of whom 652 were established staff, 383 were research staff and students, and 29 visiting workers. Of the staff in established posts, 192 were in medical schools, 81 in other university departments, 75 in other non-university departments and 28 in toxicology departments. Forty pharmacologists were established in other research units.3 Since 1964, 11 B.Sc. (Pharmacology) courses have been started. In 1971-72 there were 69 students in the final year of all B.Sc. Pharmacology courses. By 1974-75, 134 students are expected in the final year of these courses.4 Of 413 students specializing in pharmacology who graduated in 1971, 74% had taken a pharmacy qualification. Overall, 26% continued in academic courses, 11% went into industry, 56% into hospital or retail pharmacy. Only 1% were unemployed.5 Of 68 students completing postgraduate courses in pharmacology in 1971, 20% went into university teaching, 26% into industry and only 1% were unemployed. At present there are 260 students in postgraduate training in pharmacology departments.6 During 1970 and 1971 appointments exceeded losses in all sections giving an overall annual gain of 58.5. The total demand was estimated at 73 per year over this time. The predicted size of pharmacology departments in 1974-75 could lead to a maximum annual demand of 95 per year for these next three years.7 Up to January 1972, the supply of, and demand for pharmacologists seems to have been near balance from the unemployment and vacancy rates reported.However, in 1971, the supply of pharmacologists exceeded significantly the identifiable demand from pharmacology and toxicology departments. Thus there was a considerable demand from unknown employers. In the future there will be a considerable increase in the supply of specialist pharmacologists. We cannot predict if this will be balanced by demand in the absence of information about the growth in demand from the unknown employers.8 Taking the number of professors as an index of academic status, pharmacology has improved its standing, especially in the non-medical school departments. Now there are 40 professors in 51 departments compared with 25 in 42 departments in 1964.9 Overall, the composition of departments has not changed much since 1964. Academic departments still draw on each other for their pharmacologists whereas industrial departments draw equally from other industrial departments and academic departments. The total proportion of medically qualified pharmacologists has fallen to 14% (from 25% in 1964) and these pharmacologists are still concentrated heavily in medical school departments. In industrial departments, only 3% have a medical qualification.10From the replies of 94 out of 410 recent graduates specializing in pharmacology, the courses are in general interesting and effective. However, both students and employers considered that not enough statistics and mathematics as applied to pharmacology were taught. Of the respondents, 84% also wanted more teaching on the clinical use of drugs.

Education, Pharmacy↗
PubMed2002

Integration of safety pharmacology endpoints into toxicology studies.

In the ILSI Human Toxicity Program, human toxicity was identified with 94% in studies of 1 month or less duration. Safety pharmacology studies and 1 month toxicity studies are prerequisites of INDs. These studies contributed in 69% to the predictivity of human toxicity. Correlating data from pharmacology and toxicology data will therefore enhance the predictivity of human toxicity. The ILSI Human Toxicity Program also showed that non-rodent toxicology studies were more predictive of human toxicity than rodents. Consequently, the usage of non-rodents, especially dogs, produces data more relevant to the safety of humans. Integration of data from safety pharmacology and pharmacological endpoints from integrated toxicology studies, which cover a wide dose range, allow data interpretation also concerning chronic effects. Differences in relation to chronic exposure and species specific pharmacodynamic effects can be taken into consideration. In vivo data in pharmacology are taken from a larger number of species. Usually, pharmacokinetic data and histopathology are often lacking in pharmacology (e.g. guinea pig). Studies in a smaller number of species, which are incorporating pharmacology, pharmacodynamic and toxicology, allow also crossinterpretation with data from clinical chemistry, haematology and histopathology. Endpoints relating to behaviour (functional observation battery/FOB) and cardiovascular toxicity can be integrated into regulatory toxicology. Technical progress in non-invasive methodology and refined measurements for pharmacological parameters and standardization of study design allow the incorporation into regulatory toxicity studies today. The limitations of conducting pharmacological measurements in regulatory toxicology studies are acknowledged. Safety pharmacology studies should complement toxicity studies in terms of choice of species and dose regimen. Ethical usage of animals, especially dogs or monkeys, can only be justified in the future, when more clinically relevant data can be gained from fewer in vivo studies. Multidisciplinary co-operation between pharmacology, pharmacokinetics and toxicology will lead to refinements and reduction of in-vivo studies when functional parameters are integrated into regulatory studies.

Animals↗
PubMed2005

Finnish nurses' and nursing students' pharmacological skills.

UNLABELLED: PURPOSES AND OBJECTIVES: The purposes of this study were to investigate the pharmacological skills of Finnish nurses and graduating nursing students, to determine how pharmacological skills are related to background factors and to identify differences between nurses and students and, finally, to examine how the instrument used, the Medication Calculation Skills Test, works. BACKGROUND: Pharmacology is a relevant and topical subject. In several studies, however, pharmacological skills of nurses and nursing students have been found insufficient. In addition, pharmacology as a subject is found to be difficult for both nursing students and nurses. DESIGN AND METHODS: The study was evaluative in nature; the data were collected using the Medication Calculation Skills Test, developed for the purposes of this study. The instrument was used to gather information on background factors and self-rated pharmacological and mathematical skills and to test actual skills in these areas. RESULTS: Results concerning pharmacological skills are reported in this paper. The maximum Medication Calculation Skills Test score was 24 points. The mean score for nurses was 18.6 and that for students 16.3. Half of (50%) the students attained a score of 67% and 57% of nurses attained a score of 79%. CONCLUSIONS: Nurses and students had some deficiencies in their pharmacological skills. Nurses had better pharmacological skills than students according to both self-ratings and actual performance on the test. RELEVANCE TO CLINICAL PRACTICE: It is vitally important that nurses have adequate pharmacological skills to administer medicines correctly. This study showed that the Medication Calculation Skills Test seems to work well in measuring pharmacological skills, even though it needs further evaluation. Findings from this study can be used when planning the nursing curriculum and further education for Registered Nurses.

Adult↗
PubMed2003

Information technology in veterinary pharmacology instruction.

Veterinary clinical pharmacology encompasses all interactions between drugs and animals and applies basic and clinical knowledge to improve rational drug use and patient outcomes. Veterinary pharmacology instructors set educational goals and objectives that, when mastered by students, lead to improved animal health. The special needs of pharmacology instruction include establishing a functional interface between basic and clinical knowledge, managing a large quantity of information, and mastering quantitative skills essential to successful drug administration and analysis of drug action. In the present study, a survey was conducted to determine the extent to which veterinary pharmacology instructors utilize information technology (IT) in their teaching. Several IT categories were investigated, including Web-based instructional aids, stand-alone pharmacology software, interactive videoconferencing, databases, personal digital assistants (PDAs), and e-book applications. Currently IT plays a largely ancillary role in pharmacology instruction. IT use is being expanded primarily through the efforts of two veterinary professional pharmacology groups, the American College of Veterinary Clinical Pharmacology (ACVCP) and the American Academy of Veterinary Pharmacology and Therapeutics (AAVPT). The long-term outcome of improved IT use in pharmacology instruction should be to support the larger educational mission of active learning and problem solving. Creation of high-quality IT resources that promote this goal has the potential to improve veterinary pharmacology instruction within and across institutions.

Animals↗
PubMed1989

Instruction in clinical pharmacology: changes in the wind.

We have presented some views on past, present and potential trends for teaching clinical pharmacology in the medical curriculum. Clinical pharmacology as subject matter in the medical curriculum has been operationally defined for our purposes as: (1) the application of fundamental principles of basic pharmacology to rational drug therapy in humans; and (2) the application of appropriate nuances of the human pharmacology of individual drugs to their use in particular disease states. In terms of improving the results of drug therapy, arguments were advanced for the importance of teaching clinical pharmacology at all levels in the medical curriculum and in postgraduate medical education. The introduction of so many new and potent pharmaceuticals over the past 25 years requires well educated and skilled medical practitioners adept and well versed in the fundamental principles of basic and applied pharmacology, so as to achieve the most prudent, effective and economically sound use of these drugs as possible. This creates a challenge to medical educators, particularly those involved in teaching clinical pharmacology, to devise innovative teaching techniques and curricular changes that foster these goals. In an attempt to address these challenges, we have reviewed some innovative teaching approaches and curricular reforms, both published and unpublished, that have already met with success, and we have also discussed some future trends in teaching both undergraduate and graduate physicians the fundamental principles of rational drug therapy. The challenges and issues involved in these future trends have been identified and will be addressed in subsequent articles in this journal. These will be concerned with teaching clinical pharmacology: (1) in basic medical pharmacology courses; (2) to upperclass medical students; and (3) in continuing medical education programs. Subsequent articles will also deal with new and innovative teaching modalities for clinical pharmacology and with the role of the drug industry in these modalities.

Education, Medical↗
PubMed1990

The role of pharmacological profiling in safety assessment.

The profiling of new drug candidates for general pharmacological properties requires a systematic examination of the functional effects of agents in a variety of in vitro and in vivo assays. Both the behavioral and physiological consequences of drug treatment are monitored in models of central nervous system, cardiovascular, autonomic, gastrointestinal, and renal functions. Broad functional profiling provides valuable information to the preclinical pharmacologist with respect to the selectivity of new agents and may serve to identify new and useful therapeutic indications of investigational drugs. At the same time, knowledge of the effects on these physiological systems can also play an important role in safety assessment. Pharmacological activity of a new agent that is both unintended and undesirable can be referred to as "pharmacological toxicity." In general, the spectrum of toxicities disclosed in pharmacological profiling includes a variety of acute functional or physiological effects which are not life-threatening and are readily reversible. On rare occasions, unanticipated and life-threatening pharmacological effects (e.g., convulsions, arrhythmias) are detected which can seriously detract from the usefulness of a new agent and may therefore deter the drug development process. It should also be noted that repeated exposure to acute pharmacological effects may lead to less obvious chronic findings, such as target organ effects or tumor formation in animals. The interpretation of pharmacological toxicity with respect to the safety profile of a new drug candidate is dependent not only upon the types of reactions observed and the doses at which they occur but also upon the nature of the effects elicited as to whether they represent expected extensions of the primary mechanism of action of a compound or constitute reactions unrelated to the primary pharmacological activity. The ultimate impact of pharmacological toxicity, as with all adverse findings in preclinical assessment, is dependent upon the projected therapeutic margin of safety as well as the risk-to-benefit ratio for new drug entities. In addition to supplementing the existing armamentarium of preclinical safety studies, pharmacological profiling can also play an important role in (1) the selection of new drug candidates with reduced toxic potential, (2) the design and conduct of preclinical toxicology studies, (3) the investigation of preclinical and clinical safety issues, and (4) the identification of potential functional effects to be monitored most closely in clinical trials of new drug entities.

Animals↗
PubMed2003

Methodological differences in clinical trials evaluating nonpharmacological and pharmacological treatments of hip and knee osteoarthritis.

CONTEXT: Randomized controlled trials have been developed essentially in the context of pharmacological treatments (ie, oral drugs; intra-articular injection; and topical, intramuscular, and intravenous treatments), but assessment of the effectiveness of nonpharmacological treatments (ie, surgery, arthroscopy, joint lavage, rehabilitation, acupuncture, and education) presents specific issues. OBJECTIVES: To compare the quality of articles of nonpharmacological and pharmacological treatments of hip and knee osteoarthritis and to identify specific methodological issues related to assessment of nonpharmacological treatments. DESIGN AND SETTING: We searched MEDLINE and the Cochrane Central Register of Controlled Trials for articles of randomized controlled trials published between January 1, 1992, and February 28, 2002, in 28 general medical and specialty journals with high impact factors and assessing nonpharmacological and pharmacological treatments in patients with hip or knee osteoarthritis. MAIN OUTCOME MEASURES: The quality of the methods reported in the selected articles was assessed by 2 independent reviewers using the Jadad scale, the Delphi list, and guidelines found in the Users' Guides to the Medical Literature. Investigators also used a checklist of items developed by the authors to analyze study characteristics. RESULTS: A total of 110 articles were included in the analysis; 50 (45.5%) assessed nonpharmacological treatments and 60 (54.5%) assessed pharmacological treatments. Reports of nonpharmacological treatments had a lower global quality score than did reports of pharmacological treatments as measured by the Jadad scale (mean [SD] score, 1.4 [1.3] vs 3.0 [1.3]) and the Delphi list (mean [SD] score, 5.2 [1.5] vs 7.5 [1.1]). Lack of reporting adequate random sequence generation and intention-to-treat analyses were found in both nonpharmacological and pharmacological articles. Nonpharmacological treatments were less often compared with a placebo than were pharmacological treatments (28.0% of articles vs 71.7%). Compared with pharmacological articles, nonpharmacological articles less often described blinding of patients (26.0% vs 96.7%), care providers (6.0% vs 81.7%), and outcome assessors (68.0% vs 98.3%). Care providers' skill levels could influence treatment effect in 84.0% of nonpharmacological articles vs 23.3% of pharmacological articles. CONCLUSIONS: In this analysis of reports of hip and knee osteoarthritis therapy, nonpharmacological articles scored lower than pharmacological articles in terms of quality. Assessments of nonpharmacological treatments must take into consideration additional methodological issues.

Complementary Therapies↗
PubMed1999

Hypertension in diet versus pharmacologically treated diabetics: mortality over a 5-year follow-up.

The natural history of non-insulin-dependent diabetes mellitus (NIDDM) differs markedly between patients with diet treated and pharmacologically treated disease. However, the interrelationship between hypertension and these common diabetes types has not been specifically addressed in previous studies. This study was designed to evaluate the prognostic significance and prevalence of hypertension in coronary patients with diet versus pharmacologically treated NIDDM over a 5-year follow-up period. The study sample comprised 11 515 patients aged 45 to 74 years with a previous myocardial infarction and/or anginal syndrome who had been screened but were not included in the Bezafibrate Infarction Prevention study. Among them, 9033 were nondiabetics and 2482, diabetics (987 diet treated and 1495 pharmacologically treated). The prevalence of hypertension among nondiabetics, diet-treated diabetics, and pharmacologically treated diabetics was 31%, 42%, and 43%, respectively. Crude all-cause mortality (CM) was lower in the nondiabetic patients (11.2% versus 22.0%; P<0.001). Among diabetics, 548 patients died: 81 diet treated normotensives (CM 14%); 100 diet-treated hypertensives (CM 24.4%); 205 pharmacologically treated normotensives (CM 24.2%); and 162 pharmacologically treated hypertensive patients (CM 25.0%). Age-adjusted mortality was lowest for the normotensive patients in the diet-treated group and highest for the hypertensive pharmacologically treated patients. Multivariate analysis shows that hypertension is a strong and independent predictor of increased CM in diet-treated but not in pharmacologically treated NIDDM: hazard ratio (HR) was 1.68 (95% confidence interval [CI] 1.24 to 2.29) for the diet-treated versus 1. 01 (95% CI 0.82 to 1.26) for the pharmacologically treated diabetics. The contribution of hypertension to stroke mortality was substantial for both diet treated and pharmacologically treated NIDDM: hazard ratios were 3.17 (95% CI 1.12 to 8.98) and 2.21 (95% CI 0.72 to 6.77), respectively. The increased risk of mortality associated with hypertension in relatively mild diet-treated NIDDM strongly supports the clinical benefit of early blood pressure control among diabetic patients with ischemic heart disease.

Aged↗
PubMed2005

Utilisation of human pharmacology studies with biomarkers for new drug applications in Japan.

OBJECTIVE: This study evaluated the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation conducted for new drug applications (NDAs) submitted to the Japanese regulatory authority, the Ministry of Health, Labour and Welfare (MHLW). METHODS: A total of 50 new chemical entities (NCEs) posted on the Websites, which were approved from June 2000 to November 2001, were evaluated by investigating their approval information. The utilisation of human pharmacology studies with biomarkers was evaluated by focusing on the classification referred to biomarkers for either efficacy or safety estimation and timing of studies. RESULTS: The human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted in 20 compounds classified by utilising measures of either efficacy (17 compounds) or safety (seven compounds). In 4 of 17 NCEs, some of the biomarkers in human pharmacology studies were similar to the clinical endpoints for efficacy assessment in therapeutic exploratory and/or therapeutic confirmatory studies. For safety assessment in therapeutic exploratory and/or therapeutic confirmatory studies, clinical endpoints rather than biomarkers in human pharmacology studies were used in all seven NCEs. The timing of each type of clinical study could only be obtained for 15 NCEs. Of these 15 NCEs, human pharmacology studies with biomarkers for either efficacy or safety estimation were conducted on six compounds. There were only two compounds for which human pharmacology studies with biomarkers for efficacy estimation were conducted before pivotal studies such as a therapeutic exploratory study or a bridging study. CONCLUSION: Our survey suggests that with Japanese NDAs, human pharmacology studies with biomarkers for either efficacy or safety estimation do not play a key role in accelerating drug development and maximising the knowledge gained from confirmatory trials. The relationship between a biomarker and a clinical endpoint should be investigated appropriately for accelerating drug development. We think that the utilisation of human pharmacology studies with biomarkers for either efficacy or safety estimation in the regulatory review process for NDAs should be encouraged with the advancements of drug evaluation research using an appropriate biomarker based on clinical pharmacology.

Biomarkers↗