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Volume 121 (2003)
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- Issue 4 Pages 203-
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Volume 121, Issue 6
Displaying 1-9 of 9 articles from this issue
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Reviews:Pharmacological Evaluation of the Risk of Drug-Induced Long QT Syndrome
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Munehiro HASHIMOTOArticle type: Reviews
2003 Volume 121 Issue 6 Pages 377-383
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSNonclinical assessment of potential of QT interval prolongation caused by non-antiarrhythmic drugs has been an issue for drug development because QT interval prolongation increases the risk of ventricular tachyarrhythmia, including torsade de pointes when combined with other risk factors. However, there is no scientific consensus on approaches and no international consensus on regulatory recommendations. This guideline is being developed to provide the general nonclinical testing strategy for evaluating the potential risk of QT prolongation and presents some major principles for in vitro and in vivo electrophysiology studies. The basis of this guideline is the integrated risk assessment that provides overall evaluations based on nonclinical study results and chemical/pharmacological class information to predict the potential of a test substance to prolong QT interval in humans (i.e., evidence of risk) and that contributes clinical study design and interpretation of clinical results. Safety margins are also components of integrated risk assessment. Since this guideline addresses a field of research that is in a state of rapid evolution, the proposed concept for evidence of risk and safety margins needs to be further refined based on the data being collected by international initiatives. In this article, the draft S7B guideline is outlined.
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Haruaki NAKAYAArticle type: Reviews
2003 Volume 121 Issue 6 Pages 384-392
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSIn order to prevent the drug-induced long-QT syndrome it is important to assess the risk in the early phase of drug development. Most of the drugs, which clinically prolong the QT interval and induce torsades de pointes (Tdp), are known to inhibit the rapid component of the delayed rectifier K+ current (IKr) in cardiac cells. It is acknowledged that HERG (human ether-a-go-go-related gene) encodes the channel pore protein underlying IKr. The most sensitive method to evaluate the risk would be electropharmacological assessment using patch clamp techniques. When enzymatically-dissociated native cardiac cells are used, overlapping contamination of the slow component of the delayed rectifier K+ current (IKs) makes it difficult to analyze the drug effect on IKr accurately. Therefore, heterologous expression systems of HERG channel are usually used to evaluate the inhibitory effect of drugs on IKr. Since the Xenopus oocyte system expressing HERG channels appears to be less sensitive to drug inhibition, use of a mammalian cell expression system may be desirable for the screening. A detailed analysis using various pulse protocols may be needed for the careful assessment of the HERG channel inhibition. In addition, many factors that may affect the susceptibility of patients to QT prolongation must be also taken into consideration.
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Atsushi SUGIYAMAArticle type: Reviews
2003 Volume 121 Issue 6 Pages 393-400
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSThe proarrhythmic effects of class III antiarrhythmic agents and non-cardiovascular drugs, which have been shown to prolong QT interval, were assessed using two types of in vivo canine models. First, electrophysiological effects of dofetilide, nifekalant, amiodarone, cisapride, astemizole, sulpiride, haloperidol, and sparfloxacin were assessed using halothane-anesthetized dogs. Each drug prolonged the monophasic action potential (MAP) duration and effective refractory period (ERP) at clinically recommended daily doses. The extent of increase was greater in the refractoriness than in the repolarization only for amiodarone, indicating abbreviation of the terminal repolarization period. The reverse was true for the other drugs. Next, torsadogenic action of sematilide, nifekalant, amiodarone, cisapride, terfenadine, sulpiride, and sparfloxacin was assessed using chronic complete atrioventricular block dogs with Holter ECG monitoring in the conscious state. Oral administration of 1-10 times higher doses than the clinically relevant doses of the drugs induced polymorphic ventricular tachycardia torsades de pointes (TdP), except for amiodarone. These results indicate that the prolongation and backward shift of the terminal repolarization period may be closely related to the drug-induced TdP and suggest that these in vivo models can be used to screen proarrhythmic potential of new drugs.
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Minoru HORIEArticle type: Reviews
2003 Volume 121 Issue 6 Pages 401-407
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSMolecular and cellular mechanisms underlying the QT prolongation have been elucidated largely because of the recent understanding of the generation of the congenital forms of QT prolongation; i.e., the long QT syndrome. To date, at least 7 different genes that modulate cardiac ion channels were identitied to be associated with the syndrome. In the clinical setting, the drug-induced long QT syndrome is more frequently seen and therefore important. We found several mutations as well as an SNP specific among the Japanese population in probands referred to as the secondary long QT patients, including the drug-induced cases. These findings raised the potential that there are also predisposing risk factors at patient's side.
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Review
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Atsufumi KAWABATAArticle type: Reviews
2003 Volume 121 Issue 6 Pages 411-420
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSProtease-activated receptors (PARs) are a family of G-protein-coupled-seven-trans-membrane-domain-receptors activated by specific proteases, consisting of four family members. PAR-2, a receptor activated by trypsin, tryptase or coagulation factors VIIa and Xa, is unevenly distributed throughout the mammalian body, modulating multiple physiological functions. In the gastrointestinal tract, PAR-2 is involved in gastric mucosal cytoprotection, smooth muscle motility modulation, salivary and pancreatic exocrine secretion, intestinal ionic transport, etc. In the circulatory system, endothelial PAR-2, upon activation, induces vascular relaxation by mechanisms dependent on nitric oxide or endothelium-derived hyperpolarizing factor (EDHF), resulting in hypotension in vivo. In the respiratory system, PAR-2 appears to play a dual role, being pro- and anti-inflammatory. In the nervous system, PAR-2 present in capsaicin-sensitive sensory neurons participates in processing of pain information. PAR-2 is thus involved in a variety of physiological and pathophysiological functions. PAR-2 is now considered one of the most important molecules as a target for drug development.
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Norio SAKAI, Yasuhito SHIRAI, Naoaki SAITOArticle type: Review
2003 Volume 121 Issue 6 Pages 421-434
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSProtein kinase C (PKC) is a family, which consists of at least ten subtypes. To elucidate subtype-specific functions of PKC, we have developed the methods to observe PKC translocation in real time and in the living state using PKC fused with fluorescent proteins, including GFP and DsRed. Based on the live imaging of PKC translocation, we have demonstrated that PKC showed stimulus- and subtype-specific translocation, which can recognize its specific substrate and induce its specific cellular response (PKC targeting). These findings suggest that PKC targeting is the molecular basis underlying the diversity of PKC functions. Live imaging of PKC translocation has been proved to be a beneficial tool for understanding not only PKC functions, but also PKC-mediated signal transduction pathways. We have further analyzed PKC functions in the central nervous system using transgenic mice, which can express PKC-GFP in a brain-region-specific manner.
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Technical Note
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Hideki MATSUI, Kazuhito TOMIZAWA, Masayuki MATSUSHITAArticle type: Technical Note
2003 Volume 121 Issue 6 Pages 435-439
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSProtein transduction methods have been developed utilizing the delivery of peptides and proteins into eukaryotic cells by the protein transduction domain (PTD). Initially, the PTD domain was developed from the sequences from HIV-1 TAT, HSV VP-22 and antennapedia homeoprotein. Recently, several novel PTDs were developed and has been used as a valuable strategy for transduction of therapeutic protein. We developed a novel, high efficiency PTD (11 arginine) based on the TAT sequence and used 11R for the regulation of intracellular signal cascades. PTD can deliver proteins and other bioactive compounds and therefore serves as a very useful strategy for the development of therapeutic agents.
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Keiko TAKAGI, Satoshi TAKEOArticle type: Technical Note
2003 Volume 121 Issue 6 Pages 440-446
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSCerebral infarction is induced by injecting 700-900 microspheres with a diameter of 50 µm into the right internal carotid artery of the rat. Approximately 82% of the rats with typical symptoms of stroke survived at fifteen hours after the injection of microspheres. Microsphere-induced cerebral embolism elicits the widespread formation of small emboli in the ipsilateral hemisphere and subsequent neuronal loss and/or the development of multiple infarct areas in the brain, particularly in the cortex, striatum, and hippocampus. Thus, this model is considered to mimic focal ischemia-induced human stroke or multi-infarct dementia. We have found that this model showed sustained decreases in cerebral blood flow and cerebral high-energy phosphates; accumulation of tissue lactate, glucose, and glycogen; changes in the activity of several enzymes in the tricarboxylic acid cycle; loss of mitochondrial phosphorylation activity; and decreases in neurotransmitters, acetylcholine, monoamines, and amino acids in the ipsilateral hemisphere. Accordingly, microsphere embolism is capable of inducing severe and sustained cerebral ischemia resulting in disturbances of the energy and neurotransmitter metabolism in the brain. Such ischemic damage leads to learning and memory dysfunction. This model provides useful information about the pathogenesis, prophylaxis, and therapeutics of cerebral ischemic diseases.
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Review on New Drug
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Masaki HOSAKAArticle type: Review on New Drug
2003 Volume 121 Issue 6 Pages 447-456
Published: 2003
Released on J-STAGE: May 29, 2003
JOURNAL FREE ACCESSGatifloxacin, a novel 8-methoxyquinolone, was approved in April 2002 and launched in June 2002. Gatifloxacin shows a broad spectrum of antibacterial activity against Gram-negative, Gram-positive, anaerobic, and atypical pathogens. The activity is higher than those of other quinolones against RTI pathogens of S. pneumoniae including the penicillin-resistant strains, H. influenzae, Mycoplasma, and Chlamydia. This drug strongly inhibits the type II topoisomerase, DNA gyrase, and topoisomerase IV of S. pneumoniae and S. aureus to nearly the same extent, leading to the potent activity and low resistance. After an oral administration in humans, gatifloxacin is well absorbed and distributed, and the majority is excreted in the urine as the unchanged form. Its serum half-life is 7-8 h. The clinical effectiveness was observed for various infectious diseases including RTI and UTI. The bacterial eradication rate is 94.1% for Gram-positives, 90.7% for Gram-negatives, and 97.7% for anaerobes. In particular, gatifloxacin showed a high eradication rate of 98.7% for S. pneumoniae. The total cure rate and eradication rate of gatifloxacin in clinical studies are 91.1% and 93.3%, respectively, indicating that the potent activity and good PK profile account for its clinical efficacy.
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