Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors.

The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the marmosets dosed with sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine. PR prolongation was noted after flecainide and verapamil administration, and QRS widening occurred following treatment with flecainide and quinidine. Drugs plasma levels associated with ECG changes in marmosets were similar to those in humans, except for verapamil-induced QTc prolongation. Verapamil-induced change is suggested due to body temperature decrease. These results indicate that telemetered common marmoset is a useful animal for evaluation of the ECG effects of multiple cardiac ion channel inhibitors and the influence of body temperature change should be considered in the assessment.

Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes.

Monitoring dramatic changes in intracellular calcium ion levels during cardiac contraction and relaxation, known as calcium transient, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be an attractive strategy for assessing compounds on cardiac contractility. In addition, as arrhythmogenic compounds are known to induce characteristic waveform changes in hiPSC-CMs, it is expected that calcium transient would allow evaluation of not only compound-induced effects on cardiac contractility, but also compound arrhythmogenic potential. Using a combination of calcium transient in hiPSC-CMs and a fast kinetic fluorescence imaging detection system, we examined in this study changes in calcium transient waveforms induced by a series of 17 compounds that include positive/negative inotropic agents as well as cardiac ion channel activators/inhibitors. We found that all positive inotropic compounds induced an increase in peak frequency and/or peak amplitude. The effects of a negative inotropic compound could clearly be detected in the presence of a ß-adrenergic receptor agonist. Furthermore, most arrhythmogenic compounds raised the ratio of peak decay time to peak rise time (D/R ratio) in calcium transient waveforms. Compound concentrations at which these parameters exceeded cutoff values correlated well with systemic exposure levels at which arrhythmias were reported to be evoked. In conclusion, we believe that peak analysis of calcium transient and determination of D/R ratio are reliable methods for assessing compounds' cardiac contractility and arrhythmogenic potential, respectively. Using these approaches would allow selection of compounds with low cardiotoxic potential at the early stage of drug discovery.

Factors associated with spontaneous reporting of adverse drug reactions in Japan.

PURPOSE: Spontaneous reported adverse drug reactions (ADRs) are currently the main source of pharmacovigilance activities in each country. The number of ADRs reported to the authority warns of safety risks to patients, but it also reflects the efficiency and limitations of the reporting system itself. This article explored how the accumulation of safety information, status in foreign countries (e.g., US approval), drug company attributes, and regulatory actions (e.g., early post-marketing phase vigilance; EPPV) were associated with the numbers of spontaneously reported ADRs in Japan. METHODS: All serious ADRs for drugs for which the active ingredients or route of administration were approved in Japan from 2000 through 2005 were collected from the national database. The numbers of serious ADRs within the first 2 and 3 years after launch were analyzed using the negative binominal distribution model. RESULTS: The launch lag and the presence of drugs with a similar mode of action were negatively associated with the ADR numbers, but the number of study subjects for the new drug application (NDA) showed no clear association. The number of sales representatives and the implementation of EPPV were positively associated with the ADR numbers. CONCLUSION: The accumulation of foreign post-market evidence seemed to be more important for drug safety in Japan than was the amount of pre-approval safety data. The positive impacts of sales representatives and EPPV suggested a critical role for drug companies in drug safety and also the importance of considering how best to collect information in local situations with unique regulatory requirements.

Assessment of technical protocols for novel embryonic stem cell tests with molecular markers (Hand1- and Cmya1-ESTs): a preliminary cross-laboratory performance analysis.

The Hand1- and Cmya1-ESTs are novel short-term tests for embryotoxic chemicals using genetically engineering mouse ES cells for luciferase reporter gene assays. These ESTs allow convenient determination of differentiation toxicity and cell viability in a short duration with high throughput 96-well microplates for prediction of embryotoxicity of chemicals. To assess the Hand1-EST technical protocol, we firstly compared reporter gene assay and cytotoxicity test data for a representative compound (hydroxyurea) from four different laboratories with tests carried out under the same experimental conditions. Extensive investigations of the Hand1- and Cmya1-ESTs were then performed to explore reproducibility by comparing a set of 6 well-known test chemicals, including hydroxyurea, across the laboratories. The results gave good correspondence in all four laboratories, indicating that transferability, intra-laboratory variability and inter-laboratory variability of the present technical protocols of the ESTs were sufficient to conduct further validation studies.

Analysis of pharmaceutical safety-related regulatory actions in Japan: do tradeoffs exist between safer drugs and launch delay?

BACKGROUND: Prediction and management of drug safety is a global regulatory issue. Safety-related regulatory actions (SRRAs) are taken mostly when unexpected adverse drug reactions occur. Currently, Japan is reconciled to delayed access to new drugs (ie, launch delay compared to Western countries), but may have been benefiting by free-riding on safety data accumulated in other countries prior to Japanese launch. OBJECTIVE: To identify factors that are significantly associated with SRRAs, and to discuss the challenges that Japan might have to face with increasing access to new drugs. METHODS: The SRRAs of 135 new drugs approved from January 2000 to December 2005 were analyzed to investigate association with launch lag, company and drug characteristics, market size, submission data, and regulatory status. SRRAs were measured in terms of the number of emergency safety information notifications and official safety instructions issued by the Japanese regulatory agency within 3 years after approval. A negative binomial distribution model was used for regression analysis. RESULTS: Longer launch lags and presence of drugs with similar modes of action were associated with fewer SRRAs. Bridging strategy showed increased SRRAs. No significant association was observed between SRRAs and the subject number in clinical data packages. Occurrence of SRRAs was varied among development strategy, preceding products, and regional regulations. CONCLUSIONS: The occurrence of SRRAs was associated with the accumulation of both foreign and domestic postmarketing evidence rather than with clinical trial data upon launch. Considering the paradigm shift to simultaneous global drug development and filing for regulatory approval, this study indicates the importance of intensive data collection in the early postmarketing phase and use of safety information in early markets. However, even if we would be sufficiently cautious about safety risks of new drugs, a population that enjoys first-in-class drugs probably has to bear the risks.

New cross-talk measure of near-infrared spectroscopy and its application to wavelength combination optimization.

In near-infrared spectroscopy, concentration changes in oxygenated and deoxygenated hemoglobin are calculated from the changes in the attenuation of the measurement light. This is done by solving a linear equation based on the modified Lambert-Beer law. To solve this equation, we need to know the partial optical pathlengths in the activated region in the brain. Because they are difficult to know, a wavelength-independent constant or a wavelength-dependent total optical pathlength has been substituted for these values in actual measurements. This kind of substitution inevitably produces errors, called cross-talk, when calculating concentration changes. In this paper, we propose a new cross-talk measure for dual and triple wavelength measurements, and analyze it over various wavelength combinations. The results indicate that constant substitution is not inferior to total path-length substitution in dual wavelength measurements, and that total path-length substitution is very effective for triple wavelength measurements.

Monte Carlo study of global interference cancellation by multidistance measurement of near-infrared spectroscopy.

The performance of near-infrared spectroscopy is sometimes degraded by the systemic physiological interference in the extracerebral layer. There is some systemic interference, which is highly correlated with the functional response evoked by a task execution. This kind of interference is difficult to remove by using ordinary techniques. A multidistance measurement method is one of the possible solutions for this problem. The multidistance measurement method requires estimation parameters derived from partial pathlength values of tissue layers to calculate an absorption coefficient change from a temporal absorbance change. Because partial path lengths are difficult to obtain, experimentally, we estimated them by a Monte Carlo simulation based on a five-layered slab model of a human adult head. Model parameters such as thickness and the transport scattering coefficient of each layer depend on a subject and a measurement position; thus, we assumed that these parameters obey normal distributions around standard parameter values. We determined the estimation parameters that provide a good separation performance in average for the model parameter distribution. The obtained weighting is robust to model parameter deviation and provides smaller errors on average compared to the parameters, which are determined without considering parameter distribution.

Multidistance probe arrangement to eliminate artifacts in functional near-infrared spectroscopy.

Functional near-infrared spectroscopy has the potential to easily detect cerebral functional hemodynamics. However, in practical fNIRS measurements, a subject's physical or systemic physiological activities often cause undesirable artifacts. Such activities can be evoked even by task execution. In this case, observed artifacts may correlate strongly with the task sequence, and it is difficult to eliminate them by conventional signal filtering techniques. We present a theoretical analysis and Monte Carlo simulations of layered media in which both scattering and absorption changes occur, and show that a multidistance probe arrangement is effective in removing artifacts and extracting functional hemodynamics. The probe arrangement is determined based on simulation results. Artifacts induced by nonfunctional tasks (body tilting, head nodding, and breath holding) are clearly observed when a conventional method is used; such artifacts are appreciably reduced by the proposed method. Signals evoked by single-sided finger movements are observed at both hemispheres when we use a conventional method. On the other hand, localized signals at the primary motor area are observed by the proposed method. A statistically significant increase in oxygenated hemoglobin and decrease in deoxygenated hemoglobin are simultaneously observed at the contralateral primary motor area.

Impact of shoulder, elbow, and knee joint involvement on assessment of rheumatoid arthritis using the American College of Rheumatology Core Data Set.

OBJECTIVE: To determine the most sensitive scoring method for assessment of rheumatoid arthritis (RA) disease activity using the American College of Rheumatology Core Data Set. METHODS: The subjects were 4,530 patients with RA (mean age 57.9 years, mean disease duration 12.7 years) who participated in a large observational cohort study of RA patients. The 68 joints assessed were classified into 15 joint areas, and each joint variable was categorized based on the presence or absence of swelling or pain in these areas. Multiple linear regression and analysis of variance were used to evaluate the significance of effects of these 15 joint areas on variables for assessment of RA disease activity such as patient's assessment of pain on a visual analog scale (VAS), patient's and physician's global assessment of disease activity on a VAS, HAQ (Health Assessment Questionnaire), and Japanese HAQ. RESULTS: Although the 3 most frequently affected joints were the wrist, metacarpophalangeal joints, and proximal interphalangeal joints, the 5 joints with the largest contributions to all of the variables assessed for disease activity were the shoulder, elbow, and knee joints, followed by the wrist and ankle joints. The combination of shoulder, elbow, and knee joints accounted for approximately 70% of the contribution to all the variables, while addition of the wrist and ankle joints increased this value to approximately 90%. CONCLUSION: Scoring for assessment of RA disease activity would be more sensitive if separate joints such as the shoulder, elbow, knee, wrist, and ankle joints were weighted differently.