APEC Harmonization Center: challenges and issues relating to multiregional clinical trials in the APEC region.

The Asia-Pacific Economic Cooperation (APEC) Harmonization Center (AHC) was established in 2009 with the purpose of promoting harmonization of regulatory processes for drugs and medical devices. The AHC held three training workshops on multiregional clinical trials (MRCTs); these workshops provided forums for discussing the value and potential benefits of MRCTs. Participants from regulatory agencies, the pharmaceutical industry, and academia identified many issues and made recommendations for resolving major challenges with the aim of improving the capacity of the Asia-Pacific region to carry out MRCTs.

Bioavailability and mammary excretion of bisphenol a in Sprague-Dawley rats.

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 +/- 1.3 min and 52.5 +/- 2.4 min, respectively. The systemic clearance (Cls) and the steady-state volume of distribution (Vss) averaged 107.9 +/- 28.7 m/min/kg and 5.6 +/- 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 14.7 +/- 10.9 ng/ml and 0.2 +/- 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 +/- 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 +/- 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.

Potential estrogenic effects of bisphenol-A estimated by in vitro and in vivo combination assays.

The potential estrogenic activities of bisphenol-A were investigated in vitro (E-screen and estrogen receptor competitive binding bioassays) and in vivo (uterotrophic assay). Uterotrophic responses were evaluated using mature ovariectomized Sprague-Dawley female rats treated subcutaneously with bisphenol A (1, 5, 10, 50, and 100 mg/kg/day), E2 (0.3 microgram/kg), and DES (0.3 microgram/kg) for 3 consecutive days. In a MCF-7 cell proliferation assay, E2 and DES used as positive estrogens induced maximum proliferation of MCF-7 cells at 1.0 nM, whereas BPA slightly induced MCF-7 cell proliferation at a higher level of 0.1 microM and maximum proliferation at 10 microM. In a competitive binding assay, E2 and DES showed inhibition of 17 beta-[3H]estradiol binding to the rat uterus ER with an IC50 of 1.0 nM and 0.5 nM, respectively. However, BPA had an IC50 of 5 microM, which was approximately 5,000 or 10,000-fold greater than the IC50 of E2 and DES. In uterotrophic assays, uterus (wet and blotted) and vagina weights were significantly increased at the dose of BPA 100 mg/kg/day in OVX Sprague-Dawley rats. These studies demonstrate that BPA exhibits weak estrogenic activity in all experimental systems, and thus its migration from epoxy resins or polycarbonate products should be controlled not to exceed a safety levels for humans.

Design of a wavelet interpolation filter for enhancement of the ST-segment.

A wavelet interpolation filter (WIF) is designed for the removal of motion artifacts in the ST-segment of stress ECGs. The WIF consists of two parts. One part is a wavelet transform that decomposes the stress ECG signal into several frequency bands using a Haar wavelet. The other part is an interpolation method, such as the spline technique, that is used to enhance the reconstruction performance of the signal decomposed by the wavelet transform. To evaluate the performance of the WIF, three indices are used: signal-to-noise ratio (SNR), reconstruction square error (RSE) and standard deviation (SD). The MIT/BIH arrhythmia database, the European ST-T database and the triangular wave are used for evaluation. A noisy ECG signal, corrupted by motion artifacts, is simulated by the addition of two types of random noise to the original ECG signal. For comparison, three indices for the other methods are also computed: mean, median and hard thresholding. The performance of the WIF shows that RSE, SNR and SD are 392.7, 18.3dB and 2.6, respectively, in the case of a noisy signal with an SNR of 7.1 dB. This result is much better than those for the other methods.

Evaluation of the role of imidazolidinone motif of antineoplastic 4-phenyl-1-arylsulfonylimidazolidinones using 4-phenyl-2-arylsulfonyloxazolines.

To evaluate the role of imidazolidinone moiety of potential anticancer 4-phenyl-1-arylsulfonylimidazolidinones 1 for their cytotoxicity, conformationally similar 4-phenyl-2-arylsulfonylaminooxazolines 2 were synthesized and compared their cytotoxicities with those of the corresponding 1. Compounds 2 showed much reduced activity compared to N-arylsulfo-nylimidazolidinones 1. This result might indicate that the imidazolidinone ring of 1 have the other roles for the activity as an essential structural motif in addition to conformational contribution.

Effects of ochratoxin A on cytotoxicity and cell differentiation in cultured rat embryonic cells.

In the present study, the effects of ochratoxin A (OTA) on cytotoxicity, cell differentiation, and other cell functions in the embryonic midbrain cells, which are dopaminergic, were compared to those in the limb bud cells, which are nondopaminergic, to assess the selectivity of OTA central action. Twelve-day rat embryo midbrain and limb bud cells were cultured in Dulbecco's modified Eagle's medium nutrient and Ham's F12 (1:1) mix ture containing 10% Nuserum for 96 h in the presence of various concentrations of OTA. OTA signicfiantly reduced the levels of protein, DNA and glutathione, and [H]thymidine incorporation into DNA in both embryonic midbrain and limb bud cells in a similar concentration-dependent manner. The IC50 values for cytotoxicity measured by neutral red uptake were 1.10 microM in the midbrain cells and 1.05 microM in the limb bud cells. The IC50 values of cell differentiation were 1.10 microM in the midbrain cells and 1.0 microM in the limb bud cells. The addition of exogenous glutathione (32.5 microM) did not change the OTA-induced fall in protein and DNA levels, or the IC50 values of cytotoxicity and differentiation in the midbrain and limb bud cells. Data show that OTA does not appear to exert a selective toxic dopaminergic cell action and that OTA-induced cytotoxicity and inhibition of cell differentiation were not prevented by exogenous glutathione.

Multicentre hydrogen bonds in a 2:1 arylsulfonylimidazolone hydrochloride salt.

The title compound, (S)-(+)-4-[5-(2-oxo-4, 5-dihydroimidazol-1-ylsulfonyl)indolin-1 -ylcarbonyl ]anilinium chloride (S)-(+)-1-[1-(4-aminobenzoyl)indoline-5- sulfonyl]-4-phenyl-4, 5-dihydroimidazol-2-one, C(24)H(23)N(4)O(4)S(+).Cl(-). C(24)H(22)N(4)O(4)S, crystallizes in space group C2 from a CH(3)OH/CH(2)Cl(2) solution. In the crystal structure, there are two different conformers with their terminal C(6) aromatic rings mutually oriented at angles of 67.69 (14) and 61.16 (15) degrees. The distances of the terminal N atoms (of the two conformers) from the chloride ion are 3.110 (4) and 3.502 (4) A. There are eight distinct hydrogen bonds, i.e. four N-H...Cl, three N-H...O and one N-H...N, with one N-H group involved in a bifurcated hydrogen bond with two acceptors sharing the H atom. C-H...O contacts assist in the overall hydrogen-bonding process.

Pharmacokinetic disposition and tissue distribution of bisphenol A in rats after intravenous administration.

This study examined the dose-linearity pharmacokinetics of bisphenol A, a U.S. Environmental Protection Agency (EPA) classified endocrine disruptor, in rats following iv administration. Upon iv injection of 0.2, 0.5, 1, or 2 mg/kg, serum levels of bisphenol A declined biexponentially, with mean initial distribution and elimination half-life ranges of 4-8.2 min and 38.6-62.2 min, respectively. There were no significant alterations in the systemic clearance rate (mean range 90.1-123.6 ml/min/kg) and the steady-state volume of distribution (mean range 4.6-6.0 L/kg) as a function of the administered dose. In addition, the area under the serum concentration-time curve linearly rose as the dose was increased. In a second study, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state, and levels were measured in serum and various organs. When expressed in concentration terms (e.g., amount accumulated per gram organ weight), bisphenol A was found predominantly in the lung, followed by kidneys, thyroid, stomach, heart, spleen, testes, liver, and brain. Ratios of the organ to serum bisphenol A concentrations exceeded unity for all the organs examined (ratio range 2.0-5.8) except for brain (ratio 0.75). Given the high systemic clearance and short elimination half-life, bisphenol A is unlikely to accumulate significantly in the rat.

Effect of substituents on benzenesulfonyl motif of 4-phenyl-1-arylsulfonylimidazolidinones for their cytotoxicity.

To explore the effect of substituents' on phenyl motif on sulfonyl function of novel anticancer 4-phenyl-1-benzenesulfonylimidazolidinones (1), electron donating or withdrawing substituents were introduced at 3 or 4-position and the analogs were tested against human lung (A549) and colon (HCT-15) cancer cell lines. Quantitative structure activity relationship of the 4-substituted series shows that only STERIMOL L values are well correlated. The increment of substituent's volume enhances the activity against both cell lines. The small substituent at 3-position additionally increases the activity. However naphthyl group in place of phenyl reduces the activity. Therefore the phenyl motif with sterically large substituent at 4-position and small substituent at 3-position may be important for their activity. Integration of these substituents' effects into the structural design led to discover the more potent analog, 4-phenyl-1-(N-acetylindoline-5-sulfonyl) imidazolidinone (1n).

Abnormal ventricular looping and abnormal laterality of the atrial chambers are the main morphogenetic mechanisms of cardiac lesions in cultured rat embryos treated with retinoic acid.

To establish the early morphogenetic mechanism in retinoid induced cardiac lesions, we investigated the morphology of the heart in cultured rat embryos treated with retinoic acid (RA) at 9.0 and 9.5 days post coitum (d.p.c). Wistar rat embryos were treated with RA (2 x 10(-7) M) for 6 hours from the embryonic day equivalent of 9.0 or 9.5 d.p.c. After further culture in an RA free medium for 2.5 days, embryos were fixed and examined with a stereomicroscope and a scanning electron microscope. Sixty three embryos were treated at 9.0 d.p.c., 14 embryos were treated at 9.5 d.p.c. and 30 embryos were used as control. Abnormal ventricular looping was seen in 31 embryos (49.2%) from the group treated at 9.0 d.p.c., and isomerism of right appendages occurred in 15 (23.8%). Embryos treated with RA at 9.5 d.p.c. showed a low incidence of abnormal ventricular looping (14.3%). We could summarize those abnormal looping as three variants of each looping. The mildest form was hypoplasia of the right ventricle observed in 20 cases. Both the right and left ventricles in the second variant were shifted far to the left or right (10 cases). The third variant was a heart with generalized hypoplasia of both ventricles (3 cases). The incidence of branchial arch anomalies was higher at 9.5 d.p.c. than at 9.0 d.p.c. (71.4% and 30.2%, respectively). Abnormalities in the ventricular looping and the atrial laterality at 9.0 d.p.c. suggest that RA induces derangement in the development of laterality, while at 9.5 d.p.c., the abnormality of the migration of neural crest cells is the principal mechanism.

Cardiovascular disease in patients with dysvascular amputation.

Cardiovascular diseases are the most common causes of morbidity and mortality in individuals with peripheral vascular disease (PVD). Among patients who have undergone lower extremity amputation as a result of PVD, the prevalence of concomitant cardiovascular disease may be as high as 75%. Comorbid heart disease may complicate the postamputation course of recovery, delay initiation of rehabilitation training, and inhibit the achievement of maximal functional independence. A variety of methods have been used to assess cardiac status and risk in amputation patients undergoing physical training; these have included clinical evaluation, resting electrocardiography, and continuous dynamic electrocardiography during either standard physical therapy exercise or adapted ergometry. Several conditioning training programs have been developed to improve the cardiovascular fitness of patients with dysvascular amputation, the results of which have been favorable. These assessment and intervention strategies have extensive applicability in the clinical management of patients with dysvascular amputation.

Application of a wavelet adaptive filter to minimise distortion of the ST-segment.

A wavelet adaptive filter (WAF) for the removal of baseline wandering in ECG signals is described. The WAF consists of two parts. The first part is a wavelet transform that decomposes the ECG signal into seven frequency bands using Vaidyanathan-Hoang wavelets. The second part is an adaptive filter that uses the signal of the seventh lowest-frequency band among the wavelet transformed signals as primary input and a constant as reference input. To evaluate the performance of the WAF, two baseline wandering elimination filters are used, a commercial standard filter with a cutoff frequency of 0.5 Hz and a general adaptive filter. The MIT/BIH database and the European ST-T database are used for the evaluation. The WAF performs better in the average power of eliminated noise than the standard filter and adaptive filter. Furthermore, it shows a lower ST-segment distortion than the standard filter and the adaptive filter.

Ocular manifestations of AIDS.

AIDS causes severe depression of the immune system through selective infection of CD4+ T lymphocytes. As such, certain infections and neoplasms occur in these patients often with ocular involvement. Among these, cytomegalovirus retinitis is by far the most common and remains a leading cause of visual loss. Intravenous ganciclovir and foscarnet, the two Food and Drug Administration-approved treatments for cytomegalovirus retinitis, are effective in most cases, but recurrences are the rule. In addition, these virustatic drugs require lifelong administration and dose-limiting toxicity affects many of these patients. Ongoing investigation into current and alternative therapies has produced some promising developments which are discussed here. Also reviewed are recent findings associated with other opportunistic pathogens and neoplasms that affect the eye in AIDS, including varicella-zoster virus, Toxoplasma gondii, and lymphoma.