Transformation of 5,6-dimethoxy-2-amino-1-tetralol hydrochloride into 5,6-dimethoxy-2-tetralone

The reduction procedure of 5,6-dimethoxy-2-amino-1-tetralone with sodium bis-(2-methoxy)-aluminum hydride, followed by palladium on charcoal in the presence of HClO₄ gave a major reduction product of 5,6-dimethoxy-2-amino-tetralin, along with a small amount of a transformed 5,6-dimethoxy-2-tetralone. The isolated intermediate, 5,6-dimethoxy-2-amino-1-tetralol hydrochloride yielded exclusively 5,6-dimethoxy-2-tetralone under catalytic acidic conditions (acid treatment). The unusual rearangement was verified on the basis of IR, NMR and the result of elemental analysis. A plausible mechanism for the rearrangement is discussed.     

对液化石油气燃烧产物接触者尿致突变性的研究

应用鼠伤寒沙门菌株ＴＡ９８及其新的衍生菌株ＹＧ１０２１和ＹＧ１０２４检测了液化石油气（ＬＰＧ）燃烧产物接触者尿的致突变性。吉果表明，在有大鼠Ｓ_９已β－葡萄糖醛酸酶存在时，尿样显示较强的致突变性。尿样对ＹＧ１０２４的致突变性明显高于ＴＡ９８，而对ＹＧ１０２１的致突变性与ＴＡ９８相近。提示ＬＰＧ燃烧产物接触者尿中致突变物主要是以葡萄糖醛酸贰结合状态存在的芳香胺类物质。同时也证明ＹＧ１０２４在检测该尿样的致突变性上比ＴＡ９８更为敏感。     

Kinetics of diphenylhydantoin elimination in rats

Concentrations of diphenylhydantoin (DPH) in the blood of male Sprague-Dawley rats after intravenous injection of 10 and 40 mg/kg ¹⁴C-DPHwere determined over a sufficiently wide range to permit comparison of rates of decline at the same absolute and relative concentrations. This comparison leads to the conclusion that the elimination of DPH in the rat cannot be described by first-order or simple Michaelis-Menten kinetics but that it is qualitatively consistent with product inhibition of DPH metabolism.Supported in part by grant GM 19568 from the National Institutes of Health.On leave from the School of Pharmacy, University of Sydney, Sydney, Australia.     

Pharmacovigilance-related topics at the level of the International Conference on Harmonisation (ICH)

Marketing authorisations for medicines need to be based on the universal criteria quality, safety and efficacy, whilst taking into account local public health needs. With view to using resources efficiently and avoiding delay in access to medicines, scientific standards for investigating quality, safety and efficacy should be universal too. A major step to achieve this was taken in 1990 when the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was established between authorities and industry in the European Union (EU), Japan and the United States. Since then more than 50 ICH Guidelines have been published, out of which six are specific to pharmacovigilance. They refer to management and expedited reporting of individual adverse drug reaction (ADR) cases, including electronic formats, periodic reporting of worldwide data and planning of pharmacovigilance. Their development has to be seen in the context of initiatives taken in the three ICH Regions to strengthen pharmacovigilance. Most recently this involves making use of risk management concepts, reflecting new thinking of proactivity in pharmacovigilance. Moreover, consideration is given to regional and international cooperation beyond the ICH Regions.     

Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions

We investigated whether dissimilar biochemical fractions originating in anatomically discrete sections of the pomegranate (Punica granatum) fruit might act synergistically against proliferation, metastatic potential, and phosholipase A2 (PLA2) expression of human prostate cancer cells in vitro . Proliferation of DU 145 human prostate cancer cells was measured following treatment with a range of therapeutically active doses of fermented pomegranate juice polyphenols (W) and sub-therapeutic doses of either pomegranate pericarp (peel) polyphenols (P) or pomegranate seed oil (Oil). Invasion across Matrigel by PC-3 human prostate cancer cells was measured following treatment with combinations of W, P and Oil such that the total gross weight of pomegranate extract was held constant. Expression of PLA2, associated with invasive potential, was measured in the PC-3 cells after treatment with the same dosage combinations as per invasion. Supra-additive, complementary and synergistic effects were proven in all models by the Kruskal-Wallis non-parametric H test at p < 0.001 for the proliferation tests, p < 0.01 for invasion, and p < 0.05 for PLA2 expression. Proliferation effects were additionally evaluated with CompuSyn software median effect analysis and showed a concentration index CI < 1, confirming synergy. The results suggest vertical as well as the usual horizontal strategies for discovering pharmacological actives in plants.     

Performance characteristics of 10 home mechanical ventilators in pressure-support mode: a comparative bench study

OBJECTIVE: Inspiratory pressure (Pi) support delivered by a bilevel device has become the technique of choice for noninvasive home ventilation. Considerable progress has been made in the performance and functionality of these devices. The present bench study was designed to compare the various characteristics of 10 recently developed bilevel Pi devices under different conditions of respiratory mechanics. DESIGN: Bench model study. SETTING: Research laboratory, university hospital. MEASUREMENTS: Ventilators were connected to a lung model, the mechanics of which were set to normal, restrictive, and obstructive, that was driven by an ICU ventilator to mimic patient effort. Pressure support levels of 10 and 15 cm H(2)O, and maximum were tested, with "patient" inspiratory efforts of 5, 10, 15, 20, and 25 cm H(2)O. Tests were conducted in the absence and presence of leaks in the system. Trigger delay, trigger-associated inspiratory workload, pressurization capabilities, and cycling were analyzed. RESULTS: All devices had very short trigger delays and triggering workload. Pressurization capability varied widely among the machines, with some bilevel devices lagging behind when faced with a high inspiratory demand. Cycling was usually not synchronous with patient inspiratory time when the default settings were used, but was considerably improved by modifying cycling settings, when that option was available. CONCLUSIONS: A better knowledge of the technical performance of bilevel devices (ie, pressurization capabilities and cycling profile) may prove to be useful in choosing the machine that is best suited for a patient's respiratory mechanics and inspiratory demand. Clinical algorithms to help set cycling criteria for improving patient-ventilator synchrony and patient comfort should now be developed.     

Is there a close relationship between changes in amplitudes of distortion product otoacoustic emissions and hair cell damage after exposure to realistic industrial noise in guinea pigs?

In long-term experiments in awake guinea pigs (n=12), distortion product otoacoustic emissions (DPOAEs) at various frequencies were measured repeatedly over 6–8 months. About 9 weeks after the first measurement, the animals were exposed to industrial noise (car industry, maximal intensity about 110 dB SPL) for 2 h. The amplitudes of DPOAE were measured prior to noise exposure and 10 min, 70 min, 1 day and 2 days after the noise exposure and then once every week. Three to four months after noise exposure, the animals were killed, and the cochleae were prepared for scanning electron microscopy. The row of inner hair cells (IHCs) was complete in all animals, while the rows of outer hair cells (OHCs) showed a considerable hair cell loss in some of the animals without a correlation to the change in amplitudes of DPOAE. However, a closer relationship between the decline of amplitudes of DPOAE and the number of missing and changed OHCs (fused stereocilia bundles, missing tip links) could be established. The number of lost OHC does not reflect the decline in DPOAE in all cases. This discrepancy must be considered when the degree of hearing loss needs to be established from changed DPOAE.     

Characterization of two novel mutations of the antithrombin gene observed in Japanese thrombophilic patients

We investigated the molecular basis of reduced functional levels of antithrombin (AT) in two individuals suffering from thromboembolic events. In each case direct sequencing of amplified DNA revealed 13,260-13,262 del in one patient and 2511C>A in the other patient, predicting a heterozygous E381del and P16H, respectively. Both patients had no 20210A allele and factor V Leiden mutation. To understand the molecular mechanism responsible for antithrombin deficiency, stable expression experiments were performed using HEK293 cells transfected with the expression vector containing the wild-type or the mutated recombinant cDNA. In these experiments, the media levels of the two mutated antithrombins were the same as that of wild type, but the specific activity of the E381del mutant decreased significantly compared with that of wild type. These results showed that the E381del mutation was responsible for type II deficiency, whereas the other mutation, P16H, did not produce any definite abnormality which could contribute to antithrombin deficiency.