Effects of estrogen on autotomy in normal and ovariectomized rats.

Gonadal hormones may modulate analgesia responses induced by acute stress in humans and rats. To evaluate the effects of gonadal hormones in modifying neuropathic pain, we measured autotomy changes following sciatic nerve resection in ovariectomized rats and in the presence of estrogen replacement. Two groups of female rats were subjected to ovariectomy and sham surgery. Each group was then divided into two subgroups receiving subcutaneously sesame oil with or without estradiol benzoate (5 microg/day/rat). All rats then underwent sciatic nerve resection in one hindlimb. Degree of self-mutilation was measured daily for 8 weeks. Estradiol treatment resulted in significantly lower autotomy scores in ovariectomized rats (3.6 +/- 0.6 vs. 5.5 +/- 0.3, p < 0.01) and in sham-operated rats (3.4 +/- 0.7 vs. 5.1 +/- 0.4, p < 0.05). The results of this study indicate that estrogen can modify the autotomy behavior, an indicator of neuropathic pain, in rats after nerve injury.     

Inhibitory effect of triterpenes from Crataegus pinatifida on HIV-I protease.

The methanol extracts of the leaves of Crataegus pinnatifida showed potent inhibitory activities against HIV-1 protease at a concentration of 100 micrograms/ml. The subsequent fractionation and isolation of the extract gave two active compounds. Their structures were identified as uvaol (1) and ursolic acid (2) by spectral data. These active compounds inhibit HIV-1 protease with IC50 values of 5.5 and 8.0 microM, respectively.     

(-)-Epiafzelechin: cyclooxygenase-1 inhibitor and anti-inflammatory agent from aerial parts of Celastrus orbiculatus.

An inhibitor of cyclooxygenase (COX)-1 activity of prostaglandin H2 synthase was isolated from aerial parts of Celastrus orbiculatus Thunb. (Celastraceae), an oriental folk medicine for rheumatoid arthritis by activity-guided column chromatographic methods. The COX inhibitor was identified as (-)-epiafzelechin, a member of flavan-3-ols by the structural analysis with HR-EI-mass, 1H-NMR and 13C-NMR spectral data. The compound exhibited a dose-dependent inhibition on the COX activity with an IC50 value of 15 microM. (-)-Epiafzelechin exhibited about 3-fold weaker inhibitory potency on the enzyme activity than indomethacin as a positive control. (-)-Epiafzelechin exhibited significant anti-inflammatory activity on carrageenin-induced mouse paw edema when the compound (100 mg/kg) was orally administrated at 1 h before carrageenin treatment.     

An antioxidant lignan and other constituents from the root bark of Hibiscus syriacus

A new lignan named as hibiscuside, (+)-pinoresinol 4-O-[beta-glucopyranosyl (1--->2)-alpha-rhamnoside] (1), and a known lignan, syringaresinol (2) were isolated from the root bark of Hibiscus syriacus together with two feruloyltyramines (3,4) and three known isoflavonoids (5,6,7). The structures of these compounds have been established on the basis of their NMR, mass UV spectra. Among these phenolic compounds, 6"-O-acetyldaidzin (5), 6"-O-acetylgenistin (6), and 3-hydroxydaidzein (7) with IC(50) values of 8.2, 10.6, and 4.1 microM, respectively, significantly inhibited lipid peroxidation in rat liver microsomes. Hibiscuside (1), E- and Z-N-feruloyl tyramines (3,4) exhibited moderate antioxidant activity.     

Acyl-CoA:Cholesterol Acyltransferase Inhibitory Activity of Lignans Isolated from Schizandra, Machilus and Magnolia Species

Fifteen lignans were isolated from the fruits of SCHIZANDRA CHINENSIS, the leaves of MACHILUS THUNBERGII, and the flower buds of MAGNOLIA DENUDATA. They were identified as gomisins, schizandrin, wuweizisu, schizantherin, licarins, and machilin, which inhibited rat liver ACAT with IC (50) values of 25-200 microM. Comisin N is the most potent inhibitor with IC (50) value of 25 microM in these lignans.     

Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence

Rationale: Tolerance to abused drugs may impact on patterns of abuse, and in the case of agonist therapies, may be beneficial in that it reduces the reward value of a given dose of abused drug. Cocaethylene, a psychoactive metabolite resulting from concurrent alcohol and cocaine consumption, was examined because of its use in human research studies of drug reward mechanisms, and its potential as a model compound for an agonist based therapy for cocaine dependence. Objective: Comparisons were made between cocaine and cocaethylene in the acute development of tolerance to the neurochemical and behavioral effects of cocaine. With chronic exposure, tolerance to the behavioral effects of cocaine was examined. Methods: In awake rats with a microdialysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3-h infusion of cocaine or cocaethylene and a subsequent cocaine challenge was administered while extracellular dopamine and locomotion were monitored. Chronic IV treatment with cocaine, cocaethylene, and a water control was accomplished for 7 days using osmotic minipumps attached to jugular catheters. Animals were then challenged with an IV bolus of cocaine. Results: With acute treatment, the IV bolus of cocaethylene at the beginning of the infusion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extracellular concentration of dopamine. However, after that initial increase, levels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A 1-week infusion of cocaine or cocaethylene resulted in tolerance to the behavioral activating effects of a subsequent cocaine challenge. Conclusions: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both acutely, and after 7 days. The relevance of these data for the use of cocaethylene as a model compound for an agonist approach to therapy for cocaine dependence is discussed. Received: 22 January 1999 / Final version: 16 April 1999     

Menadione-induced vascular endothelial dysfunction and its possible significance

Although several studies have shown that treatment with menadione leads to endothelial cell cytotoxicity, investigations of menadione's effects on blood vessels are limited. Our previous studies have shown that menadione can indirectly induce alterations in vasomotor tone through platelet cytotoxicity. To determine if menadione affects vascular function, we investigated the effect of menadione on blood vessels using the isolated rat aortic rings in vitro organ bath system. Treatment with menadione directly resulted in contraction of aortic rings with endothelium but did not cause any effect on aortic rings without endothelium. Menadione irreversibly inhibited the acetylcholine- and histamine-induced relaxation of aortic rings with endothelium in a time- and concentration-dependent manner. Menadione treatment potentiated phenylephrine- and serotonin-induced vasoconstriction in aortic rings with endothelium. These in vitro results were observed at concentrations of menadione that are highly relevant to human therapeutics with menadione. When menadione was administrated intravenously to rats, blood pressure increased significantly in a concentration-dependent manner. Furthermore, menadione infusion suppressed the blood pressure reduction induced by acetylcholine. By demonstrating that menadione caused in vitro endothelial dysfunction (i.e., decreased relaxation and increased vasoconstriction in the organ bath experiments) and confirming that these results were consistent with in vivo observations, we have provided evidence suggesting that a quinone such as menadione can alter vasomotor tone through endothelial dysfunction. Such dysfunction could possibly contribute to vascular diseases.     

Pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) to patients with peritoneal carcinomatosis

The pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) was characterized in patients with peritoneal carcinomatosis. Cisplatin was added into the perfusate with escalating doses from 100 mg/m2 to 400 mg/m2. The hyperthermic perfusion was maintained for 90 minutes with a flow rate of 1.5 L/min and a target peritoneal temperature of 42.5 degrees C after a tumor debulking procedure. Samples of both the perfusate and blood were obtained during the perfusion and 30 minutes after the perfusion. Cisplatin plasma and perfusate concentrations were determined by flameless atomic absorption spectrometry with a lower limit of detection of 2 ng/ml and a coefficient of variation (CV) < 10%. Fifty-six patients were enrolled in the study. The mean (+/- SD) percentage of cisplatin present in the perfusate at the completion of perfusion was 27.8% +/- 20% of the total dose. The maximum cisplatin concentrations in the perfusate were 10 times higher than those in plasma. The area under the concentration-time curve (AUC) of the perfusate was 13 times higher than the AUC of plasma. A two-compartment model with an additional peritoneal cavity compartment fits to the data best based on the Akaike information criterion. However, the interpatient variability was considerably high (CV < 100%). In conclusion, cisplatin administered by hyperthermic peritoneal perfusion resulted in a pharmacological advantage by obtaining higher and direct drug exposure to the tumor in the peritoneal cavity while limiting systemic absorption and toxicity. Using a complex two-compartment model, the authors were able to characterize the pharmacokinetics of cisplatin given intraperitoneally via this technique.     

Employee drinking practices and work performance

OBJECTIVE: The purpose of this study was to examine the independent effects of a variety of drinking indicators on self-reported work performance. METHOD: Data from a cross-sectional mailed survey (response rate = 71%) of managers, supervisors and workers (N = 6,540) at 16 worksites were analyzed. Average daily volume was computed from frequency and usual quantity reports. Drinking on the job included drinking during any of six workday situations. The CAGE was used to indicate alcohol dependence. Employees were also asked how frequently they drank to get high or drunk. Work performance was measured through a series of questions about work problems during the prior year. The number of times respondents experienced work performance problems was regressed on the four drinking measures, and a variety of demographic characteristics, job characteristics and life circumstances that might also negatively affect work performance. RESULTS: The frequency of self-reported work performance problems increased, generally, with all four drinking measures. In a multivariate model that controlled for a number of demographics, job characteristics and life-situations, average daily volume was no longer significantly associated with work performance but the other three drinking measures were. Interestingly, although moderate-heavy and heavy drinkers reported more work performance problems than very light, light, or moderate drinkers, the lower-level-drinking employees, since they were more plentiful, accounted for a larger proportion of work performance problems than did the heavier drinking groups. CONCLUSIONS: Employers should develop clear policies limiting drinking on the job and, in addition to employee assistance programs for problem drinkers, should develop worksite educational interventions aimed at informing all employees about the relationship between drinking behaviors and work performance.     

Stability, blood partition and plasma protein binding of ipriflavone, an isoflavone derivative

It is generally recognized that the partition between plasma and blood cells, the immediate centrifugation of blood samples after collection for the measurement of 'true' in vivo concentrations and free drug concentrations in plasma are important determinants of the pharmacokinetics and/or pharmacodynamics of drugs. Therefore, the stability, blood partition between plasma and blood cells, and factors influencing the binding of ipriflavone to 4% human serum albumin (HSA) using an equilibrium dialysis technique were evaluated. Ipriflavone was unstable in rat liver homogenate and various pH solutions ranging from 1 to 13, except pH 8, rat blood and plasma and human plasma when incubated in a water-bath shaker for 24 h kept at 37 degrees C and at a rate of 50 oscillations/min. The recoveries of spiked amounts of ipriflavone at 24 h pH solutions ranging from 1 to 12 were 67.0, 78.1, 87.9, 89.6, 84.2, 87.4, 85.5, 99.3, 88.0, 76. 6, 79.4 and 81.5%, respectively. Ipriflavone was very unstable in pH 13 solution; only 0.814% of ipriflavone was recovered after 30 min incubation. Ipriflavone was stable for up to 3 h incubation in human gastric juices. Ipriflavone reached equilibrium fast (within 30 s of being mixed manually) between plasma and blood cells and the equilibrium plasma/blood cells partition ratios were independent of the initial rabbit blood concentrations of ipriflavone: 0.2, 2, and 10 microg/mL; the values were in the range of 0.900-2.45. The binding of ipriflavone to 4% HSA was 96.6+/-0.407% at ipriflavone concentrations ranging from 2 to 100 microg/mL, but it was dependent on HSA concentrations (0.5-6%), incubation temperature (4, 22 and 37 degrees C), 'the buffer' pHs (5.8, 6.4, 7.0, 7.4 and 8.0), and addition of salicylic acid (150-300 microg/mL) and sulphisoxazole (100-300 microg/mL). However, the binding was independent of buffers containing various concentrations of chloride ion (0-0.546%), glucose (0 and 5%), alpha-1-acid glycoprotein (0-0.32%) and heparin (0-40 U/mL), and addition of its metabolites (M1 and M5, 5 microg/mL).