Enteric glial cell activation protects enteric neurons from damage due to diabetes in part via the promotion of neurotrophic factor release.

BACKGROUND: Diabetes can result in pathological changes to enteric nervous system. Our aim was to test the dynamic changes of enteric neurons and identify the role of enteric glial cells (EGCs) in regulating enteric neuron expression in diabetic rats. METHODS: A single injection of streptozotocin (STZ) was used to establish diabetic rats. Animals were randomly distributed into diabetic 1-, 4-, 8-, and 16-week groups, as well as age-matched control groups. The PGP9.5- and glial fibrillary acidic protein (GFAP)-immunopositive cells were quantified by immunohistochemistry. The protein levels of PGP9.5, ChAT, nNOS, S-100ß, and c-fos were determined by western blotting. The levels of nerve growth factor (NGF), neurotrophin 3 (NT-3), and glial cell-derived neurotrophic factor (GDNF) were tested by ELISA. KEY RESULTS: An increase in blood glucose and a decrease in body weight were observed following STZ administration. PGP9.5 expression did not change in the diabetic ileum. However, ChAT increased after 16 weeks, and nNOS decreased after 8 and 16 weeks in the ilea of diabetic rats. The absence of degeneration of enteric neurons during the acute stage of the disease could be the consequence of the up-regulation of GFAP, S-100ß, and c-fos. Moreover, the content of NGF, NT-3, and GDNF in the ileum increased by varying degrees after 1 and/or 4 weeks of diabetes. Using 2 co-culture models of EGCs and SH-SY5Y cells in a high glucose condition, the supportive role of EGCs was further confirmed. CONCLUSIONS & INFERENCES: Enteric glial cell activation can protect enteric neurons from damage due to diabetes in the acute stage of the disease, in part via the promotion of neurotrophin release.

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients.

WHAT IS KNOWN AND OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is a life-saving system used for critically ill patients with cardiac and/or respiratory failure. The pharmacokinetics (PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO. METHODS: A literature search was conducted using the PubMed and EMBASE databases with the following keywords: "extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO" and "PK OR pharmacokinetics OR pharmacokinetic*" and "anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*." RESULTS AND DISCUSSION: Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin-tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher-than-standard dose was used in patients treated with ECMO. Additionally, voriconazole exhibited high mean peak concentrations during ECMO. WHAT IS NEW AND CONCLUSION: The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that contribute to PK changes for each drug. Finally, it is important to develop dosing guidelines based on PK/PD modelling studies that can be used in clinical practice.

Effect of ketogenic diet and other dietary therapies on anti-epileptic drug concentrations in patients with epilepsy.

WHAT IS KNOWN AND OBJECTIVE: The ketogenic diet (KD) is an effective high-fat, adequate-protein, low-carbohydrate diet for patients with refractory epilepsy. The aim of this study was to investigate the potential effects of the KD and other dietary therapies on the concentrations of anticonvulsants in patients with epilepsy. METHODS: Patients with epilepsy who were treated with the KD and other dietary therapies for more than 30 days with at least one measurement performed both before and during the diet were evaluated. The mean serum concentrations and the mean serum concentrations per weight per daily dose per bioavailability (F) of anti-epileptic drugs (AEDs) before and during the treatment were assessed. We also compared the rates of events out of reference ranges of the AEDs between before and during the KD and other dietary therapies. We compared the serum albumin, alanine transaminase and aspartate transaminase data of patients with valproic acid before and during the KD. RESULTS AND DISCUSSION: One-hundred thirty-nine patients including 81 male patients were enrolled. The median age of the patients was 2.91 (0.15-15.46) years. The median duration of the dietary therapies was 153 (35-2307) days. After the dietary therapies, the serum concentrations of carbamazepine, lamotrigine, levetiracetam, topiramate and valproic acid decreased, whereas that of phenobarbital slightly increased. However, statistical significance was found only with valproic acid (67.07±25.89 µg/mL vs 51.00±20.19 µg/mL, P<.05). The serum concentrations per weight per daily dose per drug F significantly decreased for valproic acid (1.38±1.39×10-2 vs 0.82±0.82×10-2  µg d mL-1  F-1 ) and phenobarbital (6.66±7.20×10-2 vs 4.75±4.07×10-2  µg d mL-1  F-1 , P<.05). The rate of occurrence of events out of reference ranges significantly increased with valproic acid (36.08% vs 57.23%, P<.05). WHAT IS NEW AND CONCLUSIONS: Most anti-epileptic drug serum concentrations remained stable during the KD and other related dietary therapies except those of valproic acid. Therefore, serum concentrations of valproic acid should be monitored when the KD and other dietary therapies are concomitantly administered.

Chronopharmacology of analgesic effect and tolerance induced by six narcotic analgesics in mice.

Narcotic analgesics, especially morphine, exert significantly different effects depending on the time within one day. The objective of this study was to observe whether the dosing time of 6 narcotic analgesics in mice affected their efficacy, pain tolerance and recovery of tolerance. The chronopharmacology of these 6 narcotics was evaluated using a hot-plate model. Maximum possible effect (MPE) of morphine showed a significant 24 h rhythm, which was higher during the dark phase and lower during the light phase (P<0.05). Conversely, MPEs of fentanyl and bucinnazine groups during the light phase exceeded those during the dark phase (P<0.05). Pain tolerance developed after drug administration at 9:00 am or 9:00 pm for 5 days, of which bucinnazine produced lower tolerance at 9:00 am. After a 2-day washout period, the mice rapidly recovered from tolerance at 3:00 pm for 5-day morphine dosing at 9:00 pm, and for fentanyl dosing at 9:00 am. Not all narcotic analgesics displayed significant circadian variations, and the dosing time-dependent effects also depended on the types of narcotics. Therefore, the time of administration is crucial in clinical pain treatment. Chronotherapy may be more effective to relieve pain while reducing side effects.

Optimizing EEMCO guidance for the assessment of dry skin (xerosis) for pharmacies.

PURPOSE: People with dry skin (xerosis) are common in community pharmacies, but there is no consistent guidance for community pharmacists to evaluate and alleviate dry skin. Through evaluating any difference of the clinical scoring systems of EEMCO guidance between a dermatologist and pharmacists and the efficacy of moisturizers for the treatment of dry skin recommended by community pharmacists, we aim to validate a dry skin guidance through the help of community pharmacists. These results provide insight into how community pharmacists can help patients with dry skin. METHODS: The clinical scoring systems of EEMCO guidance used in this study comprised analog scales, the overall dry skin score (ODS), and the specific symptom sum score (SRRC) system. All pictures of the dry skin scored by pharmacists were visually evaluated by a dermatologist. The efficacy of the moisturizers was determined by the difference of the scales on day 0 and on day 28. RESULTS: In this study, 387 patients with dry skin from 157 community pharmacies were evaluated by pharmacists. Visual scale with divisions, ODS and SRRC that were evaluated by pharmacists on day 0 and day 28 were moderately reliable by a dermatologist. All parameters of dry skin were significantly improved by the moisturizers which were recommended by community pharmacists on day 28. CONCLUSION: Visual scale, ODS and SRRC can be generally measured to evaluate dry skin in community pharmacies with moderate degree of reliability. This finding has possible applications for investigating the assessment of the community pharmacists on clinical scoring system of dry skin and moisturizers.

Comparative pharmacokinetics and bioequivalence of two 50 mg atenolol tablet formulations in healthy Korean male volunteers.

Atenolol is a selective ß1 receptor antagonist that is available as a racemic mixture. The objective of this study was to compare the pharmacokinetics and evaluate the bioequivalence of 50 mg atenolol test and reference formulations in 24 healthy Korean male volunteers.This study was a single-dose, randomized, open-label, 2 period crossover study. 24 healthy Korean male volunteers randomly received 50 mg of either test or reference atenolol formulations in a 2×2 crossover study. There was a 1 week washout period between doses. The area under the curve (AUC)0-24 h and Cmax of 50 mg atenolol were the primary criteria for evaluation of bioequivalence.The mean ± standard deviation (SD) values of the Cmax, Tmax, AUC0-24 h, AUC0-∞, ke, and t1/2 of the test and reference formulations were 268.4 (78.96) and 256.9 (79.34), 2.750 (0.9555) and 3.104 (1.053), 1 981 (729.2) and 1 872 (604.8), 2228 (697.1) and 2 187 (628.5), 0.1332 (0.02748) and 0.1421 (0.04223), 5.419 (1.110) and 5.442 (2.357), respectively. The 90% confidence intervals for AUC0-24 h and Cmax were 0.9037-1.166 and 0.9169-1.1987, respectively. These results were within the accepted bioequivalence range of 0.80-1.25, which satisfied the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. In conclusion, the findings of this study indicate that the 2 formulations of 50 mg atenolol that were tested are bioequivalent. Therefore, these formulations may be prescribed interchangeably.

Quercetin induced tissue-type plasminogen activator expression is mediated through Sp1 and p38 mitogen-activated protein kinase in human endothelial cells.

BACKGROUND: Wine polyphenol quercetin upregulates tissue-type plasminogen activator (t-PA) transcription in cultured human umbilical cord vein endothelial cells (HUVECs). However, the regulatory elements and signaling pathways involved in this regulation are unknown. OBJECTIVES: We aimed to localize quercetin-responsive t-PA promoter elements, identify the proteins that bind these elements, and decipher signaling pathways involved in the regulation of t-PA. METHODS: To localize quercetin-responsive elements, HUVECs were transiently transfected with various t-PA promoter-reporter constructs. Element functionality was evaluated by mutational analysis. Nuclear protein-t-PA element interactions were evaluated by electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) analysis. Mitogen-activated protein kinase (MAPK) inhibitors were used to determine the signaling pathways involved in t-PA regulation. MAPK inhibition effects were evaluated by real-time PCR, immunoblotting analysis, and transfections. Coimmunoprecipitation was used to evaluate MAPK and transcription factor interaction. RESULTS: Deletion of the t-PA promoter region - 288 to - 250 resulted in loss of quercetin responsiveness. This region contains putative Sp1-binding elements, which we termed Sp1a and Sp1b. Sp1b mutation abolished the quercetin-inducible response, whereas Sp1a mutation had no effect. EMSA and ChIP analysis demonstrated quercetin-enhanced Sp1 binding to Sp1b. Inhibition of p38 MAPK abrogated basal and quercetin-induced t-PA expression and promoter activity, as well as quercetin-induced Sp1 binding to Sp1b. Quercetin enhanced p38 MAPK and Sp1 physical association, which was similarly diminished by p38 MAPK inhibition. CONCLUSIONS: We showed, for the first time, the presence of a functional Sp1-binding element in the t-PA promoter controlling quercetin induction via the p38 MAPK pathway. Understanding these mechanisms may provide new insights into polyphenol cardioprotective effects.

Effects of Panax ginseng extract on exercise-induced oxidative stress.

AIM: This study was designed to study the effects of Panax ginseng extract (PGE) on lipid peroxidation and scavenger enzymes induced by an acute exhaustive exercise in sedentary humans. METHODS: Seven healthy male subjects performed 2 exhaustive incremental exercises on the treadmill before and after 8 weeks' PGE ingestion (2 g each time, 3 times a day) as the control and PGE exercise, respectively. VO2, HR, and exercise duration during exercise were measured. Blood samples were collected at rest, and immediately, 10 and 30 min after each test and used to measure malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD). RESULTS: PGE administration significantly increased exercise duration until exhaustion by 1.5 min (p<0.05). MDA was significantly elevated following both trials (p<0.01), however, it was attenuated after PGE administration (p<0.01). CAT and SOD activities following exercise were significantly elevated, but the activities following control exercise were much lower than those following PGE exercise. CONCLUSIONS: These results suggest that the elevation in CAT and SOD activities as scavenger enzymes after PGE administration result in decrease of MDA level as one of PGE action mechanisms and consequently, prolong exercise duration until exhaustion. These findings support scientific claims that ginseng has ergogenic properties in facilitating recovery from exhaustive exercise.

Abnormal liver function associated with occupational exposure to dimethylformamide and glutathione S-transferase polymorphisms.

Dimethylformaide (DMF) is a major solvent predominately used in synthetic leather and resin production. Many human and animal studies have linked the cause of hepatoxicity to DMF. Previously, the authors demonstrated the significant dose-response relationship between abnormal liver function tests and DMF exposure and the interaction with hepatitis B virus (HBV) infection in Taiwanese workers. Because the toxic effect of various chemicals can be modified by metabolic traits, the study also investigated the influence of the glutathione S-transferases (GSTM1 and GSTT1) on the toxic effect of DMF. The average DMF exposure concentration was 23.87 ppm (range 5.2-86.6 ppm) in the high-exposure (>/=5 ppm) group and 2.41 ppm (range 0.9-4.3 ppm) in the low-exposure (<5 ppm) group. There were 13 of 44 (29.6%) abnormal liver function tests (elevations of either glutamate oxaloacetate transaminase (GOT) or glutamate pyruvate transaminase (GPT)) among the high DMF exposure workers, two of 22 (9.1%) abnormal liver function tests among the low DMF exposure workers. Chronic liver disease as determined by ultrasonography was present in seven of 44 (15.9%) high DMF exposure workers, and 0 of 22 (0%) low DMF exposure workers. There were 11 of 34 (32.4%) abnormal liver function tests among the GSTT1 null genotype workers, and four of 32 (12.5%) abnormal liver function tests among the GSTT1-positive genotype workers. Compared with the low DMF exposure workers, the adjusted odds ratio and 95% confidence intervals for abnormal liver function tests was 6.78 (0.94-48.7) for the high DMF exposure workers. Compared with the GSTT1-positive genotype workers, the adjusted odds ratio and 95% confidence intervals for abnormal liver function tests was 4.41 (1.15-16.9) for the GSTT1 null genotype workers. Compared with the low DMF group with GSTT1-positive genotype workers, the odds ratio (adjusted for HBV status) of abnormal liver function test was 12.38, 95% CI=(1.04-146.9) for the high DMF group with GSTT1 null genotype workers. This study indicates that abnormal liver function and chronic liver disease are associated with DMF exposure, and there are more than multiplicative interaction effects on abnormal liver function tests between the DMF exposure and the GSTT1 genotype.

Biological monitoring of environment exposure to safrole and the Taiwanese betel quid chewing.

A rapid and sensitive biological monitoring (BM) method for assessing exposure to the environmental carcinogen safrole has been developed. The method is an isocratic high-performance liquid chromatographic (HPLC) analysis of urinary dihydroxychavicol (DHAB) and eugenol, the urinary metabolites of safrole. Good linearity, precision, and accuracy were demonstrated. A recovery of 98.8 +/- 5.4% (SD, n = 3) was found for DHAB and 84.1 +/- 3.4% (n = 3) for eugenol. The quantitation limits of the method were 8 ng for DHAB and 10 ng for eugenol. The validity of the method was demonstrated by a linear dose-response relationship observed in rats given oral doses of safrole at 30, 75, and 150 mg/kg body weight. The method was also used to monitor the environmental exposure to the Taiwanese betel quid (TBQ) chewing, because TBQ used in Taiwan not only contains areca (betel) nut, slaked lime, and catechu but also Piper betle inflorescence or its leaves. Both of the latter have a high content of safrole. The feasibility of the method to monitor TBQ chewing was demonstrated by an analysis of 153 spot human urine samples. The results showed that the p value of the nonparametric group comparison was < 0.001 for DHAB and 0.832 for eugenol. The TBQ chewers also exhibited a significantly higher rate of urinary DHAB (but not eugenol) than the nonchewers with an odd ratio of 3.47 (95% CI, 1.61-7.51). However, when only the eugenol-positive subjects were taken into analysis, the ratio rose to 24.38 (95% CI, 3.00-197.90).

Slurry sampling for the determination of arsenic, cadmium, and lead in mainstream cigarette smoke condensate by graphite furnace-atomic absorption spectrometry and inductively coupled plasma-mass spectrometry.

The slurry sampling technique has been applied for the determination of As, Cd, and Pb in mainstream cigarette smoke condensate (MS CSC) by graphite furnace-atomic absorption spectrometry (GF-AAS) and inductively coupled plasma-mass spectrometry (ICP-MS). The MS CSC of the 1R4F Reference Cigarette was collected by electrostatic precipitation and was subsequently prepared as two slurry samples with and without the dispersing agent Triton X-100. Comparison of results determined by ICP-MS analyses of the 1R4F MS CSC slurry samples with those from the conventional microwave digestion method revealed good agreement. The precision of Triton X-100 slurry sampling and of microwave-assisted digestion was better than 10% RSD, and both were superior to slurry sampling without use of Triton X-100. The accuracy of the analytical results for the Triton X-100 slurry sample was further verified by graphite furnace-atomic absorption spectrometry (GF-AAS). For GF-AAS, the method limits of detection are 1.6, 0.04, and 0.5 microg x L(-1) for As, Cd, and Pb, respectively. For ICP-MS, the method limits of detection are 0.06, 0.01, and 0.38 microg x L(-1) for As, Cd, and Pb, respectively. The MS CSC of the 1R4F Reference Cigarette was collected in accordance with the Federal Trade Commission (FTC) smoking regime (35 mL puff volume of 2-s puff duration at an interval of 60 s) and the concentrations of As, Cd and Pb were 6.0+/-0.5, 69.3+/-2.8, and 42.0+/-2.1 ng/cigarette, respectively.

Decreased white blood cell counts in semiconductor manufacturing workers in Taiwan.

OBJECTIVES: To assess the systematic health effects on the liver, kidney, and haematological function tests of workers in semiconductors in Taiwan. METHODS: 926 workers of a semiconductor plant in Taiwan in July 1995 were investigated. Complete blood tests including liver, kidney, and haematological functions were available from 227 workers. RESULTS: There was a significantly lower mean (SD) white blood cell (WBC) count in male workers of photolithography (5870 (1190)/mm(3), p=0.003) and implantation (6190 (1150)/mm(3), p=0.018) than that of male control workers (7350 (1660)/mm(3)). There was a significantly higher prevalence of leukopenia in male photolithography workers (6 of 20; 30%) than in male control workers (1 of 18; 5.6%), the crude odds ratio (OR) was 7.3 (95% confidence interval (95% CI) 1 to 55.6), and the multivariate adjusted OR was 8.1 (95% CI 0.83 to 78.3). The tests for serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma glutamyl transferase (RGT), and creatinine were not significant among male workers. Female workers in photolithography had abnormal SGPT and RGT of borderline significance, the multivariate adjusted ORs were 9.6 (95% CI 0.86 to 107) and 6.35 (95% CI 0.53 to 75.8), respectively. CONCLUSIONS: This study suggests that leukopenia is a potential health effect in male fabrication workers of the semiconductor industry. The tasks of the process, maintenance, and equipment engineers which consisted mostly of men put them at risk for intermittent short term peak exposure to glycol ethers, ionising radiation, arsenic, or other toxins. The findings of this medical surveillance are significant; however, a further investigation of the aetiological factors and the subsequent health effects is necessary.

Effects of bergenin, the major constituent of Mallotus japonicus against D-galactosamine-induced hepatotoxicity in rats.

The hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus, were evaluated against D-galactosamine (GalN)-induced liver damage in rats. Bergenin (50, 100 and 200 mg/kg) was given orally once daily for 7 successive days and then GalN 400 mg/kg was injected intraperitoneally to rats at 24 and 96 h after the final administration of bergenin. Pretreatment with bergenin reduced the increased enzyme activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase, gamma-glutamyltransferase and the elevated level of malondialdehyde induced by GalN. Bergenin restored the decreased hepatic contents of glutathione as well as the decreased activities of glutathione S-transferase and glutathione reductase by GalN towards normalization, suggesting that the hepatoprotective effects of bergenin may consist in maintaining adequate levels of hepatic glutathione for the removal of xenobiotics. The present results indicate that bergenin has hepatoprotective effects against GalN-induced hepatotoxicity in rats.

Protective effects of acetylbergenin against carbon tetrachloride-induced hepatotoxicity in rats.

The present study was undertaken to investigate whether or not the hepatoprotective activity of acetylbergenin was superior to bergenin in carbon tetrachloride (CCl4)-intoxicated rat. Acetylbergenin was synthesized by acetylating bergenin, which was isolated from Mallotus japonicus. The hepatoprotective effects of acetylbergenin were examined against CCl4-induced liver damage in rats by means of serum and liver biochemical indices. Acetylbergenin was administered orally once daily for 7 successive days, then a 0.5 ml/kg mixture of CCl4 in olive oil (1:1) was intraperitoneally injected at 12 h and 36 h after the final administration of acetylbergenin. Pretreatment with acetylbergenin reduced the elevated serum enzymatic activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and gamma-glutamyltransferase in a dose dependent fashion. Acetylbergenin also prevented the elevation of hepatic malondialdehyde formation and depletion of glutathione content dose dependently in CCl4-intoxicated rats. In addition, the decreased activities of glutathione S-transferase and glutathione reductase were restored to almost normal levels. The results of this study strongly suggest that acetylbergenin has potent hepatoprotective activity against CCl4-induced hepatic damage in rats by glutathione-mediated detoxification as well as having free radical scavenging activity. In addition, acetylbergenin doses of 50 mg/kg showed almost the same levels of hepatoprotective activity as 100 mg/kg of bergenin, indicating that lipophilic acetylbergenin is more active against the antihepatotoxic effects of CCl4 than those of the much less lipophilic bergenin.

Abnormal liver function associated with occupational exposure to dimethylformamide and hepatitis B virus.

N,N-Dimethylformamide (DMF) has excellent solvent properties and is used intensively in the production of synthetic leather and resins. It has caused hepatoxicity in human and animal studies. Hepatitis B virus (HBV) and hepatitis C virus infections are reported to be the major causes of chronic liver diseases (including liver cirrhosis and liver cancer) in Taiwan. This study examined the dose-response relationship of the observed abnormal liver function among the DMF-exposed workers and the interactions among DMF, other chemical exposures, HBV infection, and potential confounders on liver abnormalities. The average DMF exposure concentration was 11.6 ppm (median, 5.9 ppm; range, 0.1 to 86.6 ppm); 65 of 176 workers (36.9%) had high (> 10 ppm) DMF exposure, 37 (21%) had middle (> 5 ppm, < or = 10 ppm) exposure, and 74 (42%) had low (< or = 5 ppm) exposure. There were 24 of 65 abnormal liver function test results (LFTs) (36.9%) (elevations of either glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, or gamma-glutamyl transpeptidase) among the workers with high DMF exposure, 10 of 37 abnormal LFTs (27%) among workers with middle DMF exposure, and 11 of 74 abnormal LFTs (22%) among workers with low DMF exposure. Compared with the workers having low DMF exposure, the HBV, drinking, body mass index (BMI), sex, duration of employment, epichlorohydrin, and toluene exposure adjusted odds ratios (ORs) (and 95% confidence intervals [CIs]) for abnormal LFTs were 1.62 (0.61, 4.28) for workers with middle DMF exposure and 2.93 (1.27, 6.8) for those with high DMF exposure, and there was a significant dose response between DMF exposure and the prevalence of abnormal LFTs (P = 0.006). There were significant associations between abnormal LFTs and HBV carriers (adjusted OR: 3.11; 95% CI: 1.29, 7.5; P = 0.01) and between abnormal LFTs and increased BMI (adjusted OR: 2.2; 95% CI: 1.02, 4.72; P = 0.041). Ultrasonography showed significant associations between chronic liver diseases and HBV carrier status, increased BMI, and high cumulative (> 100 ppm-years) DMF exposure (respectively, adjusted OR: 9.58, 95% CI: 1.79, 51.4, P = 0.007; adjusted OR: 13.2, 95% CI: 1.32, 132, P = 0.025; and adjusted OR: 6.2, 95% CI: 1.14, 34.1, P = 0.032). Drinking and BMI were significantly associated with fatty liver (respectively, adjusted OR: 4.9, 95% CI: 1.39, 17.3, P = 0.012; and adjusted OR: 7.93, 95% CI: 1.6, 39.3, P = 0.01). In conclusion, this study demonstrated that (1) a significant dose-response relationship existed between liver function abnormalities and DMF exposure among workers in Taiwan, (2) HBV carrier status or increased BMI had synergistic effects with DMF in causing liver abnormalities (abnormal LFTs and clinical chronic liver diseases).

Effects of acetylbergenin against D -galactosamine-induced hepatotoxicity in rats.

The hepatoprotective effects of acetylbergenin were examined against D -galactosamine (GalN)-induced liver damage in rats, compared with that of bergenin reported previously. Acetylbergenin was synthesized from acetylation of bergenin, isolated from Mallotus japonicus, to increase lipophilic and physiological activities. Acetylbergenin was administered orally once daily for 7 days and then GalN (400 mg kg(-1), i.p.) was injected at 24 h and 96 h after the final administration of acetylbergenin. Acetylbergenin reduced the elevated serum enzyme activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase and gamma -glutamyltransferase and the formation of hepatic malondialdehyde induced by GalN. Acetylbergenin also significantly restored towards normalization the decreased levels of glutathione and the decreased activities of glutathione S-transferase and glutathione reductase induced by GalN. Therefore, these results suggest that acetylbergenin has hepatoprotective effects against GalN-induced hepatotoxicity by inhibiting lipid peroxidation and maintaining an adequate level of GSH for the detoxification of xenobiotics as underlying hepatoprotective mechanisms. In addition, lipophilic acetylbergenin showed more activity in the hepatoprotection than that of the much less lipophilic bergenin reported previously.

Dimethylacetamide, ethylenediamine, and diphenylmethane diisocyanate poisoning manifest as acute psychosis and pulmonary edema: treatment with hemoperfusion.

CASE REPORT: A 27-year-old man, employed by a synthetic fiber company, had been exposed to dimethylacetamide, ethylenediamine, and diphenylmethane diisocyanate in a confined space continuously for 4-6 hours per day for 3 days before admission. Hallucinations and delusions were noted at admission; pulmonary edema developed subsequently. The electroencephalogram showed diffuse moderate cortical dysfunction and slow waves at 4-7 Hz, 20-80 microV. Seizures, liver injury, and rhabdomyolysis were noted on the 4th hospital day. The patient was treated by hemoperfusion with a decrease in urine dimethylacetamide from 3,265 mg/g to 4 mg/g creatinine over 4 days. Serial urinary dimethylacetamide and electroencephalogram correlated with the clinical condition.

N-Methyl-D-aspartate receptor antagonists enhance the head-twitch response, a 5-hydroxytryptamine2 receptor-mediated behaviour, in reserpine-treated mice.

In this study, N-methyl-D-aspartate (NMDA)-receptor antagonists enhanced the head-twitch response induced by 5-hydroxytryptamine (5-HT) in reserpine-treated mice. To minimize the risk of any indirect involvement of NMDA-receptor antagonists (D(-)-2-amino-5-phosphonopentanoic acid (AP-5), D(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP), (+)-5-methyl-10,11-dihydroxy-5H-dibenzo-[a,d]-cyclohepten-5,10-imi ne (MK-801), ketamine, dextrorphan and dextromethorphan) with 5-HT neurones, vesicle stores of monoamines, especially 5-HT, were depleted with reserpine. In addition, the enhancement of 5-HT-induced head-twitch response was inhibited by apomorphine and NMDA as well as ritanserin in reserpine-treated mice. These results support our previous conclusion that NMDA receptors play important roles in the glutamatergic modulation of 5-HTergic function at the postsynaptic 5-HT2 receptors in mice.

The antihypertensive and cardioprotective effects of (-)-MJ-451, an ATP-sensitive K(+) channel opener.

ATP-sensitive K(+) (K(ATP)) channel openers have been shown to be a potential class of therapeutic agents for the control of cardiovascular diseases, including angina, arrhythmias, and hypertension. In this study, the pharmacological activity of 6-cyano-3S,4R-dihydro-2, 2-dimethyl-2H-3-hydroxy-4-[5S-(1-hydroxymethyl)-2-oxo-1-pyrrolidinyl] -1-benzopyran ((-)-MJ-451), a synthetic K(ATP) opener, was evaluated in anesthetized rat models and in isolated rat thoracic rings. Results demonstrated that intravascular injection of (-)-MJ-451 (0. 02, 0.05 and 0.1 mg/kg) produced an immediate, dose-related reduction in mean arterial blood pressure in anesthetized spontaneously hypertensive rats (SHR), which persisted for more than 3 h and was not accompanied by reflex tachycardia. The hemodynamic changes were completely abolished by pretreatment with glibenclamide (4 mg/kg, i.v. bolus), a selective K(ATP) channel blocker. In isolated thoracic aorta, (-)-MJ-451 (10 nM-3 microM) produced a concentration-dependent vasodilator effect on the phenylephrine (0.3 microM)-induced vasoconstriction. Moreover, (-)-MJ-451 relaxed the thoracic aorta contracted by low (5, 20 and 30 mM), but not high (40 and 60 mM) concentrations of extracellular potassium. In addition, (-)-MJ-451 showed cardioprotective effects in the rat model of 45-min left coronary artery occlusion followed by 1-h reperfusion. In myocardial ischemia, pretreatment with (-)-MJ-451 (2, 5 and 10 microg/kg, i.v. bolus) significantly reduced the incidence of ventricular fibrillation and the mortality, also reducing the total number of ventricular premature contractions, total duration of ventricular tachycardia and ventricular fibrillation. A significant reduction in infarct size was noted in three (-)-MJ-451 (2, 5 and 10 microg/kg)-treated groups. Also, the cardioprotective effects of (-)-MJ-451 were virtually abolished by pretreating the rats with glibenclamide (4 mg/kg, i.v. bolus). In conclusion, (-)-MJ-451, through opening the K(ATP) channel, exerted antihypertensive and cardioprotective effects. Therefore, it is suggested that (-)-MJ-451 has potential in the treatment of hypertension or acute myocardial infarction.