Biomedical subjects

M Chang

Publications and source records attributed to M Chang.

At least 73 records · Page 4Linked to original sources

PubMed1999

Indoor air quality investigations at five classrooms.

Five classrooms, air-conditioned or naturally ventilated, at five different schools were chosen for comparison of indoor and outdoor air quality. Temperature, relative humidity (RH), carbon dioxide (CO2), sulphur dioxide (SO2), nitric oxide (NO), nitrogen dioxide (NO2), particulate matter with diameter less than 10 microns (PM10), formaldehyde (HCHO), and total bacteria counts were monitored at indoor and outdoor locations simultaneously. Respirable particulate matter was found to be the worst among parameters measured in this study. The indoor and outdoor average PM10 concentrations exceeded the Hong Kong standards, and the maximum indoor PM10 level was even at 472 micrograms/m3. Air cleaners could be used in classrooms to reduce the high PM10 concentration. Indoor CO2 concentrations often exceeded 1,000 microliters/l indicating inadequate ventilation. Lowering the occupancy and increasing breaks between classes could alleviate the high CO2 concentrations. Though the maximum indoor CO2 level reached 5,900 microliters/l during class at one of the sites, CO2 concentrations were still at levels that pose no health threats.

Air Conditioning↗

PubMed1999

A complex containing RNA polymerase II, Paf1p, Cdc73p, Hpr1p, and Ccr4p plays a role in protein kinase C signaling.

Yeast contains at least two complex forms of RNA polymerase II (Pol II), one including the Srbps and a second biochemically distinct form defined by the presence of Paf1p and Cdc73p (X. Shi et al., Mol. Cell. Biol. 17:1160-1169, 1997). In this work we demonstrate that Ccr4p and Hpr1p are components of the Paf1p-Cdc73p-Pol II complex. We have found many synthetic genetic interactions between factors within the Paf1p-Cdc73p complex, including the lethality of paf1Delta ccr4Delta, paf1Delta hpr1Delta, ccr4Delta hpr1Delta, and ccr4Delta gal11Delta double mutants. In addition, paf1Delta and ccr4Delta are lethal in combination with srb5Delta, indicating that the factors within and between the two RNA polymerase II complexes have overlapping essential functions. We have used differential display to identify several genes whose expression is affected by mutations in components of the Paf1p-Cdc73p-Pol II complex. Additionally, as previously observed for hpr1Delta, deleting PAF1 or CDC73 leads to elevated recombination between direct repeats. The paf1Delta and ccr4Delta mutations, as well as gal11Delta, demonstrate sensitivity to cell wall-damaging agents, rescue of the temperature-sensitive phenotype by sorbitol, and reduced expression of genes involved in cell wall biosynthesis. This unusual combination of effects on recombination and cell wall integrity has also been observed for mutations in genes in the Pkc1p-Mpk1p kinase cascade. Consistent with a role for this novel form of RNA polymerase II in the Pkc1p-Mpk1p signaling pathway, we find that paf1Delta mpk1Delta and paf1Delta pkc1Delta double mutants do not demonstrate an enhanced phenotype relative to the single mutants. Our observation that the Mpk1p kinase is fully active in a paf1Delta strain indicates that the Paf1p-Cdc73p complex may function downstream of the Pkc1p-Mpk1p cascade to regulate the expression of a subset of yeast genes.

Base Sequence↗

PubMed1999

Effect of trilinolein on strophanthidin-induced ventricular tachycardia in guinea pigs.

Trilinolein, a triacylglycerol with linoleic acid, was found to inhibit Ca2+ influx in cardiomyocytes. The purpose of this study was to evaluate the effects of trilinolein on ventricular arrhythmia induced by intravenous strophanthidin in guinea pigs anesthetized with intraperitoneal urethane. After strophanthidin- induced ventricular tachycardia, treatment with trilinolein (0.1, 1, 10 and 100 microg/kg) or control (0.04% propylene glycol) did not terminate ventricular tachycardia. However, 1, 10 and 100 microg/kg trilinolein could narrow the width of the QRS complex during ventricular tachycardia. Pretreatment with trilinolein before strophanthidin administration did not prevent the occurrence of ventricular tachycardia; the doses of strophanthidin required to induce arrhythmias (ventricular extrasystole and ventricular tachycardia) were similar in guinea pigs pretreated with trilinolein or control. However, there were fewer ventricular extrasystoles in guinea pigs pretreated with trilinolein than in the control group (ANOVA, p < 0.01). Moreover, the ventricular extrasystoles were fewer in guinea pigs pretreated with higher doses of trilinolein (100 microg/kg, 103 +/- 60; 10 microg/kg, 188 +/- 86) than lower doses of trilinolein (1 microg/kg, 366 +/- 102; 0.1 microg/kg, 436 +/- 145). This study demonstrated that trilinolein was not effective in terminating or preventing strophanthidin-induced ventricular tachycardia. However, trilinolein could improve ventricular depolarization and suppress ventricular extrasystoles.

Analysis of Variance↗

PubMed1999

Quality-adjusted survival after treatment for acute myeloid leukemia in childhood: A Q-TWiST analysis of the Pediatric Oncology Group Study 8821.

PURPOSE: To describe quality-of-life considerations in post-remission therapies for children with acute myelogenous leukemia. PATIENTS AND METHODS: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to Pediatric Oncology Group Trial 8821, which compared randomized assignment with intensive consolidation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). Nonrandomized assignment to allogeneic bone marrow transplantation (allo BMT) on the basis of availability of a matched related donor was also evaluated. A 25-patient cohort provided data for modeling chronic graft-versus-host disease. The Q-TWiST analysis was performed based on the intent-to-treat principle. RESULTS: As previously reported, the 3-year event-free survival was not significantly different between the randomized arms (CC v ABMT). At a median follow-up of 5 years (of the censoring distribution), the CC group had less time in toxicity (TOX) and more time without symptoms or toxicity (TWiST), relapse-free time, and alive time than patients assigned to ABMT (none of these were statistically significant). Compared with the CC group, allo BMT patients spent more time in TOX (P <.001), more time in TWiST (P =.06), and had more relapse-free time (P =.03) and time alive (P =.07). Allo BMT was superior to ABMT with greater time in TWiST (P =.02), relapse-free time (P =.01), and time alive P =.002). CONCLUSION: The Q-TWiST analysis is a powerful decision aid in choosing among alternative therapies. Prospective information on patient preferences will facilitate future trials evaluating treatment outcomes. Refinements in the Q-TWiST method could be included to further enhance the power of this patient care decision-making tool.

Acute Disease↗

PubMed1999

Histology and tissue chemistry of tidemark separation in hamsters.

Adult articular cartilage is divided by the tidemark into a deep calcified layer and a more superficial uncalcified layer. Histologic examination of articular cartilage from the knee joint of golden Syrian hamsters 123 days of age or older revealed defects at the tidemark in the tibia. Defects ranged from small separations of the calcified and uncalcified layers along the tidemark to progressively larger defects apparently formed by dissolution. These larger defects appeared as cavities in the noncalcified cartilage, had smooth rather than rough edges, frequently contained coalesced debris, and often resulted in a bulge in the articular surface. Occasionally, these large defects broke through the articular surface. Defects were not observed in tibial cartilage of younger (<90 days old) hamsters or in femoral cartilage from hamsters of any age. Exercise neither protected against nor increased the severity of the defects. Collagen cross-linking by pyridinoline was examined as a function of age and increased from 1,090 to 3,062 micromoles of pyridinoline/mole of hydroxyproline over the period of 1-9 months of age but was not correlated with defect formation. With increasing age, these focal tidemark defects could lead to osteoarthrosis-like cartilage lesions.

Age Factors↗

PubMed1999

[A physical performance battery assessing low/high extremity functional fitness in older Japanese women].

The aim of this study was to establish a physical performance test battery to assess the wide variation of functional fitness in older Japanese women. The criteria for sampling low/high extremity functional fitness were the amount of physical activities that older women perform on a regular basis and the distance they could move by foot. Seventeen tests related to the activities parallel to daily living (APDL) were completed for 178 women, aged 60 to 91 years. Principal component analysis of the 17 performance tests in the reference group (n = 140) yielded 5 components accounting for 63.5% of the total variance. Fourteen test items were heavily loaded on the 1st principal component, so that 31.4% of the total variance was accounted for by this component. Considering these results as well as test-retest reliability, kurtosis, and skewness of each item, the following four items were selected as a combination of test battery: (X1) repetition of the bicipital flexion/extension, (X2) walking around two cones and sitting on a chair, (X3) moving beans with chopsticks, and (X4) functional reach. Principal component analysis was again applied to these four variables so as to obtain the first principal component score of each person. As a result, the following equation was drawn: the first principal component score = 0.063X1 - 0.055X2 + 0.098X3 + 0.042X4 - 2.65. The scores averaged 0.68 +/- 0.27 for the exercise group (n = 19) (those who played croquet or other similar sports activities consistently twice or more a week); and -0.76 +/- 0.55 for the sedentary group (n = 19) (those who did no exercise and confined their activities to the home). Biserial correlation coefficient as an index of criterion-related validity was 0.67 (P < 0.05) between the scores in the exercise and sedentary groups. These results indicate that a wide range of functional fitness among older Japanese women can be assessed by the four tests.

Aged↗

PubMed1998

Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma.

Little is known about the immune responses induced by recombinant adenoviral (Ad) vectors in humans. The humoral and cellular immune responses were therefore analyzed in 21 patients with localized malignancy (mesothelioma), who received intrapleurally high doses of a replication-defective Ad5 vector carrying a suicide gene. Eight of 21 patients had pretreatment titers of neutralizing antibodies (NAb) to Ad at > or =1:100. Peripheral blood mononuclear cells (PBMCs) proliferated in response to adenoviral 5 structural proteins before treatment in 17 of 21 patients. Preexisting humoral and cellular immunity did not preclude gene transfer. Vector instillation induced high titers of nonneutralizing and neutralizing anti-Ad antibody (4- to 341-fold increase in 18 of 20 patients) in a dose-dependent manner. Three patients generated antibodies to the transgene, herpes simplex virus thymidine kinase. Ad5-specific proliferation of PBMCs increased significantly (>3-fold) after vector administration in 12 of 21 patients in a dose-dependent manner. Thus, replication-defective Ad5 administered intrapleurally induced significant humoral and cellular immune responses that induced no obvious adverse clinical sequelae.

Adenoviridae↗

PubMed1998

CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry.

Isolated murine splenic B cells undergo spontaneous apoptosis. Motifs containing unmethylated CpG dinucleotides in bacterial DNA or in synthetic oligodeoxynucleotides (ODN) are known to activate murine B cells. Now we show that ODN that induce spleen B cell cycle entry also inhibit spontaneous apoptosis in a sequence-specific fashion. Reversal of the CG to GC abolished activity. Methylation of the central cytosine decreased activity. When CpG is preceded by a cytosine or followed by a guanine, activity was abolished. Other substitutions at the same positions had no effect. Dose-response curves for apoptosis protection and G1 entry suggested that a uniform population of ODN recognition sites controlled downstream ODN effects. A CpG ODN with a nuclease-resistant phosphorothioate backbone (S-ODN) was also active, and increased the levels of c-myc, egr-1, c-jun, bclXL, and bax mRNA and c-Myc, c-Jun, Bax, and BclXL protein in spleen B cells. Levels of c-myb, myn, c-Ki-ras, and bcl2 mRNA remained unchanged. When protein synthesis was inhibited, at 16 h ODN-induced cell cycle entry was abolished and apoptosis protection was partially preserved. Under these conditions, c-Myc was still present, but c-Jun and BclXL were not detected. Our results suggest that CpG containing ODN motifs provide signals for both survival and cell cycle entry. Single base changes determine whether this signal proceeds through a rate-limiting step governing at least two steps in apoptosis (plasma membrane transition, DNA cleavage) and two phases of the cell cycle (G1 and S phase entry). This biologic action is associated with increased c-Myc, c-Jun, and BclXL expression.

Animals↗

PubMed1998

Analysis of autoantibodies against RNA polymerases using immunoaffinity-purifed RNA polymerase I, II, and III antigen in an enzyme-linked immunosorbent assay.

Autoantibodies against RNA polymerases (RNAP) have been reported to occur in patients with a wide variety of connective tissue diseases (CTD), including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). The frequency of anti-RNAP antibodies has been reported to vary widely between different CTD diseases in studies examining different patient populations. Furthermore, these studies have been limited by the fact that methods have not previously been available for detecting antibodies against RNAP which are both rapid and quantitative. We have developed an enzyme-linked immunosorbent assay (ELISA) for rapidly quantitating antibodies against RNAP I, II, and III. We have utilized both the ELISA and the immunoprecipitation of 35S-labeled HeLa cells to analyze sera from a large cohort of well-characterized Caucasian CTD patients for the presence of anti-RNAP antibodies. We found excellent concordance for the presence of anti-RNAP antibodies using immunoprecipitation and ELISA. Anti-RNAP antibodies occurred predominantly among female patients with the diffuse form of SSc and were detected in 8/36 (22%) of Caucasian patients with diffuse SSc and 1/53 (2%) with limited SSc. Anti-RNAP antibodies occurred in 1/42 (2%) of patients with SLE. Anti-RNAP antibodies did not occur in MCTD (0/49). Antibodies against RNAP were rare among antinucleolar-reactive sera, occurring in only 3/200 (1.5%). The RNAP ELISA provides a validated method which can be rapidly utilized in a clinical diagnostic laboratory setting to identify SSc patients who are at risk for developing diffuse SSc with multiorgan involvement and hypertensive renal crisis.

Adult↗

PubMed1998

Basic fibroblast growth factor is neither necessary nor sufficient for the development of retinal neovascularization.

Basic fibroblast growth factor (FGF2) is constitutively expressed in the retina and its expression is increased by a number of insults, but its role in the retina is still uncertain. This study was designed to test the hypothesis that altered expression of FGF2 in the retina affects the development of retinal neovascularization. Mice with targeted disruption of the Fgf2 gene had no detectable expression of FGF2 in the retina by Western blot, but retinal vessels were not different in appearance or total area from wild-type mice. When FGF2-deficient mice were compared with wild-type mice in a murine model of oxygen-induced ischemic retinopathy, they developed the same amount of retinal neovascularization. Transgenic mice with a rhodopsin promoter/Fgf2 gene fusion expressed high levels of FGF2 in retinal photoreceptors but developed no retinal neovascularization or other abnormalities of retinal vessels; in the ischemic retinopathy model, they showed no significant difference in the amount of retinal neovascularization compared with wild-type mice. These data indicate that FGF2 expression is not necessary nor sufficient for the development of retinal neovascularization. This suggests that agents that specifically antagonize FGF2 are not likely to be useful adjuncts in the treatment of retinal neovascularization and therapies designed to increase FGF2 expression are not likely to be complicated by retinal neovascularization.

Animals↗

PubMed1998

Pharmacokinetics and pharmacodynamics of single and multiple oral doses of a novel 5-lipoxygenase inhibitor (ABT-761) in healthy volunteers.

OBJECTIVE: This study evaluated the safety, pharmacokinetics and pharmacodynamics of ABT-761 [R(+)-N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1- methyl-2-propynyl]-N-hydroxyurea], a new N-hydroxyurea analog. METHODS: This was a randomized, double-blind, placebo-controlled, single- and multiple-dose (15-day) study of ABT-761 (50 to 200 mg/day) in healthy, nonsmoking adult male volunteers. The pharmacokinetics were evaluated by investigation of the time- and dose-dependent effects of ABT-761, and the pharmacologic selectivity of ABT-761 was evaluated based on calcium ionophore-stimulated leukotriene B4 (LTB4) and thromboxane B2 (TXB2) biosynthesis ex vivo in whole blood. RESULTS: After single and multiple doses, mean observed time to reach maximum concentration values of ABT-761 ranged from 4.0 to 7.5 hours. Mean values for maximum concentration and area under the plasma concentration-time curve from 0 to 24 hours increased approximately linearly with dose. Mean terminal half-life and apparent volume of distribution during the terminal elimination phase of ABT-761 ranged from 15.4 to 17.8 hours and 69.5 to 78.9 L, respectively, and was dose independent. Steady state was reached on day 11 after multiple dosing. Less than 0.05% of unchanged ABT-761 was recovered in urine within the 24-hour period after day 15 dosing. Population ABT-761 plasma concentration at which 50% of the maximum possible inhibition was observed for LTB4 inhibition was 0.24 microgram/ml. No differences in mean TXB2 inhibition were observed between the subjects receiving ABT-761 and placebo. CONCLUSIONS: These results indicate that ABT-761 is a potent and selective inhibitor of 5-lipoxygenase and the pharmacokinetics of ABT-761 are time and dose independent between 50 and 200 mg/day after single and multiple dosing.

Administration, Oral↗

PubMed1998

BCL-2 expression does not not correlate with patient outcome in pediatric acute myelogenous leukemia.

Although the Bcl-2 protein inhibits apoptosis (programmed cell death) of lymphoid cells induced by a variety of stimuli, its effects on myeloid cell short- and long-term survival after chemotherapy are less defined. We sought to elucidate the short- and long-term effect of Bcl-2 in a well-studied myeloid cell line (HL-60) treated with specific anti-AML chemotherapy. HL-60 cells overexpressing Bcl-2 (HL-60/BCL-2) were more resistant than parental HL-60 cells to multiple chemotherapeutic agents in short-term apoptosis and viability assays. Significantly, HL-60/BCL-2 cells retained greater long-term proliferative capacity than HL-60 cells when treated with low doses of doxorubicin. To assess the importance of Bcl-2 expression in pediatric AML we correlated clinical outcome and levels of Bcl-2 protein in 22 patient specimens. The correlation did not achieve statistical significance with patient response to chemotherapy or long-term outcome, suggesting that analysis of larger numbers of patient samples would not be useful. Our study suggests that although Bcl-2 clearly promotes short and long-term survival in a myeloid cell line, measurement of Bcl-2 levels alone are not sufficient to be of prognostic significance in pediatric AML.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Inhibition of glutathione S-transferase activity by the quinoid metabolites of equine estrogens.

The risk factors for women developing breast and endometrium cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy (ERT) in particular has been correlated with a slight increased cancer risk, although the numerous benefits of ERT may negate this harmful side effect. Equilenin and equilin are equine estrogens which make up between 30% and 45% of the most widely prescribed estrogen replacement formulation, Premarin (Wyeth-Ayerst). In this study we have synthesized the catechol metabolites of equilenin [4-hydroxyequilenin (4-OHEN)] and equilin [4-hydroxyequilin (4-OHEQ)] and examined how changing unsaturation in the B ring affects the formation of o-quinone GSH conjugates and the ability of the o-quinones and/or GSH conjugates to inhibit glutathione S-transferase (GST). Interestingly, both 4-OHEN and 4-OHEQ autoxidized to o-quinones without the need of oxidative enzyme catalysis. 4-OHEN-o-quinone reacts with GSH to give two mono-GSH conjugates and one diadduct. The behavior of 4-OHEQ was found to be more complex than 4-OHEN as conjugates resulting from 4-OHEN were detected in addition to the 4-OHEQ GSH adducts. Both 4-OHEN and 4-OHEQ were found to be potent inhibitors of GST-catalyzed conjugation of GSH with 1-chloro-2,4-dinitrobenzene. In contrast, the endogenous catechol estrogens, 4-hydroxyestrone (4-OHE) and 2-hydroxyestrone (2-OHE), were without effect unless tyrosinase was present to convert the catechols to o-quinones. Scavengers of reactive oxygen species and metal chelators had no effect on GST inhibition by catechol estrogens with the exception of the catalase which protected GST activity. Kinetic studies showed that 4-OHEN was a potent irreversible inactivator of GST. Preincubation of the enzyme with 4-OHEN showed a time-dependent increase in inhibitory effect, and gel filtration did not restore GST activity confirming the irreversible nature of the enzyme inactivation. Analysis of the Kitz-Wilson plot gave a dissociation constant of the reversible enzyme-inhibitor complex (Ki = 620 microM) and a rate constant of conversion of the reversible enzyme-inhibitor complex to the irreversibly inhibited enzyme (k2 = 7.3 x 10(-)3 s-1). These data suggest that 4-OHEN is an irreversible inactivator with relatively low affinity for GST; however, once formed the 4-OHEN enzyme complex is rapidly converted to the irreversibly inhibited enzyme. The inhibition mechanism likely involves oxidation of the catechol estrogens to o-quinones and covalent modification and/or oxidation of critical amino acid residues on GST. In addition, hydrogen peroxide generated through redox cycling of the o-quinone and/or semiquinone radical and GSH could cause oxidative damage to GST.

Animals↗

PubMed1998

Effect of hemodialysis on the pharmacokinetics of 19-nor-1alpha,25-dihydroxyvitamin D2.

The vitamin D2 analogue 19-nor-1alpha,25-dihydroxyvitamin D2 (paricalcitol) has been tested for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease. Clinical studies have shown that paricalcitol reduces serum parathyroid hormone (PTH) levels with minimal potential to cause hypercalcemia, a common side effect of vitamin D3 therapy. Paricalcitol is typically administered intravenously after hemodialysis (HD). Because the administration of paricalcitol before or during dialysis would be desirable, the effect of HD on paricalcitol pharmacokinetics was investigated. Six patients requiring HD received a single dose of paricalcitol, 0.08 microg/kg, intravenously approximately 2 hours before HD, and blood samples were collected by venipuncture immediately before and 15 minutes after HD. Also, pairs of pre- and postdialyzer blood samples were collected approximately 1 and 2 hours after the start of HD. Plasma concentrations of paricalcitol in the samples were determined by a specific high-performance liquid chromatography (HPLC)/radioreceptor assay (RRA) with a lower limit of quantification of 40 pg/mL. Compared with previous pharmacokinetic studies in HD patients, plasma concentrations (100 to 250 pg/mL) during the 4-hour period were consistent with predicted values for this dose, and there was no apparent increase in paricalcitol clearance during HD. Pre- and postdialyzer plasma concentrations of paricalcitol were compared statistically using a paired t-test. Postdialyzer concentrations tended to be slightly higher than those predialyzer, but the differences were not statistically significant (P = 0.11). Thus, HD essentially had no effect on plasma concentrations of paricalcitol, suggesting that paricalcitol can be administered at any time during dialysis.

Aged↗

PubMed1998

Pharmacological characteristics of MJ-451, a new benzopyran- derived ATP-sensitive potassium channel opener, in guinea pig isolated trachea.

In this study, we determined the pharmacological activities of MJ-451 (6-cyano-3S,4R-dihydro-2, 2-dimethyl-2H-3-hydroxy-4-[2-oxo-5S-1-hydroxmethyl)-1-pyrrolidinyl ]-1 -benzopyran) in guinea pig isolated trachea and compared its effects with those of cromakalim. MJ-451 (0.1-10 micromol/l) and cromakalim (0.01-1 micromol/l) produced concentration-dependent relaxation of guinea pig isolated trachea precontracted with carbachol (0.5 micromol/l) or histamine (1 micromol/l). MJ-451 (0.03-30 micromol/l), as well as cromakalim (0.03-30 micromol/l), caused a complete and concentration-dependent relaxation of guinea pig isolated trachea precontracted with 20 mmol/l KCl, but did not inhibit the spasmogenic effect of 80 mmol/l KCl. However, theophylline (30-3,000 micromol/l) caused a complete and concentration-dependent relaxation of guinea pig isolated trachea precontracted with either 20 or 80 mmol/l KCl. Propranolol (0.1 micromol/l) markedly antagonized the relaxant action of isoprenaline, but not that of MJ-451 in carbachol-contracted isolated trachea. 8-(p)-sulfophenyltheophylline (150 micromol/l), a selective P1 purinoceptor antagonist, had no effect against the tracheal relaxation induced by MJ-451, but markedly depressed the concentration-response curve of 5'-N-ethylcarboxamidoadenosine. Charybdotoxin (10 micromol/l), a large-conductance Ca2+-activated K+ channel blocker, failed to modify the relaxant activity of MJ-451 in carbachol-contracted isolated trachea. The ATP-sensitive K+ channel blocker, glibenclamide (0.1, 1 and 10 micromol/l) concentration-dependently antagonized the relaxant activity of MJ-451 in carbachol-contracted isolated trachea. It is concluded that MJ-451 is a selective ATP-sensitive K+ channel opener in the tracheal smooth muscle of the guinea pig.

Animals↗

PubMed1998

Histamine H3 receptor-mediated inhibition of excitatory synaptic transmission in the rat dentate gyrus in vivo.

We investigated the effects of histamine H3-receptor ligands on hippocampal synaptic transmission by using anesthetized rats in vivo. The medial perforant path was stimulated, and the population excitatory postsynaptic potential (pEPSP) and population spike were recorded from the granule cell layer of the dentate gyrus. Intracerebroventricular injection of the H3-receptor agonist (R)-alpha-methylhistamine decreased both the pEPSP and population spike, while H3-receptor antagonists, clobenpropit and thioperamide, increased both the pEPSP and population spike. These results suggest that the histaminergic system plays a role in inhibition of hippocampal synaptic excitation via the H3 receptor.

Animals↗

PubMed1998

Absorption, distribution, metabolism, and excretion of atevirdine in the rat.

Atevirdine mesylate (U-87201E) is a highly specific nonnucleoside inhibitor of human immunodeficiency virus type 1 reverse transcriptase. The absorption, metabolism, and excretion of atevirdine were investigated in male and female Sprague-Dawley rats after oral administration of nonradiolabeled atevirdine mesylate at doses of 20 mg/kg/day or 200 mg/kg/day for 8 days, with [14C]atevirdine mesylate single doses of 10 mg/kg or 100 mg/kg on study days 1 and 10. The distribution of [14C]atevirdine mesylate was also evaluated by whole-body autoradiography in male and female Sprague-Dawley, pregnant Sprague-Dawley, and male Long-Evans rats after a single 10 mg/kg oral dose. Plasma levels of atevirdine and its N-desethyl and O-desmethyl metabolites were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection, urine and feces were profiled for atevirdine and metabolites by HPLC with radiochemical detection, major metabolites in urine were isolated and identified by nuclear magnetic resonance and mass spectrometry, and minor urinary metabolites were identified by liquid chromatography/mass spectrometry. Atevirdine was rapidly absorbed. The pharmacokinetics of atevirdine were nonlinear. Gender differences in the pharmacokinetics and metabolism of atevirdine were observed, consistent with the involvement of cytochrome P450 3A. Atevirdine effectively crossed the blood-brain barrier and had a high rate of maternal-fetal transfer. At the low doses, <2% of the dose was excreted as unchanged parent drug, while atevirdine constituted 9%-25% of the dose at the high doses. The metabolism of atevirdine was extensive in the rat and involved N-deethylation, O-demethylation, hydroxylation at the C-6 position of the indole ring, and hydroxylation of the pyridine ring.

Animals↗

PubMed1997

A multiplicity of mediators: alternative forms of transcription complexes communicate with transcriptional regulators.

The already complex process of transcription by RNA polymerase II has become even more complicated in the last few years with the identification of auxiliary factors in addition to the essential general initiation factors. In many cases these factors, which have been termed mediators or co-activators, are only required for activated or repressed transcription. In some cases the effects are specific for certain activators and repressors. Recently some of these auxiliary factors have been found in large complexes with either TBP, as TBP-associated factors (TAFs) in the general factor TFIID, or with pol II and a subset of the general factors, referred to as the 'holoenzyme'. Although the exact composition of these huge assemblies is still a matter of some debate, it is becoming clear that the complexes themselves come in more than one form. In particular, at least four forms of TFIID have been described, including one that contains a tissue-specific TAF and another with a cell type-specific form of TBP. In addition, in yeast there are at least two forms of the 'holoenzyme' distinguished by their mediator composition and by the spectrum of transcripts whose expression they affect. Genetic and biochemical analyses have begun to identify the interactions between the components of these complexes and the ever increasing family of DNA binding regulatory factors. These studies are complicated by the fact that individual regulatory factors often appear to have redundant interactions with multiple mediators. The existence of these different forms of transcription complexes defines a new target for regulation of subsets of eukaryotic genes.

Animals↗