bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shaker‐type Kv1 channel blockers increase the peristaltic activity of guinea‐pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system
Authors: Vianna‐Jorge Rosane , Oliveira Cyntia F , Garcia Maria L , Kaczorowski Gregory J , Suarez‐Kurtz Guilherme 
Published: January 2003

A constant intraluminal pressure system was used to evaluate the effects of Kv1 channel blockers on the peristaltic activity of guinea‐pig ileum.
The nortriterpene correolide, a non‐selective inhibitor of all Kv1 sub‐types, causes progressive and sustained reduction of the pressure threshold for eliciting peristaltic contractions.
Margatoxin (MgTX), alpha‐dendrotoxin (α‐DTX) and dendrotoxin‐K (DTX‐K), highly selective peptidyl inhibitors of certain Kv1 sub‐types, cause immediate reduction of the pressure threshold. This effect subsides with time, irrespective of the peptides' concentration in the bath. In preparations pretreated with saturating concentrations of MgTX, correolide further stimulates the peristaltic activity.
Iberiotoxin (IbTX), a selective inhibitor of the high‐conductance Ca2+‐activated K+ (BK) channels, and charybdotoxin (ChTX), which inhibits Kv1.2 and Kv1.3 as well as BK channels, fail to stimulate the peristaltic activity.
Blockade of muscarinic receptors by atropine reduces, and occasionally suppresses the peristaltic activity of guinea‐pig ileum. In atropine‐treated preparations, correolide and MgTX retain their abilities to reduce the pressure threshold and are able to restore the peristaltic reflex in the preparations where this reflex was suppressed by atropine.
The stimulatory effect of correolide and MgTX in atropine‐treated preparations is abolished by subsequent addition of selective antagonists of both NK1 and NK2 receptors.
In conclusion, blockade of Kv1, particularly Kv1.1 channels, increases the peristaltic activity of guinea‐pig ileum by enhancing the release of neurotransmitters at the enteric nervous system. In contrast, stimulation of the myogenic motility by blockade of BK channels does not affect the threshold for the peristaltic reflex.

British Journal of Pharmacology (2003) 138, 57–62. doi:10.1038/sj.bjp.0705023
Inhibition of hEAG1 and hERG1 potassium channels by clofilium and its tertiary analogue LY97241
Authors: Gessner Guido , Heinemann Stefan H 
Published: January 2003

We investigated the inhibition of hEAG1 potassium channels, expressed in mammalian cells and Xenopus oocytes, by several blockers that have previously been reported to be blockers of hERG1 channels.
In the whole‐cell mode of mammalian cells, LY97241 was shown to be a potent inhibitor of both hEAG1 and hERG1 channels (IC50 of 4.9 and 2.2 nM, respectively). Clofilium, E4031, and haloperidol apparently inhibited hEAG1 channels with lower potency than hERG1 channels, but they cannot be considered hERG1‐specific.
The block of hEAG1 channels by LY97241 and clofilium was time‐, use‐, and voltage‐dependent, best explained by an open‐channel block mechanism.
Both drugs apparently bind from the intracellular side of the membrane at (a) specific site(s) within the central cavity of the channel pore. They can be trapped by closure of the activation gate.
In inside‐out patches from Xenopus oocytes, hEAG1 block by clofilium was stronger than by LY97241 (IC50 of 0.8 and 1.9 nM, respectively). In addition, hEAG1 block by clofilium was much faster than by LY97241 although there was no difference in the voltage dependence of the on‐rate of block.
Physico‐chemical differences of clofilium and the weak base LY97241 determine the access of the drugs to the binding site and thereby the influence of the recording mode on the apparent block potencies. This phenomenon must be considered when assessing the inhibitory action of drugs on ion channels.

British Journal of Pharmacology (2003) 138, 161–171. doi:10.1038/sj.bjp.0705025
The anti‐relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine
Authors: Mcgeehan Andrew J , Olive M Foster 
Published: January 2003

The effects of the anti‐relapse compound acamprosate (calcium acetylhomotaurinate) on the conditioned rewarding effects of ethanol, cocaine and morphine were studied using the conditioned place preference (CPP) paradigm. During 3 days of drug conditioning, mice were pretreated with saline or acamprosate (30, 100 or 300 mg kg−1 i.p.) 10 min prior to the administration of ethanol (2 g kg−1 i.p.), cocaine (15 mg kg−1 i.p.) or morphine (10 mg kg−1 i.p.), and subsequently confined to one of two distinct conditioning chambers. On the following day, mice were tested for the expression of CPP. Acamprosate dose‐dependently reduced the development of CPP to ethanol and cocaine but not morphine. When tested as the conditioning drug, acamprosate alone produced neither a conditioned place preference nor aversion. These data suggest that acamprosate can suppress the conditioned rewarding effects of ethanol and certain classes of abused substances.British Journal of Pharmacology (2003) 138, 9–12. doi:10.1038/sj.bjp.0705059
The effects of the human MDR1 genotype on the expression of duodenal P‐glycoprotein and disposition of the probe drug talinolol
Authors: Siegmund Werner , Ludwig Karen , Giessmann Thomas , Dazert Peter , Schroeder Eike , Sperker Bernhard , Warzok Rolf , Kroemer Heyo K. , Cascorbi Ingolf 
Published: January 2003

Background and objectivesA single‐nucleotide polymorphism (SNP) of the human multidrug‐resistance gene in wobble position of exon 26 reportedly predicts expression and function of P‐glycoprotein in human enterocytes and lymphocytes. Several other allelic variants of MDR1 have been identified, some of which lead to amino acid exchange with as yet unknown functional relevance.MethodsIn healthy white volunteers, we investigated the influence of the hereditary variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21 and the influence of 7 frequent or putative functional SNPs on duodenal MDR1 messenger ribonucleic acid (n = 32) and immunoreactive P‐glycoprotein (n = 37) expression. Moreover, the disposition of the probe drug talinolol was evaluated in 55 subjects after oral administration (100 mg) and in 23 subjects after intravenous administration(30 mg).ResultsDuodenal MDR1 messenger ribonucleic acid and P‐glycoprotein, as assessed by real‐time polymerase chain reaction (TaqMan) and immunostaining, were not influenced by any MDR1 polymorphism studied. Talinolol disposition was not affected by the exon 26 mutation C3435T. In carriers of the TT/TA variants of G2677T/A, the area under the serum concentration‐time curve values of oral talinolol were slightly but significantly elevated compared with those in carriers of at least 1 wild‐type allele (P < .05, Kruskal‐Wallis test; P = .014, Mann‐Whitney U test). However, multiple comparisons with combinations of putative functional SNPs did not confirm a significant influence of the MDR1 genotype on talinolol disposition.ConclusionsWe did not identify any influence of MDR1 genotypes on duodenal expression of P‐glycoprotein and disposition of talinolol in humans.Clinical Pharmacology & Therapeutics (2002) 72, 572–583; doi: 10.1067/mcp.2002.127739
Cytochrome P450 3A4 and P‐glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin
Authors: Paine Mary F. , Wagner David A. , Hoffmaster Keith A. , Watkins Paul B. 
Published: January 2003

BackgroundThe intravenous 14C‐erythromycin breath test (ERMBTIV) does not measure aggregate liver and intestinal cytochrome P450 (CYP) 3A4 activity. Accordingly, we evaluated an oral stable‐labeled (13C) formulation of the test (ERMBToral) as an alternative CYP3A4 phenotyping probe.MethodsAfter an overnight fast, 14 young healthy volunteers (5 women and 9 men) received the ERMBTIV (0.07 μmol, 3 μCi), followed by the ERMBToral (500 mg). The next morning, the CYP3A4 inhibitor troleandomycin (500 mg) was given, and both ERMBTs were repeated. After at least 24 hours, the CYP3A4 and P‐glycoprotein inducer rifampin (600 mg; INN, rifampicin) was given daily for 7 days, and both ERMBTs were repeated 24 hours after the last dose of rifampin. Plasma samples were collected for 10 hours with each administration of the ERMBToral, and erythromycin levels were measured by liquid chromatography‐mass spectrometry. Finally, the effect of troleandomycin on erythromycin transport was examined in Caco‐2 cell monolayers.ResultsCompared with baseline values, the median ERMBTIV and ERMBToral results and erythromycin apparent oral clearance (CL/F) all significantly decreased, by at least 70%, with troleandomycin treatment (P = .001 for each comparison). With rifampin treatment, the median ERMBTIV result and CL/F increased 2‐fold (P ≤ .01), but the median ERMBToral result was unchanged (P = .30). There were no rank‐order correlations between the ERMBTIV and ERMBToral results or between either ERMBT result and CL/F within each treatment group (P ≥ .07). In addition, troleandomycin had no effect on erythromycin transport in Caco‐2 cells (P ≥ .20).ConclusionsThe ERMBToral was influenced by processes in addition to intestinal and hepatic CYP3A4 activity and therefore did not provide a straightforward measure of aggregate CYP3A4 phenotype. The erythromycin‐rifampin interaction cannot be attributed to CYP3A4 induction alone and probably also reflected intestinal P‐glycoprotein induction.Clinical Pharmacology & Therapeutics (2002) 72, 524–535; doi: 10.1067/mcp.2002.128387
Single‐dose and steady‐state pharmacokinetics of celecoxib in children
Authors: Stempak Diana , Gammon Janet , Klein Julia , Koren Gideon , Baruchel Sylvain 
Published: January 2003

Background and ObjectiveCelecoxib is a member of a novel group of agents that selectively inhibit cyclooxygenase 2 (COX‐2). COX‐2 inhibitors have emerged as an important class of drugs because of the lower incidence of side effects when compared with traditional nonsteroidal anti‐inflammatory drugs, which inhibit both cyclooxygenase 1 and COX‐2. Because children often differ from adults with respect to drug disposition, the objective of this study was to determine the single‐dose and steady‐state pharmacokinetics of celecoxib in pediatric patients.MethodsCelecoxib plasma concentrations were determined at intervals over 12 hours after a 250‐mg/m2 dose and again 1 week later after twice‐daily dosing (steady state).ResultsPeak plasma concentrations (1234 ± 528 μg/L) were achieved 3 hours after drug administration. The area under the celecoxib plasma concentration‐time curve was 7709 ± 3176 μg/L · h, the elimination half‐life (t½) was 3.7 ± 1.1 hours, the apparent volume of distribution was 7.9 ± 7.8 L/kg, and the lower oral clearance of the drug was 1.4 ± 1.0 L · h−1 · kg−1. Statistical analysis revealed a significantly higher apparent oral clearance and longer t½ (P < .05) at steady state compared with pharmacokinetics after a single dose. In addition, when the results were compared in children and adults, the drug was cleared approximately twice as fast in children and had a t½ that was approximately half as long.ConclusionsThis is the first report of celecoxib pharmacokinetics in children, and the results indicate that there are significant differences between children and adults with respect to celecoxib disposition; hence these data may have implications when dosing schedules are planned for this population.Clinical Pharmacology & Therapeutics (2002) 72, 490–497; doi: 10.1067/mcp.2002.129322
Neurobehavioral Changes Resulting from Recombinase Activation Gene 1 Deletion
Authors: Cushman Jesse , Lo Jeannette , Huang Zhi , Wasserfall Clive , Petitto John M. 
Published: January 2003

ABSTRACTRecombinase activation gene 1 (RAG-1) function is essential for V(D)J recombination in T-cell-receptor and immunoglobulin rearrangements whereby the immune system may encode memories of a vast array of antigens. The RAG-1 gene is also localized to neurons in the hippocampal formation and related limbic regions that are involved in spatial learning and memory as well as other parameters of neurobehavioral performance. Since the unique ability to encode memory is shared by the immune system and the brain, we tested the hypothesis that loss of the RAG-1 gene in the brain would influence learning and memory performance and examined several different domains of behavior in RAG-1-knockout and control mice. Compared to control mice, RAG-1-knockout mice exhibited increased locomotor activity in an open field under both dim and bright lighting conditions and decreased habituation (reduction in the expected decline in locomotor activity with increasing familiarity with the novel environment in a 1-h test session) in bright lighting. RAG-1-knockout mice also showed reduced levels of fearfulness for some measures of fear-motivated behavior in both the open-field behavior test and elevated-plus maze test. Contrary to our hypothesis, no differences in spatial learning and memory were found between the groups, although modest differences were observed visible-platform testing in the Morris water maze. Neither prepulse inhibition, a measure of sensorimotor gating, nor reflexive acoustic startle responses differed between the RAG-1-knockout and control mice. It remains to be determined if these changes are due to the loss of RAG-1 gene expression in the brain, are due to the absence of the gene in the immune system (e.g., the loss of cytokines with neuromodulatory activities), or are due to some combination of both effects. Study of the neurobiological actions of RAG-1 in the brain may provide new insights into important processes involved in normal brain function and disease.
Simultaneous Detection of 15 Human Cytokines in a Single Sample of Stimulated Peripheral Blood Mononuclear Cells
Authors: de Jager Wilco , te Velthuis Henk , Prakken Berent J. , Kuis Wietse , Rijkers Ger T. 
Published: January 2003

ABSTRACT
Cytokines secreted by cells of the immune system can alter the behavior and properties of immune or other cells. At a site of inflammation, sets of cytokines interact with immune cells, and their combined effect is often more important than the function of one isolated component. Conventional techniques, such as enzyme-linked immunosorbent assays, generally require large quantities of cells to characterize a complete cytokine profile of activated lymphocytes. The Bio-Plex system from Bio-Rad Laboratories combines the principle of a sandwich immunoassay with the Luminex fluorescent-bead-based technology. We developed a multiplex cytokine assay to detect different cytokines simultaneously in culture supernatant of human peripheral blood mononuclear cells stimulated with antigen and with mitogen. Fifteen human cytokines (interleukin 1α [IL-1α], IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-18, gamma interferon, and tumor necrosis factor alpha) were validated with a panel of healthy individuals, rheumatoid arthritis patients, and juvenile idiopathic arthritis patients. Comparing the multiplex assay with a regular enzyme-linked immunosorbent assay technique with this donor panel resulted in correlation coefficients for all cytokines ranging from 0.75 to 0.99. Intra-assay variance proved to be less then 10%, whereas interassay variability ranged between 10 and 22%. This multiplex system proved to be a powerful tool in the quantitation of cytokines. It will provide a more complete picture in differences between activated lymphocyte cytokine profiles from healthy individuals and those from patients with chronic inflammatory diseases.
Functional and Morphological Development of Lymphoid Tissues and Immune Regulatory and Effector Function in Rhesus Monkeys: Cytokine-Secreting Cells, Immunoglobulin-Secreting Cells, and CD5+B-1 Cells Appear Early in Fetal Development
Authors: Makori Norbert , Tarantal Alice F. , Lü Fabien X. , Rourke Tracy , Marthas Marta L. , McChesney Michael B. , Hendrickx Andrew G. , Miller Christopher J. 
Published: January 2003

ABSTRACTLittle is known regarding the timing of immune ontogeny and effector function in fetal humans and nonhuman primates. We studied the organization of lymphocyte and antigen-presenting cell populations in developing lymphoid tissues of rhesus monkey fetuses during the second and third trimesters (65 to 145 days of gestation; term = 165 days). Immunoglobulin-secreting and cytokine-secreting cells were detected at day 80. The thymus, spleen, lymph nodes, and intestinal mucosa were examined for cells expressing CD3, CD5, CD20, CD68, p55, and HLA-DR. In the spleens of 65-day-old fetuses (early second trimester), the overwhelming majority of total lymphocytes were CD5+CD20+B-1 cells. The remaining lymphocytes were CD3+T cells. By day 80, splenic B and T cells were equal in number. Intraepithelial CD3+CD5−T cells and lamina propria CD20+CD5+B cells were present in the intestines of 65-day-old fetuses. By day 80, numerous CD20+CD5+B cells were present in the jejunums and colons and early lymphocyte aggregate formation was evident. The spleens of 80- to 145-day-old fetuses contained immunoglobulin M (IgM)-secreting cells, while IgA-, IgG-, interleukin-6-, and gamma interferon-secreting cells were numerous in the spleens and colons. Thus, by the second trimester, the lymphoid tissues of the rhesus monkey fetus have a complete repertoire of properly organized antigen-presenting cells, T cells, and B cells.
Keratinocyte Expression of Human β Defensin 2 following Bacterial Infection: Role in Cutaneous Host Defense
Authors: Dinulos James G. H. , Mentele Laurel , Fredericks L. Page , Dale Beverly A. , Darmstadt Gary L. 
Published: January 2003

ABSTRACT

Human β defensin 2 (hβD-2) is thought to play an important role in cutaneous immune defense. We hypothesized that (i) keratinocyte expression of hβD-2, measured by reverse transcription-PCR, would be upregulated in response to challenge with pathogenic bacteria, particularly highly adherent strains of
Streptococcus pyogenes
and
Staphylococcus aureus
, and (ii) hβD-2 would have potent antimicrobial activity against pathogenic but not commensal organisms. Expression of hβD-2 was induced consistently by
S
.
aureus
,
Staphylococcus epidermidis
,
Escherichia coli
, and
Pseudomonas aeruginosa
, whereas strains of
S
.
pyogenes
were poor and variable inducers of hβD-2. No correlation was found between levels of bacterial adherence and keratinocyte expression of hβD-2.
S
.
pyogenes
was significantly more sensitive to killing by hβD-2 than
S
.
epidermidis
. We conclude that the ability to induce hβD-2 expression in combination with sensitivity to its antimicrobial effects may contribute to the rarity of skin infections with the gram-negative bacterial organisms, whereas lack of stimulation of hβD-2 expression by
S
.
pyogenes
may be important in its ability to evade innate defenses and cause skin disease. Induction of expression of hβD-2 but relative tolerance to it may enable
S
.
epidermidis
to survive on the skin surface and modulate hβD-2 expression when the stratum corneum barrier is disrupted.
Immunoglobulin G Antibodies against the Endosymbionts of Filarial Nematodes (
Wolbachia
) in Patients with Pulmonary Dirofilariasis
Authors: Simón F. , Prieto G. , Morchón R. , Bazzocchi C. , Bandi C. , Genchi C. 
Published: January 2003

ABSTRACT

The dog parasite
Dirofilaria immitis
can infect humans. Patients with pulmonary dirofilariasis were tested for immunoglobulin G (IgG) antibodies against the surface protein of
Wolbachia
, the bacterial endosymbiont of
D
.
immitis
. These patients showed significantly higher IgG titers than healthy individuals from areas in which
D
.
immitis
was endemic as well as areas in which it was not endemic. Titration of anti-
Wolbachia
surface protein IgG could become useful for diagnostic applications.
Effect of Multiple Freeze-Thaw Cycles on Detection of Measles, Mumps, and Rubella Virus Antibodies
Authors: Pinsky Norman A. , Huddleston Jeanne M. , Jacobson Robert M. , Wollan Peter C. , Poland Gregory A. 
Published: January 2003

ABSTRACT
We investigated the effect of multiple freeze-thaw cycles on mumps, measles, and rubella virus serum antibody levels with whole-virus immunoglobulin G enzyme-linked immunoassays. Fresh serum samples from nine healthy adult volunteers were divided into six sets of five aliquots each. Samples were taken through a total of 10 freeze-thaw cycles and stored at 4°C until assayed. Each assay measurement was done in replicates of five, and the mean value was reported. After completing 10 freeze-thaw cycles, we found no clinically or statistically significant effect on measured antibody levels and found no discernible detrimental effect on the ability to measure these antibodies by enzyme-linked immunoassays.
Systemic Immunoresponses in Mice after Repeated Exposure of Lungs to Spores of
Streptomyces californicus
Authors: Jussila J. , Pelkonen J. , Kosma V.-M. , Mäki-Paakkanen J. , Komulainen H. , Hirvonen M.-R. 
Published: January 2003

ABSTRACT

Microbial growth in moisture-damaged buildings is associated with respiratory and other symptoms in the occupants.
Streptomyces
spp. are frequently isolated from such buildings. In the present study, we evaluated the responses of mice after repeated exposure to spores of
Streptomyces californicus
. Mice were exposed via intratracheal instillation to six doses (at 7-day intervals) of the spores of
S. californicus
, originally isolated from the indoor air of a moisture-damaged building, at three dose levels (2 × 10
3
, 2 × 10
5
, and 2 × 10
7
spores). Inflammation and toxicity, including changes in cell populations in the lungs, lymph nodes, and spleen, were evaluated 24 h after the last dosage. The exposure provoked a dose-dependent inflammatory cell response, as detected by the intense recruitment of neutrophils, but the numbers of macrophages and lymphocytes in the airways also increased. The cellular responses corresponded to the dose-dependent increases in inflammation- and cytotoxicity-associated biochemical markers (i.e., levels of albumin, total protein, and lactate dehydrogenase) in bronchoalveolar lavage fluid. The spore exposure increased the number of both activated and nonactivated T lymphocytes. Also, the amounts of CD3
−
CD4
−
and unconventional CD3
−
CD4
+
lymphocytes in the lung tissue were augmented. Interestingly, the spore exposure decreased cells in the spleen. This effect was strongest at the dose of 2 × 10
5
spores. These results indicate that the spores of
S. californicus
are capable of provoking both immunostimulation in lungs (inflammation) and systemic immunotoxicity, especially in the spleen. The immunotoxic effect resembled that caused by chemotherapeutic agents, originally isolated from
Streptomyces
spp. Thus,
S. californicus
must be considered a microbial species with potential to cause systemic adverse health effects in occupants of moisture-damaged buildings.