Background and purpose:
The histamine H
4
receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In ...this report, we describe the
in vitro
and
in vivo
anti‐inflammatory properties of a potent histamine H
4
receptor antagonist, A‐940894 (4‐piperazin‐1‐yl‐6,7‐dihydro‐5H‐benzo6,7cyclohepta1,2‐dpyrimidin‐2‐ylamine).
Experimental approach:
We have analysed the pharmacological profile of A‐940894 at mouse native, rat recombinant and human recombinant and native, histamine H
4
receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan‐induced peritonitis.
Key results:
A‐940894 potently binds to both human and rat histamine H
4
receptors and exhibits considerably lower affinity for the human histamine H
1
, H
2
or H
3
receptors. It potently blocked histamine‐evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine‐induced shape change of mouse bone marrow‐derived mast cells and chemotaxis of human eosinophils
in vitro
. In a mouse mast cell‐dependent model of zymosan‐induced peritonitis, A‐940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D
2
levels. Finally, A‐940894 has good pharmacokinetic properties, including half‐life and oral bioavailability in rats and mice.
Conclusions and Implications:
These data suggest that A‐940894 is a potent and selective histamine H
4
receptor antagonist with pharmacokinetic properties suitable for long‐term
in vivo
testing and could serve as a useful tool for the further characterization of histamine H
4
receptor pharmacology.
Histamine H
3 receptors regulate the release of a variety of central neurotransmitters involved in cognitive processes. A-349821 ((4′-(3-((
...R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone) is a novel, non-imidazole H
3 receptor ligand, displaying high affinity for recombinant rat and human H
3 receptors, with p
K
i values of 9.4 and 8.8, respectively, and high selectivity for the H
3 receptor versus H
1, H
2, and H
4 histamine receptors. A-349821 is a potent H
3 receptor antagonist in a variety of models using recombinant human and rat receptors, reversing agonist induced changes in cyclic AMP formation (p
K
b = 8.2 and p
K
b = 8.1, respectively),
35
S
-GTPγS binding (p
K
b = 9.3 and p
K
b = 8.6, respectively) and calcium levels (human p
K
b = 8.3). In native systems, A-349821 competitively reversed agonist induced inhibition of electric field stimulated guinea-pig ileum (p
A
2 = 9.5) and histamine-mediated inhibition of
3
H
-histamine release from rat brain cortical synaptosomes (p
K
b = 9.2). Additionally, A-349821 inhibited constitutive GTPγS binding at both rat and human H
3 receptors with respective pEC
50 values of 9.1 and 8.6, demonstrating potent inverse agonist properties. In behavioral studies, A-349821 (0.4
mg/kg—4
mg/kg) potently blocked (
R)-α-methylhistamine-induced dipsogenia in mice. The compound also enhanced cognitive activity in a five-trial inhibitory avoidance model in spontaneously hypertensive rat (SHR) pups at doses of 1–10
mg/kg, with the 1
mg/kg dose showing comparable efficacy to a fully efficacious dose of ciproxifan (3
mg/kg). These doses of A-349821 were without effect on spontaneous locomotor activity. Thus, A-349821 is a novel, selective non-imidazole H
3 antagonist/inverse agonist with balanced high potency across species and favorable cognition enhancing effects in rats.
Background and purpose: The histamine H4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In ...this report, we describe the in vitro and in vivo anti‐inflammatory properties of a potent histamine H4 receptor antagonist, A‐940894 (4‐piperazin‐1‐yl‐6,7‐dihydro‐5H‐benzo6,7cyclohepta1,2‐dpyrimidin‐2‐ylamine).
Experimental approach: We have analysed the pharmacological profile of A‐940894 at mouse native, rat recombinant and human recombinant and native, histamine H4 receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan‐induced peritonitis.
Key results: A‐940894 potently binds to both human and rat histamine H4 receptors and exhibits considerably lower affinity for the human histamine H1, H2 or H3 receptors. It potently blocked histamine‐evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine‐induced shape change of mouse bone marrow‐derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell‐dependent model of zymosan‐induced peritonitis, A‐940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D2 levels. Finally, A‐940894 has good pharmacokinetic properties, including half‐life and oral bioavailability in rats and mice.
Conclusions and Implications: These data suggest that A‐940894 is a potent and selective histamine H4 receptor antagonist with pharmacokinetic properties suitable for long‐term in vivo testing and could serve as a useful tool for the further characterization of histamine H4 receptor pharmacology.
EAU Guidelines on Chronic Pelvic Pain Fall, M.; Baranowski, A.P.; Fowler, C.J. ...
European urology,
12/2004, Letnik:
46, Številka:
6
Journal Article
Recenzirano
On behalf of the European Association of Urology (EAU) guidelines for diagnosis, therapy and follow-up of chronic pelvic pain patients were established.
Guidelines were compiled by a working group ...and based on current literature following a systematic review using MEDLINE. References were weighted by the panel of experts.
The full text of the guidelines is available through the EAU Central Office and the EAU website (
www.uroweb.org). This article is a short version of this text and summarises the main conclusions from the guidelines on management of chronic pelvic pain.
A guidelines text is presented including chapters on prostate pain and bladder pain syndromes, urethral pain, scrotal pain, pelvic pain in gynaecological practice, role of the pelvic floor and pudendal nerve, general treatment of chronic pelvic pain and neuromodulation. These guidelines have been drawn up to provide support in the management of the large and difficult group of patients suffering from chronic pelvic pain.
Background: Physically active physicians are more apt to counsel patients about exercise.
Purposes: The purpose of this study was to determine the effect of a physician fitness program on resident ...physician cardiovascular fitness, physical activity behavior/stage of change, and physical activity counseling behavior/attitudes.
Methods: A prospective, intervention study with measurements at baseline (before intervention), 3 months (immediately after intervention), and 6 months (3 months after intervention) evaluated a multifaceted exercise program for 48 internal medicine residents. Resident physician cardiovascular fitness, energy expenditure, physical activity stage of change, knowledge, attitudes, and counseling behavior were measured.
Results: Resident physician fitness significantly declined over time (baseline VO
2
-170 = 29.1 ml/kg/min, first follow-up VO
2
-170 = 27.3 ml/kg/min, and second follow-up VO
2
-170 = 26.2 ml/kg/min; p =. 001). Although there was no change in overall energy expenditure, the number of resident physicians in the precontemplation or contemplation stage of change significantly declined with a corresponding increase in the number in a "higher" stage of change at first (p =. 0034) and second follow-up (p =. 024). There was a nonsignificant increase in self-reported patient counseling. Resident physician counseling confidence and perceived success significantly improved at first follow-up only (p =. 01 and p =. 03, respectively).
Conclusion: Although resident physician fitness and energy expenditure did not improve after intervention, a significant improvement in resident physician physical activity stage of change and attitudes toward patient counseling was noted. Randomized controlled trials are needed to confirm whether these changes are attributable to the intervention.
'Tahiti' lime fruits (Citrus X 'Tahiti'), also known as 'Persian' lime, a reputed host of Caribbean fruit fly, Anastrepha suspensa (Loew), were investigated for presence of natural infestations of ...the pest. The fruits were commercially grown and harvested for the fresh market in Dade and Collier counties, FL, within the year-round geographic breeding range of the pest. Samples were unwashed, unsorted, ungraded, random aggregates obtained from packinghouses and included damaged, deformed, and rotted fruits as well as sound yellow and green fruits. Samples were held over sand for at least 30 d to collect emergent larvae and pupae. Immediately after the holding period, fruits were cut open and the peel, albedo, and pulp were visually inspected for larvae and pupae. In total, 102,384 fruits (9.307 metric tons) from 184 different groves and 60 harvest dates during the period from May 1990 to May 1991 were examined. No Caribbean fruit flies were detected, providing evidence that 'Tahiti' limes do not contain natural infestation levels of this pest that pose a high risk of its spread
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