Use of an inverse agonist radioligand [3H]A-317920 reveals distinct pharmacological profiles of the rat histamine H3 receptor.

Selective radioligands for histamine H(3) receptors have been used to characterize H(3) receptor pharmacology by radioligand binding assays and to determine H(3) receptor distribution by tissue autoradiography. Here we report the synthesis and receptor binding characterization of [(3)H]A-317920 (furan-2-carboxylic acid(2-[4-[3-([3,5-(3)H]4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl]-1-methyl-2-oxo-ethyl)-amide), a high affinity inverse agonist radioligand for the rat H(3) receptor. The binding of [(3)H]A-317920 to rat cortical and cloned H(3) receptors revealed fast on- and slower off-rate kinetics with calculated K(d) values in agreement with those determined in saturation binding assays (0.2 nM for both receptors). Further, we compared [(3)H]A-317920 with the agonist [(3)H](N)-alpha-methylhistamine ([(3)H]NalphaMH) as radioligand tools to study receptor pharmacology. Agonists and antagonists displaced [(3)H]NalphaMH with one-site binding characteristics and Hill slopes approached unity. In contrast, although antagonists exhibited one-site binding, [(3)H]A-317920 displacement by agonists was best fit by two-site binding models, and the potencies of the high affinity, GDP-sensitive sites correlated with the potencies defined in [(3)H]NalphaMH binding. Unlike [(125)I]iodoproxyfan, [(3)H]A-317920 exhibits potent and selective binding to rat H(3) receptors with low binding to non-H(3) sites, including cytochrome P450. These findings show that [(3)H]A-317920 is a potent rat H(3) receptor antagonist radioligand and has utility for studying H(3) receptor pharmacology.

Molecular modeling and pharmacological analysis of species-related histamine H(3) receptor heterogeneity.

Presynaptic histamine H(3) receptors (H(3)R) regulate neurotransmitter release in the central nervous system, suggesting an important role for H(3) ligands in human diseases such as cognitive disorders, sleep disturbances, epilepsy, or obesity. Drug development for many of these human diseases relies upon rodent-based models. Although there is significant sequence homology between the human and rat H(3)Rs, some compounds show distinct affinity profiles. To identify the amino acids responsible for these species disparities, various mutant receptors were generated and their pharmacology studied. The N-terminal portion was shown to determine the species differences in ligand binding since a chimeric H(3)R containing N-terminal human and C-terminal rat receptor sequences exhibited similar pharmacology to the human receptor. Sequence analysis and molecular modeling studies suggested key amino acids at positions 119 and 122 in transmembrane region 3 play important roles in ligand recognition. Mutant receptors changing amino acids 119 or 122 of the human receptor to those in the rat improved ligand binding affinities and functional potencies of antagonist ligands, confirming the significant role that these amino acids play in species-related pharmacological differences. A model has been developed to elucidate the ligand receptor interactions for H(3)Rs, and pharmacological aspects of this model are described.

A comparison of the bioavailability of oral and intramuscular dexamethasone in women in late pregnancy.

OBJECTIVE: To compare the bioavailability of oral and intramuscular (i.m.) dexamethasone in third-trimester pregnant women. METHODS: Oral and i.m. dexamethasone levels were compared in a randomized, parallel, crossover bioavailability study involving 11 gravid women in the third trimester of pregnancy. Subjects were randomized to receive either 6 mg of i.m. or 8 mg of oral dexamethasone. The following week, the alternative regimen was administered. Serial blood samples were obtained after drug administration. Dexamethasone concentrations were measured by radioimmunoassay. Total area under the curve was compared for the oral and i.m. groups using a paired t test. RESULTS: Eight of the 11 women completed the study through 12 hours; all 11 women completed the study through 6 hours. Among the 11 women, peak levels of dexamethasone occurred 30 minutes after i.m. injection (mean +/- standard deviation, 101.7 +/- 19.2 ng/mL) and 120 minutes after oral administration (65.9 +/- 20.5 ng/mL). Area under the curve did not differ significantly between those receiving i.m. dexamethasone (258.3 +/- 50.0 ng/minute/mL) and those receiving oral dexamethasone (251.8 +/- 59.7 ng/minute/mL) when measured 6 hours after administration of the drug. Terminal half-lives were similar in the i.m. and oral groups. Similar findings were noted among the eight women who were studied through 12 hours. This study had a power of 87% to detect a 20% difference in area under the curve between the two groups. CONCLUSION: The bioavailability of 8 mg of oral dexamethasone is similar to that of a 6-mg IM dose, as determined by the area under the curve.

Coping patterns and related characteristics in patients with IBD.

This article describes a study designed to examine the coping behaviors, personality, and mood characteristics of 150 nonhospitalized adults with inflammatory bowel disease (IBD). Self-report questionnaires and interviews were used to collect the data. Coping responses were measured with the Jalowiec Coping Scale. The Eysenck Personality Questionnaire (EPQ) and Beck Depression Inventory (BDI) were used to ascertain other characteristics. Data were analyzed using analysis of variance (ANOVA), Pearson's correlation coefficient (r), and descriptive statistics. IBD patients scored significantly higher on using problem-oriented coping patterns than on using affective-oriented methods. The results suggest that coping patterns in IBD patients are remarkably effective in contributing to lifestyle satisfaction. It can be inferred that adaptive efforts of IBD patients can be enhanced if health professionals consider coping patterns in the assessment process and if they actively support a sense of control in these patients.

In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties.

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-benzo[6,7]cyclohepta[1,2-d]pyrimidin-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.

Inflammatory bowel disease impact and patient characteristics.

A major purpose of this survey was to describe the impact of inflammatory bowel disease on the daily life of 150 nonhospitalized adults. A complementary purpose was to examine patient characteristics and their relationship to perceived impact. Self-report questionnaires and interviews were used to collect the data. Most patients reported a low to moderate impact of the disease on daily life. Greatest impact was reported in the areas of elimination, worry, recreation and leisure activities, sleep and rest. Among patient characteristics that correlated positively with the impact variable were age, under 35 years, female gender, depressed mood, and affective-oriented coping style. The findings suggest that nurses and other health professionals may enhance patient adaptation and life satisfaction by focusing efforts on patient characteristics that are amenable to change and on areas of life where the disease impact is experienced most intensively.

Antibiotic use in pregnancy and drug-resistant infant sepsis.

OBJECTIVE: We sought to evaluate the effect of antepartum and intrapartum antibiotic use on antimicrobial-resistant neonatal sepsis. STUDY DESIGN: We analyzed perinatal outcomes for 8474 pregnancies (8593 live births) delivered at 6 hospitals. Data were collected regarding maternal antibiotic use and perinatal course, neonatal cultures, and outcomes. The diagnosis of confirmed neonatal sepsis required at least one positive blood or cerebrospinal fluid culture. Neonatal cultures were evaluated on the basis of the occurrence and timing of maternal antibiotic exposure. RESULTS: There were 96 neonates with confirmed sepsis (11.2/1000 live births). Sepsis was 19.3-fold more common after preterm birth (57 vs 3. 1/1000; P <.001), with 76% of septic infants being delivered preterm. Forty-five percent of pathogens were ampicillin resistant. Ampicillin resistance increased with preterm birth (50% vs 26%; P =. 04), antepartum antibiotics (57% vs 34%; P =.03), intrapartum antibiotics (55% vs 28%; P <.01), and any prenatal antibiotic exposure (52% vs 22%; P =.01). Infection with an organism resistant to at least one maternal antibiotic was more common with intrapartum antibiotic exposure than with antepartum exposure only (57% vs 17%; P =.01). Regarding early-onset sepsis (n = 55), ampicillin resistance was more common with intrapartum antibiotics (50% vs 16%; P <.01), and resistance to at least one maternally administered antibiotic was more frequent with intrapartum exposure (56.7% vs 0%; P <.01). CONCLUSIONS: Maternal antibiotic treatment is associated with neonatal sepsis by organisms resistant to ampicillin and to maternally administered antibiotics.