Similar rapid onset of action and magnitude of effect of fexofenadine and cetirizine as assessed by inhibition of histamine-induced wheal-and-flare reaction.

BACKGROUND: Histamine-induced wheal-and-flare studies are useful, objective tests for determining differences in the peripheral H1-receptor blockade activities of antihistamines. OBJECTIVE: To evaluate the time of occurrence of 95% inhibition of histamine-induced wheal and flare after administration of fexofenadine hydrochloride, 180 mg, or cetirizine, 10 mg. METHODS: Forty-two volunteers (aged 18-60 years) were included in a randomized, double-blind, crossover study. Skin prick tests were undertaken using histamine (100 mg/mL) before treatment and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0 hours after treatment. Wheal and flare areas were evaluated, and the time to occurrence of 95% inhibition and the frequency of subjects exhibiting 95% inhibition before median time to 95% inhibition were calculated. RESULTS: Mean +/- SD time to 95% wheal inhibition was 2.46 +/- 0.71 hours with fexofenadine and 2.55 +/- 0.57 hours with cetirizine. The estimated mean difference between fexofenadine and cetirizine (-7 minutes in favor of fexofenadine; 2-sided 95% confidence interval, -21 to +7 minutes) was not statistically significant (P = .34). For wheal, 29% of subjects receiving fexofenadine and 24% receiving cetirizine achieved 95% inhibition before the median time of inhibition (2.5 hours). An exact permutation test yielded a P = .37. For flare, 26% of subjects receiving fexofenadine and 10% receiving cetirizine achieved 95% inhibition before the median time of inhibition (3 hours; P = .12 by exact permutation test). CONCLUSIONS: Fexofenadine and cetirizine have comparable onset of action times and similar frequencies of inhibition, as evaluated by the occurrence of 95% inhibition of histamine-induced wheal and flare.     

Evaluation of the inflammatory response in sera from acute ischemic stroke patients by measurement of IL-2 and IL-10

Objectives  

We compared the concentrations of the proinflammatory cytokine interleukin-2 (IL-2) with the anti-inflammatory cytokine interleukin-10 (IL-10) in serial serum samples from improved and expired acute ischemic stroke (AIS) patients to determine their prognostic usefulness.     

Oral health status and treatment needs of children attending special schools in South India: a comparative study

The aim of this study was to assess and compare oral health status and treatment needs of children with special healthcare needs (SHCN) between the ages of 5 and 15, with a matched group of healthy children, in Udupi District of South India. A cross‐sectional study of 265 children with SHCN was compared to 310 healthy children to assess differences in periodontal status, dentition status, treatment needs, and dentofacial anomalies using the WHO criteria. Chi‐square, t‐test, and Z‐tests were performed to compare different variables. p≤ 0.05 was considered statistically significant. A significantly higher prevalence of caries (89.1%), malocclusion, and poorer periodontal status was observed among children with SHCN compared to the healthy control group. Improving the oral health of these children will require maintaining good oral hygiene practices, which can be achieved with appropriate target‐based oral health approaches.     

A study of twin births in rural communities of Gujarat

The incidence and the factors that influence twinning were studied in six villages of Dholka Taluka, a rural field training centre. The twinning rate was 10.10 per 1000 maternities. The monozygotic and dizygotic twinning rates were 4.53 and 5.56, respectively by applying Weinberg's differential formula. In three fourths of the twin births, both twins were of same sex while in one fourth, they were of opposite sex. The twinning rates increased significantly with increase in parental age and pregnancy order of mother.     

In vivo inhibition of oestrone sulphatase and dehydroepiandrosterone sulphatase by oestrone-3-O-sulphamate

Many tumours in endocrine-sensitive tissues, such as the breast and endometrium, are hormone-dependent and the hydrolysis of oestrone sulphate (EIS) to oestrone by oestrone sulphatase (EI-STS) is a major source of oestrogen in such tumours. Oestrone-3-O-sulphamate (EMATE) has been shown to be a potent EI-STS inhibitor in vitro, and in this study its ability to inhibit enzyme activity in vivo was examined. EMATE was initially administered to female rats for 7 days, after which liver EI-STS activity was measured. As EMATE also inhibits a related sulphatase in vitro, dehydroepiandrosterone sulphatase (DHA-STS), its effect on the activity of this enzyme in vivo was also investigated. DHA-STS has a pivotal role in regulating the synthesis of another steroid with potent oestrogenic properties, androstenediol. Administration of EMATE almost completely inhibited liver EI -STS (99%) and DHA-STS (99%) activities and was active when given by the oral or subcutaneous routes. After a single dose of EMATE or following the cessation of multiple doses for 10 days, liver EI-STS activity remained inhibited (>95%) for up to 7 and 10 days, respectively. Other compounds, such as 4-hydroxytamoxifen and the “pure” anti-oestrogen ICI 182,780, which are reported to inhibit EI-STS activity in vitro, did not inhibit activity in vivo. In a preliminary study, EMATE, when injected over a 12-day period, effectively reduced the growth of EI S-stimulated nitrosomethyl-urea-induced mammary tumours in ovariectomised rats and inhibited tumour sulphatase activity in treated animals.     

Constitutive activity of G-protein coupled receptors: emphasis on serotonin receptors

Several lines of evidence indicate that G-protein coupled receptors (GPCR) may exist in a state that allows a tonic level of stimulation in vivo (constitutive activity). Several native forms of GPCR, when expressed in recombinant cell lines, display significant signal transduction stimulation in the absence of activating ligand. Many GPCR, including three serotonin receptors, display robust constitutive activation upon the mutation of a single amino acid, indicating mutations producing inappropriate constitutive activation may be etiological factors in diseases. If constitutive activity of GPCR is as common a phenomenon as some researchers suspect, this would suggest significant alterations in the classical model of ligand-receptor interactions. One of the most significant implications of constitutive activity for pharmacologists and medicinal chemists, is the possibility of developing drugs that lower the level of constitutive activity. Such compounds have been termed inverse agonists . These drugs, in theory, would have different physiological effects, and therefore possibly different therapeutic potential, than classical competitive receptor antagonists ( neutral antagonists ). Theoretical issues concerning constitutive activity in the GPCR family and some of the evidence supporting the existence of constitutive activity in the GPCR family is reviewed. Studies are presented demonstrating the procedures for producing and characterizing constitutive activated forms of serotonin receptors, including the demonstration of inverse agonist activity of drugs on these receptors.     

Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease

BACKGROUND: Caspase gene expression has previously been reported in terminal Alzheimer disease (AD) brain, but, currently, little is known about the temporal pattern of caspase gene expression relative to the onset and clinical progression of AD. OBJECTIVE: To derive a profile of caspase gene expression and proapoptotic indexes as a function of the clinical and neuropathologic progression of AD dementia. SETTING AND PATIENTS: Postmortem survey of nursing home patients characterized clinically by Clinical Dementia Rating (CDR) and neuropathologically by Consortium to Establish a Registry for Alzheimer's Disease criteria. DESIGN AND OUTCOME MEASURES: To assess messenger RNA expression of caspase-1, -2L, -2S, -3, -5, -6, -7, -8, and -9; apoptotic cell death by TUNEL assay; and poly (ADP-ribose) polymerase cleavage in postmortem brain tissue samples from cognitively normal (CDR 0), high risk of developing AD dementia (CDR 0.5), and severe dementia (CDR 5) cases. RESULTS: Compared with CDR 0 cases, elevated messenger RNA expression of caspase-1 and caspase-7 in the entorhinal cortex of CDR 0.5 cases coincided with increased poly (ADP-ribose) polymerase cleavage but not apoptotic cell injury. In the entorhinal cortex of CDR 5 cases, we found elevation of caspase-1, -2L, -3, -5, -6, -7, -8, and -9 and a greater than 4-fold increase in TUNEL-positive cells. Caspase messenger RNA expression was closely associated with neurofibrillary tangle and, to a lesser extent, neuritic plaque density. CONCLUSIONS: Proapoptotic mechanisms may be at play early in the onset of AD (before overt signs of apoptosis) and may be a conditional factor for later apoptotic cell injury or death. These data have relevance to potential therapeutic interventions for AD using selective caspase inhibitors.