Synthesis and biological evaluation of analogues of bacterial lipid I.

Bacterial Lipid I analogues containing different anomeric groups at the muramic acid moiety were synthesized and screened in MurG enzyme assays run in the presence and absence of cell wall membranes. The results obtained in this study help elucidate the role of the lipid diphosphate in the recognition of Lipid I by MurG.

Antibacterial activity of synthetic analogues based on the disaccharide structure of moenomycin, an inhibitor of bacterial transglycosylase.

Moenomycin is a natural product glycolipid that inhibits the growth of a broad spectrum of Gram-positive bacteria. In Escherichia coli, moenomycin inhibits peptidoglycan synthesis at the transglycosylation stage, causes accumulation of cell-wall intermediates, and leads to lysis and cell death. However, unlike Esc.

The effect of platelet-activating factor (PAF) on nasal airway resistance in healthy subjects is not mediated by nitric oxide.

Background: The nose is an important source of nitric oxide (NO) in man, but the relevance of NO production to the response to inflammatory mediators is not clear.

Methods: In this study, we evaluated the effect of NO inhibition on nasal airway resistance (NAR) at baseline, after an acute challenge with platelet-activating factor (PAF), a potent proinflammatory factor, and after an acute challenge with bradykinin (BK), both of which are mediators of allergic rhinitis in man. Eight healthy subjects were enrolled in the study.

Chemistry and cellular aspects of cationic facial amphiphiles.

A series of compounds containing a bile acid core and a polyamine side chain have been synthesized to evaluate their ability to promote the uptake of DNA into cells. These compounds differ from conventional cationic lipids because they contain a positively charged chain attached to a facial amphiphile rather than to a hydrophobic moiety. Formulations of several of the designed compounds were found to dramatically increase the cellular uptake of both plasmid and oligonucleotide DNA.

Pharmacologic actions of the second generation leukotriene B4 receptor antagonist LY29311: in vivo pulmonary studies.

We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]pro poxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) acute airway obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with the divalent cationic ionophore A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid).

Recent developments in solid- and solution-phase methods for generating carbohydrate libraries.

Carbohydrates and glycoconjugates have attracted a great deal of attention in recent years because of the key roles they play in biological processes. The development of carbohydrate-based libraries is a crucial step towards investigating the details of carbohydrate-mediated interactions, exploring the molecular diversity intrinsic to carbohydrates and identifying novel therapeutically interesting carbohydrate-containing drugs. This review describes recent advancements in solid- and solution-phase methods that relate to the generation of carbohydrate and glycoconjugate libraries.

Intestinal transport of gentamicin with a novel, glycosteroid drug transport agent.

Purpose: The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin.

Methods: Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC.

Pharmacologic actions of the second-generation leukotriene B4 receptor antagonist LY293111: in vitro studies.

The in vitro actions were investigated of LY293111, a potent and selective leukotriene B4 (LTB4) receptor antagonist, on human neutrophils, human blood fractions, guinea pig lung membranes, and guinea pig parenchymal and tracheal strips. The IC50 for inhibiting [3H]LTB4 binding to human neutrophils was 17.6 +/- 4.

Detection of IgG and IgA against the mycobacterial antigen A60 in patients with extrapulmonary tuberculosis.

Background: Diagnosis of extrapulmonary tuberculosis is often difficult to establish using standard methods. Serological techniques based on detection of antibodies against mycobacterial antigen A60 have shown good sensitivity and specificity in pulmonary tuberculosis. The present study was undertaken to define the diagnostic accuracy of testing for IgG and IgA against A60 in extrapulmonary tuberculosis.

Design of compounds that increase the absorption of polar molecules.

Hydrophilic drugs are often poorly absorbed when administered orally. There has been considerable interest in the possibility of using absorption enhancers to promote absorption of polar molecules across membrane surfaces. The bile acids are one of the most widely investigated classes of absorption enhancers, but there is disagreement about what features of bile acid enhancers are responsible for their efficacy.

Lack of effect of nitric oxide inhibition on bronchial tone and methacholine-induced bronchoconstriction in man.

The role of nitric oxide (NO) as a bronchodilator has been studied in humans with controversial results. The aim of the present study was to investigate the role of endogenous NO on bronchial tone by studying whether nitric oxide synthase (NOS) inhibition with NGnitro-L-arginine-methyl-ester (L-NAME) influences basal bronchial tone, or potentiates methacholine-induced bronchoconstriction. In a preliminary experiment in five subjects, a significant reduction in exhaled NO was found after delivering L-NAME (15 mg in saline) (from 3.

Characterization of platelet-activating factor acetylhydrolase in human bronchoalveolar lavage.

Platelet-activating factor (PAF) is a mediator produced in human airways during acute and chronic inflammatory lung diseases. The levels of PAF are regulated by acetylhydrolase (AH), the enzyme that converts PAF to lyso-PAF. To determine whether AH was present in human bronchoalveolar lavage (BAL) fluid, BAL was obtained from normal donors (n = 18) and from adult patients with mild bronchial asthma (n = 15) or with lung fibrosis (n = 15).

Urinary endothelin excretion in patients with acute lung injury.

Increase in circulating levels of endothelin (ET), a potent vasoconstrictive and mitogenic endothelium-derived peptide, has been proposed as a marker of endothelium dysfunction in acute lung injury (ALI). In the present study, we have measured levels of immunoreactive ET (irET) by radioimmunoassay, in arterial (irETart), venous (irETven) and urine (irETur) samples obtained from 10 patients with ALI and 10 healthy volunteers. Arterovenous ratio, 24 h urine excretion and renal clearance of the peptide were calculated, to obtain indices of endogenous ET metabolism.

Evaluation of IgA-mediated humoral immune response against the mycobacterial antigen P-90 in diagnosis of pulmonary tuberculosis.

Background: Serologic methods for diagnosis of tuberculosis have been widely investigated owing to their low cost and rapid technical execution. Sensitivity and specificity of different tests have been reported to be largely variable.

Study Objectives: To evaluate the IgA-mediated humoral immune response against the mycobacterial antigen P-90 as a tool for diagnosis of pulmonary tuberculosis.

Endothelin abnormalities in patients with pulmonary embolism.

Background: Endothelin (ET) is an endothelium-derived multifunctional peptide involved in the local regulation of the vascular tone.

Study Objectives: To assess changes of endogenous ET production/excretion in the acute phase (36 h from the event) of pulmonary embolism (PE).

Participants: Ten patients with acute PE, nine patients with acute lung injury (ALI), and 12 healthy volunteers (HVs).

Carbohydrate-based combinatorial libraries.

Carbohydrate-based combinatorial libraries are tremendously valuable for studying the role of sugars in biology and for expanding accessible molecular diversity needed in broad-based drug screening programs. This review discusses the issues that are relevant to the successful implementation of comprehensive carbohydrate-based combinatorial library programs. In addition, details of oligosaccharide and glycoconjugate libraries constructed using both solid phase and solution phase strategies are presented.

Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency: effect of 12 months' growth hormone replacement therapy.

We have described impairment of the respiratory function in adult patients with childhood-onset growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient before and after 6 and 12 months of recombinant GH treatment. Ten adults diagnosed as GH deficient in childhood, ten adults diagnosed as GH deficient in adulthood and ten healthy subjects entered the study.

Cationic facial amphiphiles: a promising class of transfection agents.

A promising class of compounds for DNA transfection have been designed by conjugating various polyamines to bile-acid-based amphiphiles. Formulations containing these compounds were tested for their ability to facilitate the uptake of a beta-galactosidase reporter plasmid into COS-7 cells. Dioleoyl phosphatidyl ethanolamine (DOPE) formulations of some of the compounds were several times better than Lipofectin at promoting DNA uptake.

Aerosolized LTB4 produces delayed onset increases in pulmonary gas trapping.

Airway obstruction, as measured by increases in postmortem pulmonary gas trapping, and lung inflammatory changes were examined in guinea pigs exposed for up to 4 h to aerosols of leukotriene B4 (LTB4) or its non-chemotactic isomer, 6-trans-12-epi-LTB4. Airway obstruction and cytological responses in isomer-exposed animals were similar to those of unexposed control animals. LTB4-exposed animals had minimal inflammatory changes at 0.

IgA immune response against the mycobacterial antigen A60 in patients with active pulmonary tuberculosis.

Searching for IgG and IgM against the mycobacterial antigen A60 has been recognized as a potential diagnostic tool for pulmonary tuberculosis. The role of detection of anti-A60 IgA in improving diagnostic accuracy of serology is not well known. In this study we measured with ELISA serum levels of both anti-A60 IgG and IgA in 216 subjects.

Impairment of lung volumes and respiratory muscle strength in adult patients with growth hormone deficiency.

Little is known of the respiratory function in patients with growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient in childhood. Ten patients diagnosed as GH deficient in childhood and ten healthy subjects entered the study.