Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy

BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.     

Suppression of hemopoiesis during CCl4-induced hepatic fibrosis: Role of systemic endotoxemia

CCl₄-induced hepatic fibrosis in mice was accompanied by insufficiency of bone marrow myelo- and erythropoiesis. Polymyxin B completely abolished these changes. This phenomenon can be explained by the development of macrophage endotoxin tolerance during hepatic fibrosis. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 8, pp. 172–175, August, 2000     

Increased expression of the CD80 accessory molecule by alveolar macrophages in asthmatic subjects and its functional involvement in allergen presentation to autologous TH2 lymphocytes

Background: Alveolar macrophages (AMs) are more efficient antigen-presenting cells in allergic individuals than in nonatopic subjects. Objective: We studied whether this difference may be correlated to increased expression of membrane costimulatory molecules, such as the B7 molecules (CD80 and CD86). Methods: Eleven subjects with allergic asthma sensitized to Dermatophagoides pteronyssinus and 5 healthy nonatopic volunteers underwent bronchoalveolar lavage, and the costimulatory molecule expression on AMs was evaluated. Peripheral blood T cells, either freshly isolated or as established D pteronyssinus -specific cell lines, were cultured with autologous monocytes or AMs as antigen-presenting cells. In vitro allergen-induced proliferation and cytokine production were evaluated in the presence of B7-blocking reagents. Results: Allergic individuals had a significantly higher proportion of AMs expressing the CD80 molecule than control subjects (28.5% ± 14.8% vs 1.4% ± 1.2%; P < .001), whereas no difference was observed in CD86 expression (2.0% ± 2.3% vs 1.1% ± 0.6; P > .1). In a large proportion of the asthmatic subjects we studied, AMs were presenting soluble antigens (tetanus toxoid and streptolysin-O) to freshly isolated T cells more efficiently than AMs from nonatopic control subjects. Finally, both T-cell proliferation and cytokine production of D pteronyssinus- specific established T-cell lines were inhibited by a CD80-blocking antibody in a dose-dependent manner. Conclusion: Costimulation by means of CD80 expressed by AMs is probably involved in the amplification of the allergen-specific T-lymphocyte response in the airways of asthmatic subjects. (J Allergy Clin Immunol 1999;103:1136-42.)     

Lipopolysaccharide augments IgG and IgE responses of mice to the latex allergen Hev b 5

Background: LPS is a common contaminant in the health care environment and in latex examination gloves. Objective: We sought to investigate the role of LPS in enhancing the immune responses of mice to inhaled latex allergen. Methods: As our model allergen, we used a fusion protein containing the potent latex allergen Hev b 5. BALB/c mice were lightly anesthetized and given repeated intranasal doses of saline, LPS, and/or Hev b 5. The doses were given in 2 courses separated by a 6-week period, with the first course consisting of 6 doses and the second consisting of 3 doses. Results: After the first set of immunizations, mice given Hev b 5 alone had no detectable IgG1 or IgE responses to Hev b 5, whereas mice given the antigen along with LPS had significant responses (IgG1, 0.73 U ± 0.05; IgE, 0.88 U ± 0.2). No enhancement of specific IgG2a was observed. A stimulatory effect of LPS on all 3 immunoglobulin types was apparent after the second course. Lymphocytes from mice immunized with LPS and Hev b 5 had increased proliferation to Hev b 5 and its fusion partner. Conclusions: LPS may be an important immunoadjuvant for the development of allergic reactions to latex protein allergens. (J Allergy Clin Immunol 199;102:977-83.)     

Comparison of the efficacy of budesonide and fluticasone propionate aqueous nasal spray for once daily treatment of perennial allergic rhinitis

Background: Intranasal corticosteroids, such as budesonide and fluticasone propionate, are widely prescribed in the treatment of perennial allergic rhinitis. Once daily budesonide dry powder and fluticasone propionate aqueous suspension have been found to provide similar efficacy in controlling symptoms of perennial allergic rhinitis. Objective: The purpose of this study was to assess the efficacy and safety of treatment with once daily budesonide aqueous nasal spray. Methods: This study involved a multicenter, blinded, randomized, parallel-group, placebo-controlled trial of adults with perrenial allergic rhinitis. Patients (n = 273) recorded daily nasal symptoms for 8 to 14 days (baseline) and 6 weeks (treatment). Results: Budesonide decreased combined symptoms to a significantly greater extent than did fluticasone (P = .03); both treatments significantly decreased mean combined nasal symptoms scores compared with placebo. Of the 3 nasal symptoms assessed (ie, nasal blockage, runny nose, and sneezing), nasal blockage was significantly (P = .009) more decreased with budesonide compared with fluticasone. Both treatments also significantly improved runny nose and sneezing compared with placebo. Improvement in combined nasal symptom scores of the budesonide-treated group reached statistical significance within 36 hours compared with placebo (P = .01); in those patients treated with fluticasone, significant improvement compared with placebo was first observed within 60 hours. Adverse events were mild and transient. Conclusions: Once daily budesonide aqueous nasal spray, 256 μg, was significantly better in controlling the symptoms of perrenial allergic rhinitis than once daily fluticasone propionate, 200 μg, especially nasal blockage. Both treatments were superior to placebo. Budesonide may have a faster onset of action than fluticasone. (J Allergy Clin Immunol 1998;102:902-8.)     

Specific IgE to cross-reactive carbohydrate determinants strongly affect the in vitro diagnosis of allergic diseases

BACKGROUND: Cross-reacting carbohydrate determinants (CCDs) are antigenic structures shared by allergenic components from taxonomically distant sources. The case history of a patient with a great discrepancy between skin test and specific IgE results led us to investigate the role of these determinants in his specific case and in an allergic population. OBJECTIVE: We sought to determine the role of CCDs in causing false-positive and clinically irrelevant results in in vitro tests. METHODS: The involvement of CCDs was studied by specific IgE inhibition by using glycoproteins with a known carbohydrate structure. Direct and inhibition assays were performed by commercially available systems, in-house ELISA, and the immunoblotting technique. The binding to the periodate-oxidated carbohydrate structure of glycoproteins and allergenic extracts was also evaluated. A comparative study between skin test and specific IgE responses to the antigens studied was carried out in 428 consecutive allergic subjects. RESULTS: All the tests performed suggested that cross-reacting carbohydrate epitopes were the cause of false-positive specific IgE results in one of the commercial systems and the high reactivity in all the solid-phase in vitro tests. None of the cross-reacting carbohydrate allergens yielded a positive skin test response. Periodate treatment caused variable degrees of reduction of IgE binding to the different antigens studied, indicating that CCDs played a different role in each of them. About 41% of patients allergic to pollen had specific IgE for a glycoprotein, without a positive skin test response to the same molecule. CONCLUSIONS: CCDs must be taken into account when evaluating the clinical relevance of positive results in in vitro specific IgE assays, at least in the diagnosis of patients with pollen allergy. Commercial systems should be carefully assessed for the ability to detect specific IgE for carbohydrate determinants to avoid false-positive or clinically irrelevant results.     

Role of Thy 1.2+ cells in hemopoietic regulation in cytostatic-induced hemosuppression

Effect of Thy 1.2⁺ cells (direct and mediated by stromal elements) on the growth of granulomonocyte and erythroid colonies in the bone marrow is studied on CBA mice with cytostatic disease induced by single injection of adriamycin, cyclophosphamide, and 5-fluorouracil in maximum permissible doses. It is shown that Thy 1.2⁺ cells stimulate colony formation in regenerating bone marrow, the effect depending on functional activity of hemopoiesis-inducing microenvironment. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol 125, No. 5, pp. 509–513, May, 1998     

A comparative study of the effects of dimebon,obsidan, finoptin,and cordaron on the functional state of ischemic focus and size of necrotic zone in experimental myocardial infarction

Dimebon, an antihistamine agent, exerts a moderate antianginal effect, improving the function of ischemic focus in the myocardium and decreasing the necrotic zone in experimental myocardial infarction. Dimebon is less active than obsidan, finoptin (except for the size of the necrotic zone), and cordaron. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 12, pp. 642–644, December, 1996     

T lymphocytes that infiltrate nasal polyps have a specialized phenotype and produce a mixed TH1 /TH2 pattern of cytokines

Background: Nasal polyps (NPs) are inflammatory reactions in the nasal mucosa the etiology and pathogenesis of which remains unknown. Objective: The purpose of this study was to study in detail the phenotype and function of T lymphocytes infiltrating NPs by analyzing the expression of surface markers and cytokine secretion. Methods: NP tissue samples and peripheral blood were obtained from 18 patients. Mononuclear cells were purified from these samples, and their phenotype was investigated by triple-color immunofluorescence and flow cytometric analysis. Cytokine production was determined in cultures by using an ELISA technique. Results: NP lymphoid cells mainly consisted of T lymphocytes. These T lymphocytes showed a CD45RO+CD45RA– phenotype and expressed pan-T cell molecules; the CD8+ subset was predominant. NP T cells showed a lower density of CD28, CD3, and TCR-αβ compared with T cells from peripheral blood. NP T lymphocytes expressed the activation markers DR and CD69 and exhibited the adhesion molecule profile CD54+, CD62L–, and CD103+ CD49d^low . Virtually all NP T cells bore CD95 (FAS), but they did not undergo apoptosis, either spontaneously or induced by CD95 cross-linking with the mAb CH11. The pattern of cytokines secreted by NP T lymphocytes was characterized by the spontaneous and simultaneous production of IFN-γ and IL-5. Neither IL-2 nor IL-4 were detectable in nonstimulated cultures. Conclusion: This study defines the T lymphocytes that infiltrate NPs as memory T cells in an activated status, with homing properties related to the mucosal immune system. They are resistant to anti-CD95-mediated apoptosis and produced a mixed T_H1 /T_H2 cytokine pattern as defined by the simultaneous production of IFN-γ and IL-5. (J Allergy Clin Immunol 1998;102:953-60.)     

Comparison of the effects of terfenadine with fexofenadine on nasal provocation tests with allergen

BACKGROUND: Fexofenadine, the hydrochloride salt of terfenadine active metabolite, is a nonsedative, noncardiotoxic antihistamine derivative for the treatment of allergic rhinitis. OBJECTIVE: We sought to compare the effects of terfenadine and fexofenadine on nasal provocation tests with allergen. METHODS: A preliminary provocation test (screening phase) was performed in 25 patients with a history of seasonal allergic rhinitis to grass pollen to determine the combined nasal reaction threshold, which was defined as 2 of the 3 following criteria: (1) at least a 40% decrease in peak nasal inspiratory flow and/or a 30% decrease in minimal cross-sectional area as measured by acoustic rhinometry, nasal secretions of 0.5 g, and 5 to 10 sneezes per minute. Patients were then included into a double-blind, randomized, 2-way crossover study to receive terfenadine or fexofenadine 120 mg 2 hours before provocation. Rhinorrhea, sneezing, peak nasal flow, and minimal nasal cross-sectional area, as well as symptom scores for nasal congestion and itchiness, were recorded at each allergen concentration up to the reaction threshold. The whole study was performed out of allergy season. RESULTS: Fexofenadine was as potent as terfenadine in limiting pruritus and nasal congestion. Rhinorrhea and sneezing were better controlled by fexofenadine than by terfenadine. Overall, the allergen concentration necessary to reach the combined reaction threshold was increased after treatment with both drugs. Comparison between screening and each treatment phase indicated that the shift in allergen concentration to reach the reaction threshold was significantly greater after fexofenadine than after terfenadine (P =. 033). CONCLUSION: After oral administration, fexofenadine provided better protection than terfenadine against the immediate allergic reaction.     

Functional interaction between various glutamate receptors

The interaction of glutamate with various receptors in glutamatergic neurons and functional interaction between glutamate receptors are reviewed. It is hypothesized that metabotropic receptors perform defensive functions in the brain by protecting neurons from neurotoxic effects caused by excessive glutamate release. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, 130, No. 9, pp. 244–251, September, 2000     

Inhibition of IL-2-Dependent proliferation of human lymphocytes and of the expression of interleukin-2 receptors by synthetic peptide fragments of α-2 interferon

It is shown that biologically active peptides inhibit the concanavalin A-induced generation of cells which may proliferate in response to exogenous recombinant interleukin-2. Determination of the number of CD25-containing cells showed that synthetic peptides are able to lower not only the number of CD25-containing cells but the level of its expression as well. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 117, N ^o 1, pp. 65–68, January, 1994 Presented by I. P. Ashmarin, Member of the Russian Academy of Medical Sciences     

School as a risk environment for children allergic to cats and a site for transfer of cat allergen to homes

BACKGROUND: Many children are allergic to furred pets and avoid direct pet contact. The school may be a site of indirect exposure to pet allergens, which may induce or maintain symptoms of allergic diseases. OBJECTIVE: We sought to investigate airborne levels of cat allergen (Fel d 1) at schools and in homes with or without cats and to study clothes as a route for dissemination of allergens between homes and school. METHODS: Airborne cat allergen was collected with personal samplers from (1) children attending classes with many (>25%) or few (<10%) cat owners and (2) homes with or without cats. A recently developed amplified ELISA assay, which detects low levels of airborne cat allergen in pet-free environments, was used. Dust samples were collected from clothes and mattresses. RESULTS: There was a 5-fold difference in the median levels of airborne cat allergen between classes with many and few cat owners (2.94 vs 0.59 ng/m3; P <.001). The median airborne cat allergen concentration in classes with many cat owners was significantly higher than that found in the homes of non-cat owners (P <.001) but lower than that found in homes with cats (P <.001). Allergen levels in non-cat owners' clothes increased after a school day (P <.001). Non-cat owners in classes with many cat owners had higher levels of mattress-bound cat allergen (P =.01). CONCLUSION: The results indicate significant exposure to cat allergen at school. Allergen is spread through clothing from homes with cats to classrooms. There the allergen is dispersed in air and contaminates the clothes of children without cats. The allergen levels in non-cat owners' homes correlate with exposure to cat allergen at school.     

Study of cardioprotective effect of α-tocopherol and panthenol using an experimental model of ischemized-reperfused isolated heart

Using an experimental ischemia-reperfusion model it is found that combined treatment with α-tocopherol and panthenol markedly increases the content of endogenous antioxidant tocopherol during total ischemia and reperfusion, i.e., it improves the antioxidant state of the postischemized myocardium, thus preventing possible damage caused by stepped-up production of active oxygen forms during reoxygenation. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 117, N ^o 6, pp. 574–576, June, 1994 Presented by P. V. Sergeev, Member of the Russian Academy of Medical Sciences     

A cross-sectional survey of sensitization to Aspergillus oryzae–derived lactase in pharmaceutical workers

BACKGROUND: The presence of IgE-mediated occupational respiratory sensitization to microbial enzymes has been well documented in a variety of industries. Aspergillus oryzae -derived lactase is used as a dietary aid for patients with lactose intolerance. OBJECTIVE: In 1993, a cross-sectional survey of 94 pharmaceutical workers exposed to lactase for a mean duration of 23 months and 24 nonexposed recently hired employees was initiated to identify lactase-sensitized workers and potential risk factors that could be used in making recommendations for preventing future cases of lactase sensitization. METHODS: The survey included a physician-administered questionnaire, skin prick testing to lactase enzyme and a panel of common aeroallergens, and spirometry. RESULTS: Twenty-seven of 94 lactase-exposed workers (29%) had positive skin test responses to lactase. These workers were 9 times more likely to have upper or lower respiratory symptoms compared with workers with negative skin test responses. Atopic workers were 4 times more likely to have lactase skin sensitivity than nonatopic workers. However, atopy was not a risk factor for the development of upper and/or lower respiratory symptoms. Lactase skin reactivity was not observed in the 24 nonexposed employees. CONCLUSION: This cross-sectional survey revealed that atopic workers were more likely to have lactase sensitization and that lactase-sensitized workers were more likely to have upper and/or lower respiratory symptoms, but atopy was not a risk factor for upper or lower respiratory symptoms. In spite of these findings, the company allowed only nonatopic, nonlactase-sensitized workers to continue working in high lactase-exposure areas with careful symptom monitoring and use of protective clothing. Although this strategy was successful in total prevention of new cases of occupational respiratory disease after 5 years, the results of this cross-sectional survey do not support exclusion of atopic workers from working with industrial enzymes.     

Effects of topical corticosteroids on inflammatory mediator–induced eicosanoid release by human airway epithelial cells

Background: Airway epithelial cells are among the first cells to come in contact with aerosolized corticosteroids. However, the relative potencies and time course of action of the several commonly used aerosolized corticosteroids on eicosanoid production by airway epithelial cells are unknown. Objectives: This study compared the effects of fluticasone, budesonide, and triamcinolone on eicosanoid output by human airway epithelial cells in vitro. We also determined the spectrum of eicosanoids affected and the mechanism for corticosteroid action. Methods: Cultured BEAS-2B airway epithelial cells (a transformed cell line) were exposed to corticosteroids (1 nmol/L to 1 μmol/L) for 2 to 48 hours and then assayed for basal- and bradykinin (BK)-stimulated eicosanoid output. The eicosanoid profile was identified by HPLC in tritiated arachidonic acid prelabelled cells, and PGE₂, the major eicosanoid product, was quantitated by RIA. The effect of corticosteroids on the immunoreactivity of key proteins involved in eicosanoid metabolism (ie, cyclooxygenase [COX], phospholipase A2 [PLA₂], and Clara cell protein, a PLA₂ inhibitor) was determined by Western blotting. Results: Eicosanoid output was largely confined to prostaglandins with values of 5 ± 2 and 82 ± 35 ng PGE₂/10⁶ cells for basal- and BK stimulation, respectively (n = 8). All 3 corticosteroids inhibited basal- and BK-induced PGE₂ output in a dose- and time-dependent manner. Fluticasone and budesonide completely eliminated PGE₂ output in nanomolar concentrations in contrast to triamcinolone, which required micromolar concentration. The rank order of potency was: fluticasone = budesonide > triamcinolone. The time course of action for PGE₂ inhibition also differed, with budesonide acting more slowly than the other 2 corticosteroids (P = .04). All 3 corticosteroids markedly reduced COX2 with little effect on COX1, cPLA₂ (Type IV), or iPLA₂ (Type VI) immunoreactivity or their relative distribution in cytosol versus membrane fractions. Clara cell protein immunoreactivity was undetectable in control and corticosteroid-treated cell lysates. Conclusion: These results show that in a human airway epithelial cell line, the 3 inhaled corticosteroids commonly used to treat asthma differ in onsets of action as inhibitors of prostaglandin synthesis and vary considerably in potency. All 3 corticosteroids act mechanistically in similar fashion by inhibiting COX2 synthesis. (J Allergy Clin Immunol 1999;103:1081-91.)     

Mechanisms of modulation of GABA-induced currents in isolated cerebellar cells by tacrine

Tacrine, when applied by the concentration clamp technique to isolated Purkinje cells from rat cerebellum, dose-dependently reduced the amplitude of GABA-activated chloride currents recorded by the patch clamp technique. Half-maximal inhibition (IC₅₀) of currents activated by 2 μM GABA was observed at a tacrine concentration of 107 μM. Tacrine produced a right shift of the dose-response curves for GABA-induced currents without affecting their peak amplitudes. It is suggested that suppression of GABA-induced currents caused by tacrine can not be attributed to its interaction with the benzodiazepine site of the GABA_A receptor. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 5, pp. 539–542, May, 1999