Reversal of antibiotic resistance in Gram-positive bacteria by the antihistaminic azelastine.

Antibiotic resistance represents a serious problem that complicates microbial infection. The use of 'helper compounds' capable of enhancing the antimicrobial activity of antibiotics is being investigated. Azelastine, a new generation antihistaminic, possesses certain antibacterial activity and is capable of inducing alteration in the bacterial membrane permeability. Hence, we hypothesized that it could reverse resistance to antibiotics. Azelastine significantly increased the antibacterial activity of eight antibiotics belonging to five different classes (ß-lactams, macrolides, fluoroquinolones, aminoglycosides and tetracyclines) against nine Gram-positive clinical isolates: five Staphylococcus aureus, two Staphylococcus epidermidis and two Enterococcus faecium, seven of which were multi-drug resistant, reversing their resistance to the tested antibiotics. The synergistic effects of azelastine with the studied antibiotics increased with raising the pH from 5 to 8. Antibiotics did not affect the ability of azelastine to alter the permeability of a liposomal artificial membrane model, an effect thought to be critical for the interaction with antibiotics. The findings of this study present azelastine as a potential 'helper compound' that could reverse the resistance of multi-drug resistant Gram-positive clinical isolates to antibiotics.

In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates

Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 fg/ml azelastine was also determined and reached up to 3.36 h.

Membrane permeability alteration of some bacterial clinical isolates by selected antihistaminics

Several antihistaminics possess antibacterial activity against a broad spectrum of bacteria. However, the exact mechanism of such activity was unclear. Hence, the aim of this study is to investigate their mechanism of antibacterial activity especially their effect upon the permeability of the bacterial cytoplasmic membrane. The effects of azelastine, cetirizine, cyproheptadine and diphenhydramine were studied using Gram-positive and Gram-negative multiresistant clinical isolates. Leakage of 260 and 280 nm UV-absorbing materials was detected upon treatment with the tested antihistaminics; indicative of membrane alteration. Using an artificial membrane model, cholesterol-free negatively-charged unilamellar liposomes, confirmed the effect of antihistaminics upon the membrane permeability both by showing an apparent membrane damage as observed microscopically and by detection of leakage of preloaded dye from the liposomes colorimatrically. Moreover, examination of the ultrastructure of cells treated with azelastine and cetirizine under the transmission electron microscope substantiated the detected abnormalities in the cell wall and membrane. Furthermore, the effect of pretreating certain isolates for both short and long periods with selected antihistaminics was followed by the viable count technique. Increased vulnerability towards further exposure to azelastine was observed in cells pretreated with azelastine for 2 days and those pretreated with azelastine or cetrizine for 30 days.

Membrane permeability alteration of some bacterial clinical isolates by selected antihistaminics.

Several antihistaminics possess antibacterial activity against a broad spectrum of bacteria. However, the exact mechanism of such activity was unclear. Hence, the aim of this study is to investigate their mechanism of antibacterial activity especially their effect upon the permeability of the bacterial cytoplasmic membrane. The effects of azelastine, cetirizine, cyproheptadine and diphenhydramine were studied using Gram-positive and Gram-negative multiresistant clinical isolates. Leakage of 260 and 280 nm UV-absorbing materials was detected upon treatment with the tested antihistaminics; indicative of membrane alteration. Using an artificial membrane model, cholesterol-free negatively-charged unilamellar liposomes, confirmed the effect of antihistaminics upon the membrane permeability both by showing an apparent membrane damage as observed microscopically and by detection of leakage of preloaded dye from the liposomes colorimatrically. Moreover, examination of the ultrastructure of cells treated with azelastine and cetirizine under the transmission electron microscope substantiated the detected abnormalities in the cell wall and membrane. Furthermore, the effect of pretreating certain isolates for both short and long periods with selected antihistaminics was followed by the viable count technique. Increased vulnerability towards further exposure to azelastine was observed in cells pretreated with azelastine for 2 days and those pretreated with azelastine or cetrizine for 30 days.

In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates.

Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 µg/ml azelastine was also determined and reached up to 3.36 h.

Incidence analyses of bladder cancer in the Nile delta region of Egypt.

Bladder cancer is the most common malignancy among Egyptian males and previously has been attributed to Schistosoma infection, a major risk factor for squamous cell carcinoma (SCC). Recently, transitional cell carcinoma (TCC) incidence has been increasing while SCC has declined. To investigate this shift, we analyzed the geographical patterns of all bladder cancers cases recorded in Egypt's Gharbiah Population-Based Cancer Registry from 1999 through 2002. Data on tumor grade, stage, and morphology, as well as smoking, community of residence, age and sex, were collected on 1209 bladder cancer cases. Age-adjusted incidence rates were calculated for males, females, and the total population for the eight administrative Districts and 316 communities in Gharbiah. Incidence Rate Ratios (IRR) and 95% confidence intervals (CI) were computed using Poisson Regression. The male age-adjusted incidence rate (IR) in Gharbiah Province was 13.65/100,000 person years (PY). The District of Kotour had the highest age-adjusted IR 28.96/100,000 among males. The District of Kotour also had the highest IRR among all Districts, IRR=2.15 95% CI (1.72, 2.70). Kotour's capital city had the highest bladder cancer incidence among the 316 communities (IR=73.11/100,000 PY). Future studies on sources and types of environmental pollution and exposures in relation to the spatial patterns of bladder cancer, particularly in Kotour District, may improve our understating of risk factors for bladder cancer in the region.

Analysis of RhoC expression and lymphovascular emboli in inflammatory vs non-inflammatory breast cancers in Egyptian patients.

Understanding the molecular factors that distinguish inflammatory breast cancer (IBC) from non-IBC is important for IBC diagnosis. We reviewed the records of 48 IBC patients and 64 non-IBC patients from Egypt. We determined RhoC expression and tumor emboli and their relationship to demographic and reproductive characteristics. Compared with non-IBC patients, IBC patients had significantly lower parity (P=0.018) and fewer palpable tumors (P<0.0001). IBC tumors showed RhoC overexpression more frequently than non-IBC tumors (87% vs. 17%, respectively) (P<0.0001). Tumor emboli were significantly more frequent in IBC tumors than non-IBC tumors (Mean+/- SD: 14.1+/-14.0 vs. 7.0+/-12.9, respectively) (P<0.0001). This study illustrates that RhoC overexpression and tumor emboli are more frequent in tumors of IBC relative to non-IBC from Egypt. Future studies should focus on relating epidemiologic factors to molecular features of IBC in this population.

Differences in Reliability of Reproductive History Recall Among Women in North Africa.

Breast cancer is the most common cancer among women in North Africa. Women in this region have unique reproductive profiles. It is essential to obtain reliable information on reproductive histories to help better understand the relationship between reductive health and breast cancer. We tested the reliability of a reproductive history-based questionnaire. We interviewed 25 breast cancer patients and 25 non-cancer controls from hospitals in Morocco and Egypt about their reproductive history in colloquial Arabic. The questions included pregnancy history, breastfeeding practices, menstruation, contraceptive use and knowledge of breast screening and re-interviewed the same women after 2 weeks. Two-way paired t-test was used to compare observed mean changes in response, and the Fishers Exact test was used for small-cell data. Pearson's correlation test was used to estimate the correlation of subjects' responses to continuous questions between the first and second interview. For categorical questions, percentage of agreement was calculated along with Cohen's Kappa Coefficient values. Moroccan subjects showed good to excellent agreement for responses to all demographic and reproductive questions (r = 0.87 to 0.99). Egyptian subjects had excellent agreement for these questions(r = 0.87 to 0.99), except for those regarding duration of oral contraceptive pill use and reported age at menarche (r = 0.72 and 0.59, respectively). We showed highly correlated responses to most reproductive questions. Duration of contraception use and age at first pregnancy elicited slightly less than reliable responses. In Egypt, responses relating to self-reported age at menarche were less reliable than those given by Moroccan subjects. Future epidemiological studies should take these differences into account when constructing reproductive history questionnaires.