Conclusions: In summary, the examples reported in the present review highlight the dual nature of cationic liposomes: carriers and agents that modulate cellular responses (1). Most cationic lipids transport hydrophilic materials (DNA, RNA, proteins) into the cell but can also modify specific cellular activities(immunostimulatory and anti-inflammatory properties). Novel strategies, based on the co-existence of these two functions, have already been elaborated successfully.Combining the immunostimulatory activity of cationic liposomes with their carrier property could be a way to act simultaneously on the immune system and the target cell.
1)Lonez C, Vandenbranden M, Ruysschaert JM. Cationic liposomal lipids: From gene carriers to cell signaling. Prog Lipid Res. (2008), 47(5):340-7
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National Surveillance of Antibiotic Resistance in Iran
SABERI M 1,2, HOSSEINIDOST,SR 3, HOSSEINI,SGA 3
1Department of Pharmacology and Toxicology, 2Chemical Injuries Research Center, 3Mollecular Cell Investigation Center, Faculty of Medicine, Baqiyatallah University of Medical Sciences, P.O. Box 19568, Tehran, Iran
Background: Over usage and inappropriate use of antibiotics has fueled a major increase in prevalence of multi-drug resistant pathogens, leading some to speculate that we are nearing the end of antibiotic era. Based on several reports from the most important hospitals, microbial resistance to the available antibiotics become a novel complex medical problem and is one reason of death in impatiens. Event the out patients with uncomplicated infection after staying in the hospital have acquired new resistant infection with the progress to the morbidity and mortality. In this study, the pattern of bacterial resistance was evaluated in hospitals of five important states of Iran.
Methods: The samples were collected from impatients who had infections unresponsiveness to the routine classic treatments . After culturing and isolation of the bacteria, using disc diffusion and minimum inhibitory concentration (MIC), the sensitivity tests to the appropriate antibiotics for each sample was achieved. Results: The type of bacteria were including; pneumococcus (9%), staphylococcous positive coagolase (4%) and negative coagolase (21.3%), pseudomonas aeruginosa (18.9%), klebsiella (25.6%), Ecoli (26.8%), shigella (1%), proteus (0.2%) and acintobacter (1%). Among these bacteria staphylococcus aureous, pseudomonas aeruginosa, klebsiella and acintobacters showed the most resistance to the even new appropriate antibiotics, and some species were completely resistant to the tested antibiotics, includiug cefepime and tozocine (pipeacilline plus Tazobactam).
Conclusions: This study showed a high and dangerous nasocomial microbial resistance, which needs intensive sanitary programs and hospital disinfection to control nasocomial infections. Also the clinician should determine whether antimicrobial therapy is warranted for a given patient and is one agent or combination of agents necessary to eradicate the infection with optimal dose, duration, and route of administration.
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Nonmedical factor influencing the prescribing of antibacterials
SABO A, TOMIĆ Z, HORVAT O, MIKOV M, VASOVIĆ V, JAKOVLJEVIĆ V, RAŠKOVIĆ A
Faculty of Medicine Novi Sad Serbia
Background: Antibacterials (AB) are drugs with very specific indications. However, this indications are not always strictly followed. The reasons are numerous- from empirical treatment, inadequate or inappropriate diagnosis, absence of treatment guidelines etc. In addition, numerous non medical reasons influence prescription pattern of AB, and often significantly contribute to bacterial resistance development. This is particularly important in areas with high consumption of AB. The aim of this work was to analyse some of non medical factors influencing high use of AB in Serbia. Usage of AB in Serbia has been high for many years, with tendency to increase during the last few years (table).
Use of antibacterials (J01) in Serbia
Year
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DDD/1000 inhabitants/year
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1989*
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24
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1995*
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25
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2005
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33.5
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2007
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45.7
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(*Data from own studies; for 2005 and 2007 data were taken from yearly report published by National drug agency)
Results: Some of the reasons to high consumption of AB in Serbia:
1.) During the past 15 years numerous private pharmacies were open, where all drugs can be obtained without prescripition. In one municipality with private and state pharmacy during the one month total of 11350 DDD of AB were obtained, 13% of them without prescription, mostly in private pharmacy. More than 95% of the buyers did not go previously to the doctors, and bought AB as a part of self medication. More than 60% of AB belonged to doxicycline. The reason for this choice was low price and once daily administration. Ampicillin was on second place being old, well known drug. 2.) The control of prescribing of AB by the doctors is still not everyday practice. 3.) Introduction of the controll of precribing AB in outpatient practice as well as in Clinics lowered use of AB for app. 30%, without influencing the treatment of the patients, leading at the same time to significant pharmacoeconomic improvement. 4.) While the doctors do not strictly follow the guideline for the treatment of bacterial infections, simple infections are often treated with expensive AB, as well as with combinations of two or three AB leading to the effect of overtreatment and resistance developroment. 5.) Pharmaceutical industry did found open space for advertising. In situation of weak control and weak implementation of guidelines, doctors often follow industry`s advertising guidelines, what leads to unnecessary high usage of some of them. The example is usage of cefepime, whose usage increased for the last year more than twice.
Conclusion: Implementation of guidelines, educative efforts, law reforms are necessary to lower ind improve use and prescribing practice of AB.
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SABZEVARI O, PAYDAR H
Dept. of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IRAN
Background: Strategic location of liver between intestinal tract and the rest of the body facilitates its task of maintaining metabolic homeostasis, secretory and excretory functions in the body. Therefore, the key organ in the body is the dominant target site of specific toxins. Accordingly, liver disorders are numerous and varied. Species of Scrophularia, Plantago psyllium and Fumaria officinalis have been used in traditional medicine as a remedy for liver diseases. In the present study, effect of aqueous-methanolic extract of Plantago psyllium, Fumaria officinalis and total extracts of aerial parts of five Scrophularia species, collected from north-eastern of Iran, were investigated against acetaminophen-induced acute liver damage and mortality rate, and compared to a known hepatoprotective plant, Silybum marianum.
Methods: This study included 72 male mice (24 mice per treatment, weight: 20 3 g, aerage SD). Tumor growth and animal survival was compared over 21 days between the following treatments: A) 20 mg/kg of drug X given every 6 h, B) 20 mg/kg of drug Y given every 6 h, or C) placebo. All doses were given as iv bolus. Unbound plasma concentrations in each mouse were determined after doses 1, 21, 41, 61, & 81 at three of the following time points: 0.25, 0.5, 1, 2, 3.5, & 6 h by ultrafiltration and validated LC-MS/MS assays. Population PK/PD models were developed in software XYZ to describe the PK, tumor growth, and animal survival. Dosage regimens were compared by Monte Carlo simulations.
Results: Acetaminophen produced 100% mortality at the dose of 1 g/kg in mice, while pre- and post-treatment of animals with Plantago psyllium and Fumaria officinalis extracts (300 & 500 mg/kg, orally twice daily for three days) reduced the mortality rate. The extracts at the employed doses, significantly lowered the acetaminophen-induced rise in the serum transaminases (SGOT and SGPT). Liver sections were also studied histopathologically to confirm the biochemical results. Pretreatment of animals with S. striata and S. variagata extracts (100 mg/kg, i.p., twice daily for 48 hrs) reduced the mortality rate and significantly lowered the rise in serum transaminases (SGOT and SGPT). Post-treatment of animals with four successive doses of S. striata and S. variagata extracts were reduced the mortality rate and significantly lowered the rise in the measured serum transaminases.
Conclusions: The results indicate that the crude extracts of Plantago psyllium, Fumaria officinalis, Scrophularia striata and Scrophularia variagata exhibited hepatoprotective action against acetaminophen-induced liver injury and reduced the mortality rate, which is comparable to that of Silybum marianum, a known hepatoprotective. These findings further validate the traditional use of plants in hepatic damage.
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Under-treated painful condition may lead patients to opioid abuse
1SAEIDIAN SR, 2SAIIAH BM
Jundishapour University of medical sciences, Ahvwaz Iran
Objective: To find the prevalence of Opioid abuse caused by a poorly treated painful disease.
Introduction (Background): Despite the physician reluctance to prescribe Opioids, the use of Opioid drugs for acute and chronic non-cancer pain are increasing. Although these drugs provide an important analgesic effect, they impose the risk of substance abuse to the addiction prone patients. The systematic literature reviews among the patients treated with Opioid drugs for acute or sub- acute painful conditions could not adequately answer whether the risk for iatrogenic addiction among these patients is relatively high. In order to get the incidence of Opioid abuse in a society in which the Opioid drugs are not easily available to treat painful conditions, this study was designed.
Design: By doing a pilot study the prevalence of Opioid- abuse following a poorly treated painful disease among the patients with the Opioid was determined and the size of the study participant was estimated. All the participants were evaluated via a psychiatric interview to determine the existence of Opioid abuse based on the criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM ²V). Also Minnesota Multiphasic Personality Inventory (MMPI) test was performed for all the patients. Provided they claimed a painful condition lead them to the Opioid abuse, a thorough physical examination was performed to find the somatic signs of the nociception.
Results: Twenty-six out of two hundred fifty participants had an organic source of pain.
Conclusion: Opioids are useful drugs in the treatment of acute and chronic non-cancer painful conditions. But inappropriate indications and problems with the overuse along with the problems of under prescribing due to the fear of addiction and regular dose control could urge the patients to Opioid abuse even criminal diversion.
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Vaccination in Patients with Cancer: Strategies to Prevent Influenza and Pneumococcal Disease
SAFDAR A
M.D. Anderson Cancer center
BACKGROUND: Cordblood-derived (CB) is an important source of mostly unprimed stem cells. We sought to generate CB-derived dendritic cells (DC) immunotherapy against influenzavirus.
METHODS: Recombinant hemagglutinin (rHA) of H1N1 was expressed by vector pPSC12 cloned baculovirus in SF9 cells. Generation of Immature DCs. Umbilical cord blood units discarded from the MDACC CB bank was used after IRB approval. DC loading and maturation: in the presence of GM-CSF and IL-4, immature dendritic cells were loaded with rHA protein. Immature DCs were suspended at a concentration of 4 x 107 cells/ml, mixed with rHA and incubated for 10 minutes on ice in an electroporation cuvette. T-cell priming and re-Stimulation: matured loaded DCs were incubated at a ratio of 1:10 with autologous non-adherent PBMCs (typically 50% CD3+), plus IL-12. ELISpot Assay was performed using standard method. ELISpots for putative HA peptide epitopes were performed similarly using 1x 105 - 2x 105 lymphocytes incubated overnight in 3.75 μg/ml peptide. T-cell specificity and functionality was then demonstrated by 51Cr CTL lysis.
RESULTS: rHA-specific lymphocytes demonstrate identifiable HLA-restriction. HA-primed lymphocytes (HLA DRbeta1*1503) from a different CB demonstrated a nine-fold increase in statistically large spots when restimulated with the DR15-262 epitope (p<0.00002). These data suggest that 1 in 1,900 of the HA-specific T-cells were DR15-262 restricted in a highly-specific fashion. Total ELISpot numbers (p<0.0002) and total IFN-gamma release (p<0.00004) between lymphocytes restimulated with DR15-262 and the control peptide were statistically distinct as well. Incubation of peptide DR15-262 in conjunction with HA-primed/DR15- lymphocytes or in conjunction with adenoviral hexon-primed (irrelevant) lymphocytes did not demonstrate significant numbers of IFN-gamma spots. 51Cr CTL assay demonstrates the generation of HA-specific cytotoxic T-cell effectors. Naïve cord blood T-cells were stimulated three times with rHA-loaded dendritic cells; specific lysis of rHA-loaded autologous DC was double that of unloaded control targets at an E:T ratio of 5:1 (p=0.05).
CONCLUSIONS: The results demonstrate that, despite the generally naïve CB lymphocytes, influenza HA-specific responses can be generated ex vivo and could be potentially be used to enhance immune reconstitution following allogeneic stem cell transplantation.
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Designing Peptidic Magic Bullets Against Bacteria
SAHAL D1, DEWAN PC, ANANTHARAMAN A, CHAUHAN VS
International Centre for Genetic Engineering and Biotechnology, New Delhi110067, India
Background: In the midst of rampant drug resistance, understanding the mechanisms of drug action can aid faster evolution of better drugs. Aim: To find roles of aromaticity, helicity and valency in the action of de novo designed antimicrobial peptides.
Methods: An amphipathic, cationic decapeptide Ac-GXR+K+XHK+XWA-NH2 was designed and peptides with X= didehydrophenylalanine (Fm, aromatichelical) / -aminoisobutyric acid (Um, aliphatichelical)/ phenylalanine (Fm, aromaticrandom) synthesized. Lysine branched bivalent dendrimers of all three (Ud, Fd, Fd) and a non-helical diastereoisomer (nhFd) of Fd were also synthesized. Minimum Inhibitory (MIC) and Bactericidal (MBC) concentrations against E.coli and S.aureus, FACS, fluorescence and electron microscopy, RPHPLC and gel electrophoretic methods were used to study mode of action.
Results: Bacteriostatic effects were nil (Um), mild and transient (Fm) and strong and persistent (Fm). Even though at par in binding to Lipopolysaccharide, Fm and Fm, but not Um, caused outer membrane permeabilization. Inner membrane permeabilization was attenuated and membrane architecture rehabilitated with Fm but not Fm. RPHPLC revealed that Fm was translocated into E.coli while Um and fragments of Fm were detected in the medium. Among monomers, only Fm was modestly antibiotic MICs 110 M (E.coli), 450 M (S.aureus). However, its dendrimer Fd, was potent against both gram-negative E.coli (MIC 2.5 M,MBC 5 M) and gram-positive Methicillin resistant S.aureus (MIC 5 M,MBC 7.5 M). nhFd retained some activity against E.coli (MIC 5 M, MBC 25 M) but was inactive against S.aureus (MIC 55 M, MBC 150 M). Fd is a potent, non-cytotoxic, fairly stable, bacterial cell permeabilizing and penetrating antimicrobial peptide.
Conclusions: (1) Dendrimerization represents a scaffold for potentiation of antimicrobial peptides and the presence of F in helical fold confers activity against both E.coli and S.aureus. (2) Potency comes from targeting both membranes and interior of cell. (2) In comparison to the subdued and sequential “membrane followed by cell interior” mode of action of the Fm, the strong and simultaneous “membrane along with cell interior” targeting by Fd potentiates and broadens its action across the gram negative-gram positive divide.
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Stenotrophomonas maltophilia Bloodstream Infections in Haematology and Non-Haematology Patients- A 5-year survey in Southwest Wales
EL-BOURI KW, SALAMAT AA
NPHS Swansea Microbiology and Dept. of Haematology, ABM University NHS Trust, Singleton Hospital, Sketty Lane, Swansea, Wales, UK.
Background: Stenotrophomonas maltophilia is an aerobic, ubiquitous gram-negative bacillus which is of low pathogenicity and is rarely involved in causation of community-acquired infections. However it is increasingly becoming a hospital-acquired pathogen in patients who are immunocompromised, intensively treated or having long-term vascular lines.
Aims: 1) To carry out a retrospective study of all cases of bacteraemia caused by S. maltophilia in both haematology and other hospital patients over a 5-year period from the beginning of 2003 till 2008 in a 1500-bed tertiary referral university teaching hospital; 2) to determine 30-day mortality attributable to S. maltophilia; 3) to establish possible risk factors for S. maltophilia sepsis; 4) to determine total isolates of S. maltophilia and the susceptibility patterns.
Methods: The study involved retrieving patient data from laboratory information management systems and the National Public Health Laboratory Service’s Datastore program using S. maltophilia as the key word.
Results. Over this period there were 1041 isolates of S. maltophilia from various clinical specimens from 585 patients. There were 90 episodes of bacteraemia in 69 patients during the survey period. Bacteraemias in 15 of the patients were regarded as contaminants on clinical grounds. Of the 54 patients with significant sepsis due to S.maltophilia, eighteen patients were suffering from haemato- oncological malignancies (9 had acute myeloid leukaemia, AML), while 16 were intensive care patients 4 of whom had burns, and 20 were general medical/surgical patients. The 30-day mortality rate for all patients was 46% (25/54) and in haemato-oncology patients it was 65% (11/17). The possible risk factors that were evident were immunosuppression especially in patients with AML and the use of broad-spectrum antibiotics especially the carbapenems where 63% (34/54) of all patients were recently on either meropenem or imipenem.
In haemato-oncology patients 82% (14/17) of patients were on carbapenems.
The susceptibility of S. maltophilia strains (isolates from all sites) tested by BSAC methods were as follows: amoxicillin (7%), co-amoxiclav (9%), aztreonam (26%), ciprofloxacin (11%), erythromycin (9%), gentamicin (19%), co-trimoxazole (87%), tigecycline (93%), timethoprim (3%) and piperacillin/tazobactam (88%).
Conclusions: S.maltophilia can cause significant morbidity and mortality in hospitalized patients especially those who are immunocompromised or under intensive care and the appropriate antimicrobials should be considered when it is isolated. The excessive use of carbapenems and other antibiotics may be selecting for S. maltophilia infections. Further research is urgently needed to develop antimicrobials that are active against S. maltophilia.
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Polyclonal Rabbit Antiserum Against Porcine-SP-A Able to Detect Human SP-A Using Immunochemical Methods
Kubrusly FS1; Sakauchi D2, Dias SC1, Iourtov D3, Gebara VCBC1, Horton DSPQ2; Piazza RM F4, Precioso AR1, 5, Mascaretti RS 1,5, Rebello CM1,5 & Raw I1
1Centro de Biotecnologia; 2Serviço de Controle de Qualidade; 3Laboratório de Surfactante Pulmonar; 4Laboratório Especial de Microbiologia; Unidade de Pesquisa Experimental da Faculdade de Medicina. 1,2,3,4 Instituto Butantan, 5USP, São Paulo, Brasil
Background: The lung collectins SP-A and SP-D are present in a number of biological fluids and secretions what could make them disease markers. The bronchoalveolar lavage (BAL) is a sample that permits to detect the proteins secreted by the lung epithelium; therefore BAL is extensively employed as well as the serum to determine the surfactant protein concentrations. The immunochemical methods to measure the surfactant proteins in these samples are mainly some variations of ELISA, most of them, using two different monoclonal antibodies (sandwich variant). Supported by the observed cross-reactivity among surfactant proteins of different mammalian species we produce polyclonal antibodies for human SP-A immunodetection using porcine SP-A as the antigen.
Methods: New Zealand female rabbits were immunized intramuscularly with a mixture of 300 micrograms of porcine SP-A and the complete Freund adjuvant. After 8 days, a booster injection of 150 microgramas of the protein mixed with incomplete Freund adjuvant was given. The bleeding was conducted on day 0 and 30. An indirect ELISA was done using human SP-A (hSP-A) purified from patients with rheumatoid arthritis as the human antigen calibrator and h-SP-A was directly coated onto microtiter wells. The calibration curve range was 0.312 to 5.0 g/ml using the antibody dilution 1:1,000. The curve range was based on the fact that no patient develops ARDS if at least 1.2 g/ml of SP-A was measured in the BAL. Immunoblot analysis: Pool of human BAL samples were resolved by SDS/PAGE under reducing conditions and electrophoretically transferred to PVDF membranes before incubation with the polyclonal anti-porcine SP-A (1:500).
Results: The hSP-A detection limit using anti-porcine SP-A (1:1,000) was 0.625 g/ml. The Western blot results showed that the antibody recognized specifically hSP-A in the pool of human BAL samples.
Conclusions: The anti-porcine SP-A is a promissory reagent to immunodetect human SP-A in the body fluids.
Supported by Fundação Butantan, FAPESP, CNPq and Sadia
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A Promising Future for Cancer Immunotherapy in an Oil-Rich Country like Kuwait: An Invitation for Pharmaceutical and Non-Pharmaceutical International Collaboration
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