Mechanism Of Oxidative DNA Damage And Apoptosis Induced By Doxorubicin Through Generation Of Reactive Oxygen Species
MIZUTANI H1, HIRAKU Y2, TADA-OIKAWA S2, OIKAWA S2, IKEMURA K1, MURATA M2, KAWANISHI S3
1College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan; 2Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan; 3Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka, Japan
Background: The anticancer mechanism of doxorubicin (DOX), an anthracycline antibiotic, is believed to involve DNA damage and apoptosis through topoisomerase II inhibition and reactive oxygen species (ROS). However, the precise mechanism of DNA damage and apoptosis induced by DOX remains to be clarified. We investigated the mechanism of DNA damage and apoptosis induced by DOX.
Methods: We used human leukemia cell line HL-60 and its H2O2-resistant HP100 cells. Apoptosis induced by DOX was detected by DNA ladder formation. Detection of peroxide and m in cells treated with DOX was analyzed on a flow cytometer. Measurement of caspase-3 activity was used by DEVD-AFC, a caspase-3 synthetic substrate. Measurement of 8-oxodG, a marker of oxidative DNA damage, was used by HPLC-ECD. In addition, we analyzed DOX-induced DNA damage, using 32P-labeled DNA fragments.
Results: DOX-induced DNA ladder formation could be detected earlier in HL-60 cells than in HP100 cells, suggesting the involvement of H2O2-mediated pathways in apoptosis. Flow cytometry revealed that H2O2 formation preceded the increase in m and caspase-3 activation. Poly (ADP-ribose) polymerase (PARP) and NAD(P)H oxidase inhibitors prevented DOX-induced DNA ladder formation in HL-60 cells. Moreover, DOX significantly induced formation of 8-oxodG, in HL-60 cells at 1 h, but not in HP100 cells. DOX-induced apoptosis was mainly initiated by oxidative DNA damage in comparison with the ability of other topoisomerase inhibitors to cause DNA cleavage and apoptosis. Moreover, DOX caused site-specific oxidative DNA damage in the presence of copper(II), which may contribute to apoptosis.
Conclusions: These results suggest that the critical apoptotic trigger of DOX is considered to be oxidative DNA damage by the DOX-induced direct H2O2 generation, although DOX-induced apoptosis may involve topoisomerase II inhibition. This oxidative DNA damage causes indirect H2O2 generation through PARP and NAD(P)H oxidase activation, leading to the m increase and subsequent caspase-3 activation in DOX-induced apoptosis.
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Chitosan-Ca-Alginate Microparticles As Carriers For Colon Delivery Of 5-Aminosalicylic Acid After Peroral Administration
Mladenovska K1, Cruaud O2, Goracinova K1, Efremova D1, Davitkovska E1, Venier-Juliene MC2, Popovski E3, Richomme P4
1Ss "Cyril and Methodious University", Faculty of Pharmacy, Skopje, Macedonia; 2University d'Angers, Angers, France; 3Ss "Cyril and Methodious University", Faculty of Natural Science, Skopje, Macedonia; 4SONAS, UFR des Sciences Pharmaceutiques, Angers, France
Background: 5-aminosalicylic acid (5-ASA) is widely used for its local effects in the treatment of inflammatory bowel diseases (IBD). The optimum oral 5-ASA delivery system requires technology that protects the drug during microencapsulation and distribution in the stomach and small intestine. For these requirements, a new chitosan-Ca-alginate microparticulated colon drug delivery system was prepared and characterized.
Methods: Microparticles were prepared by spray-drying technique. SEM was used to analyze particles’ size and surface morphology and for polymers localization, CLSM was used. Polymers interactions were evaluated using X-ray and DSC, while for 5-ASA stability, 1HNMR spectra in H2O/D2O were recorded. Influence of formulation variables on microparticles’ properties was evaluated and for multiple response optimization, mixed 2- and 3-level fractional factorial design was used. Drug release studies in different pHs and in rat cecal content were performed. Biodistribution and therapeutic effect of 5-ASA were tested in rats in which colonic inflammation was induced.
Results: Particles with zeta potential between -34 and 10 mV were obtained, with mean diameter less than 15 m, calcium content between 2.5 and 5% and encapsulation efficacy between 50 and 70%. Chitosan was localised dominantly in the particle wall, while for alginate, homogeneous distribution throughout the particles was observed. Thermograms and X-ray diffractograms indicated molecularly dispersed drug within the particles. Stability of 5-ASA during microencapsulation and in different pHs was also confirmed. Anomalous (non-Fickian) transport mechanism in 5-ASA release was determined, controlled by polymer relaxation, erosion and degradation. Biodistribution and efficacy studies in the animal model of inflammation confirmed the controlled release and colon specific delivery of 5-ASA.
Conclusion: The described 5-ASA loaded chitosan-Ca-alginate microparticulated system might be successfully used for clinical treatment of IBD.
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Swaziland Demographic and Health Survey 2006–2007 with Special Focus on the Prevalence Of HIV
MASUKU R1, MNGADI PT2, ZWANE IT2
1. Swaziland Central Statistics Office, Mbabane, Swaziland.
2. University of Swaziland, Faculty of Health Sciences, Mbabane, Swaziland.
Background: The 2006-07 Swaziland Demographic and Health Survey (SDHS) was a national-level sample survey which was implemented by the Central Statistical Office (CSO) at the request of the Ministry of Health and Social Welfare (MOHSW). The principal objective of the survey was to provide up-to-date information on prevalence of HIV among other things. The aim was to identify behaviours that protect or predispose the population to HIV infection, examine social, economic, and cultural determinants of HIV, and determine HIV prevalence among males, females and children age 2 years and older.
Methodology: Children age 2 to 14 years and older adults age 50 years and above in half the households selected for the SDHS sample were eligible for the HIV testing. Over 13.000 women, men and children living in the households selected for the survey were test. HIV prevalence data was obtained from finger stick dried blood spots voluntarily provided by the women and men 18 years and over who were interviewed and children 2-14 years whose parents gave consent and were members of households interviewed in the survey. Children age 15-17 were also asked to provide consent in addition to obtaining parental consent.
The data was processed by office editing, coding of open-ended questions, data entry, double-entry verification, and resolving inconsistencies found by computer programmes developed for the SDHS. The SDHS data entry and editing programmes used CSPro, a computer software package specifically designed for processing survey data such as that produced by DHS surveys.
Results: The results indicate that 26 % of adults are HIV infected; 31% of women and 20% of men are infected. Prevalence is higher in urban than rural areas, 37% and 29% respectfully. Almost one in two women age 25-29 is HIV-positive. Prevalence is highest among those who are divorced, separated, and widowed. Prevalence increases with number of lifetime partners and 17% of couples were discordant
Conclusion: This information provide data to assist policymakers and programme implementers to monitor and evaluate existing programmes and to design new strategies for demographic, social and health policies in Swaziland. The survey also provides data to monitor the country’s achievement towards the Millennium Development Goals.
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Antimicrobial Resistance In Major Pathogens Of Surgical Site Infection In Iran Hospitals
MOBASHERIZADEH S1, MEMARZADEH M2, IRAJ B1, KHORVASH F3, MOSTAFAVIZADEH K3, ABNESHAHIDI SA4, RASTI SJ1
1Isfahan University of Medical Science, Isfahan, Iran, 2Department of Surgery Isfahan University of Medical Science, Isfahan ,Iran, 3 Department of Infectious Disease and Research Center Isfahan University of Medical Science, Isfahan, Iran, 4 Research and Development Center of Saadi Hospital, Isfahan ,Iran
Objective: Surgical site infections are a significant problem which limits the potential benefits of surgical interventions. The impact on hospital costs and postoperative length of stay is considerable. The increased occurrence of antimicrobial-resistant microorganism is a major medical concern. We determine the resistance to antibiotics in major pathogens isolated from surgical site infection in our hospitals in Isfahan, Iran.
Methods: Antimicrobal susceptibility of bacterial isolated from surgical site infection in two university hospitals from 2005 to 2006 was monitored by Epsilometer test E (E-test®;AB BIODISK Co. Sweden).Data was analyzed by Whonet 5.3 software. Quality control was tested by E.coli ATCC 25922 and Staphylococcus aureus ATCC 29213. Results: The most frequent pathogens were Staphylococcus aureus(36.8%) followed by Klebsiella spp.(17.1%), E. coli (15.1%), Pseudomonas aeruginosa, (12.5%) and coagulase negative Staphyloccoci(8.6%). The susceptibility rates Staphylococcus aureus to oxacillin with minimum inhibitory concentration rang(0.094-256µg/ml) were 32.3% , vancomycin with MIC rang(0.38-32µg/ml) were 94.8% and clindomycin with MIC rang(0.047-256µg/ml) were 41.7%%. In gram negative bacteria the most active antibiotic was imipenem and meropenem. The susceptibility rates of Klebsiella to imipenem,meropenem, cefepime, ciprofloxacin, ceftazidime, and ceftriaxone were 94.9%,86.1%,23.5%,20%. The susceptibility rates of E.coli to imipenem,meropenem, cefepime, ciprofloxacin, ceftazidime, and ceftriaxone were 95.8%, 92.2%, 36.9%, 50%, 32.5%, 28.6%.
Conclusion: In Iran, like other countries antimicrobial resistance is a serious clinical problem among healthcare facilities. Each healthcare facility should have an antimicrobial use committee. Surveillance of antimicrobial resistance should be improved and antimicrobial restriction is also an important intervention.
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The Psychological Outcome Of Male Constitutional Delay Short Stature
MOBBS EJ
The Royal Alexandra Hospital for Children, Westmead, Sydney, NSW Australia
Background: Growth is said to be the defining feature of childhood, with genetic and environmental factors influencing the rate of growth and the final stature. Studies have demonstrated that idiopathic short stature, familial short stature and constitutional delay of growth male children often respond to growth treatment: Mental health outcome studies of male short stature have varied but these studies have been difficult to compare due to differences in cohort age groups and differences in assessment tools. However past studies have investigated psychological outcome as being dependent on height (short versus tall).
Methods: A novel approach was devised to measure how adult male final height was dependent upon the mental health status for those treated (Rx+, n=27) and untreated (Rx-, n=21) with growth promoting products as children defined as having constitutional delay. The respondents were assessed by the SCL-90-R psychological distress and psychopathology instrument and allocated into either a clinical, distressed group, or a non-clinical, non-distressed group.The Rx+ respondents had received as children (1) oral oxandrolone or (2) intramuscular injections of testosterone esters; other oral preparations may have been used but growth hormone was not used.
Results: (1) The main finding was that there was a significant relationship between psychological distress and height outcome for the group (Rx+ Rx-) in psychological distress and the group (Rx+ Rx-) not in psychological distress. Chi-Square p<0.03. (2) The average gain in height from treatment in the non-psychologically distressed group was 1.8 cm and the for psychologically distressed 1.4 cm.
Conclusion(s): (1) Those not in psychological distress were height advantaged. (2) Had the psychological state not been controlled then the outcome findings would have been decidedly confounded. (3) The height improvement for the treated cohort can be compared with similar modest increases using recombinant growth hormone for growth promotion in other studies. (4) When male children present for investigation and possible treatment for growth promotion they should be assessed for their mental health status as this may well be a predictive factor on adult height outcome which further longitudinal studies may resolve.
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Phase III Study Of Combined Neoadjuvant Chemotherapy And Letrozol In Locally Advanced Breast Cancer
MOHAMMADIANPANAH M, OMIDVARI SH, AHMADLOO N, MOSALAEI A
Shiraz University of Medical Sciences, Shiraz, Iran
Background: Despite early detection of breast cancer, locally advanced breast carcinomas account for a remarkable fraction of all breast carcinomas. The optimal management for these patients remains a major therapeutic challenge. Neoadjuvant chemotherapy is now considered the standard of care for these patients. Adjuvant and neoadjuvant endocrine therapy with aromatase inhibitors has an established role in the postmenopausal women with hormone receptor-positive invasive breast cancer. This two arm randomized clinical study aimed to evaluate the efficacy and safety of the combined neoadjuvant chemotherapy and letrozol in postmenopausal women with locally advanced breast carcinoma.
Methods: Fifty eligible women with pathologically proven locally advanced breast cancer were enrolled. Chemotherapy consisted of a median 3 cycles (range 2-4 cycles) of CAF regimen (Cyclophosphamide 600 mg/m2, doxorubicin 60 mg/m2, 5-FU 600 mg/m2) every three weeks. Patients in study arm (n=25) received daily letrozol 2.5 mg combined with neoadjuvant chemotherapy for a median time of nine weeks (range 6-12 weeks). Patients in control arm (n=25) received neoadjuvant chemotherapy alone for same time. All patients underwent modified radical mastectomy 3 weeks after the last cycle of chemotherapy. Pathologic response rate was the primary end-point of the study.
Results: Five (20%) of patients in study group and three (12%) of patients in control arm had inflammatory breast cancer. Overall pathologic response rate was 96% and 68% in study and control arm respectively (p=0.023). Complete pathologic response rate was 28% and 4% in study and control arm respectively (p=0.049). All patients had a resectable disease after neoadjuvant treatments. There was no difference in terms of treatment-related toxicity rates between two arms. Hematologic toxicity was the most frequent treatment-related toxicity in both arms.
Conclusions: The present study suggests that the addition of concurrent letrozol to the neoadjuvant chemotherapy significantly improves the response rates. Whether this approach confers a survival advantage remains to be determined.
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Magnetic Nanoparticles For Controlled Delivery Of Methotrexate
MOHAMMADI-SAMANI S1*, NEMATI ZA2, MIRI R3, SOTOUDEH S4
1Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz university of Medical Sciences, Shiraz, Iran, 2Materials Science and Engineering Department, Sharif University of Technology, Tehran, Iran, 3Faculty of Pharmacy, Shiraz university of Medical Sciences, Shiraz, Iran, 4Science and Research Branch of Azad University, Tehran, Iran
Background: Cancer is a major cause for morbidity and mortality in industrialized countries. For patients with advanced disease, chemotherapy based on methotrexate is currently the mainstay of treatment. We have developed a novel water-dispersible oleic acid (OA)-Pluronic-coated iron oxide magnetic nanoparticle formulation that can be loaded easily with high doses of water insoluble anticancer agents.
Methods: Nanoparticles of iron oxide was synthesized by mixing Aqueous solutions of 0.1 M Fe(III) (30 mL) and 0.1 M Fe(II) (15 mL) and dropwise adding of 3 mL of 5 M ammonia solution over 1 min under continuous stirring on a magnetic stirrer plate. The stirring continued for 20 min under a nitrogen-gas atmosphere. The iron oxide nanoparticle yield, determined by weighing of the lyophilized sample of the preparation. Formulations of iron oxide nanoparticles were developed, first by optimizing the amount of OA required to coat iron oxide nanoparticles completely, and then by optimizing the amount of pluronic required to form an aqueous dispersion of OA coated nanoparticles. To study the effect of OA, formulations with different weight ratios of OA to iron oxide nanoparticles were prepared. For this purpose, OA was added from 60-240 mg corresponding to same weight of iron oxide nanoparticles. After the coating of nanoparticle with pluronic, methotreate was loaded to particles.
Results: The loading efficiency was more than 90 % in optimized condition. Neither the formulation components nor the drug loading affected the magnetic properties of the core iron oxide nanoparticles. The release pattern was uniform in water for 8 hrs under in vitro conditions.
Conclusion: This system could be used to deliver anticancer drug methotrexate to the tumor site by using an appropriate external magnetic field. Based on the release pattern it would be practical to target the drug in higher concentration in tumor site than the other sites of the body.
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Trial Of Lamivudine In Hepatitis B Surface Antigen Carriers With Persistence Hepatitis B Core IgM Antibody
MOHAMMED ALI HY
Dean, Technical & Health Institute-Zakho, Department of Microbiology & Immunology, College of Medicine, University of Dohuk, Kurdistan Region-Iraq
Background: The persistence of hepatitis B core IgM antibody in hepatitis B surface antigen carrier is a risk factor with hidden danger and forecast existence of liver damage. A trial of lamivudine in such subset of carriers was carried on for the first time in this study.
Methods: A total of 62 hepatitis B surface antigen with hepatitis e antibody individuals (age range, 25-45 years) with persistence hepatitis B core IgM antibody were randomized to receive either 100 mg lamivudine (32/62) or placebo (30/62) daily for 6 months.
Results: Among lamivudine group, hepatitis B core IgM antibody seroclearance achievement rate was 81.3% and HBsAg seroconversion rate was 9.4 % compared to 6.3% and 3.3% in placebo group respectively. A number of adverse clinical events were observed, but were of mild nature and tolerable by the participants who completed the study.
Conclusion: Trial of lamivudine in this subset of hepatitis B surface antigen carriers proven to be safe and efficacious. More studies are needed prior to recommending the drug for routine use on selected HBV carriers.
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