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Sample records for anti-retroviral drug sensitivities

  1. The emergence of drug resistant HIV variants and novel anti-retroviral therapy

    Institute of Scientific and Technical Information of China (English)

    Koosha Paydary; Parisa Khaghani; Sahra Emamzadeh-Fard; SeyedAhmad SeyedAlinaghi; Kazem Baesi

    2013-01-01

    After its identification in 1980s, HIV has infected more than 30 million people worldwide. In the era of highly active anti-retroviral therapy, anti-retroviral drug resistance results from insufficient anti-retroviral pressure, which may lead to treatment failure. Preliminary studies support the idea that anti-retroviral drug resistance has evolved largely as a result of low-adherence of patients to therapy and extensive use of anti-retroviral drugs in the developed world;however, a highly heterogeneous horde of viral quasi-species are currently circulating in developing nations. Thus, the prioritizing of strategies adopted in such two worlds should be quite different considering the varying anti-retroviral drug resistance prevalence. In this article, we explore differences in anti-retroviral drug resistance patterns between developed and developing countries, as they represent two distinct ecological niches of HIV from an evolutionary standpoint.

  2. Global HIV-1 transmitted drug resistance in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

    DEFF Research Database (Denmark)

    Baxter, J D; Dunn, D; White, E;

    2015-01-01

    of resistance testing in START trial participants. METHODS: In the Strategic Timing of AntiRetroviral Treatment (START) trial, baseline genotypic resistance testing results were collected at study entry and analysed centrally to determine the prevalence of TDR in the study population. Resistance was based...

  3. Anti-retroviral drugs do not facilitate hepatitis C virus (HCV) infection in vitro.

    Science.gov (United States)

    Sandmann, Lisa; Wilson, Matthew; Back, David; Wedemeyer, Heiner; Manns, Michael P; Steinmann, Eike; Pietschmann, Thomas; von Hahn, Thomas; Ciesek, Sandra

    2012-10-01

    An estimated 4 to 5 million people are co-infected with HIV/HCV worldwide. Recently observed outbreaks of acute HCV infection among HIV-positive men who have sex with men (MSM) have been linked to behavioral factors such as high risk sexual practices and recreational drug use. However, at the molecular level, many drugs such as glucocorticoids or cyclosporine A have been found to modulate viral replication. Thus, it is conceivable that drugs used in highly active antiretroviral therapy (HAART) may heighten susceptibility to HCV infection and contribute to the recent outbreaks. We therefore performed a comprehensive screen of antiretroviral drugs covering all available drug classes both individually and in typical combinations used during HAART to probe for direct effects on HCV cell entry, replication, new particle assembly and release. Importantly, no significant enhancement or inhibition of HCV cell entry, replication or new particle production was detected. While raltegravir and ritonavir boosted atazanavir reduce HCV replication, a tenfold reduction of HCVcc entry by the CCR5 antagonist maraviroc was observed. In conclusion, commonly used HAART agents do not specifically enhance HCV replication. Thus recent epidemic outbreaks of acute HCV in HIV-infected MSM are unlikely to be related to enhancing effects of HAART drugs.

  4. Formulation and characterization of solid lipid nanoparticles for an anti-retroviral drug darunavir

    Science.gov (United States)

    Bhalekar, Mangesh; Upadhaya, Prashant; Madgulkar, Ashwini

    2017-02-01

    Darunavir, an anti-HIV drug having poor solubility in aqueous and lipid medium, illustrates degradation above its melting point, i.e. 74 °C, thus, posing a challenge to dosage formulation. Despite, the drug suffers from poor oral bioavailability (37%) owing to less permeability and being poly-glycoprotein and cyp3A metabolism substrate. The study aimed formulating a SLN system to overcome the formulation and bioavailability associated problems of the drug. Based on the drug solubility and stable dispersion findings, lipid and surfactant were chosen and nanoparticles were prepared using hot-homogenization technique. Optimization of variables such as lipid concentration, oil-surfactant and homogenization cycle was carried and their effect on particle size and entrapment efficiency was studied. Freeze-dried SLN further characterized using SEM, DSC and PXRD analysis revealed complete entrapment of the drug and amorphous nature of the SLN. In vitro pH release studies in 0.1 N HCl and 6.8 pH buffer demonstrated 84 and 80% release at the end of 12th h. The apparent permeability of the SLN across rat intestine was found to be 24 × 10-6 at 37 °C at the end of 30 min while at 4 °C the same was found to be 5.6 × 10-6 prompting involvement of endocytic processes in the uptake of SLN. Accelerated stability studies revealed no prominent changes upon storage.

  5. Genetic variation of the HIV-1 integrase region in newly diagnosed anti-retroviral drug-naïve patients with HIV/AIDS in Korea.

    Science.gov (United States)

    Kim, J-Y; Kim, E-J; Choi, J-Y; Kwon, O-K; Kim, G J; Choi, S Y; Kim, S S

    2011-08-01

    The survival time of HIV/AIDS patients in Korea has increased since HAART (highly active anti-retroviral therapy) was introduced. However, the occurrence of drug-resistant strains requires new anti-retroviral drugs, one of which, an integrase inhibitor (INI), was approved by the US Food and Drug Administration (FDA) in 2007. INIs have been used for therapy in many countries and are about to be employed in Korea. Therefore, it is important to identify basic mutant variants prior to the introduction of INIs in order to estimate their efficacy. To monitor potential drug-resistant INI mutations in Korean HIV/AIDS patients, the polymorphism of the int gene was investigated together with the pol gene using a genotypic assay for 75 randomly selected Korean HIV-1 patients newly diagnosed in 2007. The drug-resistant mutation sequences were analysed using the Stanford HIV DB and the International AIDS Society resistance testing-USA panel (IAS-USA). Seventy strains of Korean subtype B were compared with foreign subtype-B strains, and there were no significantly different variants of the int gene region in the study population. Major mutation sites in the integrase (E92Q, F121Y, G140A/S, Y143C/R, Q148H/R/K and N155H) were not detected, and only a few minor mutation sites (L74M, V151I, E157Q, V165I, I203M, S230N and D232N) were identified in 21 strains (28%). Resistance due to mutations in the pol gene was observed in a single strain (1.3%) resistant to protease inhibitors (PIs) and in four strains (5.3%) resistant to reverse transcriptase inhibitors (RTIs). In summary, this demonstrates that INIs will be susceptible to drug naïve HIV/AIDS patients in Korea.

  6. Humanized mice recapitulate key features of HIV-1 infection: a novel concept using long-acting anti-retroviral drugs for treating HIV-1.

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    Marc Nischang

    Full Text Available BACKGROUND: Humanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART when added to food pellets, and of long-acting (LA antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient. METHODS/PRINCIPAL FINDINGS: NOD/shi-scid/γ(cnull (NOG mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor. A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79% and 14/14 (100% mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir. CONCLUSIONS/SIGNIFICANCE: This report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment

  7. Anti-Retroviral Lectins Have Modest Effects on Adherence of Trichomonas vaginalis to Epithelial Cells In Vitro and on Recovery of Tritrichomonas foetus in a Mouse Vaginal Model.

    Science.gov (United States)

    Chatterjee, Aparajita; Ratner, Daniel M; Ryan, Christopher M; Johnson, Patricia J; O'Keefe, Barry R; Secor, W Evan; Anderson, Deborah J; Robbins, Phillips W; Samuelson, John

    2015-01-01

    Trichomonas vaginalis causes vaginitis and increases the risk of HIV transmission by heterosexual sex, while Tritrichomonas foetus causes premature abortion in cattle. Our goals were to determine the effects, if any, of anti-retroviral lectins, which are designed to prevent heterosexual transmission of HIV, on adherence of Trichomonas to ectocervical cells and on Tritrichomonas infections in a mouse model. We show that Trichomonas Asn-linked glycans (N-glycans), like those of HIV, bind the mannose-binding lectin (MBL) that is part of the innate immune system. N-glycans of Trichomonas and Tritrichomonas bind anti-retroviral lectins (cyanovirin-N and griffithsin) and the 2G12 monoclonal antibody, each of which binds HIV N-glycans. Binding of cyanovirin-N appears to be independent of susceptibility to metronidazole, the major drug used to treat Trichomonas. Anti-retroviral lectins, MBL, and galectin-1 cause Trichomonas to self-aggregate and precipitate. The anti-retroviral lectins also increase adherence of ricin-resistant mutants, which are less adherent than parent cells, to ectocervical cell monolayers and to organotypic EpiVaginal tissue cells. Topical application of either anti-retroviral lectins or yeast N-glycans decreases by 40 to 70% the recovery of Tritrichomonas from the mouse vagina. These results, which are explained by a few simple models, suggest that the anti-retroviral lectins have a modest potential for preventing or treating human infections with Trichomonas.

  8. An audit on virological efficacy of anti-retroviral therapy in a specialist infectious disease clinic.

    LENUS (Irish Health Repository)

    Reyad, A

    2009-06-01

    We have assessed the efficacy of anti retroviral therapy (ART) using undetectable viral load (VL) (<50 RNA copies\\/ml) as a marker of virological success, in patients who have Human Immunodeficiency Virus (HIV) attending the Department of Infectious Disease. A cross-sectional review of patients\\' case notes was used to obtain their demographics and treatment details. 79% (253) of the hospital case notes of clinic population was available for analysis, which represents 90% of those receiving ART in the clinic. 166\\/253 of the cohort were receiving treatment at the time of this study and 95% (157\\/166) of these were on treatment for greater than 6 months. The total virological success rate is 93%, which is comparable to other centres and are as good as those from published clinical trials. 56% of those on therapy who have virological failure were Intravenous Drug Users (IVDUs). Case by case investigation for those with treatment failure is warranted.

  9. In vivo mitochondrial function in HIV-infected persons treated with contemporary anti-retroviral therapy: a magnetic resonance spectroscopy study.

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    Brendan A I Payne

    Full Text Available Modern anti-retroviral therapy is highly effective at suppressing viral replication and restoring immune function in HIV-infected persons. However, such individuals show reduced physiological performance and increased frailty compared with age-matched uninfected persons. Contemporary anti-retroviral therapy is thought to be largely free from neuromuscular complications, whereas several anti-retroviral drugs previously in common usage have been associated with mitochondrial toxicity. It has recently been established that patients with prior exposure to such drugs exhibit irreversible cellular and molecular mitochondrial defects. However the functional significance of such damage remains unknown. Here we use phosphorus magnetic resonance spectroscopy ((31P-MRS to measure in vivo muscle mitochondrial oxidative function, in patients treated with contemporary anti-retroviral therapy, and compare with biopsy findings (cytochrome c oxidase (COX histochemistry. We show that dynamic oxidative function (post-exertional ATP (adenosine triphosphate resynthesis was largely maintained in the face of mild to moderate COX defects (affecting up to ∼10% of fibers: τ½ ADP (half-life of adenosine diphosphate clearance, HIV-infected 22.1±9.9 s, HIV-uninfected 18.8±4.4 s, p = 0.09. In contrast, HIV-infected patients had a significant derangement of resting state ATP metabolism compared with controls: ADP/ATP ratio, HIV-infected 1.24±0.08×10(-3, HIV-uninfected 1.16±0.05×10(-3, p = 0.001. These observations are broadly reassuring in that they suggest that in vivo mitochondrial function in patients on contemporary anti-retroviral therapy is largely maintained at the whole organ level, despite histochemical (COX defects within individual cells. Basal energy requirements may nevertheless be increased.

  10. An autoimmune disease prevented by anti-retroviral drugs

    OpenAIRE

    Beck-Engeser Gabriele B; Eilat Dan; Wabl Matthias

    2011-01-01

    Abstract Background Both Aicardi-Goutières syndrome, a Mendelian mimic of congenital infection, and the autoimmune disease systemic lupus erythematosus can result from mutations in the gene encoding the enzyme Trex1. In mice, the absence of Trex1 causes severe myocarditis. The enzyme is thought to degrade endogenous retroelements, thus linking them to autoimmune disease. However, inhibition of reverse transcription by the inhibitor zidovudine (AZT) did not ameliorate the disease, weakening th...

  11. Tratamiento antirretroviral en pacientes con sida y micobacteriosis Anti-retroviral treatment in patients with AIDS and mycobacterial diseases

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    Marcelo E. Corti

    2005-08-01

    Full Text Available La tuberculosis y otras micobacteriosis constituyen asociaciones o coinfecciones frecuentes en pacientes con sida y se asocian con una elevada mortalidad. En esta revisión se actualizan los tratamientos de las principales enfermedades micobacterianas asociadas al sida (tuberculosis y micobacteriosis por Mycobacterium avium, con especial énfasis en las interacciones farmacológicas entre antimicobacterianos, principalmente rifampicina y claritromicina, y fármacos antirretrovirales. Se analizan los esquemas de tratamiento, su duración, la quimioprofilaxis primaria y secundaria y el momento óptimo de iniciación del tratamiento antirretroviral. Finalmente se describe el síndrome inflamatorio de reconstitución inmune y su tratamiento.Tuberculosis and other mycobacterial diseases are frequent coinfections in AIDS patients with an increased related mortality. In this review we have updated the treatment of the main mycobacterial diseases (tuberculosis and Mycobacterium avium disease, under the scope of pharmacological interactions between antimycobacterial drugs, specially rifampicin and clarithromycin, and anti-retroviral drugs. Antimycobacterial treatment schemes, their duration, primary and secondary chemoprophylaxis and the optimal time to start the anti-retroviral therapy are analized. Finally, the immnune reconstitution inflammatory syndrome and its treatment are discussed.

  12. Access to highly active antiretroviral therapy for injection drug users: adherence, resistance, and death Acesso de usuários de drogas injetáveis ao tratamento anti-retroviral altamente potente: aderência, resistência e mortalidade

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    David Vlahov

    2006-04-01

    Full Text Available Injection drug users (IDUs continue to comprise a major risk group for HIV infection throughout the world and represent the focal population for HIV epidemics in Asia and Eastern Europe/Russia. HIV prevention programs have ranged from HIV testing and counseling, education, behavioral and network interventions, drug abuse treatment, bleach disinfection of needles, needle exchange and expanded syringe access, as well as reducing transition to injection and primary substance abuse prevention. With the advent of highly active antiretroviral therapy (HAART in 1996, dramatic clinical improvements have been seen. In addition, the treatment's impact on reducing HIV viral load (and therefore transmission by all routes provides a stronger rationale for an expansion of the focus on prevention to emphasize early identification and treatment of HIV infected individuals. However, treatment of IDUs has many challenges including adherence, resistance and relapse to high risk behaviors, all of which impact issues of access and ultimately effectiveness of potent antiretroviral treatment. A major current challenge in addressing the HIV epidemic revolves around an appropriate approach to HIV treatment for IDUs.Os usuários de drogas injetáveis (UDI ainda representam um importante grupo de risco para a infecção pelo HIV no mundo em geral, além de constituir o grupo central das epidemias de HIV na Ásia e no Leste Europeu e Rússia. Os programas de prevenção do HIV variam, desde a testagem sorológica e aconselhamento, educação, intervenções comportamentais e em redes, tratamento da dependência química, desinfecção de agulhas com água sanitária, troca de agulhas e ampliação do acesso a seringas, além da redução da transição ao uso injetável e a prevenção primária da dependência química. Com o advento da terapia anti-retroviral altamente potente (HAART, em 1996, houve uma melhora clínica dramática. Além disso, o impacto do tratamento

  13. Anxiety-like behaviour is attenuated by gabapentin, morphine and diazepam in a rodent model of HIV anti-retroviral-associated neuropathic pain.

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    Wallace, Victoria C J; Segerdahl, Andrew R; Blackbeard, Julie; Pheby, Timothy; Rice, Andrew S C

    2008-12-19

    Neuropathic pain is commonly associated with affective disorders such as anxiety and depression. We have previously characterised a rodent model of HIV, anti-retroviral-associated neuropathy in which rats develop hypersensitivity to a punctate mechanical stimulus and display anxiety-like behaviour in the open field paradigm. To assess the potential of this behavioural paradigm for the assessment of pain related co-morbidities in rodent models of pain, here we test the sensitivity of this anxiety-like behaviour to the analgesic agents gabapentin and morphine in comparison to the known anxiolytic drug diazepam. We found that gabapentin (30 mg/kg, i.p.) and morphine (2.5 mg/kg, i.p.), which reduce mechanical hypersensitivity in these rats, significantly reduces measures of thigmotaxis in the open field. The effect of gabapentin and morphine did not differ significantly from diazepam (1 mg/kg, i.p.). This study highlights the potential use of this rodent model and behavioural paradigm in the validation of the affective component of novel analgesic pharmacological targets and elucidation of underlying pathophysiological mechanisms.

  14. Anti-Retroviral Strategies for AIDS and Related Diseases

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    Mark A Wainberg

    1991-01-01

    Full Text Available The replication cycle of human immunodeficiency virus type 1 (HIV-1 and other retroviruses consists of four stages: attachment of the virus to specific receptors on the cell surface; uncoating of the viral nucleic acid and conversion to DNA; production of viral RNA and proteins; and assembly and liberation of progeny virus from the cell. Each of these steps represents a potential target for antiviral chemotherapy. Combinations of drugs which act against different steps in the viral replication cycle might be expected to have synergistic potential. Zidovudine (AZT is the most widely used drug to date for impeding the replication of HIV-1. Although AZT therapy has been reasonably successful, it has not been free from toxicity. In addition, there have been several reports of isolation of AZT-resistant variants of HIV-1.

  15. HIV reverse transcriptase gene mutations in anti-retroviral treatment naïve rural people living with HIV/AIDS.

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    Mohanakrishnan, K; Kasthuri, A; Amsavathani, S K; Sumathi, G

    2015-01-01

    This study is designed to find out the mutational variations of reverse transcriptase (RT) gene of HIV, after the traditional drug usage among anti-retroviral therapy naïve rural people living with HIV/AIDS. HIV Reactive patients, who were exposed for indigenous medicines such as Siddha, Ayurveda etc., for a minimum period of 6 months were taken for this study. Among 40 patients, two samples (5.55%) demonstrated high-level mutational resistance variations for nucleoside RT inhibitor (NRTI) and non-NRTI. The predominant polymorphisms detected were K122E (91.7%), V60I (91.7%), V35T (89%), Q207E (89%), D177E (89%), T200A (86.1%), S48T (83.33%), K173A (80.6%).

  16. Immune reconstitution inflammatory syndrome in HIV-infected patients with mycobacterial infections starting highly active anti-retroviral therapy

    Energy Technology Data Exchange (ETDEWEB)

    Buckingham, S.J.; Haddow, L.J.; Shaw, P.J.; Miller, R.F. E-mail: rmiller@gum.ucl.ac.uk

    2004-06-01

    AIM: To describe the radiological appearances of immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-infected patients with mycobacterial infections starting highly active anti-retroviral therapy (HAART). MATERIALS AND METHODS: Five consecutive HIV infected patients with IRIS due to mycobacterial infection were studied. Intercurrent infection and poor drug compliance were excluded as causes of presentation. The chest radiological appearances at the time of starting HAART and at the time of diagnosis of IRIS were compared. RESULTS: In these five patients there was clinical and radiological deterioration, occurring between 10 days and 7 months after starting HAART, leading to unmasking of previously undiagnosed mycobacterial infection or to worsening of mycobacterial disease. All five patients had HAART-induced increases in CD4+ T lymphocyte counts and reductions in peripheral blood HIV 'viral load'. Chest radiographic abnormalities due to IRIS included marked mediastinal lymphadenopathy in three patients--severe enough to produce tracheal compression in two patients (one of whom had stridor)--and was associated with new pulmonary infiltrates in two patients. The other two patients had new infiltrates, which in one patient was associated with a pleural effusion. CONCLUSION: These cases illustrate the diverse chest radiographic appearances of IRIS occurring after HAART in patients with mycobacterial and HIV co-infection. Marked mediastinal lymphadenopathy occurred in three of these five patients (with associated tracheal narrowing in two patients); four patients developed pulmonary infiltrates and one had an effusion. The cases further highlight that the onset of IRIS may be delayed for several months after HAART is started.

  17. Predictors of mortality among HIV-infected patients initiating anti retroviral therapy at a tertiary care hospital in Eastern India

    Institute of Scientific and Technical Information of China (English)

    Ananya Bhowmik; Subhasis Bhandari; Rajyasree De; Subhasish Kamal Guha

    2012-01-01

    Objective: To assess early mortality and identify its predictors among the ART naive HIV-infected patients initiating anti retroviral therapy (ART) available free of cost at the ART Centres.Methods: A retrospective cohort analysis of routinely collected programme data was done for assessing mortality of all ART naive adult patients who received first-line ART at a government tertiary care hospital in eastern India during 1st March 2009 and 28th February 2010. Bivariate and multiple regression analyses of the baseline demographic, clinical and laboratory records using SPSS 15.0 were done to identify independent predictors of mortality. Results: The mortality rate at one year was estimated to be 7.66 (95% CI 5.84-9.83) deaths/100 patient-years and more than 50% of the deaths occurred during first three months of ART initiation with a median time interval of 73 days. Tuberculosis was the major cause of death. ART naive patients with baseline serum albumin <3.5 mg/dL were eight (OR 7.9; 95% CI: 3.8-16.5) at risk of death than those with higher serum albumin levels and patients with CD4 count <100 cells/μL were two times (OR 2.2;95% CI: 1.1-4.4) at risk of death compared to higher CD4 counts. Conclusions: Risk of mortality is increased when ART is initiated at advanced stages of immunosuppression denoted by low serum albumin levels and CD4 cell counts. This highlights the importance of early detection of HIV infection, early management of opportunistic infections including tuberculosis and timely initiation of the antiretroviral drugs in the resource-limited countries, now available free in the Indian national ART programme.

  18. Clients’ Satisfaction with Anti Retroviral Therapy Services at Hamidia Hospital Bhopal

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    Bhagat Vimal Kishor, Pal D K, Lodha Rama S, Bankwar Vishal

    2011-01-01

    Full Text Available Background: The HIV/AIDS pandemic is a major public health problem with an estimated 33.33 million people living with the virus globally. Free antiretroviral treatment was initiated in India 2004. Patients’ satisfaction is one of the commonly used outcome measures of patient care. Objective: To assess the satisfaction of people living with HIV/AIDS with services provided at anti retroviral therapy Centre Hamidia Hospital Bhopal. Material and Methods: A hospital based cross-sectional study was undertaken from August 2008 to July 2009 on all the registered people living with HIV/AIDS (PLWHA following antiretroviral treatment at Hamidia Hospital Bhopal. Data was collected and by using pre-designed & pre-tested questionnaire and analyzed using Epi-info version 3.5.3. Results: For most of the questions regarding satisfaction on the care services of the center, participants responded positively (excellent & good.The overall mean satisfaction score was “Excellent”. Conclusion: The services of the Center were rated positively (Excellent and above.The hospital management should work to strengthen the clinic services by helping the ART clinic staff to involve patients in the treatment process and recognize their opinions on follow up.

  19. Economic evaluation of task-shifting approaches to the dispensing of anti-retroviral therapy

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    Foster Nicola

    2012-09-01

    Full Text Available Abstract Background A scarcity of human resources for health has been identified as one of the primary constraints to the scale-up of the provision of Anti-Retroviral Treatment (ART. In South Africa there is a particularly severe lack of pharmacists. The study aims to compare two task-shifting approaches to the dispensing of ART: Indirectly Supervised Pharmacist’s Assistants (ISPA and Nurse-based pharmaceutical care models against the standard of care which involves a pharmacist dispensing ART. Methods A cross-sectional mixed methods study design was used. Patient exit interviews, time and motion studies, expert interviews and staff costs were used to conduct a costing from the societal perspective. Six facilities were sampled in the Western Cape province of South Africa, and 230 patient interviews conducted. Results The ISPA model was found to be the least costly task-shifting pharmaceutical model. However, patients preferred receiving medication from the nurse. This related to a fear of stigma and being identified by virtue of receiving ART at the pharmacy. Conclusions While these models are not mutually exclusive, and a variety of pharmaceutical care models will be necessary for scale up, it is useful to consider the impact of implementing these models on the provider, patient access to treatment and difficulties in implementation.

  20. Adesão à terapêutica anti-retroviral por indivíduos com HIV/AIDS assistidos em uma instituição do interior paulista Adhesión a la terapéutica anti-retroviral por los individuos con VIH/SIDA de uno servicio del interior paulista Adhesion to anti-retroviral therapy by individuals with HIV/AIDS attended at an institution in the interior of São Paulo

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    Elucir Gir

    2005-10-01

    -retrovirales desde hace en promedio 5 años. La cantidad diaria de comprimidos anti-retrovirales varió de 3 a 24. Como principales dificultades de la adhesión mencionaron: sabor, tamaño, cantidad, olor de los comprimidos (40,0%; efectos colaterales (14,4%; factores psicológicos (13,7%; diferentes horarios de medicación (10,8%. Cuanto a las facilidades, el 26,2% relató horarios coincidentes de los comprimidos; el 16,4% ninguna facilidad y el 16,0% ingestión condicionada a algún hábito. Esos datos requieren de la enfermería mayor vigilancia supervisada, acciones educativas e intervenciones.Inadequate adherence to highly active anti-retroviral therapy (HAART provokes important secondary effects in people living with aids. The objective was to identify the factors that make HAART adherence easy or difficult, according to aids patients attended at a university hospital in the state of São Paulo, Brazil. We interviewed 200 diagnosed aids patients using HAART for at least 6 months. Patients were interviewed individually, using a semi-structured design. Qualitative and quantitative analysis was used. 59% of the participants were men; average age was 38.2 years; 51% did not finish basic education; 50.5% did not perform any remunerated work. Patients had been using anti-retroviral agents for an average time of 5 years. The number of anti-retroviral pills ranged from 3 to 24. The main difficulties mentioned for adherence were: taste, size, number, smell of pills (40.0%; intense collateral effects (14.4%; psychological factors (13.7%; different times to take the pills (10.8%. Patients mentioned the following facilitators: coincidence of times to take the drugs (26.2%, no facility (16.4%, and administration associated to some habit (16.0%. The nursing group needs to reinforce supervised surveillance, educational and intervention actions.

  1. Cost-effectiveness of anti-retroviral therapy at a district hospital in southern Ethiopia

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    Robberstad Bjarne

    2009-07-01

    Full Text Available Abstract Background As the resource implications of expanding anti-retroviral therapy (ART are likely to be large, there is a need to explore its cost-effectiveness. So far, there is no such information available from Ethiopia. Objective To assess the cost-effectiveness of ART for routine clinical practice in a district hospital setting in Ethiopia. Methods We estimated the unit cost of HIV-related care from the 2004/5 fiscal year expenditure of Arba Minch Hospital in southern Ethiopia. We estimated outpatient and inpatient service use from HIV-infected patients who received care and treatment at the hospital between January 2003 and March 2006. We measured the health effect as life years gained (LYG for patients receiving ART compared with those not receiving such treatment. The study adopted a health care provider perspective and included both direct and overhead costs. We used Markov model to estimate the lifetime costs, health benefits and cost-effectiveness of ART. Findings ART yielded an undiscounted 9.4 years expected survival, and resulted in 7.1 extra LYG compared to patients not receiving ART. The lifetime incremental cost is US$2,215 and the undiscounted incremental cost per LYG is US$314. When discounted at 3%, the additional LYG decreases to 5.5 years and the incremental cost per LYG increases to US$325. Conclusion The undiscounted and discounted incremental costs per LYG from introducing ART were less than the per capita GDP threshold at the base year. Thus, ART could be regarded as cost-effective in a district hospital setting in Ethiopia.

  2. CD4 lymphocyte response following anti-retroviral therapy in HIV/AIDS patients - A study in Osmania General Hospital

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    Srinivasa Rao Nanyam; Ravala Siddeswari; Budithi Sudarsi; Barla Suryanarayana; Challagali Prabhu Kumar; Thatikala Abhilash

    2016-01-01

    The present study aims serial four year assessment of CD4 cell response after initiation of anti-retroviral therapy (ART) in patients with HIV/AIDS attending Osmania General Hospital, Hyderabad. It was a retrospective hospital based observational study. We included 110 HIV/AIDS who were on ART. Data was collected over a period of 04 years from 2005 to 2008 in the ART Centre, Upgraded Department of General Medicine, Osmania General Hospital. Data regarding CD4 cell count over 4 years was asse...

  3. Combination of anti-retroviral drugs and radioimmunotherapy specifically kills infected cells from HIV infected individuals

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    Dina Tsukrov

    2016-09-01

    Full Text Available Eliminating virally infected cells is an essential component of any HIV eradication strategy. Radioimmunotherapy (RIT, a clinically established method for killing cells using radiolabeled antibodies, was recently applied to target HIV-1 gp41 antigen expressed on the surface of infect-ed cells. Since gp41 expression by infected cells is likely down-regulated in patients on an-tiretroviral therapy (ART, we evaluated the ability of RIT to kill ART-treated infected cells us-ing both in vitro models and lymphocytes isolated from HIV-infected subjects. Human peripheral blood mononuclear cells (PBMCs were infected with HIV and cultured in the presence of two clinically relevant ART combinations. Scatchard analysis of the 2556 human monoclonal anti-body to HIV gp41 binding to the infected and ART-treated cells demonstrated sufficient residual expression of gp41 on the cell surface to warrant subsequent RIT. This is the first time the quantification of gp41 post-ART is being reported. Cells were then treated with Bismuth-213-labeled 2556 antibody. conjugated to the human monoclonal antibody 2556, which binds to HIV gp41. Cell survival was quantified by Trypan blue and residual viremia by p24 ELISA. Cell surface gp41 expression was assessed by Scatchard analysis. The experiments were repeated using PBMCs isolated from blood specimens obtained from 15 HIV-infected individuals: ten on ART and five ART-naive. We found that 213Bi-2556 killed ART-treated infected PBMCs and reduced viral production to undetectable levels. ART and RIT co-treatment was more effective at reducing viral load in vitro than either therapy alone, indicating that gp41 expression under ART was sufficient to allow 213Bi-2556 to deliver cytocidal doses of radiation to infected cells. This study provides proof of concept that 213Bi-2556 may represent an innovative and effective targeting method for killing HIV-infected cells treated with ART, and supports continued development of 213Bi-2556 for co-administration with ART towards an HIV eradication strategy.

  4. Cost estimates of HIV care and treatment with and without anti-retroviral therapy at Arba Minch Hospital in southern Ethiopia

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    Robberstad Bjarne

    2009-04-01

    Full Text Available Abstract Background Little is known about the costs of HIV care in Ethiopia. Objective To estimate the average per person year (PPY cost of care for HIV patients with and without anti-retroviral therapy (ART in a district hospital. Methods Data on costs and utilization of HIV-related services were taken from Arba Minch Hospital (AMH in southern Ethiopia. Mean annual outpatient and inpatient costs and corresponding 95% confidence intervals (CI were calculated. We adopted a district hospital perspective and focused on hospital costs. Findings PPY average (95% CI costs under ART were US$235.44 (US$218.11–252.78 and US$29.44 (US$24.30–34.58 for outpatient and inpatient care, respectively. Estimates for the non-ART condition were US$38.12 (US$34.36–41.88 and US$80.88 (US$63.66–98.11 for outpatient and inpatient care, respectively. The major cost driver under the ART scheme was cost of ART drugs, whereas it was inpatient care and treatment in the non-ART scheme. Conclusion The cost profile of ART at a district hospital level may be useful in the planning and budgeting of implementing ART programs in Ethiopia. Further studies that focus on patient costs are warranted to capture all patterns of service use and relevant costs. Economic evaluations combining cost estimates with clinical outcomes would be useful for ranking of ART services.

  5. Improved outcomes from HIV/TB co-infection in Singapore following a switch to earlier anti-retroviral therapy

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    Barnaby Young

    2014-11-01

    Full Text Available Introduction: Recent clinical trials have provided clear evidence to support early anti-retroviral therapy (ART in patients with HIV/TB co-infection and low CD4 counts. We investigated how this has changed treatment and outcomes in Singapore. Materials and Methods: A retrospective review was performed with inpatient and outpatient records for all subjects diagnosed with HIV/TB co-infection from 2006 to 2011 attending the Tuberculosis Control Unit, Tan Tock Seng Hospital, Singapore. Data for subjects with a presenting CD4<200 cell/mm3 were extracted and split into two groups, “Delayed”: ART more than 8/52 after starting TB treatment, and “Early”: ART within 8/52 of starting TB treatment. Results: One hundred thirty-four out of 180 subjects in the database met the inclusion criteria for this study, 89 in the delayed group and 45 in the early. No statistically significant differences in baseline demographics between the two groups were identified. Both groups presented with markedly low CD4 counts, with overall 60% <50cells/mm3. Median CD4 counts were lower in the delayed ART group (37 vs 50, p=0.015. Prevalence of other opportunistic infections at TB diagnosis was not significantly different (20%, but TB in the early ART group was more likely to include extra-pulmonary disease (46% vs 57%, p=0.038. Four cases were culture negative, 2 multi-drug resistant and 10 (7.8% were isoniazid mono-resistant. There was a significant trend to earlier ART with more recent TB diagnosis (p<0.001. In the first 365 days after TB diagnosis, 11 deaths occurred in the delayed ART group, and 0 in the early (p=0.033. A Kaplan-Meier time-to-event analysis demonstrated a clear separation in the frequency of death or opportunistic infections at eight weeks (Figure 1, p<0.001. Immune reconstitution disease was significantly more likely in the early ART group, but did not result in death (9% vs 38%, p<0.001. Treatment interruptions due to adverse drug events (ADE

  6. Demographic and HIV-specific characteristics of participants enrolled in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

    DEFF Research Database (Denmark)

    Sharma, S; Babiker, A G; Emery, S;

    2015-01-01

    OBJECTIVES: The risks and benefits of initiating antiretroviral treatment (ART) at high CD4 cell counts have not been reliably quantified. The Strategic Timing of AntiRetroviral Treatment (START) study is a randomized international clinical trial that compares immediate with deferred initiation...

  7. Evaluation of Potential Anti-Pathogenic and Anti-Retroviral Effects of a Proprietary Bioactive Silicate Alka-Vita™/Alka-V6™/Alkahydroxy™ (AVAH

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    D Townsend

    2010-12-01

    Full Text Available Summary: Alka-Vita™/Alka-V6™/Alkahydroxy™ (AVAH, a modified sodium silicate dietary supplement manufactured by Cisne Enterprises Inc. (Odessa, TX was evaluated for its in vitro anti-retroviral and anti-pathogenic effects. Effects on nitric oxide (NO dependent antiviral activities were measured in neutrophils using standard assays. Assays for inhibition of HIV-II reverse transcriptase (RT, HIV-II protease (PR and glucohydrolase [glucuronidase (GH-1 and glucosidase (GH-2] important for viral replication, coat assembly and virulence respectively, were performed using standard kits. Higher NO (~ 2 fold was detected in neutrophil medium indicating an increase NO mediated antipathogeic activity. Results suggest that the product significantly decreased HIV-RT activity in a dose dependent manner (ED50= 20.4 mM. HIV-PR activity decreased (IC50=14.6 mM with increasing product concentration. The product also decreased the HIV-II virulence by inhibiting the GH-1 (IC50= 34.29 mM and GH-2 (IC50=14.6 mM activity which decreased protein glucosylation and glucuronylation. Changes in surface EPS carbohydrates assed in Pseudomonas aeruginosa suggested a modulatory effect on various carbohydrates and therefore the composition of EPS. Industrial relevance: Pathologies caused by retroviral agents and microorganisms are prevalent both in developed and developing countries.  Indiscriminate use of single target medical drugs has resulted in the development of resistance in these pathogens. Development of novel therapeutic  agents that can effect multiple intrinsic and extrinsic targets in host and the pathogen may prove to be more effective and are less likely to promote drug induced selection. The effectiveness of Alka-Vita™/Alka-V6™/Alkahydroxy™ (AVAH in mitigating various virulence and survival pathways in pathogens is promising. Additionally, it was also effective in inducing a NO mediated immune response.

  8. Rinossinusites em crianças infectadas pelo HIV sob terapia anti-retroviral Rhinosinusitis in HIV-infected children undergoing antiretroviral therapy

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    Carlos Diógenes Pinheiro Neto

    2009-02-01

    Full Text Available A associação dos inibidores de protease (IP à terapia anti-retroviral provocou mudanças importantes na morbidade e mortalidade de pacientes infectados pelo HIV. OBJETIVOS: Avaliar o impacto desta associação na prevalência de rinossinusite (RS e na contagem sérica de linfócitos CD4 em crianças infectadas pelo HIV. CASUÍSTICA E MÉTODOS: A forma de estudo foi cross-sectional com 471 crianças infectadas pelo HIV. Em 1996, inibidores de protease foram liberados para terapia anti-retroviral. Desta forma, dois grupos de crianças foram formados: as que não fizeram uso de IP e as que fizeram uso desta droga após 1996. A prevalência de RS e a contagem sérica de linfócitos CD4 foram comparadas entre estes grupos. RESULTADOS: 14,4% das crianças infectadas pelo HIV apresentaram RS. A RS crônica foi mais prevalente que a RS aguda em ambos os grupos. Crianças menores de 6 anos tratadas com a associação de IP apresentaram maior prevalência de RS aguda. A associação de IP esteve associada à maior contagem de linfócitos CD4 séricos com menor prevalência de RS crônica. CONCLUSÕES: A terapia com IP esteve associada ao aumento na contagem de linfócitos CD4. Crianças abaixo dos 6 anos em uso de IP apresentaram menor tendência à cronificação da doença.The association of protease inhibitors (PI to antiretroviral therapy has generated sensible changes in morbidity and mortality of HIV-infected patients. AIM: Aims at evaluating the impact of this association on the prevalence of rhinosinusitis (RS and CD4+ lymphocyte count in HIV-infected children. METHODS: Retrospective cross-sectional study of the medical charts of 471 HIV-infected children. In 1996, protease inhibitors were approved for use as an association drug in antiretroviral therapy. Children were divided into two groups: one which did not receive PI and another which received PI after 1996. The prevalence of RS and CD4+ lymphocyte counts were compared between these groups

  9. Helminthic Infections Rates and Malaria in HIV-Infected Pregnant Women on Anti-Retroviral Therapy in Rwanda

    Science.gov (United States)

    Ivan, Emil; Crowther, Nigel J.; Mutimura, Eugene; Osuwat, Lawrence Obado; Janssen, Saskia; Grobusch, Martin P.

    2013-01-01

    Background Within sub-Saharan Africa, helminth and malaria infections cause considerable morbidity in HIV-positive pregnant women and their offspring. Helminth infections are also associated with a higher risk of mother-to-child HIV transmission. The aim of this study was to determine the prevalence of, and the protective and risk factors for helminth and malaria infections in pregnant HIV-positive Rwandan women receiving anti-retroviral therapy (ART). Methodology and principle findings Pregnant females (n = 980) were recruited from health centres in rural and peri-urban locations in the central and eastern provinces of Rwanda. Helminth infection was diagnosed using the Kato Katz method whilst the presence of Plasmodium falciparum was identified from blood smears. The prevalence of helminth infections was 34.3%; of malaria 13.3%, and of co-infections 6.6%. Helminth infections were more common in rural (43.1%) than peri-urban (18.0%; p<0.0005) sites. A CD4 count ≤350 cells/mm3 was associated with a higher risk of helminth infections (odds ratio, 3.39; 95% CIs, 2.16–5.33; p<0.0005) and malaria (3.37 [2.11–5.38]; p<0.0005) whilst helminth infection was a risk factor for malaria infection and vice versa. Education and employment reduced the risk of all types of infection whilst hand washing protected against helminth infection (0.29 [0.19–0.46]; p<0.0005);). The TDF-3TC-NVP (3.47 [2.21–5.45]; p<0.0005), D4T-3TC-NVP (2.47 [1.27–4.80]; p<0.05) and AZT-NVP (2.60 [1.33–5.08]; p<0.05) regimens each yielded higher helminth infection rates than the AZT-3TC-NVP regimen. Anti-retroviral therapy had no effect on the risk of malaria. Conclusion/significance HIV-positive pregnant women would benefit from the scaling up of de-worming programs alongside health education and hygiene interventions. The differential effect of certain ART combinations (as observed here most strongly with AZT-3TC-NVP) possibly protecting against helminth infection warrants further

  10. Quality of life among people living with acquired immune deficiency syndrome receiving anti-retroviral therapy: a study from Nepal

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    Giri S

    2013-09-01

    Full Text Available Smith Giri, Maniraj Neupane, Sushil Pant, Utsav Timalsina, Sagar Koirala, Santosh Timalsina, Sashi Sharma Department of Medicine, Tribhuvan University Teaching Hospital, Kathmandu, Nepal Purpose: The present study was undertaken to determine the impact of acquired immune deficiency syndrome (AIDS on the quality of life of affected individuals in Nepal. Patients and methods: A cross sectional study was done among 70 individuals attending the Anti-Retroviral Therapy clinic of the University Hospital in Nepal. Quality of life (QOL was evaluated using World Health Organization Quality of life questionnaire (WHO QOL-BREF instrument. Statistical analysis was done using SPSS Version 17.0. Results: The median scores with interquartile range (IQR in four domains of QOL in descending order were physical (61; IQR 22, social (58; IQR 33, environmental (56; IQR 13, and psychological (54; IQR 8. Older age was associated with lower perceived overall QOL. Females were more likely to have lower QOL scores in the social and psychological domains. Higher CD4 counts and a married status were significant predictors of higher QOL scores in the environmental domain. Conclusion: Being older, female, single, and having advanced clinical stage is associated with lower QOL scores in people living with AIDS. Lowest QOL scores were seen in the psychological domain suggesting the need of psychological interventions. Keywords: quality of life, AIDS, Nepal, WHO QOL-BREF

  11. Circulating heat shock protein 60 levels are elevated in HIV patients and are reduced by anti-retroviral therapy.

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    Itaru Anraku

    Full Text Available Circulating heat shock protein 60 (Hsp60 and heat shock protein 10 (Hsp10 have been associated with pro- and anti-inflammatory activity, respectively. To determine whether these heat shock proteins might be associated with the immune activation seen in HIV-infected patients, the plasma levels of Hsp60 and Hsp10 were determined in a cohort of 20 HIV-infected patients before and after effective combination anti-retroviral therapy (cART. We show for the first time that circulating Hsp60 levels are elevated in HIV-infected patients, with levels significantly reduced after cART, but still higher than those in HIV-negative individuals. Hsp60 levels correlated significantly with viral load, CD4 counts, and circulating soluble CD14 and lipopolysaccharide levels. No differences or correlations were seen for Hsp10 levels. Elevated circulating Hsp60 may contribute to the immune dysfunction and non-AIDS clinical events seen in HIV-infected patients.

  12. [Successful treatment of HIV-associated chronic inflammatory demyelinating polyneuropathy by early initiation of highly active anti-retroviral therapy].

    Science.gov (United States)

    Kume, Kodai; Ikeda, Kazuyo; Kamada, Masaki; Touge, Tetsuo; Deguchi, Kazushi; Masaki, Tsutomu

    2013-01-01

    A 47-year-old man with HIV infection presented with lower leg dominant dysesthesia, muscle weakness and sensory ataxia of 3 month's duration. Nerve conduction studies (NCS) showed demyelination change in the median and tibial nerves and sensory nerve action potential (SNAP) in the sural nerve was not evoked. Somatosensory evoked potential (SEP) showed the delayed N9 latency. Diagnose of HIV-associated chronic inflammatory demyelinating polyneuropathy (CIDP) was made. Although the CD4 lymphocyte counts were relatively preserved (466/μl), highly active anti-retroviral therapy (HAART) was started according to a new guideline for the use of antiretroviral agents in HIV-1-infected adults and adolescents recommending early initiation of treatment. After six months, HIV1-RNA was not detected and the CD4 lymphocyte counts showed a recovering trend (585/μl). His symptoms had disappeared, except for dysesthesia in the tip of a toe. Repeated NCS demonstrated full recovery from the demyelination and appearance of SNAP in the sural nerve. The improvement of his symptoms and NCS findings has been maintained for two years. Although effectiveness of immunotherapies such as oral prednisone, high-dose immunoglobulins and plasmapheresis have been reported in HIV-associated CIDP, early initiation of HAART may be also important for favorable prognosis in HIV-associated CIDP.

  13. Effect of Micronutrient and Probiotic Fortified Yogurt on Immune-Function of Anti-Retroviral Therapy Naive HIV Patients  

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    J. Dik F. Habbema

    2011-10-01

    Full Text Available Background: Micronutrient supplementation has been shown to reduce the progression of HIV but does not have an effect on the intestinal barrier or the intestinal microbiota of HIV patients. Studies have suggested that probiotics could potentially complement micronutrients in preserving the immune-function of HIV patients. Objective: Assess the impact of micronutrient supplemented probiotic yogurt on the immune function of HIV patients. Design: We performed a randomized, double blind, controlled trial with CD4 count as primary outcome among HIV patients naïve to anti-retroviral treatment. Secondary outcomes included hematological parameters, incidence of diarrhea and clinical symptoms. A total of 112 HIV patients were randomized to receive a micronutrient fortified yogurt with (n = 55 or without additional probiotic Lactobacillus rhamnosus GR-1 (n = 57 for four weeks. Results: An average decline in CD4 count of −70 cells/μL (95% CI: −154 to −15 was observed in the micronutrient, probiotic group versus a decrease of −63 cells/μL (95% CI: −157 to −30 in the micronutrient control group (p = 0.9. Additional probiotic supplementation was well tolerated and not associated with adverse events. No difference between groups was detected in incidence of diarrhea or clinical symptoms. An improvement of hemoglobin levels was observed for all subjects, based upon a mean difference from baseline of 1.4 g/L (SD = 6 (p = 0.02. Conclusion: The addition of probiotics to a micronutrient fortified yogurt was well tolerated by HIV patients but was not associated with a further increase in CD4 count after one month.

  14. Assessment of factors influencing adherence to anti-retroviral therapy for human immunodeficiency virus positive mothers and their infected children

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    Arun Kumar De

    2012-01-01

    Full Text Available Background and Objectives: Mothers and children are biologically related and dependent. They should be considered as a single unit which is very important regarding adherence to anti-retroviral therapy (ART. Very high levels of adherence are required for effective ART. We therefore carried out this study to examine the adherence levels and different factors associated with adherence among human immunodeficiency virus (HIV-positive mothers and their HIV-positive children receiving ART. Design and Setting: A hospital-based cross-sectional study. Materials and Methods: Ninety-four HIV-positive mothers and their 94 HIV-positive children under ART attending the ART center of a tertiary care hospital were recruited in this study. Consenting mothers were asked to complete the "Case Study Form" containing socio-demographic and care-giving details. Mothers were also asked to complete the Beck′s depression inventory, State trait anxiety inventory, and Ways of coping inventory. Adherence was assessed using pill count. Criteria for good and poor adherence were defined. Current CD4 counts were retrieved from the hospital record. Results: Fifty-six percent of respondent mothers and 65.8% of respondent children showed good adherence to ART. Different factors were associated with poor adherence in both mothers and their children. Conclusion: Adherence of HIV-positive mothers and their HIV-positive children to ART is influenced by multiple factors and identification of these factors is necessary to get complete adherence to ART. There is statistically significant relationship between maternal and pediatric adherence to ART.

  15. Predictors of treatment failure and time to detection and switching in HIV-infected Ethiopian children receiving first line anti-retroviral therapy

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    Bacha Tigist

    2012-08-01

    to have treatment failure retrospectively by the authors based on their records. Hence, they were not detected and these patients were not offered second line ARTs. Conclusions Having chronic malnutrition, low CD4 at base line, chronic diarrhea after initiation of first line ART, substitution of ART drugs and age less than 3 years old were found to be independent predictors of first line ART failure in children. Most of the first line ART failure cases were not detected early and those that were detected were not switched to second line drugs in a timely fashion. Children with the above risk factors should be closely monitored for a timely switch to second line highly active anti-retroviral therapy.

  16. Incidence of WHO stage 3 and 4 conditions following initiation of anti-retroviral therapy in resource limited settings.

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    Andrea J Curtis

    Full Text Available OBJECTIVES: To determine the incidence of WHO clinical stage 3 and 4 conditions during early anti-retroviral therapy (ART in resource limited settings (RLS. DESIGN/SETTING: A descriptive analysis of routine program data collected prospectively from 25 Médecins Sans Frontières supported HIV treatment programs in eight countries between 2002 and 2010. SUBJECTS/PARTICIPANTS: 35,349 study participants with median follow-up on ART of 1.33 years (IQR 0.51-2.41. OUTCOME MEASURES: Incidence in 100 person-years of WHO stage 3 or 4 conditions during 5 periods after ART initiation. Diagnoses of conditions were made according to WHO criteria and relied upon clinical assessments supported by basic laboratory investigations. RESULTS: The incidence of any WHO clinical stage 3 or 4 condition over 3 years was 40.02 per 100 person-years (31.77 for stage 3 and 8.25 for stage 4. The incidence of stage 3 and 4 conditions fell by over 97% between months 0-3 and months 25-36 (77.81 to 2.40 for stage 3 and 28.70 to 0.64 for stage 4. During months 0-3 pulmonary tuberculosis was the most common condition diagnosed in adults (incidence 22.24 per 100 person-years and children aged 5-14 years (25.76 and oral candidiasis was the most common in children <5 years (25.79. Overall incidences were higher in Africa compared with Asia (43.98 versus 12.97 for stage 3 and 8.98 versus 7.05 for stage 4 conditions, p<0.001. Pulmonary tuberculosis, weight loss, oral and oesophageal candidiasis, chronic diarrhoea, HIV wasting syndrome and severe bacterial infections were more common in Africa. Extra-pulmonary tuberculosis, non-tuberculous mycobacterial infection, cryptococcosis, penicilliosis and toxoplasmosis were more common in Asia. CONCLUSIONS: The incidence of WHO stage 3 and 4 conditions during the early period after ART initiation in RLS is high, but greatly reduces over time. This is likely due to both the benefits of ART and deaths of the sickest patients occurring shortly

  17. Screening for Cryptococcal Antigenemia in Anti-Retroviral Naïve AIDS Patients in Benin City, Nigeria

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    Favour Osazuwa

    2012-05-01

    Full Text Available Objectives: Cryptococcus neoformans is the most incriminated fungal pathogen causing meningitis in acquired immune deficiency syndrome (AIDS patients, and is known to constitute a major cause of deaths in AIDS patients. This study thus aimed to determine the baseline sero-prevalence of Cryptococcus neoformans infection in anti-retroviral naïve (ART-naïve AIDS patients using the serum Cryptococcal antigen (crag detection method. Baseline effect of variation in CD4 counts, as well as sex and age with sero-positivity for crag were also determined.Methods: This descriptive cross-sectional study included 150 (61 males and 89 females ART-naïve AIDS patients attending the Human Immunodeficiency Virus clinic (HIV at the University of Benin Teaching hospital, Benin City, Nigeria, within the period from February 2011- July 2011. Forty (18 males and 22 females HIV positive outpatients with CD4 counts >200 cells/µl who were ART-naive were recruited and used as controls. The sero-prevalence of crag in the patients and the control group was measured using the cryptococcal antigen latex agglutination system (CALAS (Meridian Bioscience, Europe and CD4 counts were measured using flow cytometry (Partec flow cytometer, Germany.Results: Of the 150 ART-naïve AIDS patients with CD4 counts £200 cells/µL; 19 (12.7% were positive for serum Cryptococcal antigen. ART-naïve AIDS patients with CD4 count ≤50 cells/µl had the highest prevalence of serum crag. Lower CD4 counts were significantly associated with positivity for serum crag (p<0.001. Age and sex had no significant effect on the sero-positivity for serum crag. One (2.5% of the controls was sero-positive for crag. Thus, serum crag was significantly associated with AIDS but not with HIV (p<0.001.Conclusion: This study uncovers a high prevalence of crag in ART- naïve AIDS patients in Benin City. The prevalence of crag was higher in ART-naïve AIDS patients with lower CD4 counts. There is an urgent need to

  18. Algorithms for Drug Sensitivity Prediction

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    Carlos De Niz

    2016-11-01

    Full Text Available Precision medicine entails the design of therapies that are matched for each individual patient. Thus, predictive modeling of drug responses for specific patients constitutes a significant challenge for personalized therapy. In this article, we consider a review of approaches that have been proposed to tackle the drug sensitivity prediction problem especially with respect to personalized cancer therapy. We first discuss modeling approaches that are based on genomic characterizations alone and further the discussion by including modeling techniques that integrate both genomic and functional information. A comparative analysis of the prediction performance of four representative algorithms, elastic net, random forest, kernelized Bayesian multi-task learning and deep learning, reflecting the broad classes of regularized linear, ensemble, kernelized and neural network-based models, respectively, has been included in the paper. The review also considers the challenges that need to be addressed for successful implementation of the algorithms in clinical practice.

  19. Regulatory T cells in human immunodeficiency virus-infected patients are elevated and independent of immunological and virological status, as well as initiation of highly active anti-retroviral therapy

    DEFF Research Database (Denmark)

    Gaardbo, J.C.; Nielsen, S.D.; Vedel, S.J.;

    2008-01-01

    mechanisms. During recent years it has become evident that a subpopulation of T cells [T regulatory (T(regs))] play a major role in sustaining tolerance to self-antigens. To investigate the influence of initiation of highly active anti-retroviral therapy (HAART) on the T(reg) level in HIV-infected patients...

  20. Increased levels of regulatory T cells (Tregs) in human immunodeficiency virus-infected patients after 5 years of highly active anti-retroviral therapy may be due to increased thymic production of naive Tregs

    DEFF Research Database (Denmark)

    Kolte, L.; Gaardbo, J.C.; Skogstrand, K.;

    2009-01-01

    This study determines levels of regulatory T cells (T(regs)), naive T(regs), immune activation and cytokine patterns in 15 adult human immunodeficiency virus (HIV)-infected patients receiving prolonged highly active anti-retroviral therapy (HAART) who have known thymic output, and explores if naive...

  1. Patentes farmacêuticas e saúde pública: desafios à política brasileira de acesso ao tratamento anti-retroviral Pharmaceutical patents and public health: challenges for the Brazilian antiretroviral treatment policy

    Directory of Open Access Journals (Sweden)

    Constance Marie Milward de Azevedo Meiners

    2008-07-01

    Full Text Available O preço elevado de medicamentos patenteados tem intensificado o debate em torno do impacto do regime da propriedade intelectual sobre o acesso a tratamentos de saúde, merecendo destaque o caso do HIV/AIDS. A política brasileira de tratamento anti-retroviral, parte de um programa nacional que integra medidas de prevenção e promoção da saúde, permitiu o alcance de uma ampla cobertura com qualidade, tendo sido apontada como modelo para outros países. Não obstante, conforme amadurece o Programa Nacional de DST e AIDS, os gastos com a incorporação de anti-retrovirais patenteados ao esquema terapêutico para pacientes em tratamento atinge um peso, cada vez maior, em seu orçamento. O presente artigo toma em conta os desafios apresentados pelas patentes farmacêuticas à saúde pública e discute possíveis caminhos para a sustentação da política de acesso universal e gratuito ao tratamento contra HIV/AIDS no Brasil.The high prices of patented drugs have fueled the debate regarding the impact of the intellectual property system on access to treatment, with a special focus on HIV/AIDS. The Brazilian policy for antiretroviral treatment, part of a comprehensive program that includes both disease prevention and health promotion activities, has allowed the country to meet goals for coverage and quality and has been considered a model for other countries. However, as the Brazilian STD/AIDS Program reaches maturity, the increasing incorporation of patented drugs into the AIDS treatment regimen imposes an increasing burden on the country's health budget. This article discusses the public health challenges raised by pharmaceutical patents and discusses possible ways to sustain the national policy for free, universal access to HIV/AIDS treatment.

  2. Terapia anti-retroviral em indivíduos vivendo com HIV/Aids, Belo Horizonte, 2001 - 2003: o desafio da adesão

    OpenAIRE

    Palmira de Fatima Bonolo

    2005-01-01

    É consenso, entre pesquisadores e profissionais de saúde, que a adesão à terapia anti-retroviral (TARV) é um grande desafio. Os medicamentos anti-retrovirais (ARV) trouxeram excelentes resultados clínicos, mas esses benefícios são diretamente dependentes da adesão ao tratamento. Estudos têm mostrado que dentre os fatores associados com a não-adesão estão àqueles ligados ao serviço de saúde, ao regime terapêutico e ao paciente, e ao contexto sóciocultural, muitos deles passíveis de interven...

  3. Price Sensitivity of Demand for Prescription Drugs

    DEFF Research Database (Denmark)

    Skipper, Lars; Simonsen, Marianne; Skipper, Niels

    This paper investigates price sensitivity of demand for prescription drugs using drug purchase records for at 20% random sample of the Danish population. We identify price responsiveness by exploiting exogenous variation in prices caused by kinked reimbursement schemes and implement a regression ...... education and income are, however, more responsive to the price. Also, essential drugs that prevent deterioration in health and prolong life have lower associated average price sensitivity....

  4. Tenofovir induced lichenoid drug eruption.

    Science.gov (United States)

    Gupta, Mrinal; Gupta, Heena; Gupta, Anish

    2015-01-01

    Cutaneous adverse reactions are a common complication of anti-retroviral therapy. Tenofovir is a newer anti-retroviral drug belonging to the nucleotide reverse transcriptase inhibitor group. Systemic adverse effects like nausea, vomiting, diarrhea, hepatotoxicity and renal toxicity are common with tenofovir but cutaneous adverse effects are rare. Lichenoid drug eruptions are a common adverse effect seen with a large variety of drugs including antimalarials, antihypertensives, nonsteroidal anti-inflammatory drugs and diuretics. Lichenoid drug eruption is a rare cutaneous adverse effect of tenofovir with only a single case reported till date. Here, we report a case of tenofovir induced lichenoid drug eruption in a 54-year-old human immunodeficiency virus affected male who presented with generalized lichenoid eruption after 6 weeks of initiation of tenofovir and complete clearance on cessation of the drug.

  5. Price Sensitivity of Demand for Prescription Drugs

    DEFF Research Database (Denmark)

    Simonsen, Marianne; Skipper, Lars; Skipper, Niels

    2016-01-01

    We investigate price sensitivity of demand for prescription drugs, using drug purchase records for the entire Danish population. We identify price responsiveness by exploiting variation in prices caused by kinked reimbursement schemes and implement a regression kink design. The results suggest so...... price responsiveness with corresponding price elasticities ranging from −0.2 to −0.7. Individuals with chronic disease and especially individuals above the age of 65 respond less to the price of drugs.......We investigate price sensitivity of demand for prescription drugs, using drug purchase records for the entire Danish population. We identify price responsiveness by exploiting variation in prices caused by kinked reimbursement schemes and implement a regression kink design. The results suggest some...

  6. Evaluation of the Impact of Anti-Retroviral Therapy on the Prevalence of Oral Lesions in Human Immunodeficiency Virus Infected Patients

    Directory of Open Access Journals (Sweden)

    P. Davoodi

    2013-10-01

    Full Text Available Introduction & Objective: Oral lesions have important diagnostic and prognostic roles in HIV infected patients. It seems that HAART reduces the prevalence of oral lesions. The aim of the present study was to evaluate the prevalence of oral lesions in HIV infected patients on/not on HAART. Materials & Methods: In this retrospective study, 40 HIV infected patients receiving HAART and 40 who were not on HAART were evaluated in Behavioral Consultation Center in Kermanshah. The diagnosis of the oral lesions was recorded by using established presump-tive clinical criteria. Data were gathered and analyzed using SPSS version 16 by chi-square test. Results: In the current study 80 HIV infected patients with mean age of 38.86 were chosen. 72.5% and 27.5% of participants were male and female respectively. The most common le-sions in those receiving HAART were hairy leukoplakia, hairy tongue and oral pigmentation. However the prevalence of these lesions had declined in comparison to those who were not on HAART but the difference was not significant (P>0.05. Although comparing lesions in the two groups showed no significant difference, the total number of lesions significantly reduced in patients receiving HAART (P=0.046 Conclusion: According to the results of the present study using anti retroviral therapy leaded to reduction in the oral lesions in HIV infected patients. However, more research in this field seems necessary. (Sci J Hamadan Univ Med Sci 2013; 20 (3:215-222

  7. T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV-infected children on anti-retroviral therapy in Nairobi, Kenya.

    Science.gov (United States)

    Buechler, M B; Newman, L P; Chohan, B H; Njoroge, A; Wamalwa, D; Farquhar, C

    2015-09-01

    HIV-infected children are less capable of mounting and maintaining protective humoral responses to vaccination against measles compared to HIV-uninfected children. This poses a public health challenge in countries with high HIV burdens. Administration of anti-retroviral therapy (ART) and revaccinating children against measles is one approach to increase measles immunity in HIV-infected children, yet it is not effective in all cases. Immune anergy and activation during HIV infection are factors that could influence responses to measles revaccination. We utilized a flow cytometry-based approach to examine whether T cell anergy and activation were associated with the maintenance of measles-specific immunoglobulin (Ig)G antibodies generated in response to measles revaccination in a cohort of HIV-infected children on ART in Nairobi, Kenya. Children who sustained measles-specific IgG for at least 1 year after revaccination displayed significantly lower programmed cell death 1 (PD-1) surface expression on CD8(+) T cells on a per-cell basis and exhibited less activated CD4(+) T cells compared to those unable to maintain detectable measles-specific antibodies. Children in both groups were similar in age and sex, CD4(+) T cell frequency, duration of ART treatment and HIV viral load at enrolment. These data suggest that aberrant T cell anergy and activation are associated with the impaired ability to sustain an antibody response to measles revaccination in HIV-infected children on ART.

  8. Retention of HIV-Infected Children in the First 12 Months of Anti-Retroviral Therapy and Predictors of Attrition in Resource Limited Settings: A Systematic Review.

    Science.gov (United States)

    Abuogi, Lisa L; Smith, Christiana; McFarland, Elizabeth J

    2016-01-01

    Current UNAIDS goals aimed to end the AIDS epidemic set out to ensure that 90% of all people living with HIV know their status, 90% initiate and continue life-long anti-retroviral therapy (ART), and 90% achieve viral load suppression. In 2014 there were an estimated 2.6 million children under 15 years of age living with HIV, of which only one-third were receiving ART. Little literature exists describing retention of HIV-infected children in the first year on ART. We conducted a systematic search for English language publications reporting on retention of children with median age at ART initiation less than ten years in resource limited settings. The proportion of children retained in care on ART and predictors of attrition were identified. Twelve studies documented retention at one year ranging from 71-95% amongst 31877 African children. Among the 5558 children not retained, 4082 (73%) were reported as lost to follow up (LFU) and 1476 (27%) were confirmed to have died. No studies confirmed the outcomes of children LFU. Predictors of attrition included younger age, shorter duration of time on ART, and severe immunosuppression. In conclusion, significant attrition occurs in children in the first 12 months after ART initiation, the majority attributed to LFU, although true outcomes of children labeled as LFU are unknown. Focused efforts to ensure retention and minimize early mortality are needed as universal ART for children is scaled up.

  9. Crystalluria in HIV/AIDS patients on highly active anti-retroviral therapy in the Kumasi metropolis; a cross sectional study

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    Richard K. D. Ephraim

    2014-01-01

    Full Text Available Background: Crystalluria is associated with some highly active anti-retroviral therapies (HAART′s used in the management of HIV/AIDS. Aims: This study used light microscopy to establish the prevalence of crystalluria among HIV/AIDS patients on HAART and identified the routine crystals present in their urine. Materials and Methods: In this simple randomised cross-sectional study, 200 HIV/AIDS participants, comprising 150 on HAART and 50 HAART-naοve were recruited from the HIV clinic at the Komfo Anokye Teaching Hospital (KATH. Urine and blood samples were collected, for urinalysis and the determination of the CD4 count, respectively. A well-structured pre-tested questionnaire was used to obtain socio-demographic data and clinical history of the participants. Results: The prevalence of crystalluria was higher among HIV-infected persons on HAART than those not on HAART (6.7% vs 4%; P = 0.733. Calcium oxalate and triple phosphate crystals were the crystal types present in their urine (3.5% and 2.5%, respectively and was present only in HIV subjects on first line of treatment (without protease inhibitors. Participants aged between 40-50 years and those with hypersthenuria and acidic urine had the highest amount of crystalluria (41.6%, 83.3%, and 58.3%, respectively. Conclusion: HAART is associated with crystalluria in HIV patients. Light microscopy will be of disgnostic value in resource limited settings.

  10. Microfinance and HIV mitigation among people living with HIV in the era of anti-retroviral therapy: emerging lessons from Cote d'Ivoire.

    Science.gov (United States)

    Holmes, Kathleen; Winskell, Kate; Hennink, Monique; Chidiac, Sybil

    2011-01-01

    The effects of HIV/AIDS have been far-reaching in Africa. Beyond adverse health outcomes and the tremendous toll on life, AIDS has serious economic impacts on households, increasing livelihood insecurity while simultaneously depleting socio-economic resources. Although microfinance is believed to have the potential to mitigate the economic impacts of HIV by helping affected households and communities better prepare for and cope with HIV-related economic shocks, little empirical research exists on this subject. This qualitative study examines the socio-economic impacts of economic strengthening activities on people living with HIV (PLHIV) in the era of increased access to anti-retroviral therapy to determine if savings-led, community-managed microfinance is a justified activity for HIV programmes. Findings from a village savings and loan programme, implemented by CARE International in Cote d'Ivoire, revealed that when appropriate medical treatment is available PLHIV are capable of participating in and benefit from microfinance activities, which increased HIV-positive clients' access to money and economic self-sufficiency. By bringing individuals with similar experiences together, savings and loan groups also acted as self-support groups providing psychosocial support while reducing stigmatisation and increasing members' sense of dignity and self-worth.

  11. Metabolic changes associated with antiretroviral therapy in HIV-positive patients Alteraciones metabólicas asociadas a la terapia anti-retroviral en pacientes HIV-positivos Alterações metabólicas associadas à terapia anti-retroviral em pacientes HIV-positivos

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    Sabrina Esteves de Matos Almeida

    2009-04-01

    Full Text Available OBJECTIVE: To evaluate metabolic changes associated with highly active antiretroviral therapy (HAART in HIV-positive patients, and to identify risk factors associated. METHODS: Retrospective study that included 110 HIV-positive patients who where on HAART in the city of Porto Alegre (Southern Brazil between January 2003 and March 2004. Data on demographic variables, cigarette smoking, diabetes mellitus, cholesterol and triglyceride levels, stage of HIV infection, antiretroviral therapy and HCV coinfection were collected. General linear models procedure for repeated measures was used to test the interaction between HAART and HCV coinfection or protease inhibitor treatment. RESULTS: Total cholesterol, triglycerides, and glucose levels significantly increased after receiving HAART (pOBJETIVO: Evaluar las alteraciones metabólicas asociadas a la terapia anti-retroviral potente en pacientes HIV-positivos e identificar factores de riesgo asociados. MÉTODOS: Estudio retrospectivo con 110 pacientes HIV-positivos que estaban en terapia anti-retroviral potente (HAART en la ciudad de Porto Alegre (Sur de Brasil, entre enero de 2003 y marzo de 2004. Los datos colectados incluyen variables demográficas, tabaquismo, diabetes mellitas, niveles de colesterol y triglicéridos, fase de la infección viral, terapia anti-retroviral y co-infección con hepatitis C. El análisis multivariado para medidas repetidas (General Linear Model procedure for Repeated Measures fue utilizada para analizar la interacción entre el efecto de uso de HAART y el uso de inhibidores de proteasa o co-infección por hepatitis C. RESULTADOS: Fueron observados aumentos significativos en los niveles de colesterol total, triglicéridos y glucosa posterior al tratamiento con HAART (pOBJETIVO: Avaliar as alterações metabólicas associadas à terapia anti-retroviral potente em pacientes HIV-positivos e identificar fatores de risco associados. MÉTODOS: Estudo retrospectivo com 110

  12. Estudo da Adesão à Quimioprofilaxia Anti-retroviral para a Infecção por HIV em Mulheres Sexualmente Vitimadas Study of Adherence to Antiretroviral Chemoprophylaxis for HIV Infection in Sexually Abused Women

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    Jefferson Drezett

    1999-10-01

    Full Text Available Objetivos: embora não existam dados apropriados para estabelecer sua eficácia, alguns serviços tem utilizado, profilaticamente, a terapia anti-retroviral para o HIV nos casos de violência sexual. O objetivo deste estudo foi avaliar a aceitabilidade, tolerância e adesão a um esquema quimioprofilático para o HIV. Pacientes e método: foram avaliadas 62 mulheres vítimas de estupro e/ou atentado violento ao pudor com coito ectópico anal. Os agressores foram referidos como desconhecidos. A profilaxia foi iniciada dentro das primeiras 48 h da violência e mantida por 4 semanas, sendo administrados diariamente: zidovudina, 600 mg; indinavir, 2.400 mg e lamivudina, 300 mg. Resultados: a taxa de descontinuidade foi de 24,2%, sendo em 12 casos (80% decorrente de intolerância gástrica. Os efeitos colaterais estiveram presentes em 43 casos (69,4%, sendo as náuseas e vômitos os mais freqüentes. A complexidade posológica e o tempo de uso foram fatores possivelmente associados ao uso inadequado das drogas, ocorrendo em 10,6% dos casos. Conclusão: a taxa de descontinuidade da quimioprofilaxia foi semelhante à observada em outras indicações.Purpose: some medical institutions have been prophylactically ministrating anti-HIV therapy in cases of sexual violence, although there are no appropriate basic facts to establish its efficacy. The aim of the present study was to evaluate the acceptance, tolerance and adhesion of these women under a chemoprophylaxis plan for HIV. Methods: sixty-two women victims of rape and/or anal intercourse with unknown aggressors have been evaluated. Prophylaxis has been started within the first 48 h after violence and maintained for 4 weeks, with daily administration of zidovudine, 600 mg; indinavir, 2,400 mg and lamivudine, 300 mg. Results: the discontinuance rate was 24.2%, withe 12 cases (80% due to gastric intolerance. The side effects were present in 43 cases (69.4%, including nausea and vomitting as the most

  13. Abordagem metabólica e nutricional da lipodistrofia em uso da terapia anti-retroviral Metabolic and nutritional approach of lipodystrophy in the use of antiretroviral therapy

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    Claudia Daniele Tavares Dutra

    2008-08-01

    Full Text Available A terapia anti-retroviral altamente ativa, usada contra o Vírus da Imunodeficiência Humana, vem possibilitando a melhora do quadro clínico-laboratorial de portadores da Síndrome da Imunodeficiência Adquirida. Contudo, alterações metabólicas e complicações morfológicas, associadas ao uso da terapia, vêm sendo investigadas. A utilização prolongada desta terapia tem um impacto importante sobre o estado nutricional dos pacientes. Antes da sua utilização, a perda de peso e a desnutrição, conseqüências das infecções oportunistas, eram os maiores problemas nutricionais. Atualmente, o foco principal das discussões têm sido as complicações metabólicas e morfológicas, dentre elas a lipodistrofia, com a dislipidemia, a resistência à insulina, a osteopenia, e a distribuição alterada da gordura corporal, aumentando assim os riscos de doenças cardiovasculares. A nutrição desempenha um papel fundamental no suporte da saúde desses pacientes, integrando as equipes multiprofissionais, promovendo a melhora da adesão à terapia anti-retroviral e do prognóstico da doença. No entanto, para que se tenha mais conhecimento sobre a terapia, as proporções de seus efeitos adversos, e o perfil nutricional desses pacientes, a curto e a longo prazos, é de suma importância que se estude mais sobre este assunto, a fim de permitir perspectivas de um regime terapêutico mais seguro dentro de seus alcances metodológicos, proporcionando uma melhor qualidade de vida aos pacientes.The highly active antiretroviral therapy used against Human Immunodeficiency Virus provides an improvement in laboratory and clinical findings of patients with Acquired Immunodeficiency Syndrome. However, metabolic and morphologic disturbances associated with the therapy are being investigated. The drawn out use of these therapy has an important impact on the nutritional status of the patients. Before the use of this therapy, weight loss and malnutrition caused by

  14. Adherence to anti-retroviral therapy & factors associated with it: A community based cross-sectional study from West Bengal, India

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    Sobha Pahari

    2015-01-01

    Full Text Available Background & objectives: Failure to adhere to anti-retroviral therapy (ART can lead to a range of unfavourable consequences impacting upon people living with HIV (PLH and society. It is, therefore, paramount that ART adherence is measured in a reliable manner and factors associated with adherence are identified. Lack of such data from West Bengal necessitated undertaking the current study. Methods: Participants were included during August-October, 2011 from three Drop-In-Centres (DICs from the three districts of West Bengal, India. ART-adherence was calculated by using formula based on pill-count and records collected from ART-card in possession of each of the 128 consenting adult PLH. Information on self-reported adherence, socio-demography, and adherence influencing issues was also collected through interviewer-administered questionnaire. Results: Of the 128 PLH, 99 (77% and 93 (73% PLH had ≥90 per cent and ≥95 per cent adherence, respectively to ART. Conversely, subjective reporting captured much higher proportion of PLH as ′well adherent′; a finding having implications for ongoing ART programme. Factors, independently associated with poor adherence (<90%, were ′7 th to 12 th month period of ART intake′ (adjusted OR=9.5; 90% CI 1.9 - 47.3; p0 =0.02 and ′non-disclosure of HIV status to family members′ (adjusted OR=4; 90% CI 1.3 - 13; P=0.05. Results at 95 per cent adherence cut-off were similar. Interpretation & conclusions: Enabling environment, which would encourage people to disclose their HIV status and in turn seek adherence partners from families and beyond and ongoing adherence-counselling appear to be important issues in the programme. Relevance of these study findings in wider context is conceivable.

  15. Prevalence and clinical and laboratory characteristics of kidney disease in anti-retroviral-naive human immunodeficiency virus-infected patients in South-South Nigeria

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    U H Okafor

    2016-01-01

    Full Text Available Since the emergence of acquired immune deficiency syndrome (AIDS about three decades ago, several renal disorders have been reported as common complications of human immunodeficiency virus (HIV infection. These renal disorders result from diverse etiologies. The aim of this cross-sectional study was to determine the prevalence and clinical and laboratory characteristics of anti-retroviral-naοve HIV-infected patients with impaired kidney disorder in South-South Nigeria. This study was conducted on patients presenting at the University of Benin Teaching Hospital, Benin City in South-South Nigeria for six months. The patients′ demographic data and clinical, hematological and biochemical parameters were assessed. Their glomerular filtration rate (GFR was calculated and the protein excretion was assessed from the protein- creatinine ratio. Data were analyzed using statistical software program SPSS version 15.0. Threehundred and eighty-three patients with a mean age of 35.39 ± 8.78 years and a male: female ratio of 1:1 were studied; 53.3% had evidence of kidney disorder. The main clinical features in patients with kidney disorder were evidence of fluid retention, urinary symptoms, pallor and encephalopathy. The mean systolic and diastolic blood pressures were 115.33 ± 17.17 and 72.33 ± 14.31 mm Hg, respectively. The mean estimated GFR was 52.5 mL/min/1.73 m 2 . Patients with kidney disorder had higher proteinuria (P = 0.001, lower mean CD4 cell count and packed cell volume (P = 0.019 and 0.001, respectively. Kidney disorder is a common complication in HIV-infected patients, and they have clinical and laboratory anomalies. Screening of HIV/AIDS patients at the time of diagnosis will facilitate early diagnosis of kidney disorders in them.

  16. Determinantes da aderência à terapia anti-retroviral combinada em Brasília, Distrito Federal, Brasil, 1999-2000

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    Cláudio Viveiros de Carvalho

    Full Text Available A aderência ao tratamento é um dos principais problemas relacionados à terapia anti-retroviral, já que a tomada incompleta dos medicamentos pode levar à resistência viral. Efeitos colaterais podem interferir com a qualidade de vida dos pacientes. Buscou-se estimar níveis de aderência à terapia e investigar seus determinantes, através de um estudo transversal. Definiram-se dois pontos de corte como boa aderência: a tomada de pelo menos 80% ou de 95% da medicação conforme a prescrição. Realizaram-se entrevistas semi-estruturadas em uma amostra seqüencial de 150 pacientes atendidos no Hospital-Dia de Brasília. Observou-se que a média de aderência foi 85,8%. As variáveis que se mostraram significativamente associadas à baixa aderência foram: idade, escolaridade, situação de emprego, rendas pessoal e familiar, uso de substâncias ilícitas, estrutura familiar e/ou comunitária, presença de infecção oportunista no momento do diagnóstico e ocorrência de efeitos colaterais relacionados à terapia. As razões de prevalência variaram de 1,6 a 4,5. Concluiu-se que variáveis sócio-econômicas e de hábitos tiveram maior força de associação com o nível de aderência do que as relacionadas com a doença ou com o tratamento.

  17. Prevalence of renal disease in Nigerian children infected with the human immunodeficiency virus and on highly active anti-retroviral therapy.

    Science.gov (United States)

    Iduoriyekemwen, Nosakhare J; Sadoh, Wilson E; Sadoh, Ayebo E

    2013-01-01

    Access to highly active anti-retroviral therapy (HAART) has improved the prognosis of Nigerian children infected with the human immunodeficiency virus (HIV); thus, more children are surviving. Long-term exposure to HAART is potentially nephrotoxic. We therefore aimed at assessing the prevalence of renal disease in Nigerian children infected with HIV, who are on HAART. In this cross-sectional study, we studied children, aged ten months to 17 years, infected with HIV, attending the pediatric HIV clinics of the University of Benin Teaching Hospital. Demographic and clinical data were obtained by parental interview as well as from the medical records. Each child's urine was tested for albumin and microalbuminuria using multi test strips and mitral test strips, respectively. The serum creatinine level of each child was also estimated and used in calculating the glomerular filtration rate (GFR). Renal disease was defined as the presence of significant proteinuria of 1+ and above on dipstick or the presence of microalbuminuria of ≥20 mg and/or GFR renal disease was 16.2%. Microalbuminuria was seen in 11 children with renal disease (11.1%); 3 of them had significant proteinuria. GFR of less than 60 mL/min/1.73 m 2 was seen in five children (5.1%) with renal disease, but none had end-stage renal disease (GFR less than 15 mL/min/1.73 m 2 ). Renal disease was found to be significantly associated with advanced stage of HIV infection (P renal disease in HAART-treated Nigerian children is high and majority of them are asymptomatic of renal disease, but in the advanced stages of HIV infection.

  18. Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study

    DEFF Research Database (Denmark)

    Babiker, Abdel G; Emery, Sean; Fätkenheuer, Gerd

    2013-01-01

    Untreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an incr...... is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals....... with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication...

  19. Multi-scale modeling of HIV infection in vitro and APOBEC3G-based anti-retroviral therapy.

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    Iraj Hosseini

    2012-02-01

    Full Text Available The human APOBEC3G is an innate restriction factor that, in the absence of Vif, restricts HIV-1 replication by inducing excessive deamination of cytidine residues in nascent reverse transcripts and inhibiting reverse transcription and integration. To shed light on impact of A3G-Vif interactions on HIV replication, we developed a multi-scale computational system consisting of intracellular (single-cell, cellular and extracellular (multicellular events by using ordinary differential equations. The single-cell model describes molecular-level events within individual cells (such as production and degradation of host and viral proteins, and assembly and release of new virions, whereas the multicellular model describes the viral dynamics and multiple cycles of infection within a population of cells. We estimated the model parameters either directly from previously published experimental data or by running simulations to find the optimum values. We validated our integrated model by reproducing the results of in vitro T cell culture experiments. Crucially, both downstream effects of A3G (hypermutation and reduction of viral burst size were necessary to replicate the experimental results in silico. We also used the model to study anti-HIV capability of several possible therapeutic strategies including: an antibody to Vif; upregulation of A3G; and mutated forms of A3G. According to our simulations, A3G with a mutated Vif binding site is predicted to be significantly more effective than other molecules at the same dose. Ultimately, we performed sensitivity analysis to identify important model parameters. The results showed that the timing of particle formation and virus release had the highest impacts on HIV replication. The model also predicted that the degradation of A3G by Vif is not a crucial step in HIV pathogenesis.

  20. Prevalence of renal disease in Nigerian children infected with the human immunodeficiency virus and on highly active anti-retroviral therapy

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    Nosakhare J Iduoriyekemwen

    2013-01-01

    Full Text Available Access to highly active anti-retroviral therapy (HAART has improved the prognosis of Nigerian children infected with the human immunodeficiency virus (HIV; thus, more children are surviving. Long-term exposure to HAART is potentially nephrotoxic. We therefore aimed at assessing the prevalence of renal disease in Nigerian children infected with HIV, who are on HAART. In this cross-sectional study, we studied children, aged ten months to 17 years, infected with HIV, attending the pediatric HIV clinics of the University of Benin Teaching Hospital. Demographic and clinical data were obtained by parental interview as well as from the medical records. Each child′s urine was tested for albumin and microalbuminuria using multi test strips and mitral test strips, respectively. The serum creatinine level of each child was also estimated and used in calculating the glomerular filtration rate (GFR. Renal disease was defined as the presence of significant proteinuria of 1+ and above on dipstick or the presence of microalbuminuria of ≥20 mg and/or GFR <60 mL/min/1.73 m 2 . Of the 99 children recruited, 60 were males and 39 were females. The mean age of the children was 6.6 ± 3.5 years. All the children were on HAART and 85% had acquired the HIV infection by vertical transmission. The overall prevalence of renal disease was 16.2%. Microalbuminuria was seen in 11 children with renal disease (11.1%; 3 of them had significant proteinuria. GFR of less than 60 mL/min/1.73 m 2 was seen in five children (5.1% with renal disease, but none had end-stage renal disease (GFR less than 15 mL/min/1.73 m 2 . Renal disease was found to be significantly associated with advanced stage of HIV infection (P < 0.049. Our study showed that t he prevalence of renal disease in HAART-treated Nigerian children is high and majority of them are asymptomatic of renal disease, but in the advanced stages of HIV infection.

  1. Acceptance of anti-retroviral therapy among patients infected with HIV and tuberculosis in rural Malawi is low and associated with cost of transport.

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    Rony Zachariah

    Full Text Available BACKGROUND: A study was conducted among newly registered HIV-positive tuberculosis (TB patients systematically offered anti-retroviral treatment (ART in a district hospital in rural Malawi in order to a determine the acceptance of ART b conduct a geographic mapping of those placed on ART and c examine the association between "cost of transport" and ART acceptance. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cross-sectional analysis was performed on routine program data for the period of February 2003 to July 2004. Standardized registers and patient cards were used to gather data. The place of residence was used to determine road distances to the Thyolo district hospital. Cost of transport from different parts of the district was based on the known cost for public transport to the road-stop closest to the patient's residence. Of 1,290 newly registered TB patients, 1,003(78% underwent HIV-testing of whom 770 (77% were HIV-positive. 742 of these individuals (pulmonary TB = 607; extra-pulmonary TB = 135 were considered eligible for ART of whom only 101(13.6% accepted ART. Cost of transport to the hospital ART site was significantly associated with ART acceptance and there was a linear trend in association between cost and ART acceptance (chi(2 for trend = 25.4, P<0.001. Individuals who had to pay 50 Malawi Kwacha (1 United States Dollar = 100 Malawi Kwacha, MW or less for a one-way trip to the Thyolo hospital were four times more likely to accept ART than those who had to pay over 100 MW (Adjusted Odds ratio = 4.0, 95% confidence interval: 2.0-8.1, P<0.001. CONCLUSIONS/SIGNIFICANCE: ART acceptance among TB patients in a rural district in Malawi is low and associated with cost of transport to the centralized hospital based ART site. Decentralizing the ART offer from the hospital to health centers that are closer to home communities would be an essential step towards reducing the overall cost and burden of travel.

  2. Anticancer drug sensitivity by human tumor clonogenic assay.

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    Hiraki,Shunkichi

    1986-10-01

    Full Text Available The anticancer drug sensitivity of human cancers was tested by the human tumor clonogenic assay (HTCA. Of 152 human cancer specimens tested, 63 (41% formed more than 30 tumor cell colonies in control plates and could be used to evaluate the drug sensitivity of tumor cells. In 42 (93% of 45 clinical trials in 24 patients, a parallel correlation was observed between the in vitro anticancer drug sensitivity measured by the HTCA and the clinical response of tumors to anticancer drugs. These results suggest that the HTCA is a good technique for the in vitro test of the anticancer drug sensitivity of human cancers.

  3. Adesão e não-adesão à terapia anti-retroviral: as duas faces de uma mesma vivência Adhesión y no adhesión a la terapia antiretroviral: las dos caras de una misma vivencia Adhesion and non adhesion to anti-retroviral therapy: the two faces of a same experience

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    Ana Lúcia Cardoso Nogueira da Silva

    2009-04-01

    Full Text Available O objetivo do estudo foi compreender, a partir da perspectiva de portadores e familiares, os aspectos que influenciam na adesão à terapêutica anti-retroviral. Trata-se de um estudo descritivo, de natureza qualitativa, desenvolvido no período de junho de 2006 a julho de 2007, junto a 10 indivíduos portadores do HIV/Aids, acompanhados pelo Serviço de Atendimento Especializado em Aids de Campo Mourão - PR e seus familiares. Constituem fatores facilitadores da adesão: adoção de estratégias para lembrar horários e mascarar o gosto do medicamento, ausência de efeitos colaterais, número reduzido de medicamentos a serem ingeridos e capacidade para reconhecê-los, lembrança dos sintomas da doença e o apoio da rede social. A ausência destes fatores pode culminar na não-adesão.El objetivo del estudio fue comprender, a partir de la perspectiva de portadores y familiares, los aspectos que influyen en la adhesión a la terapéutica antiretroviral. Se trata de un estudio descriptivo, de naturaleza cualitativa, desarrollado en el período de junio de 2006 a julio de 2007, junto a 10 individuos portadores del VIH/SIDA, acompañados por el Servicio de Atención Especializado en SIDA de Campo Mourão - PR y sus familiares. Constituyen factores que facilitan la adhesión: adopción de estrategias para recordar horarios y enmascarar el sabor del medicamento, ausencia de efectos colaterales, número reducido de medicamentos a ser ingeridos y capacidad para reconocerlos, recuerdo de los síntomas de la enfermedad y el apoyo de la red social. La ausencia de estos factores puede culminar en la no-adhesión.The objective of the study was to understand, from the perspective of HIV bearers and family, the aspects that influence in the adhesion to the antiretroviral therapy. It is a descriptive study, of qualitative nature, carried out from June 2006 to July 2007, with 10 HIV/Aids positive individuals, attended at the Service of Specialized Care on Aids

  4. Tendências da epidemia de Aids no Brasil após a terapia anti-retroviral AIDS epidemic trends after the introduction of antiretroviral therapy in Brazil

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    Inês Dourado

    2006-04-01

    Full Text Available OBJETIVO: A terapia anti-retroviral disponível no Brasil a partir de 1996, modificou o curso da epidemia de Aids, alterando sua evolução e tendências. Nesse sentido, o estudo teve por objetivo avaliar a epidemia da Aids no Brasil, nos seus aspectos epidemiológicos. MÉTODOS: Estudo realizado a partir de bases de dados do Ministério da Saúde que caracterizavam a evolução temporal da Aids nas macrorregiões brasileiras, de 1990 a 2003. Foram utilizados modelos de regressão exponencial, ajustados à série temporal de 1990 a 1996 e estimados valores esperados para toda a série. RESULTADOS: O percentual de internações não se modificou no tempo, mas ocorreu diminuição de hospitalizações entre os usuários de terapia anti-retrovial. Houve um incremento de 2,7 vezes no número de indivíduos em uso da terapia, de 1997 a 2003. Incidência e mortalidade apresentaram crescimentos uniformes até 1995, em todas as regiões. A partir de 1996, verificou-se uma redução progressiva da mortalidade, embora a incidência continue crescendo. Em todas as regiões, exceto a Norte, as incidências esperadas foram maiores do que as observadas nos últimos anos, embora as diferenças somente tenham atingido níveis de significância estatística nas regiões Sudeste e Centro-Oeste. CONCLUSÕES: As mudanças observadas no perfil de morbi-mortalidade da epidemia de Aids no Brasil poderiam ser explicadas pelo amplo acesso a terapia anti-retroviral. Tal fato representou um impacto importante sobre a mortalidade por HIV/Aids, porém, outros fatores devem ser considerados, como idade da epidemia, medidas de prevenção, conhecimento sobre HIV/Aids e anos de escolaridade.OBJECTIVE: Universal access to antiretroviral therapy starting from 1996 has changed HIV/AIDS epidemic profile in Brazil. The objective of this study was to review the epidemiology of HIV/AIDS epidemic in Brazil. METHODS: Indicators of temporal trends were developed for Brazilian regions

  5. Visual contrast sensitivity in drug-induced Parkinsonism.

    Science.gov (United States)

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-03-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way.

  6. Visual contrast sensitivity in drug-induced Parkinsonism.

    Science.gov (United States)

    Bulens, C; Meerwaldt, J D; van der Wildt, G J; Keemink, C J

    1989-01-01

    The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way. PMID:2926418

  7. Gene sensitizes cancer cells to chemotherapy drugs

    Science.gov (United States)

    NCI scientists have found that a gene, Schlafen-11 (SLFN11), sensitizes cells to substances known to cause irreparable damage to DNA.  As part of their study, the researchers used a repository of 60 cell types to identify predictors of cancer cell respons

  8. Anti-retroviral Therapy Based HIV Prevention Among a Sample of Men Who Have Sex with Men in Cape Town, South Africa: Use of Post-exposure Prophylaxis and Knowledge on Pre-exposure Prophylaxis.

    Science.gov (United States)

    Hugo, J M; Stall, R D; Rebe, K; Egan, J E; De Swardt, G; Struthers, H; McIntyre, J A

    2016-12-01

    Men who have Sex with Men (MSM) have been affected disproportionately by the global HIV pandemic. Rates of consistent condom-use are low and there is a need for further biomedical prevention interventions to prevent new HIV infections. Post exposure prophylaxis (PEP) can reduce the risk of HIV, but uptake among MSM is low. Pre-exposure prophylaxis (PrEP), an innovative anti-retroviral-based HIV prevention tool might be an appropriate intervention for MSM who have recently accessed PEP that involves HIV negative individuals taking daily tenofovir+emtricitabine for HIV prevention. 44 MSM, attending a primary health-care level MSM-focused sexual health clinic in Cape Town, South Africa, who had initiated PEP were enrolled in this study. Participants were followed up after 2, 4 and 12 weeks. Self-administered electronic surveys were completed at the initial, 4 and 12 week visit. Barriers and facilitators to accessing PEP and remaining adherent were examined, as was knowledge about PrEP. Thirty-two participants (80 %) were South Africa. Adherence was high and demonstrates that adherence support is feasible from a state health clinic. Reported risk behaviors in some high-risk participants did not change over time, demonstrating the need for additional longer-term HIV preventions such as PrEP. PEP users could conceivably be transitioned from PEP to PrEP.

  9. Biological studies of matrix metalloproteinase sensitive drug delivery systems

    DEFF Research Database (Denmark)

    Johansen, Pia Thermann

    due to severe side effects as a result of drug distribution to healthy tissues. To enhance ecacy of treatment and improve life quality of patients, tumor specific drug delivery strategies, such as liposome encapsulated drugs, which accumulate in tumor tissue, has gained increased attention. Several...... for delivery of drugs to specific tissues or cells utilizing biological knowledge of cancer tissue is getting increased attention. In this thesis a novel matrix metalloproteinase-2 (MMP-2) sensitive poly-ethylene glycol (PEG) coated liposomal drug delivery system for treatment of cancer was developed...... the use of MMP- 2 as a trigger for liposomal activation in tumor tissue. Thus, this new strategy provides a promising system for specific delivery of encapsulated drugs and controlled release in tumor tissues, resulting in enhanced drug bioavailability and decreased systemic side effects. In addition, we...

  10. Multitask learning improves prediction of cancer drug sensitivity

    Science.gov (United States)

    Yuan, Han; Paskov, Ivan; Paskov, Hristo; González, Alvaro J.; Leslie, Christina S.

    2016-01-01

    Precision oncology seeks to predict the best therapeutic option for individual patients based on the molecular characteristics of their tumors. To assess the preclinical feasibility of drug sensitivity prediction, several studies have measured drug responses for cytotoxic and targeted therapies across large collections of genomically and transcriptomically characterized cancer cell lines and trained predictive models using standard methods like elastic net regression. Here we use existing drug response data sets to demonstrate that multitask learning across drugs strongly improves the accuracy and interpretability of drug prediction models. Our method uses trace norm regularization with a highly efficient ADMM (alternating direction method of multipliers) optimization algorithm that readily scales to large data sets. We anticipate that our approach will enhance efforts to exploit growing drug response compendia in order to advance personalized therapy. PMID:27550087

  11. Oral manifestations of HIV infection in children and adults receiving highly active anti-retroviral therapy [HAART] in Dar es Salaam, Tanzania.

    NARCIS (Netherlands)

    Hamza, O.; Matee, M.I.N.; Simon, E.N.; Kikwilu, E.; Moshi, M.J.; Mugusi, F.; Mikx, F.H.M.; Verweij, P.E.; Ven, A.J.A.M. van der

    2006-01-01

    ABSTRACT: BACKGROUND: The aim of the study was to compare the prevalence and types of HIV-related oral lesions between children and adult Tanzanian patients on HAART with those not on HAART and to relate the occurrence of the lesions with anti-HIV drug regimen, clinical stage of HIV disease and CD4+

  12. Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model.

    Directory of Open Access Journals (Sweden)

    C Preston Neff

    Full Text Available Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP. Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.

  13. Improving Drug Sensitivity Prediction Using Different Types of Data

    OpenAIRE

    Hejase, HA; Chan, C.

    2015-01-01

    The algorithms and models used to address the two subchallenges that are part of the NCI-DREAM (Dialogue for Reverse Engineering Assessments and Methods) Drug Sensitivity Prediction Challenge (2012) are presented. In subchallenge 1, a bidirectional search algorithm is introduced and optimized using an ensemble scheme and a nonlinear support vector machine (SVM) is then applied to predict the effects of the drug compounds on breast cancer cell lines. In subchallenge 2, a weighted Euclidean dis...

  14. Improving Drug Sensitivity Prediction Using Different Types of Data.

    Science.gov (United States)

    Hejase, H A; Chan, C

    2015-02-01

    The algorithms and models used to address the two subchallenges that are part of the NCI-DREAM (Dialogue for Reverse Engineering Assessments and Methods) Drug Sensitivity Prediction Challenge (2012) are presented. In subchallenge 1, a bidirectional search algorithm is introduced and optimized using an ensemble scheme and a nonlinear support vector machine (SVM) is then applied to predict the effects of the drug compounds on breast cancer cell lines. In subchallenge 2, a weighted Euclidean distance method is introduced to predict and rank the drug combinations from the most to the least effective in reducing the viability of a diffuse large B-cell lymphoma (DLBCL) cell line.

  15. Tendência da transmissão vertical de Aids após terapia anti-retroviral no Brasil Trends in maternal-infant transmission of AIDS after antiretroviral therapy in Brazil

    Directory of Open Access Journals (Sweden)

    Ana Maria de Brito

    2006-04-01

    Full Text Available OBJETIVO: O crescimento de casos de Aids entre mulheres teve como conseqüência o aumento da transmissão vertical da infecção pelo vírus da imunodeficiência adquirida. Medidas de controle dessa modalidade de transmissão foram implementadas a partir de 1996. O objetivo do estudo foi analisar a tendência temporal da transmissão vertical de Aids em crianças brasileiras. MÉTODOS: Foram incluídas no estudo crianças nascidas entre 1990 e 2001 no Brasil. Utilizou-se o banco de casos notificados como Aids em menores de 13 anos, no período de 1990 a 2004. Modelos de regressão exponencial, ajustados à série temporal, forneceram as taxas de variação anual e os valores observados e esperados para todo o período. RESULTADOS: Observou-se tendência significativamente crescente para os casos com ano de nascimento no período anterior à introdução da terapia anti-retroviral, com taxa de crescimento em torno de 12% (tOBJECTIVE: the increase in the number of AIDS cases among women has lead to an increase in the maternal-infant transmission of human acquired immunodeficiency virus. Measures for the control of this type of transmission were implemented in Brazil in 1996. The aim of the present study was to analyze time trends in maternal-infant transmission of AIDS among Brazilian children. METHODS: The present study included children born in Brazil between 1990 and 2001. We used the database of notified AIDS cases in children 13 years of age or younger between 1990 and 2004. Exponential regression models adjusted to the time series provided the annual variation rates and observed and expected values for the period. RESULTS: We found a significant increasing trend for cases born prior to the year in which anti retroviral therapy was introduced, with an increase rate of about 12% (t<0.003 per year. Rates from different states ranged from 5.9% to 31%. The analysis of expected and observed cases for each of the country's five Regions showed a

  16. Pessoas vivendo com HIV/AIDS: variáveis associadas à adesão ao tratamento anti-retroviral Persons living with HIV/AIDS: factors associated with adherence to antiretroviral treatment

    Directory of Open Access Journals (Sweden)

    Eliane Maria Fleury Seidl

    2007-10-01

    Full Text Available O estudo objetivou descrever o comportamento de adesão ao tratamento anti-retroviral em pessoas vivendo com HIV/AIDS e investigar preditores da adesão entre as variáveis escolaridade, presença de efeitos colaterais, interrupção anterior da terapia anti-retroviral (TARV por conta própria, auto-estima, expectativa de auto-eficácia, estratégias de enfrentamento, suporte social e satisfação com a relação profissional de saúde-usuário. Adesão foi medida pelo auto-relato da perda do número de comprimidos/cápsulas dos medicamentos anti-retrovirais na última semana e mês, sendo considerada satisfatória na ocorrência de omissão inferior a 5% do total prescrito. Participaram 101 pessoas, 60,4% homens, idades entre 20 a 71 anos (M = 37,9 anos, 73,3% sintomáticos. A coleta de dados incluiu entrevista e instrumentos auto-aplicáveis. A maioria (n = 73; 72,3% relatou adesão igual ou superior a 95%. Nos resultados da regressão logística, interrupção anterior da TARV e expectativa de auto-eficácia foram preditores significativos da adesão. Faz-se necessária a qualificação da assistência pela constituição de equipes interdisciplinares, para o desenvolvimento de abordagens adequadas às dificuldades médicas e psicossociais de adesão das pessoas vivendo com HIV/AIDS.This study aimed to describe the adherence of persons living with HIV/AIDS to antiretroviral therapy (ART and to investigate adherence predictors among the following: level of schooling, presence of side effects, current or previous interruption of ART by the persons themselves, self-esteem, self-efficacy expectation, coping strategies, social support, and satisfaction with the health professional-patient relationship. Adherence was measured by self-reported number of ART pills/capsules missed during the previous week and previous month, evaluated as satisfactory when less than 5%. 101 HIV+ adults took part in this study, 60.4% males, ranging from 20 to 71 years

  17. The Drug Sensitivity of Cyclosporine A Combined with Antineoplastic Drugs in Retinoblastoma in Vitro

    Institute of Scientific and Technical Information of China (English)

    Wanli Liu; Zhongyao Wu

    2005-01-01

    Purpose: To study cyclosporine A inhibition on the fresh retinoblastoma cells in vitro and increasing the drug sensitivity after combined with different antineoplastic drugs.Methods: To study the growth curve of cyclosporine A on 27 samples of primary retinoblastoma cells by MTT assay and to study the change of the drug sensitivity by cyclosporine A combined with seven antineoplastic drugs.Results: The average IC50 of cyclosporine A on the 27 retinoblastoma cells is 67.81μg/ml and the average inhibitive rate of these samples is 26.1% when cyclosporine A is in the concentration of 2μg/ml. The inhibitive rates all got improved after the seven antineoplastic drugs combined with cyclosporine A and the increasing average inhibitive rate is more than 5.Conclusion: Cyclosporine A can inhibit retinoblastoma cells in vitro and its inhibitive effect is dose dependent. Moreover it can enhance the inhibition of multiple antineoplastic drugs on retinoblastoma cells.

  18. Mechanisms mediating the effects of alcohol and HIV anti-retroviral agents on mTORC1,mTORC2 and protein synthesis in myocytes

    Institute of Scientific and Technical Information of China (English)

    Ly; Q; Hong-Brown; Abid; A; Kazi; Charles; H; Lang

    2012-01-01

    Alcoholism and acquired immune deficiency syndrome are associated with severe muscle wasting.This impairment in nitrogen balance arises from increased protein degradation and a decreased rate of protein synthesis.The regulation of protein synthesis is a complex process involving alterations in the phosphorylation state and protein-protein interaction of various components of the translation machinery and mammalian target of rapamycin(mTOR) complexes.This review describes mechanisms that regulate protein synthesis in cultured C2C12 myocytes following exposure to either alcohol or human immunodeficiency virus antiretroviral drugs.Particular attention is given to the upstream regulators of mTOR complexes and the downstream targets which play an important role in translation.Gaining a better understanding of these molecular mechanisms could have important implications for preventing changes in lean body mass in patients with catabolic conditions or illnesses.

  19. Effect of anti retroviral therapy (ART) on CD4 T lymphocyte count and the spectrum of opportunistic infections in HIV/AIDS in Manipur.

    Science.gov (United States)

    Chitra, Yengkokpam; Urgen, Sherpa; Dayananda, Ingudam; Brajachand, Singh Ng

    2009-03-01

    Reports of variable response to antiretroviral therapy as indicated by CD4 count has been of concern as facilities for viral load estimation/drug resistance testing is not available everywhere. Hence the present study. was done to assess the magnitude of problem in high prevalence state of Manipur as evidenced by the CD4 T lymphocyte count. It was also prudent to study various OIs as extensive awareness campaigns about HIV and related morbidity with support system has been undertaken since the last decade. The study revealed that HAART must be used judiciously as 17.3% showed no improvement in CD4 T lymphocyte count. Among opportunistic infections, fungal infections predominatd in HIV/AIDS.

  20. Current trend of drug sensitivity in bovine mastitis

    Directory of Open Access Journals (Sweden)

    Rajeev Ranjan

    2010-02-01

    Full Text Available The study was conducted on 190 milk samples of bovine mastitis and 138 samples were confirmed positives for microorganisms. All the 138 samples were subjected to drug sensitivity test. The most effective antibiotic was enrofloxacin (91.67% followed by ciprofloxacin (90.15%, amikacin (87.12%, ceftriaxone (84.10%, chloramphenicol (80.31%, cefotaxime (79.55% and gentamicin (77.27%. Microorganisms were mostly resistant to drugs like streptomycin, penicillinG, ampicillin, cloxacillin, amoxycillin and neomycin in increasing order of resistance. Hence, it is suggested that the line of treatment should be based on antibiogram study of various isolates from bovine mastitis. Further, the selection of drugs after culture and sensitivity test should be based on their ability to cross blood tissue barrier or mammary parenchyma, lipophilicity and ability to work in alkaline pH. [Vet. World 2010; 3(1.000: 17-20

  1. Different combination of drugs regarding the damage on organs targeting salt sensitivity or non-salt-sensitive hypertension

    Institute of Scientific and Technical Information of China (English)

    吴琪

    2013-01-01

    Objective To study the damage on organs from salt sensitivity hypertension or non-salt-sensitive hypertension and the selection of drug combination.Methods 120 hypertensive patients including 60 cases salt-sensitive(SS)

  2. Risky sexual practice and associated factors among HIV positive adults attending anti-retroviral treatment clinic at Gondar University Referral Hospital, Northwest Ethiopia

    Science.gov (United States)

    2017-01-01

    Introduction Risky sexual practice among people living with HIV/AIDS is a public health concern because of the risk of transmission of the virus to sero-discordant partner/s. There is also the risk of re-infection with new, drug resistant viral strains between sero-concordant partners. However, there is lack of information on risky sexual practices among HIV positive adults. Therefore, this study aimed to assess risky sexual practice and associated factors among adult HIV positive clients at Gondar University Referral Hospital, Northwest Ethiopia, 2015. Methods An institution based cross sectional study was conducted at Gondar University Referral Hospital from May to June 2015. A pretested structured questionnaire was used to collect the data. Using systematic random sampling technique, a total of 513 respondents were participated in this study. The data were entered into EPI info version 3.5.3 and transferred to SPSS version 20 for analysis. Descriptive, bivariate and multivariate analyses were done. A P-value <0.05 was considered to determine the statistical significance of the association between factors (independent variables) and risky sexual practice. The Odds ratio was also used to determine the presence and the degree of association between the dependent and independent variables. Results A total of 513 respondents were participated in this study. The prevalence of risky sexual practices in the past three months was 38% (95% CI: 33.3%, 42.3%). Being in the age range of 18–29 years (AOR = 2.63, 95% CI: 1.55, 4.47) and 30–39 years (AOR = 2.29, 95% CI: 1.48, 3.53), being single (AOR = 6.32, 95%CI: 2.43, 16.44),being married (AOR = 6.06, 95% CI: 2.81, 13.07), having no child (AOR = 2.58, 95% CI: 1.17, 5.72), and a CD4 count of greater than 500/mm3 were factors significantly associated with risky sexual practices. Conclusions A considerable number of HIV positive clients had risky sexual practices. It is strongly recommended that the Regional Health Bureau

  3. HIV associated neurocognitive disorders (HAND in Malawian adults and effect on adherence to combination anti-retroviral therapy: a cross sectional study.

    Directory of Open Access Journals (Sweden)

    Christine M Kelly

    Full Text Available Little is known about the prevalence and burden of HIV associated neurocognitive disorder (HAND among patients on combination antiretroviral therapy (cART in sub-Saharan Africa. We estimated the prevalence of HAND in adult Malawians on cART and investigated the relationship between HAND and adherence to cART.HIV positive adults in Blantyre, Malawi underwent a full medical history, neurocognitive test battery, depression score, Karnofsky Performance Score and adherence assessment. The Frascati criteria were used to diagnose HAND and the Global Deficit Score (GDS was also assessed. Blood was drawn for CD4 count and plasma nevirapine and efavirenz concentrations. HIV negative adults were recruited from the HIV testing clinic to provide normative scores for the neurocognitive battery.One hundred and six HIV positive patients, with median (range age 39 (18-71 years, 73% female and median (range CD4 count 323.5 (68-1039 cells/µl were studied. Symptomatic neurocognitive impairment was present in 15% (12% mild neurocognitive disorder [MND], 3% HIV associated dementia [HAD]. A further 55% fulfilled Frascati criteria for asymptomatic neurocognitive impairment (ANI; however factors other than neurocognitive impairment could have confounded this estimate. Neither the symptomatic (MND and HAD nor asymptomatic (ANI forms of HAND were associated with subtherapeutic nevirapine/efavirenz concentrations, adjusted odds ratio 1.44 (CI. 0.234, 8.798; p = 0.696 and aOR 0.577 (CI. 0.09, 3.605; p = 0.556 respectively. All patients with subtherapeutic nevirapine/efavirenz levels had a GDS of less than 0.6, consistent with normal neurocognition.Fifteen percent of adult Malawians on cART had a diagnosis of MND or HAD. Subtherapeutic drug concentrations were found exclusively in patients with normal neurocognitive function suggesting HAND did not affect cART adherence. Further study of HAND requires more robust locally derived normative neurocognitive values and

  4. Specific Elimination of Latently HIV-1 Infected Cells Using HIV-1 Protease-Sensitive Toxin Nanocapsules.

    Science.gov (United States)

    Wen, Jing; Yan, Ming; Liu, Yang; Li, Jie; Xie, Yiming; Lu, Yunfeng; Kamata, Masakazu; Chen, Irvin S Y

    2016-01-01

    Anti-retroviral drugs suppress HIV-1 plasma viremia to undetectable levels; however, latent HIV-1 persists in reservoirs within HIV-1-infected patients. The silent provirus can be activated through the use of drugs, including protein kinase C activators and histone deacetylase inhibitors. This "shock" approach is then followed by "kill" of the producing cells either through direct HIV-1-induced cell death or natural immune mechanisms. However, these mechanisms are relatively slow and effectiveness is unclear. Here, we develop an approach to specifically target and kill cells that are activated early in the process of virus production. We utilize a novel nanocapsule technology whereby the ricin A chain is encapsulated in an inactive form within a polymer shell. Specificity for release of the ricin A toxin is conferred by peptide crosslinkers that are sensitive to cleavage by HIV-1 protease. By using well-established latent infection models, J-Lat and U1 cells, we demonstrate that only within an HIV-1-producing cell expressing functional HIV-1 protease will the nanocapsule release its ricin A cargo, shutting down viral and cellular protein synthesis, and ultimately leading to rapid death of the producer cell. Thus, we provide proof of principle for a novel technology to kill HIV-1-producing cells without effects on non-target cells.

  5. 艾滋病高效抗反转录病毒治疗后并发血脂代谢异常的干预研究%Intervention Study on the Abnormal Metabolism of Lipid Metabolism in the Treatment of HIV/AIDS with High Effective Anti Retroviral Therapy

    Institute of Scientific and Technical Information of China (English)

    李雪琴

    2015-01-01

    Highly effective anti retroviral therapy can effectively inhibit viral replication and reduce the mortality of AIDS. But antiviral treatment can affect fatty acid binding protein, lipid metabolism and lipid in the liver cells and abnormal deposition of destruction and lead to abnor-mal lipid metabolism and lipid metabolism in different often increases the risk of cardiovascular and cerebrovascular disease. Therefore, the use of highly effective anti retroviral therapy for pa-tients with abnormal lipid metabolism in patients with abnormal blood lipids should be active in-tervention.In this article, the corresponding intervention measures of the abnormal lipid metabolism in the treatment of HIV/AIDS with high efficiency and anti retroviral virus were reviewed.%高效抗反转录病毒治疗可以有效抑制病毒复制,降低艾滋病的病死率. 但是抗病毒治疗可以影响脂肪酸结合蛋白、破坏脂质代谢、脂质在肝细胞内异常沉积,导致脂质代谢异常,而血脂代谢异常常增加心脑血管疾病风险. 因此,对采用高效抗反转录病毒方法治疗后并发血脂代谢异常的艾滋病患者应进行积极干预. 本文综述了艾滋病高效抗反转录病毒治疗后出现血脂代谢异常的相应干预措施,阐述了有效改善此类患者血脂代谢异常的临床方法.

  6. [Procedure for determination of individual sensitivity to antitumor drugs].

    Science.gov (United States)

    Abduvaliev, A A; Gil'dieva, M S; Tatarskiĭ, V P

    2006-05-01

    The present paper proposes to employ the cultured tumor cells of the breast and chick fibroblasts after long-term cultivation (for above 24 days) to determine their individual drug sensitivity and, as a criterion of cell damage, to use the percent of destruction of the cell layer formed in the wells 24 hours after drug insertion. It also presents the comparative results of tests of 2 cellular models that have been used to determine the in vitro sensitivity of the cells of breast cancer and chick fibroblasts to melfalan and its complex compound with copper acetylacetonate - MOK*M. At the same time, the cytotoxic activity of MOK*M and melfalan against tumor cells has been not shown to differ greatly (16.02+/-1.85 and 15.71+/-0.65% cell layer destruction, respectively), but the same activity of MOK*M against the model of intact cells (chick fibroblasts) was much less (15.23+/-1.97%) than that of melfalan (95.39+/-1.11%). The test system proposed by the authors is of certain informative value and it may be used for the determination of the individual sensitivity of tumor cells to antitumor drugs.

  7. Suplementação de N-acetilcisteína em pacientes infectados pelo HIV submetidos ao primeiro tratamento anti-retroviral: Avaliação do efeito sobre a carga viral, TNF-α, IL-6, IL-8, β2-microglobulina, IgA, IgG e IgM, haptoglobina e α1-glicoproteína ácida N-acetylcysteine supplementation of HIV-infected patients under the first anti-retroviral treatment: Evaluation of the effect on viral load, TNF-α, IL-6, IL-8, β2-microglobulin, IgA, IgG, IgM, haptoglobin and α1-acid glycoprotein

    Directory of Open Access Journals (Sweden)

    Aricio Treitinger

    2002-03-01

    Full Text Available Indivíduos infectados pelo vírus da imunodeficiência humana (HIV- 1 apresentam aumento progressivo da carga viral, da destruição do sistema de defesa imune celular e alterações imunológicas e inflamatórias, incluindo a elevação dos níveis séricos do fator de necrose tumoral alfa (TNF-α, interleucina 8 (IL-8, β2- microglobulina, IgA, IgG e IgM, haptoglobina e α1-glicoproteína ácida.O objetivo deste estudo foi avaliar os níveis séricos destes marcadores em indivíduos submetidos ao primeiro tratamento antiretroviral, suplementados ou não com N-acetilcisteína. Participaram deste estudo, duplo cego controlado por placebo, que teve a duração de 180 dias, 24 indivíduos que iniciaram a terapia antiretroviral O Grupo Estudo foi constituído por 11 indivíduos, que receberam suplementação de 600 mg/dia de Nacetilcisteína enquanto o Grupo Controle foi constituído por 13 indivíduo que receberam placebo. Os níveis dos marcadores avaliados foram determinados no dia anterior ao início do tratamento a que foram submetidos e após 60, 120 e 180 dias. Verificou-se diminuição significativa dos níveis de TNF-α (p=0,0001, IL-6 (p>0,05, IL-8 (p=0,0001, β2-microglobulina (p=0,0005, IgA (p=0,007, IgG (p=0,001, IgM (p=0,0001, haptoglobina (p=0,0001 e α1-glicoproteína ácida (p=0.012 em decorrência do tratamento anti-retroviral. A suplementação com N-acetilcisteína, na dose utilizada neste estudo, não teve efeitos aditivos ou sinérgicos sobre as variáveis analisadas. Em conclusão, a suplementação de pacientes HIV-positivos com 600 mg/dia de N-acetilcisteína não proporcionou benefícios adicionais àqueles decorrentes do tratamento anti-retroviral.Human immunodeficiency virus infection is associated with a progressive elevation of viral load and with a continuous destruction of the immune cellular defense system which is marked by immunological and inflammatory disorders characteristic of HIV-infected individuals. These

  8. Analysis of HIV- type 1 protease and reverse transcriptase in Brazilian children failing highly active antiretroviral therapy (HAART Análise da protease e transcriptase reversa do HIV-1 em crianças com falha terapêutica em uso de terapia anti-retroviral altamente eficaz (HAART

    Directory of Open Access Journals (Sweden)

    Daisy Maria Machado

    2005-02-01

    Full Text Available The aim of this study was to evaluate the genotypic resistance profiles of HIV-1 in children failing highly active antiretroviral therapy (HAART. Forty-one children (median age = 67 months receiving HAART were submitted to genotypic testing when virological failure was detected. cDNA was extracted from PBMCs and amplified by nested PCR for the reverse transcriptase and protease regions of the pol gene. Drug resistance genotypes were determined from DNA sequencing. According to the genotypic analysis, 12/36 (33.3% and 6/36 (16.6% children showed resistance and possible resistance, respectively, to ZDV; 5/36 (14% and 4/36 (11.1%, respectively, showed resistance and possible resistance to ddI; 4/36 (11.1% showed resistance to 3TC and D4T; and 3/36 (8.3% showed resistance to Abacavir. A high percentage (54% of children exhibited mutations conferring resistance to NNRTI class drugs. Respective rates of resistance and possible resistance to PIs were: RTV (12.2%, 7.3%; APV (2.4%, 12.1%; SQV(0%, 12.1%; IDV (14.6%, 4.9%, NFV (22%, 4.9%, LPV/RTV (2.4%, 12.1%. Overall, 37/41 (90% children exhibited virus with mutations related to drug resistance, while 9% exhibited resistance to all three antiretroviral drug classes.O objetivo deste estudo foi avaliar o perfil de resistência genotípica do HIV-1 em crianças com falha terapêutica ao tratamento anti-retroviral (HAART. Quarenta e uma crianças (idade mediana = 67 meses em uso de HAART foram submetidas ao teste de genotipagem no momento da detecção de falha ao tratamento. Foi realizada extração de cDNA de células periféricas mononucleares e amplificação do mesmo (regiões da transcriptase reversa e protease do gene pol através de PCR-nested. O perfil genotípico foi determinado através do seqüenciamnto de nucleotídeos. De acordo com a análise genotípica, 12/36 (33,3% e 6/36 (16,6% crianças apresentaram, respectivamente, resistência e possível resistência ao AZT; 5/36 (14% e 4/36 (11

  9. Longitudinal comparison between plasma and seminal HIV-1 viral loads during antiretroviral treatment Comparação longitudinal entre cargas virais seminais e plasmáticas do HIV-1 durante terapia anti-retroviral

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    Lauro Ferreira da Silva Pinto Neto

    2003-12-01

    Full Text Available This study was designed to investigate the impact of anti-retroviral therapy on both plasma and seminal HIV-1 viral loads and the correlation between viral loads in these compartments after treatment. Viral load, CD4+ and CD8+ T-cell counts were evaluated in paired plasma and semen samples from 36 antiretroviral therapy-naïve patients at baseline and on days 45, 90, and 180 of treatment. Slopes for blood and seminal viral loads in all treated patients were similar (p = 0.21. Median HIV-1 RNA titers in plasma and semen at baseline were 4.95 log10 and 4.48 log10 copies/ml, respectively. After 180 days of therapy, the median viral load declined to 3.15 log10 copies/ml (plasma and 3.2 log10 copies/ml (semen. At this timepoint 22 patients presented HIV-1 viral load below 400 copies/ml in either plasma or semen, but only 9 had viral loads below 400 copies/ml in both compartments.Este estudo foi desenhado para investigar o impacto do tratamento com anti-retrovirais na evolução das cargas virais plasmáticas e seminais do HIV-1. A carga viral do HIV-1 e a contagem de linfócitos T CD4+ e CD8+ foi determinada em amostras pareadas de sangue e sêmen de 36 pacientes virgem de tratamento nos dias 0, 45, 90 e 180 após o início da terapia. As curvas de declínio das cargas virais plasmática e seminal foram semelhantes (p= 0.21. As medianas da carga viral plasmática e seminal no pré-tratamento (dia 0 foram 4.95 e 4.48 log10 cópias/ml, respectivamente. Seis meses após o início da terapia, a mediana da carga viral plasmática era 3.15 log10 cópias/ml e a seminal 3.2 log10 cópias/ml. Neste mesmo periodo, 22 pacientes apresentavam carga viral abaixo de 400 cópias/ml no plasma e/ou sêmen, enquanto apenas 9 pacientes apresentavam carga viral abaixo do limite de detecção nos dois compartimentos.

  10. Determinantes da adesão ao tratamento anti-retroviral em Brasília, DF: um estudo de caso-controle Determinants of antiretroviral treatment adherence in Brasília, Federal District: a case-control study

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    Cláudio Viveiros de Carvalho

    2007-10-01

    Full Text Available Buscou-se avaliar os fatores relacionados à adesão ao tratamento anti-retroviral no Distrito Federal. De 150 pacientes entrevistados em sete centros de referência, 35 não aderentes foram definidos como casos, sendo selecionados 70 controles aderentes, pareados por idade. Avaliaram-se variáveis sócio-demográficas, hábitos, suporte social, qualidade de vida, questões relacionadas a doença, estado clínico, tratamento e serviço. Na análise bivariada, houve associação da adesão com raça/cor, escolaridade, centros de referência em que faz acompanhamento e renda familiar. Após ajuste, cor parda, centros de referência localizado no Plano Piloto, escolaridade alta e receber apoio dos amigos quanto às necessidades permaneceram associados com adesão. Retirando raça/cor do modelo, mantiveram-se centros de referência, escolaridade, profissão, renda, apoio (contar com alguém que demonstre gostar de você e satisfação com o atendimento na farmácia de dispensação. Além dos fatores já consolidados na literatura, questões relacionadas ao apoio no âmbito micro-social e aos serviços de assistência mostraram-se associados à observância terapêutica.We sought to evaluate factors relating to adherence to antiretroviral treatment in the Federal District. Out of 150 patients interviewed at seven reference centers; 35 non-adherent subjects were considered to be cases; we selected 70 age-matched adherent individuals as controls. Variables relating to sociodemographics, habits, social support, quality of life, disease-related issues, clinical conditions, treatment and healthcare services were evaluated. Bivariate analysis showed that adherence was associated with race/color, educational level, the reference center where the patient was followed up and familial income. After adjustments, mixed race (parda, reference center location in central Brasília, high educational level and friends’ support for needs remained associated with

  11. Sensitization for Anticancer Drug-Induced Apoptosis by Betulinic Acid

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    Simone Fulda

    2005-02-01

    Full Text Available We previously described that betulinic acid (BetA, a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit clonogenic survival of tumor cells. Combined treatment with BetA and anticancer drugs acted in concert to induce loss of mitochondrial membrane potential and the release of cytochrome c and Smac from mitochondria, resulting in activation of caspases and apoptosis. Overexpression of Bcl-2, which blocked mitochondrial perturbations, also inhibited the cooperative effect of BetA and anticancer drugs, indicating that cooperative interaction involved the mitochondrial pathway. Notably, cooperation of BetA and anticancer drugs was found for various cytotoxic compounds with different modes of action (e.g., doxorubicin, cisplatin, Taxol, VP16, or actinomycin D. Importantly, BetA and anticancer drugs cooperated to induce apoptosis in different tumor cell lines, including p53 mutant cells, and also in primary tumor cells, but not in human fibroblasts indicating some tumor specificity. These findings indicate that using BetA as sensitizer in chemotherapy-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy, which warrants further investigation.

  12. The Time Delay Between Drug Intake and Bronchospasm for Nonsteroidal Antiinflammatory Drugs Sensitive Patients

    Science.gov (United States)

    2010-01-01

    A study was performed to assess the time between drug intake and drug induced hypersensitivity reaction for patients sensitive to nonsteroidal antiinflammatory drugs (NSAID) in clinical patient history and after oral provocation tests. Drug hypersensitivity ENDA questionnaires were filled for the patients with suspected sensitivity to NSAID. Oral provocation tests were performed with suspected NSAID according to the ENDA/EAACI recommendations. There were 76 patients with history of hypersensitivity reactions after use of NSAID enrolled in the study. Recorded were 154 hypersensitivity reactions to NSAID in the clinical history. In the clinical history median time of immediate reactions (76 cases, 81%) between drug intake and bronchospasm was 20 minutes [15-30 minutes]. Median time of nonimmediate reactions (18 cases, 19%) was 120 minutes [120-390 minutes]. There were 50 oral provocation tests performed, 14 of them (28%) were positive. Median time between drug intake and immediate reactions (8; 57% of cases) was 22.5 minutes [20-30 minutes] and median time of nonimmediate reactions (6; 43% of cases) was 167.5 minutes [125-206.25 minutes]. Time delay between drug intake and bronchospasm in the clinical history and after oral provocation test was not statistically different. PMID:23282984

  13. Stimuli-sensitive hydrogels: A novel ophthalmic drug delivery system

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    Singh Vinod

    2010-01-01

    Full Text Available Background: Stimuli-sensitive hydrogels are three-dimensional, hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids on stimulation, such as pH, temperature and ionic change. Aim: To develop hydrogels that are sensitive to stimuli, i.e. pH, in the cul-de-sac of the eye for providing a prolonged effect and increased bioavailability with reduction in frequency of administration. Materials and Methods: Hydrogels were formulated by using timolol maleate as the model drug, polyacrylic acid as the gelling agents, hydroxyl ethyl cellulose as the viscolizer and sodium chloride as the isotonic agent. Stirring of ingredients in pH 4 phosphate buffer at high speed was carried out. The dynamic dialysis technique was used for drug release studies. In vivo study for reduction in intraocular pressure was carried out by using albino rabbits. Statistical Analysis: Drug release studies data were used for statistical analysis in first-order plots, Higuchi plots and Peppas exponential plots. Student t-test was performed for in vivo study. Results: Viscosity of the hydrogel increases from 3.84 cps to 9.54 cps due to change in pH 4 to pH 7.4. The slope value of the Peppas equation was found to be 0.3081, 0.3743 and 0.2964. Up to 80% of drug was released in an 8 h drug release study. Sterile hydrogels with no ocular irritation were obtained. Conclusions: Hydrogels show increase in viscosity due to change in pH. Hydrogels were therapeutically effacious, stable, non-irritant and showed Fickian diffusion. In vivo results clearly show a prolonged reduction in intraocular pressure, which was helpful for reduction in the frequency of administration.

  14. AIDS na infância: acometimento cardíaco com e sem a terapia anti-retroviral tríplice combinada AIDS in childhood: cardiac involvement with and without triple combination antiretroviral therapy

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    Maria do Carmo Soares Alves Cunha

    2008-01-01

    Full Text Available OBJETIVO: Descrever a prevalência de alterações cardíacas ao ecocardiograma em crianças com AIDS acompanhadas em serviço de referência aos 18±6 meses do diagnóstico confirmado de AIDS. MÉTODOS: Estudo transversal, com corte aos 18±6 meses do diagnóstico de AIDS. Incluídas 93 crianças com diagnóstico confirmado de AIDS por transmissão vertical, sem doença maligna, que, na avaliação cardiológica, realizaram ecocardiograma (eco. De forma exploratória avaliaram-se as alterações cardíacas nos pacientes sem uso (G1 e com uso (G2 de terapia combinada anti-retroviral. RESULTADOS: Quando do diagnóstico de AIDS, as crianças tinham em média 3,07 anos e 50,50% eram do sexo feminino. Esquema de terapia combinado com anti-retrovirais foi utilizado por 47 pacientes (G2. O acometimento cardíaco esteve presente em 40 crianças (43,00%. A presença de disfunção ventricular esquerda (G1:39,10%;G2:10,60% e o aumento isolado de ventrículo esquerdo (G1:6,60%;G2:14,90% foram os achados mais freqüentes. Observou-se associação significativa entre os grupos sem e com terapia anti-retroviral combinada quanto à presença de disfunção ventricular esquerda (RP=3,42; [1,41-8,26]; p =0,02 e de desnutrição (RP=1,79; [1,00-3,20]; p=0,04. CONCLUSÃO: O acometimento cardíaco foi freqüente nas crianças com AIDS, sendo a disfunção ventricular esquerda a alteração mais observada ao ecocardiograma. Houve diferença estatisticamente significativa entre os grupos com e sem tratamento tríplice combinado quanto à presença de disfunção ventricular esquerda e de desnutrição.OBJECTIVE: To describe the prevalence of cardiac abnormalities in the echocardiogram of children with AIDS followed up in a reference service at 18±6 months of AIDS confirmed diagnosis. METHODS: A cross-section study with a cohort after 18±6 months of AIDS diagnosis. The study included a total of 93 children with a confirmed diagnosis of AIDS with vertical

  15. Distribution and drug sensitivity of pathogens in diabetic foot ulcer secretions

    Institute of Scientific and Technical Information of China (English)

    李惠琴

    2013-01-01

    Objective To investigate the distribution and drug sensitivity of pathogens isolated from diabetic foot ulcer(DFU) secretions. Methods A retrospective study was carried out on the distribution and drug sensitivity of pathogens isolated from the secretions of 218 DFU

  16. Impact of fungal drug transporters on fungicide sensitivity, multidrug resistance and virulence

    NARCIS (Netherlands)

    Waard, de M.A.; Andrade, A.C.; Hayashi, K.; Schoonbeek, H.; Stergiopoulos, I.; Zwiers, L.H.

    2006-01-01

    Drug transporters are membrane proteins that provide protection for organisms against natural toxic products and fungicides. In plant pathogens, drug transporters function in baseline sensitivity to fungicides, multidrug resistance (MDR) and virulence on host plants. This paper describes drug transp

  17. Enteropatógenos relacionados à diarréia em pacientes HIV que fazem uso de terapia anti-retroviral Enteropathogens relating to diarrhea in HIV patients on antiretroviral therapy

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    Áurea Regina Telles Pupulin

    2009-10-01

    Full Text Available A etiologia do processo diarréico na AIDS pode ser causada por vírus, bactérias, fungos, protozoários e helmintos, assim como pelo próprio HIV. Este trabalho avaliou enteropatogenos relacionados à diarréia em pacientes HIV que fazem uso de terapia anti-retroviral. Os métodos parasitológicos utilizados foram Faust, Hoffmann e Kinyoun. O isolamento e cultura dos fungos foram realizados conforme metodologia recomendada por NCCLS M27-A standard. A identificação das espécies de leveduras foi realizada através da reação em cadeia da polimerase. O isolamento de bactérias, foi feito em agar Mac Conkey e agar SS, a identificação das espécies através do Enterokit B (Probac do Brasil e métodos bioquímicos. Foram avaliados 49 pacientes, 44,9% apresentaram enteroparasitas, 48,1% Candida sp com 61,5% Candida albicans, 7,6% Candida sp e 30,7% Candida não- albicans. Foram isoladas bactérias de 72% dos pacientes, 49% Escherichia coli, 13% Salmonella parathyphi, Klebsiella sp ou Proteus e 6% Citrobacter freundii ou Yersinia sp. Houve alta prevalência de Candida sp nos pacientes HIV com diarréia e foram isoladas espécies não albicans cuja presença pode ser entendida como cúmplice ou causa da infecção.The etiology of the diarrheic process in AIDS may be caused by viruses, bacteria, fungi, protozoa or helminths, as well as HIV itself. This study evaluated enteropathogens relating to diarrhea in HIV patients who were on antiretroviral therapy. The parasitological methods used were Faust, Hoffmann and Kinyoun. Isolation and culturing of fungi were carried out in accordance with the methodology recommended by the NCCLS M27-A standard. The yeast species were identified using the polymerase chain reaction (PCR. Bacteria were isolated on MacConkey and SS agar and the species were identified using Enterokit B (Probac do Brasil and biochemical methods. Forty-nine patients were evaluated: 44.89% presented enteroparasites and 48.1% presented

  18. Adesão à terapia antiretroviral para HIV/AIDS Adhesión a la terapia anti-retroviral para el vih/sida Adherence to the antiretroviral therapy for HIV/AIDS

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    Maria Rosa Ceccato Colombrini

    2006-12-01

    Full Text Available A não-adesão à terapêutica antiretroviral altamente eficaz (HAART é considerada, no plano individual, como um dos mais ameaçadores perigos para a efetividade do tratamento da pessoa com HIV/aids e para a disseminação de vírus-resistência, no plano coletivo. Assim, o objetivo deste estudo foi analisar, mediante revisão de literatura, os fatores de risco para não-adesão à HAART, além de agrupá-los e relacioná-los à pessoa em tratamento, à doença, ao tratamento e ao serviço de saúde e suporte social. A literatura aponta para a necessidade da realização de estudos que avaliem aspectos socioculturais, crenças, qualidade do serviço prestado, relações do cliente com a equipe multiprofissional e outros referentes à raça e aos efeitos colaterais dos anti-retrovirais. Estes estudos visam a favorecer o estabelecimento de estratégias que melhorem a adesão dos clientes à HAART, ao mesmo tempo em e que contribuem para a construção e exercício da cidadania.La no adhesión a la terapéutica anti-retroviral altamente eficaz (HAART es considerada, en el plano individual, como uno de los más amenazadores peligros para la efectividad del tratamiento de la persona con VIH/SIDA y para la diseminación del virus-resistencia, en el plano colectivo. Así, el objetivo de este estudio fue analizar, mediante revisión de la literatura, los factores de riesgo para la no adhesión a la HAART, además de agruparlos y relacionarlos a la persona en tratamiento, a la enfermedad, al tratamiento y al servicio de salud y soporte social. La literatura apunta hacia la necesidad de realizar estudios que evalúen aspectos socioculturales, creencias, calidad del servicio prestado, relaciones del cliente con el equipo multi-profesional y otros referentes a la raza y a los efectos colaterales de los anti-retrovirales. Estos estudios visan a favorecer el establecimiento de estrategias que mejoren la adhesión de los clientes a la HAART, al mismo tiempo

  19. Adherence to antiretroviral therapy: a qualitative study with physicians from Rio de Janeiro, Brazil Aderência à terapia anti-retroviral: um estudo qualitativo com médicos no Rio de Janeiro, Brasil

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    Monica Malta

    2005-10-01

    Full Text Available Brazil provides free antiretroviral (ARV therapy to some 150,000 individuals living with HIV/ AIDS. ARV regimens require optimal adherence to achieve undetectable viral loads and to avoid viral resistance. Physicians play a key role to foster ARV adherence, but until now little is known about the communication between physicians/ people living with HIV/AIDS in this setting. In-depth interviews were conducted with 40 physicians treating people living with HIV/AIDS at six public reference centers in Rio de Janeiro, Brazil. Interview topics included: experiences in the treatment of people living with HIV/AIDS, relationship and dialogue with patients, barriers/facilitators to adherence, and effectiveness of available services. Barriers to ARV adherence were mainly related to the low quality of patient-provider relationship. Other barriers were related to "chaotic" patients' lifestyles, and inadequate knowledge and/or negative beliefs about HIV/AIDS and ARV effectiveness. It is necessary to improve networking between services, establish agile referral systems, and improve health professionals' integration. These structural changes could contribute to improved adherence, resulting in improved quality of life for people living with HIV/AIDS.O Brasil fornece gratuitamente terapia anti-retroviral (ARV para cerca de 150 mil pessoas vivendo com HIV/ AIDS. A terapia ARV requer aderência ótima, visando alcançar carga viral indetectável e evitar resistência viral. Os médicos desempenham papel central quanto à aderência à ARV, mas há escassa informação sobre a comunicação entre médicos/pessoas vivendo com HIV/ AIDS. Entrevistas em profundidade foram realizadas com 40 médicos assistentes de seis hospitais de referência do Rio de Janeiro, Brasil. Tópicos da entrevista incluíram: experiências relativas ao tratamento de pessoas vivendo com HIV/AIDS, relacionamento/diálogo com pacientes, barreiras/facilitadores para aderência aos servi

  20. Terapia anti-retroviral: fatores que interferem na adesão de crianças com HIV/AIDS Terapia anti-retroviral: factores que interfieren en la adherencia de niños con VIH/SIDA Antiretroviral therapy: factors interfering in the adherence of children with HIV/AIDS

    Directory of Open Access Journals (Sweden)

    Ana Claúdia Feitosa

    2008-09-01

    difficult, evidencing reports about drug forms, time of medication intake, collateral effects, shortage in the free drugs distribution, difficulty to get regular access to the health service and financial problems. The importance was revealed of getting to know the social context the child is inserted in and the difficulties in the use of antiretroviral drugs, so as to intervene efficiently and permit a better quality of life for the children.

  1. Photoactive Fluoropolymer Surfaces that Release Sensitizer Drug Molecules

    Science.gov (United States)

    Ghosh, Goutam; Minnis, Mihaela; Ghogare, Ashwini A.; Abramova, Inna; Cengel, Keith; Busch, Theresa M.; Greer, Alexander

    2015-01-01

    We describe a physical-organic study of two fluoropolymers bearing a photoreleasable PEGylated photosensitizer which generates 1O2(1Δg) [chlorin e6 methoxy tri(ethylene glycol) triester]. The surfaces are Teflon/polyvinylalcohol (PVA) nanocomposite and fluorinated silica. The relative efficiency of these surfaces to photorelease the PEGylated sensitizer [shown previously to be phototoxic to ovarian cancer cells (Kimani, S. et al J. Org. Chem 2012, 77, 10638)] was slightly higher for the nanocomposite. In the presence of red light and O2, 1O2 is formed, which cleaves an ethene linkage to liberate the sensitizer in 68–92% yields. The fluoropolymers were designed to deal with multiple problems. Namely, their success relied not only high O2 solubility and drug repellency, but that the C−F bonds physically quench little 1O2 for its productive use away from the surface. The results obtained here indicate that Teflon-like surfaces have potential uses of delivering sensitizer and singlet oxygen for applications in tissue repair and photodynamic therapy (PDT). PMID:25686407

  2. Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines

    Institute of Scientific and Technical Information of China (English)

    Nisana Tepsiri; Liengchai Chaturat; Banchob Sripa; Wises Namwat; Sopit Wongkham; Vajarabhongsa Bhudhisawasdi; Wichittra Tassaneeyakul

    2005-01-01

    AIM: To study the effect of a number of chemotherapeutic drugs on five human intrahepatic cholangiocarcinoma (CCA) cell lines. The expressions of genes that have been proposed to influence the resistance of chemotherapeutic drugs including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), glutathione-S-transferase P1 (GSTP1), multidrug resistance protein (MDR1) and multidrug resistance-associated proteins (MRPs) were also determined.METHODS: Five human CCA cell lines (KKU-100, KKU M055, KKU-M156, KKU-M214 and KKU-OCA17) weretreated with various chemotherapeutic drugs and growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Semi-quantitative levels of gene expression were determined by a reverse transcriptase polymerase chain reaction (RT-PCR). Results of IC50 values and the ratios of gene expression were analyzed by linear regression to predict their relationship. RESULTS: Among five CCA cell lines, KKU-M055 was the most sensitive cell line towards all chemotherapeutic drugs investigated, particularly taxane derivatives with IC50 values of 0.02-3 nmol/L, whereas KKU-100 was apparently the least sensitive cell line. When compared to other chemotherapeutic agents, doxorubicin and pirarubicin showed the lowest IC50 values (<5 μmol/L) in all five CCA cell lines. Results from RT-PCR showed that TS, MRP1, MRP3 and GSTP1 were highly expressed in these five CCA cell lines while DPD and MRP2 were only moderately expressed. It should be noted that MDR1 expression was detected only in KKU-OCA17 cell lines. A strong correlation was only found between the level of MRP3 expression and the IC50 values of etoposide, doxorubicin and pirarubicin (r = 0.86-0.98, ,P<0.05). CONCLUSION: Sensitivity to chemotherapeutic agents is not associated with the histological type of CCA. Choosing of the appropriate chemotherapeutic regimen for the treatment of CCA requires knowledge of drug

  3. Aspergillus nidulans galactofuranose biosynthesis affects antifungal drug sensitivity.

    Science.gov (United States)

    Alam, Md Kausar; El-Ganiny, Amira M; Afroz, Sharmin; Sanders, David A R; Liu, Juxin; Kaminskyj, Susan G W

    2012-12-01

    The cell wall is essential for fungal survival in natural environments. Many fungal wall carbohydrates are absent from humans, so they are a promising source of antifungal drug targets. Galactofuranose (Galf) is a sugar that decorates certain carbohydrates and lipids. It comprises about 5% of the Aspergillus fumigatus cell wall, and may play a role in systemic aspergillosis. We are studying Aspergillus wall formation in the tractable model system, A. nidulans. Previously we showed single-gene deletions of three sequential A. nidulans Galf biosynthesis proteins each caused similar hyphal morphogenesis defects and 500-fold reduced colony growth and sporulation. Here, we generated ugeA, ugmA and ugtA strains controlled by the alcA(p) or niiA(p) regulatable promoters. For repression and expression, alcA(p)-regulated strains were grown on complete medium with glucose or threonine, whereas niiA(p)-regulated strains were grown on minimal medium with ammonium or nitrate. Expression was assessed by qPCR and colony phenotype. The alcA(p) and niiA(p) strains produced similar effects: colonies resembling wild type for gene expression, and resembling deletion strains for gene repression. Galf immunolocalization using the L10 monoclonal antibody showed that ugmA deletion and repression phenotypes correlated with loss of hyphal wall Galf. None of the gene manipulations affected itraconazole sensitivity, as expected. Deletion of any of ugmA, ugeA, ugtA, their repression by alcA(p) or niiA(p), OR, ugmA overexpression by alcA(p), increased sensitivity to Caspofungin. Strains with alcA(p)-mediated overexpression of ugeA and ugtA had lower caspofungin sensitivity. Galf appears to play an important role in A. nidulans growth and vigor.

  4. The effect of carbon nanotubes on drug delivery in an electro-sensitive transdermal drug delivery system.

    Science.gov (United States)

    Im, Ji S; Bai, Byong Ch; Lee, Young-Seak

    2010-02-01

    An electro-sensitive transdermal drug delivery system was prepared by the electrospinning method to control drug release. A semi-interpenetrating polymer network was prepared as the matrix with polyethylene oxide and pentaerythritol triacrylate polymers. Multi-walled carbon nanotubes were used as an additive to increase the electrical sensitivity. The release experiment was carried out under different electric voltage conditions. Carbon nanotubes were observed in the middle of the electrospun fibers by SEM and TEM. The amount of released drug was effectively increased with higher applied electric voltages. These results were attributed to the excellent electrical conductivity of the carbon additive. The suggested mechanism of drug release involves polyethylene oxide of the semi-interpenetrating polymer network being dissolved under the effects of carbon nanotubes, thereby releasing the drug. The effects of the electro-sensitive transdermal drug delivery system were enhanced by the carbon nanotubes.

  5. "Every drug goes to treat its own disease…" - a qualitative study of perceptions and experiences of taking anti-retrovirals concomitantly with anti-malarials among those affected by HIV and malaria in Tanzania

    DEFF Research Database (Denmark)

    Mangesho, Peter E; Reynolds, Joanna; Lemnge, Martha;

    2014-01-01

    , and in-depth interviews with health workers responsible for HIV care and members of the clinical trial team. Data were analysed inductively to identify themes and develop theoretical narratives. RESULTS: Results suggest that people living with HIV perceived malaria to be more harmful to them due...

  6. 复方新诺明预防治疗对艾滋病患者生存状况的影响%Effect of co-trimoxazole prophylaxis used for AIDS patients under anti-retroviral therapy

    Institute of Scientific and Technical Information of China (English)

    杨文杰; 梁妍; 李洁; 马彦民; 李宁; 孙定勇; 王哲

    2014-01-01

    Objective To analyze the situation of survival among AIDS patients under co-trimoxazole prophylaxis as initial anti-retroviral therapy(ART),in Henan province during 2007-2011. Methods Information on AIDS patients receiving initial ART during 2007-2011 was collected from the Chinese HIV/AIDS Integrated Control System. Kaplan-Meier estimation was used to generate survival curves,and Cox proportional hazard regression model was used to determine associated factors of survival status. According to the previous CTX use before ART,the subjects were divided into 3 groups including who had never taken CTX,who had taken CTX and still taking now,who had taken CTX and not current taking. Results A total of 13 103 eligible AIDS patients were identified. 1 702 patients died within 6 years after the initiation of ART,with the mortality as 4.46/100 person year. Among the 455 patients who died within 3 months and 970 died within 12 months,the mortality rates were 14.15/100 person year and 7.78/100 person year,respectively. The Kaplan-Meier survival curves showed that the survival time and mortality of the patients who had taken CTX was longer AND lower than those patients who had never taken CTX when starting the ART program. Results from the log-rank test showed that the difference of two groups was statistically significant during 12 months after the ART(log-rank=5.15,P=0.02). After controlling for other variables,results from multivariable analysis of COX model showed that factors as age,gender,marital status,perion between confirmed diagnosis and receiving the ART,baseline CD4+T cells count,clinical stage,initial therapy schedule,date when starting the ART,number of symptoms at baseline,use of CTX before starting the ART and ART being skipped in the last seven days etc,were associated with the time of survival in patients after the initiation of ART. Patients who had been taking CTX at ART initiation were at lower risk of death (adjusted HR=0.71,95%CI:0.63-0.80;P=0

  7. Establishment of a drug sensitivity panel using human lung cancer cell lines.

    Directory of Open Access Journals (Sweden)

    Matsushita A

    1999-04-01

    Full Text Available We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.

  8. Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Freundlich, Joel S.; Wang, Feng; Vilchèze, Catherine; Gulten, Gulcin; Langley, Robert; Schiehser, Guy A.; Jacobus, David P.; Jacobs, Jr., William R.; Sacchettini, James C.; (Einstein); (TAM); (Jacobus)

    2009-06-30

    Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross-resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan-based inhibitors is reported, including their promising efficacy against INH-resistant strains of M. tuberculosis. Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC{sub 50} value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 {mu}g mL{sup -1} (13 {mu}M), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.

  9. Price Sensitivity of Demand for Prescription Drugs: Exploiting a Regression Kink Design

    DEFF Research Database (Denmark)

    Simonsen, Marianne; Skipper, Lars; Skipper, Niels

    This paper investigates price sensitivity of demand for prescription drugs using drug purchase records for at 20% random sample of the Danish population. We identify price responsiveness by exploiting exogenous variation in prices caused by kinked reimbursement schemes and implement a regression ...... education and income are, however, more responsive to the price. Also, essential drugs that prevent deterioration in health and prolong life have lower associated average price sensitivity....

  10. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities

    DEFF Research Database (Denmark)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B.;

    2017-01-01

    including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong...... and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88...

  11. Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells.

    LENUS (Irish Health Repository)

    Doherty, Ben

    2014-01-01

    KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer.

  12. Risk factors of non-alcoholic fatty liver disease in patients with HIV-infection after receiving highly active anti-retroviral therapy%HIV感染者进行高效抗反转录病毒治疗过程中发生非酒精性脂肪性肝病的相关因素分析

    Institute of Scientific and Technical Information of China (English)

    梁洪远; 王芳; 肖江; 赵红心; 杨涤; 韩宁; 吴亮; 倪量; 郜桂菊

    2016-01-01

    目的:分析HIV感染者进行高效抗反转录病毒治疗(HAART)后非酒精性脂肪性肝病(NAFLD)的发生情况及影响因素。方法选择2013年至2015年于本院门诊领取国家免费抗病毒药物2年并规律随访的HIV感染者,所有患者HAART治疗前均无NAFLD。回顾性分析不同年龄、性别和HAART方案患者NAFLD的发生情况及HAART 2年时的相关指标。统计患者肝功能、肾功能、血糖、血脂、乳酸、CD4+T淋巴细胞计数及BMI等数据,并对其与NAFLD的关系进行横断面分析。结果共收集99例患者,其中发生NAFLD 29例,占29.3%。发生NAFLD和未发生NAFLD患者的CD4+T淋巴细胞计数、ALT、甘油三酯、总胆固醇及乳酸水平差异有统计学意义(P均<0.05)。单因素分析显示,不同HAART方案中含TDF组合可减少NAFLD的发生率,不同年龄及性别发生NAFLD的风险无统计学差异(P均<0.05)。结论 HAART治疗过程中NAFLD发生率较高,可能与抗病毒药物所致的脂代谢紊乱及线粒体损伤等有关,使用TDF组合可能减少NAFLD的发生率,HAART过程中CD4+T淋巴细胞计数、ALT、甘油三酯、总胆固醇及乳酸水平可能对NAFLD的发生有提示作用,需要在临床中予以监测。%Objective To investigate the prevalence and risk factors of non-alcoholic fatty liver disease in patients with HIV-infection after receiving highly active antiretroviral therapy (HAART).Methods HIV-infected patients who received a government free anti-retroviral drugs and were followed-up regularly for 2 years in our hospital from 2013 to 2015 were selected. All the patients had no non-alcoholic fatty liver disease (NAFLD) before HAART. The occurrence of NAFLD between different age, gender and HAART were analyzed retrospectively. Liver functions, renal functions, serum glucose levels, serum fat levels, lactic acid levels, CD4+ T cell and BMI were recorded and the relationship with NAFLD was evaluated

  13. Stealth anti-CD4 conjugated immunoliposomes with dual antiretroviral drugs--modern Trojan horses to combat HIV.

    Science.gov (United States)

    Ramana, Lakshmi Narashimhan; Sharma, Shilpee; Sethuraman, Swaminathan; Ranga, Udaykumar; Krishnan, Uma Maheswari

    2015-01-01

    Highly active antiretroviral therapy (HAART) is the currently employed therapeutic intervention against AIDS where a drug combination is used to reduce the viral load. The present work envisages the development of a stealth anti-CD4 conjugated immunoliposomes containing two anti-retroviral drugs (nevirapine and saquinavir) that can selectively home into HIV infected cells through the CD4 receptor. The nanocarrier was characterized using transmission electron microscopy, FTIR, differential scanning calorimetry, particle size and zeta potential. The cell uptake was also evaluated qualitatively using confocal microscopy and quantitatively by flow cytometry. The drug to lipid composition was optimized for maximum encapsulation of the two drugs. Both drugs were found to localize in different regions of the liposome. The release of the reverse transcriptase inhibitor was dominant during the early phases of the release while in the later phases, the protease inhibitor is the major constituent released. The drugs delivered via anti-CD4 conjugated immunoliposomes inhibited viral proliferation at a significantly lower concentration as compared to free drugs. In vitro studies of nevirapine to saquinavir combination at a ratio of 6.2:5 and a concentration as low as 5 ng/mL efficiently blocked viral proliferation suggesting that co-delivery of anti-retroviral drugs holds a greater promise for efficient management of HIV-1 infection.

  14. Enzyme/pH dual sensitive polymeric nanoparticles for targeted drug delivery to the inflamed colon.

    Science.gov (United States)

    Naeem, Muhammad; Kim, Wooseong; Cao, Jiafu; Jung, Yunjin; Yoo, Jin-Wook

    2014-11-01

    Novel nanoparticles whose drug release profiles are controlled by both enzyme and pH were prepared for the colon-specific drug delivery using a polymeric mixture of enzyme-sensitive azo-polyurethane and pH-sensitive Eudragit S100 (ES-Azo.pu). The enzyme/pH dual sensitive nanoparticles were designed to release a drug based on a two-fold approach which specifically aimed to target drug delivery to the inflamed colon while preventing the burst release of drugs in the stomach and small intestine. Single pH-sensitive (ES) and dual sensitive (ES-Azo.pu) nanoparticles were prepared using an oil-in-water emulsion solvent evaporation method and coumarin-6 (C-6) was used as a model drug. The successful formation of ES and ES-azo.pu nanoparticles that have 214 nm and 244 nm in mean particle size, respectively, was confirmed by scanning electron microscopy and qNano. ES nanoparticles showed almost 100% of burst drug release at pH 7.4, whereas ES-Azo.pu nanoparticles prevented the burst drug release at pH 7.4, followed by a sustained release phase thereafter. Furthermore, ES-Azo.pu nanoparticles exhibited enzyme-triggered drug release in the presence of rat cecal contents obtained from a rat model of colitis. An in vivo localization study in rat gastrointestinal tract demonstrated that ES-Azo.pu nanoparticles were selectively distributed in the inflamed colon, showing 5.5-fold higher C-6 than ES nanoparticles. In conclusion, the enzyme/pH dual sensitive nanoparticles presented in this study can serve as a promising strategy for colon-specific drug delivery against inflammatory bowel disease and other colon disorders.

  15. Molecular characterization of drug-resistant and drug-sensitive Aspergillus isolates causing infectious keratitis

    Directory of Open Access Journals (Sweden)

    Niranjan Nayak

    2011-01-01

    Full Text Available Purpose: To study the susceptibilities of Aspergillus species against amphotericin B in infectious keratitis and to find out if drug resistance had any association with the molecular characteristics of the fungi. Materials and Methods: One hundred and sixty Aspergillus isolates from the corneal scrapings of patients with keratitis were tested for susceptibilities to amphotericin B by broth microdilution method. These included Aspergillus flavus (64 isolates, A. fumigatus (43 and A. niger (53. Fungal DNA was extracted by glass bead vertexing technique. Polymerase chain reaction (PCR assay was standardized and used to amplify the 28S rRNA gene. Single-stranded conformational polymorphism (SSCP of the PCR product was performed by the standard protocol. Results: Of the 160 isolates, 84 (52.5% showed low minimum inhibitory concentration (MIC values (≤ 1.56 μg/ml and were designated as amphotercin B-sensitive. Similarly, 76 (47.5% had high MICs (≥ 3.12 μg/ml and were categorized as amphotericin B-resistant. MIC 50 and MIC 90 values ranged between 3.12-6.25 μg/ml and 3.12-12.5 μg/ml respectively. A. flavus and A. niger showed higher MIC 50 and MIC 90 values than A. fumigatus. The SSCP pattern exhibited three extra bands (150 bp, 200 bp and 250 bp each in addition to the 260 bp amplicon. Strains (lanes 1 and 7 lacking the 150 bp band showed low MIC values (≤ 1.56 μg/ml. Conclusion: A. niger and A. flavus isolates had higher MICs compared to A. fumigatus, suggesting a high index of suspicion for amphotericin B resistance. PCR-SSCP was a good molecular tool to characterize Aspergillus phenotypes in fungal keratitis.

  16. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery.

    Science.gov (United States)

    He, Chaoliang; Kim, Sung Wan; Lee, Doo Sung

    2008-05-08

    Stimuli-sensitive block copolymer hydrogels, which are reversible polymer networks formed by physical interactions and exhibit a sol-gel phase-transition in response to external stimuli, have great potential in biomedical and pharmaceutical applications, especially in site-specific controlled drug-delivery systems. The drug may be mixed with a polymer solution in vitro and the drug-loaded hydrogel can form in situ after the in vivo administration, such as injection; therefore, stimuli-sensitive block copolymer hydrogels have many advantages, such as simple drug formulation and administration procedures, no organic solvent, site-specificity, a sustained drug release behavior, less systemic toxicity and ability to deliver both hydrophilic and hydrophobic drugs. Among the stimuli in the biomedical applications, temperature and pH are the most popular physical and chemical stimuli, respectively. The temperature- and/or pH-sensitive block copolymer hydrogels for biomedical applications have been extensively developed in the past decade. This review focuses on recent development of the preparation and application for drug delivery of the block copolymer hydrogels that respond to temperature, pH or both stimuli, including poly(N-substituted acrylamide)-based block copolymers, poloxamers and their derivatives, poly(ethylene glycol)-polyester block copolymers, polyelectrolyte-based block copolymers and the polyelectrolyte-modified thermo-sensitive block copolymers. In addition, the hydrogels based on other stimuli-sensitive block copolymers are discussed.

  17. Development of pH-sensitive self-nanoemulsifying drug delivery systems for acid-labile lipophilic drugs.

    Science.gov (United States)

    Zhao, Tianjing; Maniglio, Devid; Chen, Jie; Chen, Bin; Migliaresi, Claudio

    2016-03-01

    Oral administration is the most convenient way of all the drug delivery routes. Orally administered bioactive compounds must resist the harsh acidic fluids or enzyme digestion in stomach, to reach their absorbed destination in small intestine. This is the case for silibinin, a drug used to protect liver cells against toxins that has also been demonstrated in vitro to possess anti-cancer effects. However, as many other drugs, silibinin can degrade in the stomach due to the action of the gastric fluid. The use of pH-sensitive self-nanoemulsifying drug delivery systems (pH-SNEDDS) could overcome the drawback due to degradation of the drug in the stomach while enhancing its solubility and dissolution rate. In this paper we have investigated pH-sensitive self-nanoemulsifying formulations containing silibinin as model drug. Pseudo-ternary phase diagrams have been constructed in order to identify the self-emulsification regions under different pH. Solubility of silibinin in selected formulations has been assessed and stability of the pure drug and of the silibinin loaded pH-SNEDDS formulations in simulated gastric fluid had been compared. Droplet size of the optimized pH-SNEDDS has been correlated to pH, volume of dilution medium and silibinin loading amount. TEM (transmission electron microscopy) studies have shown that emulsion droplets had spherical shape and narrow size distribution. In vitro drug release studies of the optimal pH-SNEDDS indicated substantial increase of the drug release and release rate in comparison to pure silibinin and to the commercial silibinin tablet. The results indicated that pH-SNEDDS have potential to improve the biopharmaceutics properties of acid-labile lipophilic drugs.

  18. Expression of cyclooxygenase-2 mRNA in drug-sensitive cell and drug-resistant strains of ovarian cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    Xiaoyan Li; Zehua Wang

    2006-01-01

    Objective: To investigate the expression of cyclooxygenase-2 (COX-2) mRNA in drug-sensitive cell and drugresistant clones of ovarian cancer cell lines. Methods: RT-PCR and immunocytochemistry were used to investigate the expression of cyclooxygenase-2 in 3 clones drug-sensitive and 5 clones drug-resistant ovarian cancer cell. Results: Strong COX-2 mRNA expressions were detected in 3 clones of drug-sensitive cell and weak expressions were detected in 5 clones of drug-resistant cell. The protein expression of COX-2 in drug-sensitive cell was strongly positive reaction in immunocytochemistry stain and there was a weak positive reaction in 5clones of drug-resistant cell. Conclusion: The expression of COX-2 mRNA in drug-sensitive cell strains is much higher than that in drugresistant strains of ovarian cancer cell lines, providing a basis of the chemoprevention for ovarian cancer.

  19. Signatures of Drug Sensitivity in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Hua C. Gong

    2011-01-01

    Full Text Available We profiled receptor tyrosine kinase pathway activation and key gene mutations in eight human lung tumor cell lines and 50 human lung tumor tissue samples to define molecular pathways. A panel of eight kinase inhibitors was used to determine whether blocking pathway activation affected the tumor cell growth. The HER1 pathway in HER1 mutant cell lines HCC827 and H1975 were found to be highly activated and sensitive to HER1 inhibition. H1993 is a c-MET amplified cell line showing c-MET and HER1 pathway activation and responsiveness to c-MET inhibitor treatment. IGF-1R pathway activated H358 and A549 cells are sensitive to IGF-1R inhibition. The downstream PI3K inhibitor, BEZ-235, effectively inhibited tumor cell growth in most of the cell lines tested, except the H1993 and H1650 cells, while the MEK inhibitor PD-325901 was effective in blocking the growth of KRAS mutated cell line H1734 but not H358, A549 and H460. Hierarchical clustering of primary tumor samples with the corresponding tumor cell lines based on their pathway signatures revealed similar profiles for HER1, c-MET and IGF-1R pathway activation and predict potential treatment options for the primary tumors based on the tumor cell lines response to the panel of kinase inhibitors.

  20. Ototoxic drugs: difference in sensitivity between mice and guinea pigs.

    Science.gov (United States)

    Poirrier, A L; Van den Ackerveken, P; Kim, T S; Vandenbosch, R; Nguyen, L; Lefebvre, P P; Malgrange, B

    2010-03-01

    The development of experimental animal models has played an invaluable role in understanding the mechanisms of neurosensory deafness and in devising effective treatments. The purpose of this study was to develop an adult mouse model of ototoxic drug-induced hearing loss and to compare the ototoxicity in the adult mouse to that in the well-described guinea pig model. Mice are a powerful model organism, especially due to the large availability of antibodies, probes and genetic mutants. In this study, mice (n=114) and guinea pigs (n=35) underwent systemic treatment with either kanamycin or cisplatin. Auditory brainstem responses showed a significant threshold shift in guinea pigs 2 weeks after the beginning of the ototoxic treatment, while there was no significant hearing impairment recorded in mice. Hair cells and neuronal loss were correlated with hearing function in both guinea pigs and mice. These results indicate that the mouse is not a good model for ototoxicity, which should be taken into consideration in all further investigations concerning ototoxicity-induced hearing loss.

  1. [Drug sensitivity of falciparum malaria imported into France in 1995].

    Science.gov (United States)

    Longuet, C; Ramiliarisoa, O; Thor, R; Bouchaud, O; Basco, L K; Doury, J C; Le Bras, J

    1997-01-01

    The National Reference Centre for Malaria Chemosusceptibility (CNRCP) and the Tropical Medicine Institute of the Health Department for the Army (IMTSSA) monitor the chemosusceptibility of falciparum malaria introduced in France. In 1995, 353 isolates of P. falciparum are sent to the CNRCP and IMTSSA from malaria cases presenting in 49 civil and military hospitals distributed all over the french country. The patients are mostly Africans living in France and have mainly stayed in West Africa. Half of them did not take any chemoprophylaxis and a quarter took only chloroquine more or less regularly. The curative treatment, when known, is halofantrine alone in 52% of cases and quinine alone in 28% of cases. Three halofantrine failures are reported including 1 incorrect regimen and 4 quinine failures including 3 incorrect regimens. In 1995, in vitro resistance of P. falciparum isolates imported in France to the chemoprophylactic and therapeutic drugs is not worsening. In vitro quinine resistance is rare (1/108), mefloquine resistance (2/20) and halofantrine resistance (12/211) are limited, cycloguanil resistance (42/185) is stable and chloroquine resistance (84/230) is even decreasing (less selective pressure in Africa?).

  2. Ethics and Nanopharmacy: Value Sensitive Design of New Drugs.

    Science.gov (United States)

    Timmermans, Job; Zhao, Yinghuan; van den Hoven, Jeroen

    2011-12-01

    Although applications are being developed and have reached the market, nanopharmacy to date is generally still conceived as an emerging technology. Its concept is ill-defined. Nanopharmacy can also be construed as a converging technology, which combines features of multiple technologies, ranging from nanotechnology to medicine and ICT. It is still debated whether its features give rise to new ethical issues or that issues associated with nanopharma are merely an extension of existing issues in the underlying fields. We argue here that, regardless of the alleged newness of the ethical issues involved, developments occasioned by technological advances affect the roles played by stakeholders in the field of nanopharmacy to such an extent that this calls for a different approach to responsible innovation in this field. Specific features associated with nanopharmacy itself and features introduced to the associated converging technologies- bring about a shift in the roles of stakeholders that call for a different approach to responsibility. We suggest that Value Sensitive Design is a suitable framework to involve stakeholders in addressing moral issues responsibly at an early stage of development of new nanopharmaceuticals.

  3. Evaluation of contact sensitivity to topical drugs in patients with contact dermatitis

    Directory of Open Access Journals (Sweden)

    Bilge Bülbül Şen

    2013-03-01

    Full Text Available Background and Design: Topical drugs are an important group of contact allergens. The present study aimed to evaluate contact sensitivity to topical drugs in patients with contact dermatitis. Materials and Methods: Between 2003 and 2008, 129 patients were followed up at the Department of Dermatology at Ankara University School of Medicine with clinically suspected contact sensitivity to topical drugs. In this study, the patch test reactions to the European Standard Battery and topical drugs used by the patients and medicament patch test results were evaluated. Results: Positive patch test reaction to one or more allergens was found in 80 (62.0% of 129 patients included in the study. Sixty-one of the 80 patients (61/129, 47.3% had positive patch test reaction to medicaments. Medicament sensitivity was detected in 37.9% (49/129 of subjects. Nitrofurazone was found to be the most common allergen (18.6%. Discussion: The present study showed that topical drugs are a frequent cause of allergic contact dermatitis. Therefore, the probability of contact sensitivity to topical drugs should also be considered in patients with the clinical diagnosis of allergic contact dermatitis and, suspected cases should be evaluated further with patch testing in order to find the responsible allergens.

  4. Evaluation of 5-fluorouracil applicability by multi-point collagen gel droplet embedded drug sensitivity test.

    Science.gov (United States)

    Ochiai, Takumi; Nishimura, Kazuhiko; Noguchi, Hajime; Kitajima, Masayuki; Tsuruoka, Yuko; Takahashi, Yuka

    2005-07-01

    The drug sensitivity of tumor cells is one of key issues to explore individualized therapy for cancer patients. One of such methods is in vitro anticancer drug sensitivity test which is generally based on one drug concentration and contact time. In this study, 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer patients was evaluated by collagen gel droplet embedded drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Cancer cells from 19 patients were measured for 9 drug concentration/contact time conditions (cohort 1) and from 34 patients were measured for 2 drug concentration/contact time conditions (cohort 2) using CD-DST. There was not significant difference in growth inhibition rate for 1.0 microg/ml for 24 h and 0.2 microg/ml for 120 h, which gives the same area under the curve (AUC) (p=0.832) in all 53 patients (cohort 1 and 2). In cohort 1, 9 conditions were successfully measured in 18 of 19 cohort 1 patients (94.7%). The drug concentrations and growth inhibition rate approximated to logarithmic curve for all 3 contact times and 50% inhibitory concentration (IC50) values at 3 contact times could be calculated in these 18 patients. Growth inhibition rate and AUC also approximated to logarithmic curve. These values varied several orders of magnitude among patients. In vitro antitumor effect of 5-FU depended on AUC in colorectal tumor and it might support the use of continuous infusion or oral therapy which generates significant AUC with manageable toxicity. Some patients demonstrating low 5-FU sensitivity could not be indicated for 5-FU based therapy, and non-5-FU therapy should be explored for them.

  5. Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Susan K Glendinning

    Full Text Available Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects of polymorphisms found in resistant parasites, but may be complicated by differences between the gene families of target and model organisms. We tested this using the glutamate-gated chloride channel (GluCl gene family, which forms the ivermectin drug target and are candidate resistance genes. We expressed GluCl subunits from C. elegans and H. contortus in a highly resistant triple mutant C. elegans strain (DA1316 under the control of the avr-14 promoter; expression of GFP behind this promoter recapitulated the pattern previously reported for avr-14. Expression of ivermectin-sensitive subunits from both species restored drug sensitivity to transgenic worms, though some quantitative differences were noted between lines. Expression of an ivermectin-insensitive subunit, Hco-GLC-2, had no effect on drug sensitivity. Expression of a previously uncharacterised parasite-specific subunit, Hco-GLC-6, caused the transgenic worms to become ivermectin sensitive, suggesting that this subunit also encodes a GluCl that responds to the drug. These results demonstrate that both orthologous and paralogous subunits from C. elegans and H. contortus are able to rescue the ivermectin sensitivity of mutant C. elegans, though some quantitative differences were observed between transgenic lines in

  6. Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans.

    Science.gov (United States)

    Glendinning, Susan K; Buckingham, Steven D; Sattelle, David B; Wonnacott, Susan; Wolstenholme, Adrian J

    2011-01-01

    Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects of polymorphisms found in resistant parasites, but may be complicated by differences between the gene families of target and model organisms. We tested this using the glutamate-gated chloride channel (GluCl) gene family, which forms the ivermectin drug target and are candidate resistance genes. We expressed GluCl subunits from C. elegans and H. contortus in a highly resistant triple mutant C. elegans strain (DA1316) under the control of the avr-14 promoter; expression of GFP behind this promoter recapitulated the pattern previously reported for avr-14. Expression of ivermectin-sensitive subunits from both species restored drug sensitivity to transgenic worms, though some quantitative differences were noted between lines. Expression of an ivermectin-insensitive subunit, Hco-GLC-2, had no effect on drug sensitivity. Expression of a previously uncharacterised parasite-specific subunit, Hco-GLC-6, caused the transgenic worms to become ivermectin sensitive, suggesting that this subunit also encodes a GluCl that responds to the drug. These results demonstrate that both orthologous and paralogous subunits from C. elegans and H. contortus are able to rescue the ivermectin sensitivity of mutant C. elegans, though some quantitative differences were observed between transgenic lines in some assays. C

  7. Inhibition of CYP2B6 by Medicinal Plant Extracts: Implication for Use of Efavirenz and Nevirapine-Based Highly Active Anti-Retroviral Therapy (HAART in Resource-Limited Settings

    Directory of Open Access Journals (Sweden)

    Nicholas E. Thomford

    2016-02-01

    Full Text Available Highly active antiretroviral therapy (HAART has greatly improved health parameters of HIV infected individuals. However, there are several challenges associated with the chronic nature of HAART administration. For populations in health transition, dual use of medicinal plant extracts and conventional medicine poses a significant challenge. There is need to evaluate interactions between commonly used medicinal plant extracts and antiretroviral drugs used against HIV/AIDS. Efavirenz (EFV and nevirapine (NVP are the major components of HAART both metabolized by CYP2B6, an enzyme that can potentially be inhibited or induced by compounds found in medicinal plant extracts. The purpose of this study was to evaluate the effects of extracts of selected commonly used medicinal plants on CYP2B6 enzyme activity. Recombinant human CYP2B6 was used to evaluate inhibition, allowing the assessment of herb-drug interactions (HDI of medicinal plants Hyptis suaveolens, Myrothamnus flabellifolius, Launaea taraxacifolia, Boerhavia diffusa and Newbouldia laevis. The potential of these medicinal extracts to cause HDI was ranked accordingly for reversible inhibition and also classified as potential time-dependent inhibitor (TDI candidates. The most potent inhibitor for CYP2B6 was Hyptis suaveolens extract (IC50 = 19.09 ± 1.16 µg/mL, followed by Myrothamnus flabellifolius extract (IC50 = 23.66 ± 4.86 µg/mL, Launaea taraxacifolia extract (IC50 = 33.87 ± 1.54 µg/mL, and Boerhavia diffusa extract (IC50 = 34.93 ± 1.06 µg/mL. Newbouldia laevis extract, however, exhibited weak inhibitory effects (IC50 = 100 ± 8.71 µg/mL on CYP2B6. Launaea taraxacifolia exhibited a TDI (3.17 effect on CYP2B6 and showed a high concentration of known CYP450 inhibitory phenolic compounds, chlorogenic acid and caffeic acid. The implication for these observations is that drugs that are metabolized by CYP2B6 when co-administered with these herbal medicines and when adequate amounts of the

  8. Phenylephrine induced fixed drug eruption: a rare case of cross sensitivity

    Directory of Open Access Journals (Sweden)

    Mahesh Chander Gupta

    2016-08-01

    Full Text Available Fixed drug eruption (FDE is a type of dermatosis characterized by recurrent lesions at exactly the same sites with each administration of the causative agents. FDEs are common types of drug eruptions amongst all cutaneous drug-induced side effects, mostly by intermittent exposure. Multiple drugs with common chemical structure can cause same type of lesions at same site called as cross sensitivity. There are many causative agents and the incidence of FDEs for a particular drug depends on the frequency of its use. Though usually not severe or fatal, cosmetic embarrassment is main problem, especially when they recur on the previously affected sites leaving behind residual hyperpigmentation. Phenylephrine is a sympathomimetic agent, given orally for the symptomatic relief of nasal congestion. It is also commonly combined with other ingredients in preparations intended for the relief of cough and cold symptoms. Considering the frequent use of Phenylephrine, associated drug eruptions generally appear to be rare, cross sensitivity with pseudoephedrine is even rarer. In our case phenylepherine was self-administered to control cold induced congestion and patient developed FDE on vermillion of upper lip, which healed after 2 weeks leaving hyperpigmentation and reappear on same site after re-challenge also. She has history of FDEs due to pseudoephedrine on same site on lips. This is a rare case of sympathomimetics induced FDE with cross sensitivity between phenylepherine and pseudoephedrine; hence we are reporting it here. [Int J Basic Clin Pharmacol 2016; 5(4.000: 1687-1690

  9. Fatores de risco para a não adesão ao tratamento com terapia antiretroviral altamente eficaz Factores de riesgo para la no-adherencia al tratamiento con terapia anti-retroviral altamente eficiente Risk factors for non-compliance to treatment with highly effective antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Maria Rosa Ceccato Colombrini

    2008-09-01

    Full Text Available O estudo objetivou: mensurar a prevalência de não-adesão à terapia anti-retroviral altamente eficaz (HAART em pacientes com AIDS; identificar se alguns fatores relacionados na literatura estavam associados com a não-adesão; estabelecer o valor preditivo dos fatores associados à não-adesão à HAART. Foi realizado um estudo analítico de prevalência (N=60. Foram considerados os três dias anteriores à entrevista e os pacientes classificados como aderentes quando ingeriam 95% ou mais do total de comprimidos prescritos por dia. A adesão foi de 73,3%. A análise de regressão logística multivariada indicou que indivíduos da raça negra apresentaram 6,48 vezes mais risco de não-adesão; aqueles que apresentaram ausência de efeito colateral tiveram um risco 7,6 vezes maior, e a cada comprimido ingerido o risco foi de 1,12. A adesão observada foi maior que a encontrada na literatura. Os fatores sociodemográficos e culturais podem interferir na adesão à HAART.Objetivo del estudio: medir la prevalencia por falta de seguimiento al tratamiento anti-retroviral altamente eficaz (HAART en pacientes con SIDA; identificar si algunos factores relacionados en la bibliografía se encuentran asociados con la falta de seguimiento; establecer el valor preditivo de los factores asociados con la falta de seguimiento al HAART. Para lo cual fue realizado un estudio analitico de prevalencia (N=60, considerándose los tres días anteriores a la entrevista, donde aquellos pacientes con ingesta del 95% o más del total de comprimidos prescritos por día eran clasificados como seguidores del tratamiento. El seguimiento fue de 73,3%. El análisis de regresion logística multi-variable mostró que sujetos de raza negra presentaron 6,48 veces mayor riesgo de no continuar con el tratamiento; aquellos individuos sin efectos colaterales tuvieron un riesgo 7,6 veces mayor, asimismo, cada comprimido ingerido produjo un riesgo de 1,12. El seguimiento observado fue

  10. Lipodystrophy syndrome associated with antiretroviral therapy in HIV patients: considerations for psychosocial aspects Síndrome de la lipodistrofia asociado con la terapia antiretroviral en pacientes con VIH: consideraciones para los aspectos psicosociales Sindrome da lipodistrofia associada com a terapia anti-retroviral em portadores do HIV: considerações para os aspectos psicossociais

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    Ana Paula Morais Fernandes

    2007-10-01

    son necesarios para entender mejor este complejo síndrome, proveyendo nueva información para ser utilizada en el cuidado de enfermería para pacientes con VIH que están afectados por este problema.Diversos efeitos colaterais têm sido associados à terapia anti-retroviral em portadores da infecção pelo HIV, dentre esses, a síndrome da lipodistrofia apresentando hiperlipidemia e alterações na forma do corpo, com hipertrofia adiposa central e lipoatrofia periférica, relatada pelos pacientes como um visível marcador para a identificação de portadores da infecção pelo HIV. Este estudo consiste em análise da produção científica sobre aspectos psicossociais em portadores da infecção pelo HIV que apresentam lipodistrofia associada à utilização da terapia anti-retroviral. Os resultados mostram que alterações corporais podem ser suficientemente perturbadoras para o bem-estar psicossocial, afetando a qualidade de vida e aumentando o estigma da doença, ocasionando perturbações nas relações sociais. Esta revisão possibilita uma análise preliminar dos aspectos psicossocias da lipodistrofia; entretanto, outros estudos são necessários para o melhor entendimento desta complexa síndrome, trazendo novas informações a serem utilizadas no cuidado de enfermagem a portadores da infecção pelo HIV afetados por este problema.

  11. Disclosure of HIV status and its impact on the loss in the follow-up of HIV-infected patients on potent anti-retroviral therapy programs in a (post-) conflict setting: A retrospective cohort study from Goma, Democratic Republic of Congo

    Science.gov (United States)

    Akilimali, Pierre Zalagile; Musumari, Patou Masika; Kashala-Abotnes, Espérance; Kayembe, Patrick Kalambayi; Lepira, François B.; Mutombo, Paulin Beya; Tylleskar, Thorkild; Ali, Mapatano Mala

    2017-01-01

    Background The study aimed to identify the impact of non-disclosure of HIV status on the loss to follow-up (LTFU) of patients receiving anti-retroviral therapy. Methodology A historic cohort of HIV patients from 2 major hospitals in Goma, Democratic Republic of Congo was followed from 2004 to 2012. LTFU was defined as not taking an ART refill for a period of 3 months or longer since the last attendance, and had not yet been classified as ‘dead’ or ‘transferred-out’. Kaplan-Meier plots were used to determine the probability of LTFU as a function of time as inclusive of the cohort. The log-rank test was used to compare survival curves based on determinants. Cox proportional hazard modeling was used to measure predictors of LTFU from the time of treatment induction until December 15th, 2012 (the end-point). Results The median follow-up time was 3.99 years (IQR = 2.33 to 5.59). Seventy percent of patients had shared their HIV status with others (95% CI: 66.3–73.1). The proportion of LTFU was 12% (95%CI: 9.6–14.4). Patients who did not share their HIV status (Adjusted HR 2.28, 95% CI 1.46–2.29), patients who did not live in the city of Goma (Adjusted HR 1.97, 95% CI 1.02–3.77), and those who attained secondary or higher education level (Adjusted HR 1.60, 95% CI 1.02–2.53) had a higher hazard of being LTFU. Conclusion This study shows the relationship between the non–disclosure HIV status and LTFU. Healthcare workers in similar settings should pay more attention to clients who have not disclosed their HIV status, and to those living far from health settings where they receive medication. PMID:28170410

  12. Heat Shock Protein translocation induced by membrane fluidization increases tumor-cell sensitivity to chemotherapeutic drugs.

    Science.gov (United States)

    Dempsey, Nina C; Ireland, H Elyse; Smith, Carly M; Hoyle, Christine F; Williams, John H H

    2010-10-28

    Treatment of chronic lymphocytic leukemia (CLL) remains a challenge due to the frequency of drug resistance amongst patients. Improving the delivery of chemotherapeutic agents while reducing the expression of anti-apoptotic Heat Shock Proteins (HSPs) within the cancer cells may facilitate in overcoming this drug resistance. We demonstrate for the first time that sub-lethal doses of chemotherapeutic agents can be combined with membrane fluidizing treatments to produce a significant increase in drug efficacy and apoptosis in vitro. We show that fluidizers result in a transient decrease in intracellular HSPs, resulting in increased tumor-cell sensitivity and a membrane-associated induction of HSP gene expression.

  13. Validação e reprodutibilidade de uma escala de auto-eficácia para adesão ao tratamento anti-retroviral em pais ou cuidadores de crianças e adolescentes vivendo com HIV/AIDS Validity and reliability of a self-efficacy expectancy scale for adherence to antiretroviral therapy for parents and carers of children and adolescents with HIV/AIDS

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    Luciana Scarlazzari Costa

    2008-02-01

    Full Text Available OBJETIVO: Validar uma escala de auto-eficácia para adesão ao tratamento anti-retroviral em crianças e adolescentes com HIV/AIDS, levando em consideração a perspectiva dos pais/responsáveis, e avaliar a sua reprodutibilidade. MÉTODOS: O estudo foi realizado no Hospital-Dia do Centro de Referência e Treinamento em DST/AIDS de São Paulo. Foram entrevistados os pais/responsáveis de 54 crianças e adolescentes de 6 meses a 20 anos que passaram em consulta de rotina pelo serviço. Os dados de auto-eficácia foram levantados pela escala de auto-eficácia para seguir prescrição anti-retroviral (AE, que foi calculada de duas maneiras: análise fatorial e fórmula já definida. A consistência interna da escala foi verificada pelo coeficiente ade Cronbach. A validade foi avaliada pela comparação das médias dos escores entre grupos de pacientes aderentes e não aderentes ao tratamento anti-retroviral (teste de Mann-Whitney e cálculo do coeficiente de correlação de Spearman entre os escores e parâmetros clínicos. A reprodutibilidade foi verificada por meio do teste de Wilcoxon, pelo coeficiente de correlação intraclasse (CCI e pelo gráfico de Bland-Altman. RESULTADOS: A escala de AE apresentou boa consistência interna (a= 0,87 e boa reprodutibilidade (CCI = 0,69 e CCI = 0,75. Quanto à validade, a escala de AE conseguiu discriminar pacientes aderentes e não aderentes ao tratamento anti-retroviral (p = 0,002 e apresentou correlação significativa com a contagem de CD4 (r = 0,28; p = 0,04. CONCLUSÕES: A escala de AE pode ser utilizada para avaliar a adesão à terapia anti-retroviral em crianças e adolescentes com HIV/AIDS, levando em consideração a perspectiva dos pais/cuidadores.OBJECTIVE: To validate and evaluate the reproducibility of a self-efficacy (SE scale for adherence to antiretroviral therapy in children and adolescents with HIV/AIDS, taking into account the perspective of parents/guardians. METHODS: The study was

  14. Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer.

    Science.gov (United States)

    Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J; Wang, Yanhua; Huang, Gloria S

    2014-01-01

    Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.

  15. Co-treatment with the anti-malarial drugs mefloquine and primaquine highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition.

    Science.gov (United States)

    Kim, Ju-Hwa; Choi, Ae-Ran; Kim, Yong Kee; Yoon, Sungpil

    2013-11-22

    The purpose of this study was to identify conditions that will increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Currently, atovaquine (ATO), chloroquine (CHL), primaquine (PRI), mefloquine (MEF), artesunate (ART), and doxycycline (DOY) are the most commonly used anti-malarial drugs. Herein, we tested whether anti-malarial drugs can sensitize drug-resistant KBV20C cancer cells. None of the six tested anti-malarial drugs was found to better sensitize the drug-resistant cells compared to the sensitive KB cells. With an exception of DOY, all other anti-malarial drugs tested could sensitize both KB and KBV20C cells to a similar extent, suggesting that anti-malarial drugs could be used for sensitive as well as resistant cancer cells. Furthermore, we examined the effects of anti-malarial drugs in combination with an antimitotic drug, vinblastine (VIN) on the sensitisation of resistant KBV20C cells. Using viability assay, microscopic observation, assessment of cleaved PARP, and Hoechst staining, we identified that two anti-malarial drugs, PRI and MEF, highly sensitized KBV20C-resistant cells to VIN treatment. Moreover, PRI- or MEF-induced sensitisation was not observed in VIN-treated sensitive KB parent cells, suggesting that the observed effect is specific to resistant cancer cells. We demonstrated that the PRI and MEF sensitisation mechanism mainly depends on the inhibition of p-glycoprotein (P-gp). Our findings may contribute to the development of anti-malarial drug-based combination therapies for patients resistant to anti-mitotic drugs.

  16. Increased Replicative Fitness Can Lead to Decreased Drug Sensitivity of Hepatitis C Virus

    Science.gov (United States)

    Sheldon, Julie; Beach, Nathan M.; Moreno, Elena; Gallego, Isabel; Piñeiro, David; Martínez-Salas, Encarnación; Gregori, Josep; Quer, Josep; Esteban, Juan Ignacio; Rice, Charles M.

    2014-01-01

    ABSTRACT Passage of hepatitis C virus (HCV) in human hepatoma cells resulted in populations that displayed partial resistance to alpha interferon (IFN-α), telaprevir, daclatasvir, cyclosporine, and ribavirin, despite no prior exposure to these drugs. Mutant spectrum analyses and kinetics of virus production in the absence and presence of drugs indicate that resistance is not due to the presence of drug resistance mutations in the mutant spectrum of the initial or passaged populations but to increased replicative fitness acquired during passage. Fitness increases did not alter host factors that lead to shutoff of general host cell protein synthesis and preferential translation of HCV RNA. The results imply that viral replicative fitness is a mechanism of multidrug resistance in HCV. IMPORTANCE Viral drug resistance is usually attributed to the presence of amino acid substitutions in the protein targeted by the drug. In the present study with HCV, we show that high viral replicative fitness can confer a general drug resistance phenotype to the virus. The results exclude the possibility that genomes with drug resistance mutations are responsible for the observed phenotype. The fact that replicative fitness can be a determinant of multidrug resistance may explain why the virus is less sensitive to drug treatments in prolonged chronic HCV infections that favor increases in replicative fitness. PMID:25122776

  17. Salinomycin sensitizes antimitotic drugs-treated cancer cells by increasing apoptosis via the prevention of G2 arrest

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ju-Hwa; Yoo, Hye-In; Kang, Han Sung; Ro, Jungsil [Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do (Korea, Republic of); Yoon, Sungpil, E-mail: yoons@ncc.re.kr [Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do (Korea, Republic of)

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Sal sensitizes antimitotic drugs-treated cancer cells. Black-Right-Pointing-Pointer Sal sensitizes them by prevention of G2 arrest and reduced cyclin D1 levels. Black-Right-Pointing-Pointer Sal also sensitizes them by increasing DNA damage and reducing p21 level. Black-Right-Pointing-Pointer A low concentration of Sal effectively sensitized the cancer cells to antimitotic drugs. -- Abstract: Here, we investigated whether Sal could sensitize cancer cells to antimitotic drugs. We demonstrated that Sal sensitized paclitaxcel (PAC)-, docetaxcel (DOC)-, vinblastin (VIN)-, or colchicine (COL)-treated cancer cell lines, suggesting that Sal has the ability to sensitize the cells to any form of microtubule-targeting drugs. Sensitization to the antimitotic drugs could be achieved with very low concentrations of Sal, suggesting that there is a possibility to minimize Sal toxicity associated with human cancer patient treatments. Sensitization by Sal increased apoptosis, which was observed by C-PARP production. Sal sensitized the cancer cells to antimitotic drugs by preventing G2 arrest, suggesting that Sal contributes to the induction of mitotic catastrophe. Sal generally reduced cyclin D1 levels in PAC-, DOC-, and VIN-treated cells. In addition, Sal treatment increased pH2AX levels and reduced p21 levels in antimitotic drugs-treated cells. These observations suggest that the mechanisms underlying Sal sensitization to DNA-damaging compounds, radiation, and microtubule-targeting drugs are similar. Our data demonstrated that Sal sensitizes cancer cells to antimitotic drugs by increasing apoptosis through the prevention of G2 arrest via conserved Sal-sensitization mechanisms. These results may contribute to the development of Sal-based chemotherapy for cancer patients treated with antimitotic drugs.

  18. Role of pressure-sensitive adhesives in transdermal drug delivery systems.

    Science.gov (United States)

    Lobo, Shabbir; Sachdeva, Sameer; Goswami, Tarun

    2016-01-01

    Transdermal drug delivery systems (TDDS) are employed for the delivery of drugs across skin into the systemic circulation. Pressure-sensitive adhesive (PSA) is one of the most critical components used in a TDDS. The primary function of PSA is to help in adhesion of patch to skin, but more importantly it acts as a matrix for the drug and other excipients. Hence, apart from adhesion of the patch, PSA also affects other critical quality attributes of the TDDS such as drug delivery, flux through skin and physical and chemical stability of the finished product. This review article provides a summary of the adhesives used in various types of TDDS. In particular, this review will cover the design types of TDDS, categories of PSAs and their evaluation and regulatory aspects.

  19. Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems.

    Science.gov (United States)

    Jelezova, Ivelina; Drakalska, Elena; Momekova, Denitsa; Shalimova, Natalia; Momekov, Georgi; Konstantinov, Spiro; Rangelov, Stanislav; Pispas, Stergios

    2015-10-12

    Curcumin is a perspective drug candidate with pleiotropic antineoplastic activity, whose exceptionally low aqueous solubility and poor pharmacokinetic properties have hampered its development beyond the preclinical level. A possible approach to overcome these limitations is the encapsulation of curcumin into nano-carriers, incl. liposomes. The present contribution is focused on feasibility of using hybrid pH-sensitive liposomes, whereby curcumin is entrapped as a free drug and as a water soluble inclusion complex with PEGylated tert-butylcalix[4]arene, which allows the drug to occupy both the phospholipid membranes and the aqueous core of liposomes. The inclusion complexes were encapsulated in dipalmithoylphosphathydilcholine:cholesterol liposomes, whose membranes were grafted with a poly(isoprene-b-acrylic acid) diblock copolymer to confer pH-sensitivity. The liposomes were characterized by DLS, ζ-potential measurements, cryo-TEM, curcumin encapsulation efficacy, loading capacity, and in vitro release as a function of pH. Free and formulated curcumin were further investigated for cytotoxicity, apoptosis-induction and caspase-8, and 9 activation in chemosensitive HL-60 and its resistant sublines HL-60/Dox and HL-60/CDDP. Formulated curcumin was superior cytotoxic and apoptogenic agent vs. the free drug. The mechanistic assay demonstrated that the potent proapoptotic effects of pH-sensitive liposomal curcumin presumably mediated via recruitment of both extrinsic and intrinsic apoptotic pathways in both HL-60 and HL-60/CDDP cells.

  20. A pH-Sensitive Injectable Nanoparticle Composite Hydrogel for Anticancer Drug Delivery

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    Yuanfeng Ye

    2016-01-01

    Full Text Available According to previous reports, low pH-triggered nanoparticles were considered to be excellent carriers for anticancer drug delivery, for the reason that they could trigger encapsulated drug release at mild acid environment of tumor. Herein, an acid-sensitive β-cyclodextrin derivative, namely, acetalated-β-cyclodextrin (Ac-β-CD, was synthesized by acetonation and fabricated to nanoparticles through single oil-in-water (o/w emulsion technique. At the same time, camptothecin (CPT, a hydrophobic anticancer drug, was encapsulated into Ac-β-CD nanoparticles in the process of nanoparticle fabrication. Formed nanoparticles exhibited nearly spherical structure with diameter of 209±40 nm. The drug release behavior of nanoparticles displayed pH dependent changes due to hydrolysis of Ac-β-CD. In order to overcome the disadvantages of nanoparticle and broaden its application, injectable hydrogels with Ac-β-CD nanoparticles were designed and prepared by simple mixture of nanoparticles solution and graphene oxide (GO solution in this work. The injectable property was confirmed by short gelation time and good mobility of two precursors. Hydrogels were characterized by dynamic mechanical test and SEM, which also reflected some structural features. Moreover, all hydrogels underwent a reversible sol-gel transition in alkaline environment. Finally, the results of in vitro drug release profile indicated that hydrogel could control drug release or bind drug inside depending on the pH value of released medium.

  1. Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea.

    Science.gov (United States)

    Moon, Changsuk; Zhang, Weiqiang; Ren, Aixia; Arora, Kavisha; Sinha, Chandrima; Yarlagadda, Sunitha; Woodrooffe, Koryse; Schuetz, John D; Valasani, Koteswara Rao; de Jonge, Hugo R; Shanmukhappa, Shiva Kumar; Shata, Mohamed Tarek M; Buddington, Randal K; Parthasarathi, Kaushik; Naren, Anjaparavanda P

    2015-05-01

    Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.

  2. Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs.

    Science.gov (United States)

    Hsu, Chia-Chi; Wu, Ling-Chia; Hsia, Cheng-Yuan; Yin, Pen-Hui; Chi, Chin-Wen; Yeh, Tien-Shun; Lee, Hsin-Chen

    2015-09-01

    Human hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide particularly in Asia. Deregulation of cellular energetics was recently included as one of the cancer hallmarks. Compounds that target the mitochondria in cancer cells were proposed to have therapeutic potential. Biguanide drugs which inhibit mitochondrial complex I and repress mTOR signaling are clinically used to treat type 2 diabetes mellitus patients (T2DM) and were recently found to reduce the risk of HCC in T2DM patients. However, whether alteration of energy metabolism is involved in regulating the sensitivity of HCC to biguanide drugs is still unclear. In the present study, we treated four HCC cell lines with mitochondrial inhibitors (rotenone and oligomycin) and biguanide drugs (metformin and phenformin), and found that the HCC cells which had a higher mitochondrial respiration rate were more sensitive to these treatments; whereas the HCC cells which exhibited higher glycolysis were more resistant. When glucose was replaced by galactose in the medium, the altered energy metabolism from glycolysis to mitochondrial respiration in the HCC cells enhanced the cellular sensitivity to mitochondrial inhibitors and biguanides. The energy metabolism change enhanced AMP-activated protein kinase (AMPK) activation, mTOR repression and downregulation of cyclin D1 and Mcl-1 in response to the mitochondrial inhibitors and biguanides. In conclusion, our results suggest that increased mitochondrial oxidative metabolism upregulates the sensitivity of HCC to biguanide drugs. Enhancing the mitochondrial oxidative metabolism in combination with biguanide drugs may be a therapeutic strategy for HCC.

  3. Thermo-sensitive complex micelles from sodium alginate-graft-poly(N-isopropylacrylamide) for drug release.

    Science.gov (United States)

    Yu, Nana; Li, Guiying; Gao, Yurong; Jiang, Hua; Tao, Qian

    2016-05-01

    Polymer micelles with environmentally sensitive properties have potential applications in biomedicine. In this paper, thermo-sensitive complex micelles assembled from biocompatible graft copolymers sodium alginate-graft-poly(N-isopropylacrylamide) (SA-g-PNIPAM) and divalent metal ions were prepared for controlled drug release. The polymer micelles had core-corona structure, which was constituted by metal ions (Ba(2+), Zn(2+), Co(2+)) cross-linked sodium alginate as the core and thermo-sensitive PNIPAM chains as the corona. Formation of polymer micelles was determined by Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). The polymer micelles were observed as regular spheres with good polydispersity and excellent performance on drug encapsulation and release ability. The cumulative release of 5-fluorouracil (5-FU) from micelles was controlled by pH, ionic strength or temperature of surroundings. The superior properties of sensitive polymer micelles induced by metal ions are expected to be utilized in controlled drug delivery systems.

  4. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Directory of Open Access Journals (Sweden)

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  5. Non-polymeric nano-carriers in HIV/AIDS drug delivery and targeting.

    Science.gov (United States)

    Gupta, Umesh; Jain, Narendra K

    2010-03-18

    Development of an effective drug delivery approach for the treatment of HIV/AIDS is a global challenge. The conventional drug delivery approaches including Highly Active Anti Retroviral Therapy (HAART) have increased the life span of the HIV/AIDS patient. However, the eradication of HIV is still not possible with these approaches due to some limitations. Emergence of polymeric and non-polymeric nanotechnological approaches can be opportunistic in this direction. Polymeric carriers like, dendrimers and nanoparticles have been reported for the targeting of anti HIV drugs. The synthetic pathways as well polymeric framework create some hurdles in their successful formulation development as well as in the possible drug delivery approaches. In the present article, we have discussed the general physiological aspects of the infection along with the relevance of non-polymeric nanocarriers like liposomes, solid lipid nanoparticles (SLN), ethosomes, etc. in the treatment of this disastrous disease.

  6. Estudo da síndrome da ceratoconjuntivite seca de pacientes soropositivos para o vírus da imunodeficiência adquirida humana tipo 1 e com síndrome da imunodeficiência adquirida, em uso ou não de terapia anti-retroviral combinada (HAART

    Directory of Open Access Journals (Sweden)

    Rodrigues Márcia Lopes

    2004-01-01

    Full Text Available OBJETIVOS: Verificar a presença de olho seco e de alterações no epitélio conjuntival em pacientes com sorologia positiva para o HIV-1 e com AIDS; relacionar as eventuais alterações com as características e com outras condições oculares e sistêmicas dos pacientes; estudar a influência da terapia anti-retroviral combinada na ceratoconjuntivite seca (KCS, nos pacientes com AIDS. MÉTODOS: Foram estudados pacientes com confirmação laboratorial da infecção pelo HIV, divididos em 2 grupos: I. HIV+ (sem diagnóstico clínico e com contagem de CD4+ acima de 200 células/mm³ e II. pacientes com AIDS (contagem de CD4+ abaixo de 200 células e/ou manifestação clínica. Foram estudadas alterações oculares, dados laboratoriais, análise do filme lacrimal e estudo da citologia de impressão conjuntival. Método estatístico: qui-quadrado. RESULTADOS: Incluídos 43 pacientes do grupo I e 77 do grupo II. Após a introdução do HAART houve queda significativa das manifestações oculares internas; entretanto, o mesmo não ocorreu com as externas. Dos pacientes que apresentaram quadro clínico de olho seco, 65,1% eram do sexo masculino. As alterações do teste de Schirmer e tempo de ruptura do filme lacrimal não estiveram relacionados com a gravidade da doença pelo HIV e nem com a contagem de CD4+.Todos os pacientes com alterações na citologia de impressão apresentavam KCS e 88,8% pertenciam ao grupo II. Observou-se aumento da freqüência dessas alterações nos pacientes com tempo de doença superior a 4 anos. CONCLUSÃO: O decréscimo da produção lacrimal não esteve relacionado com a gravidade da infecção pelo HIV e a introdução do HAART não interferiu na freqüência da síndrome de olho seco nos pacientes HIV positivos.

  7. Systematic identification of genomic markers of drug sensitivity in cancer cells.

    Science.gov (United States)

    Garnett, Mathew J; Edelman, Elena J; Heidorn, Sonja J; Greenman, Chris D; Dastur, Anahita; Lau, King Wai; Greninger, Patricia; Thompson, I Richard; Luo, Xi; Soares, Jorge; Liu, Qingsong; Iorio, Francesco; Surdez, Didier; Chen, Li; Milano, Randy J; Bignell, Graham R; Tam, Ah T; Davies, Helen; Stevenson, Jesse A; Barthorpe, Syd; Lutz, Stephen R; Kogera, Fiona; Lawrence, Karl; McLaren-Douglas, Anne; Mitropoulos, Xeni; Mironenko, Tatiana; Thi, Helen; Richardson, Laura; Zhou, Wenjun; Jewitt, Frances; Zhang, Tinghu; O'Brien, Patrick; Boisvert, Jessica L; Price, Stacey; Hur, Wooyoung; Yang, Wanjuan; Deng, Xianming; Butler, Adam; Choi, Hwan Geun; Chang, Jae Won; Baselga, Jose; Stamenkovic, Ivan; Engelman, Jeffrey A; Sharma, Sreenath V; Delattre, Olivier; Saez-Rodriguez, Julio; Gray, Nathanael S; Settleman, Jeffrey; Futreal, P Andrew; Haber, Daniel A; Stratton, Michael R; Ramaswamy, Sridhar; McDermott, Ultan; Benes, Cyril H

    2012-03-28

    Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

  8. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.

    Science.gov (United States)

    Barretina, Jordi; Caponigro, Giordano; Stransky, Nicolas; Venkatesan, Kavitha; Margolin, Adam A; Kim, Sungjoon; Wilson, Christopher J; Lehár, Joseph; Kryukov, Gregory V; Sonkin, Dmitriy; Reddy, Anupama; Liu, Manway; Murray, Lauren; Berger, Michael F; Monahan, John E; Morais, Paula; Meltzer, Jodi; Korejwa, Adam; Jané-Valbuena, Judit; Mapa, Felipa A; Thibault, Joseph; Bric-Furlong, Eva; Raman, Pichai; Shipway, Aaron; Engels, Ingo H; Cheng, Jill; Yu, Guoying K; Yu, Jianjun; Aspesi, Peter; de Silva, Melanie; Jagtap, Kalpana; Jones, Michael D; Wang, Li; Hatton, Charles; Palescandolo, Emanuele; Gupta, Supriya; Mahan, Scott; Sougnez, Carrie; Onofrio, Robert C; Liefeld, Ted; MacConaill, Laura; Winckler, Wendy; Reich, Michael; Li, Nanxin; Mesirov, Jill P; Gabriel, Stacey B; Getz, Gad; Ardlie, Kristin; Chan, Vivien; Myer, Vic E; Weber, Barbara L; Porter, Jeff; Warmuth, Markus; Finan, Peter; Harris, Jennifer L; Meyerson, Matthew; Golub, Todd R; Morrissey, Michael P; Sellers, William R; Schlegel, Robert; Garraway, Levi A

    2012-03-28

    The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.

  9. Novel application of Eudragit RL and cholesteryl oleyl carbonate to thermo-sensitive drug delivery system.

    Science.gov (United States)

    Cetin, Emel Oyku; Gundogdu, Evren; Baspinar, Yücel; Karasulu, Ercument; Kirilmaz, Levent

    2013-12-01

    The Eudragit RL 100 and propylene glycol (PG) membranes with and without cholesteryl oleyl carbonate (COC) were prepared by the solvent casting method to pioneer a novel application of a thermo-sensitive drug delivery system. After that, the properties of these membranes were investigated by thermal, scanning, and porosity studies. Drug permeation studies through all membranes were carried out using salbuthamol sulphate (SBS) at constant temperatures (25°C and 37°C), respectively. The permeability of SBS through the membranes with COC has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the phase transition temperature (37°C) of the COC. The thermo-sensitive permeation mechanism for the membranes might be based on the structure change of the membranes caused by the phase transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RL 100 and PG membranes with and without COC might be used to develop a novel thermo-sensitive drug delivery system.

  10. Controlled drug-release system based on pH-sensitive chloride-triggerable liposomes.

    Science.gov (United States)

    Wehunt, Mark P; Winschel, Christine A; Khan, Ali K; Guo, Tai L; Abdrakhmanova, Galya R; Sidorov, Vladimir

    2013-03-01

    New pH-sensitive lipids were synthesized and utilized in formulations of liposomes suitable for controlled drug release. These liposomes contain various amounts of NaCl in the internal aqueous compartments. The release of the drug model is triggered by an application of HCl cotransporter and exogenous physiologically relevant NaCl solution. HCl cotransporter allows an uptake of HCl by liposomes to the extent of their being proportional to the transmembrane Cl(-) gradient. Therefore, each set of liposomes undergoes internal acidification, which, ultimately, leads to the hydrolysis of the pH-sensitive lipids and content release at the desired time. The developed system releases the drug model in a stepwise fashion, with the release stages separated by periods of low activity. These liposomes were found to be insensitive to physiological concentrations of human serum albumin and to be nontoxic to cells at concentrations exceeding pharmacological relevance. These results render this new drug-release model potentially suitable for in vivo applications.

  11. Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs

    Science.gov (United States)

    Gelardi, T; Caputo, R; Damiano, V; Daniele, G; Pepe, S; Ciardiello, F; Lahn, M; Bianco, R; Tortora, G

    2008-01-01

    We investigated the antitumour effect and ability to overcome the resistance to anti-EGFR drugs of enzastaurin, an inhibitor of VEGFR-dependent PKCβ signalling. Enzastaurin was evaluated alone and in combination with the EGFR inhibitor gefitinib, on growth and signalling protein expression in human cancer cells sensitive and resistant to anti-EGFR drugs, both in vitro and in nude mice. We demonstrated the marked inhibitory activity of enzastaurin against GEO colon and PC3 prostate cancer cells and their gefitinib-resistant counterparts GEO-GR and PC3-GR, accompanied by inhibition of pAkt and its effector pp70S6K, pGSK3β and VEGF expression and secretion. Moreover, enzastaurin showed a cooperative effect with gefitinib in parental and in gefitinib-resistant cells. Remarkably, these results were confirmed in vivo, where enzastaurin showed antitumour activity and cooperativity with gefitinib in mice grafted with GEO and GEO-GR tumours, incrementing their median survival and inhibiting the aforesaid protein expression and secretion in tumour specimens. In conclusion, enzastaurin by interfering with signalling proteins implicated in EGFR drug resistance markedly cooperates with gefitinib in sensitive and gefitinib-resistant tumours, thus overcoming and reverting such resistance and providing a rational basis for its development in patients resistant to anti-EGFR drugs. PMID:18665191

  12. Screening the Drug Sensitivity Genes Related to GEM and CDDP in the Lung Cancer Cell-lines

    Directory of Open Access Journals (Sweden)

    Chunyu YANG

    2009-10-01

    Full Text Available Background and objective Screening of small-cell lung cancer (SCLC and non-small cell lung cancer (NSCLC cell lines with gemcitabine hydrochloride (GEM and cisplatin (CDDP related to drug sensitivity gene might clarify the action mechanism of anti-cancer drugs and provide a new clue for overcoming drug resistance and the development of new anti-cancer drugs, and also provide theoretical basis for the clinical treatment of individual. Methods The drug sensitivity of CDDP and GEM in 4 SCLC cell lines and 6 NSCLC cell lines was determined using MTT colorimetric assay, while the cDNA macroarray was applied to detect the gene expression state related to drug sensitivity of 10 lung cancer cell line in 1 291, and the correlation between the two was analysized. Results There were 6 genes showing significant positive correlation (r≥0.632, P < 0.05 with GEM sensitivity; 45 genes positively related to CDDP; another 41 genes related to both GEM and CDDP (r≥± 0.4. Lung cancer with GEM and CDDP sensitivity of two types of drugs significantly related genes were Metallothinein (Signal transduction molecules, Cathepsin B (Organization protease B and TIMP1 (Growth factor; the GEM, CDDP sensitivity associated genes of lung cancer cell lines mainly distributed in Metallothinein, Cathepsin B, growth factor TIMP1 categories. Conclusion There existed drug-related sensitive genes of GEM, CDDP in SCLC and NSCLC cell lines; of these genes, Metallothinein, Cathepsin B and TIMP1 genes presented a significant positive correlation with GEM drug sensitivity, a significant negative correlation with CDDP drug sensitivity.

  13. NOVEL pH-SENSITIVE DRUG DELIVERY SYSTEM BASED ON NATURAL POLYSACCHARIDE FOR DOXORUBICIN RELEASE

    Institute of Scientific and Technical Information of China (English)

    Dian-xiang Lu; Xian-tao Wen; Jie Liang; Xing-dong Zhang; Zhong-wei Gu; Yu-jiang Fan

    2008-01-01

    A novel pH-sensitive nanoparticle drug delivery system (DDS) derived from natural polysaccharide pullulan for doxorubicin (DOX) release was prepared. Pullulan was functionalized by successive carboxymethylization and amidation to introduce hydrazide groups. DOX was then grafted onto pullulan backbone through the pH-sensitive hydrazone bond to form a pullulan/DOX conjugate. This conjugate self-assembled to form nano-sized particles in aqueous solution as a result of the hydrophobic interaction of the DOX. Transmission electron microscope (TEM) and dynamic light scattering (DLS)characterization showed that the nanoparticles were spherical and their size was less than 100 nm. The DOX released from the nanoparticles in a pH-sensitive manner. In vitro cytotoxicity assay indicated the pullulan/DOX nanoparticles showed comparable cytotoxicity effect with free DOX on the 4T1 mouse breast cancer cells.

  14. Sonochemically synthesized biocompatible zirconium phosphate nanoparticles for pH sensitive drug delivery application.

    Science.gov (United States)

    Kalita, Himani; Prashanth Kumar, B N; Konar, Suraj; Tantubay, Sangeeta; Kr Mahto, Madhusudan; Mandal, Mahitosh; Pathak, Amita

    2016-03-01

    The present work reports the synthesis of biocompatible zirconium phosphate (ZP) nanoparticles as nanocarrier for drug delivery application. The ZP nanoparticles were synthesized via a simple sonochemical method in the presence of cetyltrimethylammonium bromide and their efficacy for the delivery of drugs has been tested through various in-vitro experiments. The particle size and BET surface area of the nanoparticles were found to be ~48 nm and 206.51 m(2)/g respectively. The conventional MTT assay and cellular localization studies of the particles, performed on MDA-MB-231 cell lines, demonstrate their excellent biocompatibility and cellular internalization behavior. The loading of curcumin, an antitumor drug, onto the ZP nanoparticles shows the rapid drug uptake ability of the particles, while the drug release study, performed at two different pH values (at 7.4 and 5) depicts pH sensitive release-profile. The MTT assay and cellular localization studies revealed higher cellular inhibition and better bioavailability of the nanoformulated curcumin compared to free curcumin.

  15. Cytotoxic drug sensitivity of Epstein-Barr virus transformed lymphoblastoid B-cells

    Directory of Open Access Journals (Sweden)

    Olah Eva

    2006-11-01

    Full Text Available Abstract Background Epstein-Barr virus (EBV is the causative agent of immunosuppression associated lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD, AIDS related immunoblastic lymphomas (ARL and immunoblastic lymphomas in X-linked lymphoproliferative syndrome (XLP. The reported overall mortality for PTLD often exceeds 50%. Reducing the immunosuppression in recipients of solid organ transplants (SOT or using highly active antiretroviral therapy in AIDS patients leads to complete remission in 23–50% of the PTLD/ARL cases but will not suffice for recipients of bone marrow grafts. An additional therapeutic alternative is the treatment with anti-CD20 antibodies (Rituximab or EBV-specific cytotoxic T-cells. Chemotherapy is used for the non-responding cases only as the second or third line of treatment. The most frequently used chemotherapy regimens originate from the non-Hodgkin lymphoma protocols and there are no cytotoxic drugs that have been specifically selected against EBV induced lymphoproliferative disorders. Methods As lymphoblastoid cell lines (LCLs are well established in vitro models for PTLD, we have assessed 17 LCLs for cytotoxic drug sensitivity. After three days of incubation, live and dead cells were differentially stained using fluorescent dyes. The precise numbers of live and dead cells were determined using a custom designed automated laser confocal fluorescent microscope. Results Independently of their origin, LCLs showed very similar drug sensitivity patterns against 29 frequently used cytostatic drugs. LCLs were highly sensitive for vincristine, methotrexate, epirubicin and paclitaxel. Conclusion Our data shows that the inclusion of epirubicin and paclitaxel into chemotherapy protocols against PTLD may be justified.

  16. Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Kirsi Ketola

    Full Text Available BACKGROUND: Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects. METHODS AND FINDINGS: In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression. CONCLUSIONS: Taken together, our results propose novel combinatorial approaches to inhibit

  17. Chemical Biology Drug Sensitivity Screen Identifies Sunitinib as Synergistic Agent with Disulfiram in Prostate Cancer Cells

    Science.gov (United States)

    Ketola, Kirsi; Kallioniemi, Olli; Iljin, Kristiina

    2012-01-01

    Background Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects. Methods and Findings In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression. Conclusions Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell

  18. Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression.

    Science.gov (United States)

    Kotsovolou, Olga; Ingelman-Sundberg, Magnus; Lang, Matti A; Marselos, Marios; Overstreet, David H; Papadopoulou-Daifoti, Zoi; Johanson, Inger; Fotopoulos, Andrew; Konstandi, Maria

    2010-08-16

    The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(alpha)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity.

  19. pH-sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method.

    Science.gov (United States)

    Laouini, Abdallah; Koutroumanis, Konstantinos P; Charcosset, Catherine; Georgiadou, Stella; Fessi, Hatem; Holdich, Richard G; Vladisavljević, Goran T

    2013-09-25

    A novel membrane contactor method was used to produce size-controlled poly(ethylene glycol)-b-polycaprolactone (PEG-PCL) copolymer micelles composed of diblock copolymers with different average molecular weights, Mn (9200 or 10,400 Da) and hydrophilic fractions, f (0.67 or 0.59). By injecting 570 L m(-2) h(-1) of the organic phase (a 1 mg mL(-1) solution of PEG-PCL in tetrahydrofuran) through a microengineered nickel membrane with a hexagonal pore array and 200 μm pore spacing into deionized water agitated at 700 rpm, the micelle size linearly increased from 92 nm for a 5-μm pore size to 165 nm for a 40-μm pore size. The micelle size was finely tuned by the agitation rate, transmembrane flux and aqueous to organic phase ratio. An encapsulation efficiency of 89% and a drug loading of ~75% (w/w) were achieved when a hydrophobic drug (vitamin E) was entrapped within the micelles, as determined by ultracentrifugation method. The drug-loaded micelles had a mean size of 146 ± 7 nm, a polydispersity index of 0.09 ± 0.01, and a ζ potential of -19.5 ± 0.2 mV. When drug-loaded micelles where stored for 50 h, a pH sensitive drug release was achieved and a maximum amount of vitamin E (23%) was released at the pH of 1.9. When a pH-sensitive hydrazone bond was incorporated between PEG and PCL blocks, no significant change in micelle size was observed at the same micellization conditions.

  20. Sensitive Determination of Sertraline in Commercial Drugs and Its Stability Check in Simulated Gastric Juice.

    Science.gov (United States)

    Koçoğlu, Elif Seda; Bakırdere, Sezgin; Keyf, Seyfullah

    2016-11-01

    A sensitive analytical method was developed for the determination of sertraline in commercial drug samples by using GC-MS. The selected-ion monitoring mode was used at the most sensitive m/z 274 to obtain a lower detection limit. LOD/LOQ values were obtained as 1.6/5.4 ng/mL for sertraline under the optimum conditions. The calibration plot was linear between 5.0 and 2000 ng/mL with the correlation coefficient of 0.9999. The validated method was successfully applied to three different brands of drug samples for both qualitative and quantitative measurement of sertraline. In this experiment, four replicate extractions were performed for each brand, and the results were compared to the values written on the labels of the drug brands. Spiking experiments were also performed to check the effect of the matrixes on the determination, and it was observed that there was no shift in the retention time of the analyte. In addition, simulated gastric juice experiments were performed to check the stability of sertraline in the stomach for 240 min, and it was observed that there was no change in the structure of the analyte.

  1. Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys1

    Institute of Scientific and Technical Information of China (English)

    Su-qing CHEN; Hai-feng ZHAI; Yan-ying CUI; Jie SHI; Bernard LE FOLL; Lin LU

    2007-01-01

    Aim: Clonidine is an α2 adrenoceptor agonist that is frequently used to reduce withdrawal symptoms during opioid detoxification in humans. The long-term effects of clonidine on withdrawal symptoms and its effects on subsequent drug exposure have not been thoroughly documented. The aim of the study was to determine if clonidine administered during morphine withdrawal in rhesus mon-keys produces long-lasting effects on withdrawal symptoms and alters the effects of subsequently taken drugs of abuse. Methods: Adult male rhesus monkeys were treated with increasing doses of morphine for 90 d to induce opiate (narcotic)dependence. The immediate and long-lasting effects of 1 week's administration of clonidine were measured via the recording of morphine withdrawal signs and the subsequent effects of challenge injections of morphine or cocaine. Results:Monkeys chronically treated with morphine displayed withdrawal signs that lasted 2 weeks after cessation of morphine administration and displayed sensitized re-sponses to subsequent morphine and cocaine injections. Clonidine significantly reduced certain morphine withdrawal signs and overall withdrawal score, but these effects did not persist upon cessation of clonidine treatment. Sensitization to the effects of morphine and cocaine were significantly reduced in monkeys previ-ously treated with clonidine. Conclusion: Our results suggest that in addition to its short-term alleviating effect on morphine withdrawal signs, clonidine may re-duce subsequent effects of drugs of abuse after prolonged abstinence.

  2. On the Comparison of Interpersonal Sensitivity and Assertiveness between Drug-Dependent Persons and Ordinary People

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    Babak Vojudi

    2015-02-01

    Full Text Available Objective: The present study was aimed at comparing interpersonal sensitivity and assertiveness between drug-dependent persons and ordinary people. Method: The research method was causal-comparative. The statistical population of the study consisted of all narcotic addicts of Tabriz City who referred to Addiction Treatment Centers while the research was being conducted. The number of 30 addicted persons was selected through cluster sampling and 30 ordinary persons as control group through convenience sampling method. Gmbryl & Ritchie’s assertiveness questionnaire (1975 and Boyce & Parker’s Interpersonal Sensitivity Measure (IPSM 1989 were used for data collection purposes. Results: The results showed that there was a statistically significant difference between two groups in terms of interpersonal sensitivity and assertiveness. The addicts showed less assertiveness and more interpersonal sensitivity in comparison with their healthy counterparts. Conclusion: The findings show that people who are unable to express themselves and exert sensitivity in interpersonal relationships are more likely at high risk of substance dependence. However, it is possible to prevent these persons from turning to addiction by teaching them these skills.

  3. Polydopamine-based surface modification of mesoporous silica nanoparticles as pH-sensitive drug delivery vehicles for cancer therapy.

    Science.gov (United States)

    Chang, Danfeng; Gao, Yongfeng; Wang, Lijun; Liu, Gan; Chen, Yuhan; Wang, Teng; Tao, Wei; Mei, Lin; Huang, Laiqiang; Zeng, Xiaowei

    2016-02-01

    A novel pH-sensitive drug delivery system of mesoporous silica nanoparticles (MSNs) which were modified by polydopamine (PDA) for controlled release of cationic amphiphilic drug desipramine (DES) was prepared. MSNs-DES-PDA were characterized in terms of size, size distribution, surface morphology, BET surface area, mesoporous size and pore volume, drug loading content and in vitro drug release profile. MSNs-DES-PDA had high drug loading content and pH sensitivity. The DES release profiles of MSNs-DES and MSNs-DES-PDA were totally different, and the drug release of MSNs-DES-PDA accelerated with increasing acidity. MSNs-DES-PDA can be internalized into cells. In vitro experiments demonstrated that MSNs-DES-PDA had higher cytotoxicity and inhibitory effects on acid sphingomyelinase than those of free DES. This drug delivery system was beneficial for controlled release and cancer therapy.

  4. Magnesium intracellular content and distribution map in drug-resistant and -sensitive whole cells

    Directory of Open Access Journals (Sweden)

    Emil Malucelli

    2014-01-01

    Full Text Available Magnesium (Mg plays crucial structural and regulatory roles within cells. Despite the extensive amount of data about the biochemistry of Mg, a complete picture of its regulation and cellular homeostasis is lacking. Thanks to recent improvements in third generation synchrotron X-ray sources, X-ray fluorescence microscopy (XRFM is becoming a highly sensitive method for mapping elemental distributions in cells. XRFM maps the element content but not the concentration, which is a relevant variable in a biological context. We tackled this issue by combining XRFM with atomic force microscopy that was used to obtain morphological information of the sample. The aim of the present study was to compare the content and the distribution of Mg in drug-resistant and -sensitive tumor cell lines. Our data has shown a massive increase of Mg in LoVo drug-resistant cells. Moreover, the map of intracellular Mg showed marked differences in the pattern distribution between sensitive and resistant cells.

  5. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy.

    Science.gov (United States)

    Hong, Zai-Fa; Zhao, Wen-Xiu; Yin, Zhen-Yu; Xie, Cheng-Rong; Xu, Ya-Ping; Chi, Xiao-Qin; Zhang, Sheng; Wang, Xiao-Min

    2015-01-01

    Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.

  6. Swelling and drug releasing properties of poly(N-isopropylacrylamide) thermo-sensitive copolymer gels

    Institute of Scientific and Technical Information of China (English)

    Chunyue PAN; Qingde LONG; Dian YU; Yanping RAO; Nianqian WU; Xingcui LI

    2008-01-01

    A series of N,isopropylacrylamide (NIPAAm)copolymer gels with different hydrophilicities were prepared from NIPAAm, hydrophilic acrylamide (AAm) and hydrophobic butyl methacrylate (BMA). The swelling and thermo,responsive properties of PNIPAAm P (NIPAm,co,BMA) and P(NIPAm,co,AAm) copolymer hydrogels were investigated. The drug loading and releasing behaviors for two kinds of model drug with different hydrophilicities were studied. The result shows that the copolymer gels present negative thermo,sensitivities. The lower critical solution temperature (LCST), equilibrium swelling degree and the initial swelling rate increase as the hydrophilicity of gels increases when the temperature is below the LCST. With increasing gel hydrophilicity the loading ratio for sodium salicylate increases, while for salicylic acid, the reverse is observed. The initial drug releasing rate of sodium salicylate and salicylic acid also increase with increasing gel hydrophilicity. The initial drug releasing rate of sodium salicylate is significantly higher than that of salicylic acid. For salicylic acid which is less hydrophilic, the equilibrium releasing ratio at high temperature is lower than that at low temperature while for sodium salicylate which is more hydrophilic, the equilibrium releasing ratio at high temperature is almost the same as that at low temperature. Equilibrium releasing ratios of the three gels are significantly different from each other for salicylic acid when the temperature is below LCST while the equilibrium releasing ratios of the three gels are all 100% for sodium salicylate.

  7. Differential sensitivity of RIP3-proficient anddeficient murine fibroblasts to camptothecinanticancer drugs

    Institute of Scientific and Technical Information of China (English)

    Jin-xue HE; Bing YU; Guang CHEN; Ze-hong MIAO; Ying-qing WANG; Jian-ming FENG; Jia-xin LI; Lei XU; Xiao-hua LI; Wei WANG; Xia-juan HUAN; YiJIANG

    2012-01-01

    Dear Edltor,Receptor-interacting protein 3 (RIP3) is a serine/threonine protein kinase,which has extensive substrates including its cognate kinase RIP1 and multiple metabolic enzymes involv-ing oxidative phosphorylation[1,2].RIP3 has been shown to be essential for development,immunity and some physiological or pathophysiological responses to exogenous and endoge-nous stimuli[3-5].In 2009,three groups independently reported that RIP3 acted as a molecular switch between apoptosis and necrosis (also called as necroptosis)[6-8].Specifically,RIP3could turn tumor necrosis factor (TNF)-induced cell death from apoptosis to necrosis[6].Most of small-molecule antican-cer drugs elicit their anticancer effects via apoptotic induc-tion[9].However,it is unclear whether RIP3 affects the cellular sensitivity to small-molecule anticancer drugs.

  8. [Insulin sensitizer--anti-diabetic drugs, metformin and pioglitazone that can improve insulin resistance].

    Science.gov (United States)

    Korenaga, Masaaki; Kawaguchi, Koutaro; Korenaga, Keiko; Uchida, Kouichi; Sakaida, Iso

    2006-06-01

    Nonalcoholic steatohepatitis (NASH), which is considered the hepatic manifestation of the metabolic syndrome is an increasingly cause of chronic liver disease in Japan. NASH is finally lead to liver cirrhosis and hepatocellular carcinoma as viral hepatitis, therefore, medical treatment should be considered, when NASH occurs. Treatment of patients with metabolic syndrome has been focused on the management of associated conditions such as obesity, hyperlipidemia, hypertension and hyperinsulinemia. Insulin resistance, that could accelerate liver inflammation and fibrosis by up-regulation of TNFa seems to be most important factor in many cases of NASH. The insulin-sensitizing drugs, which were biguanides (metformin) and thiazolidinediones (pioglitazone) have been shown to correct not only insulin resistance but also steatosis and inflammation in the liver. Metformin and pioglitazone might be useful drugs against NASH, however further investigations were needed.

  9. Adenovirus replication as an in vitro probe for drug sensitivity in human tumors.

    Science.gov (United States)

    Parsons, P G; Maynard, K R; Little, J H; McLeod, G R

    1986-04-01

    The feasibility of using adenovirus 5 as an in vitro probe for chemosensitivity in short-term cultures of human tumors was evaluated using human melanoma cell lines and primary cultures of melanoma biopsies. A convenient immunoperoxidase method was developed for quantitating viral replication 2 days after infection. Two different approaches were explored: the host cell reactivation assay (HCR) using drug-treated virus; and the viral capacity assay using drug-treated cells. The HCR assay detected sensitivity to 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) in Mer- (methyl excision repair deficient) cell lines as decreased ability of the cells to replicate MTIC-treated virus. This test should be applicable to DNA-damaging agents and repair-deficient tumors. Adenovirus replicated readily in nonproliferating primary cultures of melanoma biopsies; application of the HCR assays to this material identified one Mer- sample of 11 tested. Herpes viruses were not suitable for use in HCR because herpes simplex virus type 1 failed to distinguish Mer- from Mer+ melanoma cells; and nonproductive infection of MTIC-sensitive lymphoid cells with Epstein-Barr virus yielded an MTIC-resistant cell line. The second assay (viral capacity) involved determination of the inhibition of replication of untreated virus in treated cells. This approach correctly predicted sensitivity to hydroxyurea and deoxyadenosine in melanoma cell lines when compared with clonogenic survival assay. Viral capacity was also inhibited by cytosine arabinoside, fluorouracil, vincristine, adriamycin, 6-mercaptopurine and ionising radiation, and may therefore be useful for detecting sensitivity to a wide range of antitumor agents.

  10. Microfluidic conceived pH sensitive core-shell particles for dual drug delivery.

    Science.gov (United States)

    Khan, Ikram Ullah; Stolch, Lukas; Serra, Christophe A; Anton, Nicolas; Akasov, Roman; Vandamme, Thierry F

    2015-01-15

    In current study, we report on the synthesis of core-shell microparticles for dual drug delivery by means of a two co-axial microfluidic device and online UV assisted free radical polymerization. Before developing pH-sensitive particles, ketoprofen loaded poly(methyl acrylate) core-ranitidine HCl loaded poly(acrylamide) shell particles were produced. Influence of inner and outer phases flow rates on particle size, shape, core diameter, shell thickness, and drug release properties was studied. All the particles were monodispersed with coefficient of variation below 5%. Furthermore, their diameter ranged from 100 to 151 μm by increasing continuous (Qc) to middle (Qm) phase flow rate ratio (Qc/Qm). Core diameter varied from 58 to 115 μm by decreasing middle (Qm) to inner (Qi) phase flow rate ratio (Qm/Qi) at constant continuous phase flow rate as confirmed by SEM images. It was observed that an optimum concentration of acrylamide (30 wt%) and an appropriate combination of surfactants were necessary to get core-shell particles otherwise Janus structure was obtained. FTIR confirmed the complete polymerization of core and shell phases. MTT assay showed variation in viability of cells under non-contact and contact conditions with less cytotoxicity for the former. Under non-contact conditions LD50 was 3.1mg/mL. Release studies in USP phosphate buffer solution showed simultaneously release of ketoprofen and ranitidine HCl for non pH-sensitive particles. However, release rates of ranitidine HCl and ketoprofen were higher at low and high pH respectively. To develop pH-sensitive particles for colon targeting, the previous shell phase was admixed with few weight percentage of pH sensitive carboxyethyl acrylate monomer. Core and shell contained the same hydrophobic and hydrophilic model drugs as in previous case. The pH-sensitive shell prevented the release of the two entrapped molecules at low pH while increasing significantly their release rate at higher pH with a maximum

  11. Codelivery of antitumor drug and gene by a pH-sensitive charge-conversion system.

    Science.gov (United States)

    Guan, Xiuwen; Li, Yanhui; Jiao, Zixue; Lin, Lin; Chen, Jie; Guo, Zhaopei; Tian, Huayu; Chen, Xuesi

    2015-02-11

    In the present study, a gene and drug codelivery system was developed by electrostatic binding of polyethylenimine-poly(l-lysine)-poly(l-glutamic acid) (PELG), polyethylenimine (PEI), cis-aconityl-doxorubicin (CAD), and DNA. Zeta potential and drug release analysis confirmed the pH-responsive charge conversion and acid-sensitive drug release functional properties of the PELG/PEI/(DNA+CAD) system. Gel retardation assay and transfection experiment showed the codelivery system had effective DNA binding ability and good transfection efficiency on HepG2 cells. The therapeutic gene p53 was further employed to study its combinational effects with CAD. Cytotoxicity assay showed the half inhibitory concentration (IC50) of the PELG/PEI/(p53+CAD) codelivery system was lower than that of the gene or the drug delivery system. Confocal laser scanning microscopy (CLSM) showed that the drug and gene could be delivered into the cells simultaneously. A significant increase of p53 gene expression was achieved after HepG2 cells treated by PELG/PEI/(p53+CAD) codelivery system. The apoptosis experiment indicated clearly that the codelivery system could lead an effective apoptosis on tumor cells, which was beneficial for the treatment of cancer. The biodistribution and tumor accumulation of the codelivery system was explored via in vivo imaging in subcutaneous xenograft and in situ tumor models. The tumor and some major organs were excised and imaged, and the results showed that the codelivery system can accumulate efficiently in tumor for both tumor models. It can be suggested from the above results that the PELG/PEI/(DNA+CAD) codelivery system will have great potential applications in cancer therapy.

  12. Sensitivity of a ribavirin resistant mutant of hepatitis C virus to other antiviral drugs.

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    Kathleen B Mihalik

    Full Text Available BACKGROUND: While ribavirin mono-therapy regimens have minimal effect on patients with chronic hepatitis C virus (HCV infections, they can be efficacious when combined with interferon. Clinical studies show that interferon-free combination therapies containing ribavirin are also efficacious, suggesting that an interferon-free therapy could be adopted in the near future. However, generation of drug resistant mutants and cross resistance to other drugs could impair the efficacy of the treatment. Therefore, understanding the mechanism of HCV resistance to ribavirin and cross resistance to other antiviral drugs could be of major importance. METHODS: We tested the ability of a J6/JFH1 derived HCV ribavirin resistant mutant to grow in tissue cultured Huh7D cells in the presence of the mutagen 5-Fluorouracil and the nucleoside analog 2'-C-Methylcytidine. Virus replication was assessed by detecting HCV antigens by immunofluorescence and by titrating virus present in the supernatants. Recovered viruses were amplified by RT-PCR and sequenced. RESULTS: The sensitivity of HCV-RR relative to parental J6/JFH1 to the tested drugs varied. HCV-RR was more resistant than J6/JFH1 to 5-Fluorouracil but was not more resistant than J6/JFH1 to 2'-C-Methylcytidine. Growth of HCV-RR in 5-Fluorouracil allowed the selection of an HCV-RR derived mutant resistant to 5-Fluorouracil (HCV-5FU. HCV-5FU grows to moderate levels in the presence of high concentrations of 5-Fluorouracil and to parental levels in the absence of the drug. Sequence of its genome shows that HCV-5FU accumulated multiple synonymous and non-synonymous mutations. CONCLUSIONS: These results indicate that determinants of resistance to ribavirin could also confer resistance to other anti-HCV drugs, shedding light toward understanding the mechanism of action of ribavirin and highlighting the importance of combination drug selection for HCV treatment. The results also show that it is possible to select a 5

  13. Sensitivity of drug-resistant mutants of hepatitis B virus to poly-IC.

    Science.gov (United States)

    Zhou, Q; Chen, E; Chen, L; Nong, Y; Cheng, X; He, M; Tang, H

    2014-01-01

    The long-term benefits of antiviral treatment are limited by the resistance of hepatitis B virus (HBV). However, the effect of interferon (IFN)α treatment on drug-resistant HBVs is so far unknown. We, therefore, investigated the effects of IFN-α inducer poly-IC on the replication of HBV mutants resistant to drugs such as lamivudine (LAM), adefovir dipivoxil (ADV) and entecavir (ETV) in mice. HBV DNA and HBV DNA intermediate (RI) were employed as markers of the virus replication and 2',5'-oligoadenylate synthase (OAS) mRNA as a marker of IFN-α/β induction. Poly-IC inhibited wtHBV replication and increased levels of OAS mRNA. Compared to the wt virus, the capacity of virus replication was reduced in most LAMr and ETVr mutants except those with mutations rtM(204V+L180M+V173L), and was similary in the ADVr mutants except rt(A121V+N236T). The virus replication was reduced after poly-IC treatment with LAMr and ADVr mutants similary to the wt virus. In contrast, ETVr mutants were resistant to the poly-IC treatment. In conclusion, the capacity of HBV replication and the sensitivity to IFN therapy are influenced by drug-resistant mutations. The IFN therapy may effectively inhibit HBV replication in particular in patients with LAMr or ADVr mutations but not in patients with ETVr mutations.

  14. Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells.

    Directory of Open Access Journals (Sweden)

    Ayako Nakano

    Full Text Available Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2, KG-1 (ABCB1 and HepG2 cells (ABCB1 and ABCG2. Interestingly, although side population (SP cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.

  15. A system for determining the pharmacology of indirect radiation sensitizer drugs on multicellular spheroids

    Energy Technology Data Exchange (ETDEWEB)

    Kaufman, N.; Bicher, H.I.; Hetzel, F.W.; Brown, M.

    1981-01-01

    We have characterized some of the physiology of multicellular spheroids of different sizes grown from Chinese hamster lung fibroblast (V79) cells. Among the parameters studied were oxygen tension distributions within the spheroid. This was achieved using ultramicroelectrodes with tip diameters of 1-5 mu and a perfusion system whereby environmental conditions such as flow, temperature, and chemical makeup of the milieu could be measured and controlled. Plateau pO/sup 2/ values of less than 10 mm Hg were consistently obtained from spheroids under various conditions. We were able to modify these distributions by use of indirect radiation sensitizer drugs such as mechlorethamine HCl (mustargen) at nontoxic doses. We have also made determinations of the inhibitory capacities of several other drugs on the respiration rate of constituent cells of multicellular spheroids in single-cell suspensions. We have concluded that there are indeed hypoxic cells in spheroids whose radioresistance may be modified by essentially nontoxic levels of indirect radiosensitizer drugs and that the system described shows great promise for screening agents which may modify radiation response.

  16. Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

    Science.gov (United States)

    Courtney, Colleen; Chatterjee, Anushree

    2014-03-01

    ``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

  17. The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity.

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    Shiau-Mei Chen

    Full Text Available MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124 participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs. We then examined which DNA repair-related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair-related genes, encoding ATM interactor (ATMIN and poly (ADP-ribose polymerase 1 (PARP1, were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.

  18. Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy.

    Directory of Open Access Journals (Sweden)

    Zai-Fa Hong

    Full Text Available Cholangiocarcinoma (CCA, a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K/protein kinase B (AKT/mammalian target of rapamycin (mTOR pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.

  19. PPO/PEO modified hollow fiber membranes improved sensitivity of 3D cultured hepatocytes to drug toxicity via suppressing drug adsorption on membranes.

    Science.gov (United States)

    Shen, Chong; Meng, Qin; He, Wenjuan; Wang, Qichen; Zhang, Guoliang

    2014-11-01

    The three dimensional (3D) cell culture in polymer-based micro system has become a useful tool for in vitro drug discovery. Among those polymers, polysulfone hollow fiber membrane (PSf HFM) is commonly used to create a microenvironment for cells. However, the target drug may adsorb on the polymeric surface, and this elicits negative impacts on cell exposure due to the reduced effective drug concentration in culture medium. In order to reduce the drug adsorption, PSf membrane were modified with hydrophilic Pluronic (PEO-b-PPO-b-PEO) copolymers, L121, P123 and F127 (PEO contents increase from 10%, 30% to 70%), by physical adsorption. As a result, the hydrophilicity of HFMs increased at an order of PSfF127>P123>L121 HFMs. The three modified membrane all showed significant resistance to adsorption of acid/neutral drugs. More importantly, the adsorption of base drugs were largely reduced to an average value of 11% on the L121 HFM. The improved resistance to drug adsorption could be attributed to the synergy of hydrophobic/neutrally charged PPO and hydrophilic PEO. The L121 HFM was further assessed by evaluating the drug hepatotoxicity in 3D culture of hepatocytes. The base drugs, clozapine and doxorubicin, showed more sensitive hepatotoxicity on hepatocytes in L121 HFM than in PSf HFM, while the acid drug, salicylic acid, showed the similar hepatotoxicity to hepatocytes in both HFMs. Our finding suggests that PSf HFM modified by PEO-b-PPO-b-PEO copolymers can efficiently resist the drug adsorption onto polymer membrane, and consequently improve the accuracy and sensitivity of in vitro hepatotoxic drug screening.

  20. Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery.

    Science.gov (United States)

    Du, Jin-Zhi; Du, Xiao-Jiao; Mao, Cheng-Qiong; Wang, Jun

    2011-11-09

    Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. Herein, we have designed a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system to overcome the challenges. The nanoparticle is capable of reversing its surface charge from negative to positive at tumor extracellular pH (∼6.8) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (∼5.0) further promotes doxorubicin release from the endocytosed drug carriers. This dual pH-sensitive nanoparticle has showed enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy.

  1. A dual drug sensitive L. major induces protection without lesion in C57BL/6 mice.

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    Noushin Davoudi

    Full Text Available Leishmaniasis is a major health problem in some endemic areas and yet, no vaccine is available against any form of the disease. Historically, leishmanization (LZ which is an inoculation of individual with live Leishmania, is the most effective control measure at least against cutaneous leishmaniasis (CL. Due to various reasons, LZ is not used today. Several live attenuated Leishmania have been developed but their use is limited. Previously, we developed a transgenic strain of L. major that harbors two suicide genes tk and cd genes (lmtkcd+/+ for use as a challenge strain in vaccine studies. These genes render the parasite susceptible to Ganciclovir (GCV and 5-flurocytosine (5-FC. The dual drug sensitive strain of L. major was developed using gene targeting technology using a modified Herpes Simplex Virus thymidine kinase gene (hsv-tk sensitive to Ganciclovir antibiotic and Saccharomyces cerevisae cytosine deaminase gene (cd sensitive to 5-flurocytosine that were stably introduced into L. major chromosome. BALB/c mice inoculated with lmtkcd+/+ developed lesions which upon treatment with GCV and 5-FC completely healed. In the current study, the transgenic lmtkcd+/+strain was assessed as a live vaccine model to determine the time necessary to develop a protective immune response. C57BL/6 mice were inoculated with the transgenic lmtkcd+/+strain, and treated at the time of inoculation (day 0 or at day 8 after inoculation. Immunized animals were challenged with wild-type L. major, and complete protection was induced in mice that were treated at day 8. The results show that in contrast to leishmanization, in group of mice inoculated with a dual sensitive L. major development and persistence of lesion is not necessary to induce Th1 response and protection.

  2. Sense and sensitivity: physical limits to multicellular sensing and drug response

    CERN Document Server

    Varennes, Julien

    2015-01-01

    Metastasis is a process of cell migration that can be collective and guided by chemical cues. Viewing metastasis in this way, as a physical phenomenon, allows one to draw upon insights from other studies of collective sensing and migration in cell biology. Here we review recent progress in the study of cell sensing and migration as collective phenomena, including in the context of metastatic cells. We describe simple physical models of sensing and migration, and we survey the experimental evidence that cells operate near the purely physical limits to their behavior. We conclude by contrasting cells' sensory abilities with their sensitivity to drugs, and suggesting potential alternatives to cell-death-based cancer therapies.

  3. SynLethDB: synthetic lethality database toward discovery of selective and sensitive anticancer drug targets.

    Science.gov (United States)

    Guo, Jing; Liu, Hui; Zheng, Jie

    2016-01-04

    Synthetic lethality (SL) is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of either gene alone is not lethal. SL reflects the biologically endogenous difference between cancer cells and normal cells, and thus the inhibition of SL partners of genes with cancer-specific mutations could selectively kill cancer cells but spare normal cells. Therefore, SL is emerging as a promising anticancer strategy that could potentially overcome the drawbacks of traditional chemotherapies by reducing severe side effects. Researchers have developed experimental technologies and computational prediction methods to identify SL gene pairs on human and a few model species. However, there has not been a comprehensive database dedicated to collecting SL pairs and related knowledge. In this paper, we propose a comprehensive database, SynLethDB (http://histone.sce.ntu.edu.sg/SynLethDB/), which contains SL pairs collected from biochemical assays, other related databases, computational predictions and text mining results on human and four model species, i.e. mouse, fruit fly, worm and yeast. For each SL pair, a confidence score was calculated by integrating individual scores derived from different evidence sources. We also developed a statistical analysis module to estimate the druggability and sensitivity of cancer cells upon drug treatments targeting human SL partners, based on large-scale genomic data, gene expression profiles and drug sensitivity profiles on more than 1000 cancer cell lines. To help users access and mine the wealth of the data, we developed other practical functionalities, such as search and filtering, orthology search, gene set enrichment analysis. Furthermore, a user-friendly web interface has been implemented to facilitate data analysis and interpretation. With the integrated data sets and analytics functionalities, SynLethDB would

  4. Microflora of conjunctiva in children and its sensitivity and resistance to antibacterial drugs

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    T. N. Vorontsova

    2012-01-01

    Full Text Available Purpose: Investigation of microflora of conjunctiva and its resistance to antibacterial drugs in healthy children and patients with various inflammatory eye diseases.Methods: We examined 402 children (421 eyes in the age from 1 month till 17 years: 62 healthy children (70 eyes and 340 pa- tients with different inflammatory diseases of anterior segment of eye (351 eyes. the smear was done in all children for plating and definition of sensitivity of microflora to antibacterial drugs by method of diffusion to agar.Results: the plating was positive even in 72.9% of healthy children who entered the hospital for the planned surgery. Most often we revealed Staphylococcus epidermidis (44.3%, Staphylococcus aureus (12.8%, Streptococcus faecalis (5.7% and Enterobacter (2.9%. In children with inflammatory diseases Staphylococcus epidermidis and Staphylococcus aureus (62.6% were found fre- quently. the analysis of data showed high level of resistance of all microflora to aminoglycosides (neomycin 37.8% and tobramycin 32.7% and chloramphenicol — 37.1%. the lowest resistance of all microflora was registered to levofloxacin (11.1% and ciprofloxacin (10.5%. In gram-negative microflora we revealed the maximal sensitivity to ciprofloxacin, in gram-positive — to levofloxacin.We detected the maximal resistance of microflora to ampicillin (66.1%, and minimal — to cephalosporines (4.5% among the antibiotics of systemic application.Conclusion: the findings allow us to recommend drops containing levofloxacin (Signicef for clinical practice in pediatric ophthalmology. 

  5. Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs.

    Science.gov (United States)

    Mei, H; Sun, S; Bai, Y; Chen, Y; Chai, R; Li, H

    2015-04-02

    Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors.

  6. Studies on psychomotoric effects and pharmacokinetic interactions of the new calcium sensitizing drug levosimendan and ethanol.

    Science.gov (United States)

    Antila, S; Järvinen, A; Akkila, J; Honkanen, T; Karlsson, M; Lehtonen, L

    1997-07-01

    Levosimendan (CAS 141505-33-1) is a calcium sensitizing drug intended for the treatment of congestive heart failure. In animal experiments levosimendan has potentiated the sedative effects of ethanol. Due to poor water solubility of the compound, ethanol is used as a diluent in the intravenous formulation. In this study the possible interactions between levosimendan and ethanol in human have been studied. Twelve healthy male volunteers were included in this double-blind, randomized, cross-over study. The study consisted of three treatment periods: levosimendan 1 mg intravenously, levosimendan combined with ethanol orally and ethanol 0.8 g/kg alone. Blood samples for determination of levosimendan and ethanol concentrations were collected for 8 h after the dosing. To observe possible pharmacodynamic interactions psychomotoric tests were made before drug administration and 1h, 2h, 3h and 6h thereafter. These tests included Digit symbol substitution test, Maddox wing, Critical Flicker fusion and VAS-test for subjective assessment of performance status. Plasma levosimendan concentrations were not changed by the concomitant ethanol administration. Ethanol did not alter the pharmacokinetics of levosimendan except the volume of distribution of central compartment which was decreased. Levosimendan did neither affect elimination of ethanol. Levosimendan did not potentiate the psychomotoric effects of ethanol neither did it have any psychomotoric effects itself. In conclusion, levosimendan is not likely to have any psychomotoric adverse effects or any clinically significant interactions with ethanol.

  7. Development of pH-sensitive pectinate/alginate microspheres for colon drug delivery.

    Science.gov (United States)

    Hsu, Fu-Yin; Yu, Ding-Syuan; Huang, Chun-Chiang

    2013-02-01

    The purposes of this study were to develop and evaluate calcium pectinate/alginate microspheres (PAMs) and to exploit their pH-sensitive properties for colon-targeted delivery of encapsulated cisplatin. PAMs were prepared using an electrospraying method. The PAMs, as cores, were then coated with Eudragit S100 using a polyelectrolyte multilayer coating technique in aqueous solution. The morphology of the microspheres was observed under scanning electron microscopy. In vitro drug release studies were performed in simulated gastrointestinal fluid, and the results indicated that approximately 5 % of the cisplatin was released from the Eudragit S100-coated PAMs, and 51 % of the cisplatin was released from the uncoated PAMs at 1 h. The release of cisplatin from the Eudragit S100-coated PAMs was more sustained in simulated gastric fluid than in simulated intestinal fluid due to the increased solubility of the coating polymer in media with pH >7.0. Drug release from the Eudragit S100-coated PAMs was best described by the Higuchi's square root model. From these results, it was concluded that Eudragit S100-coated PAMs are a potential carrier for delivery of cisplatin to the colon.

  8. Simple and sensitive method for monitoring drug-induced cell injury in cultured cells

    Energy Technology Data Exchange (ETDEWEB)

    Shirhatti, V.; Krishna, G.

    1985-06-01

    A simple, sensitive method has been developed for evaluating cell injury noninvasively in monolayer cells in culture. The cell ATP pool was radiolabeled by incubating the cells with (/sup 14/C)adenine. The uptake and incorporation of (/sup 14/C)adenine was shown to proportional to the number of cells. As determined by HPLC, about 65-70% of the incorporated /sup 14/C label was in the ATP pool, 15-20% was in the ADP pool, and the rest was in the 5'-AMP pool. When prelabeled cells were exposed to toxic drugs (acetaminophen, calcium ionophore A-23187, or daunomycin) there was a marked decrease in cell ATP with a concomitant increase in leakage of labeled nucleotides, mainly 5'-AMP and 5'IMP. The authors have shown that leakage of /sup 14/C label into the medium from the prelabeled cells may be employed for quantitation of cell injury. This new measure of toxicity was shown to correlate very well with LDH leakage from the cells, which is a well accepted measure of cell injury. The leakage of 5'-(/sup 14/C)AMP also correlated very well with the reduction of cell ATP in cardiac myocytes. This method has been used for monitoring drug-induced toxicity in liver cells, cardiac myocytes, and LB cells.

  9. Hollow fiber based quantum cascade laser spectrometer for fast and sensitive drug identification

    Science.gov (United States)

    Herbst, J.; Scherer, B.; Ruf, A.; Erb, J.; Lambrecht, A.

    2012-01-01

    Sensitive and fast identification of drugs or drug precursors is important and necessary in scenarios like baggage or container check by customs or police. Fraunhofer IPM is developing a laser spectrometer using external cavity quantum cascade lasers (EC-QCL) to obtain mid-infrared (IR) absorption spectra in the wavelength range of the specific vibrational bands of amphetamines and their precursors. The commercial EC-QCL covers a tuning range of about 225 cm-1 within 1.4 s. The system could be used for different sample types like bulk samples or liquid solutions. A sampling unit evaporates the sample. Because of small sample amounts a 3 m long hollow fiber with an inner volume smaller than 1ml is used as gas cell and wave guide for the laser beam. This setup is suitable as a detector of a gas chromatograph instead of a standard detector (TCD or FID). The advantage is the selective identification of drugs by their IR spectra in addition to the retention time in the gas chromatographic column. In comparison to Fourier Transform IR systems the EC-QCL setup shows a good mechanical robustness and has the advantage of a point light source. Because of the good fiber incoupling performance of the EC-QCL it is possible to use hollow fibers. So, a good absorption signal is achieved because of the long optical path in the small cell volume without significant dilution. In first laboratory experiments a detection limit in the microgram range for pseudo ephedrine is achieved.

  10. Highly sensitive quantitative imaging for monitoring single cancer cell growth kinetics and drug response.

    Directory of Open Access Journals (Sweden)

    Mustafa Mir

    Full Text Available The detection and treatment of cancer has advanced significantly in the past several decades, with important improvements in our understanding of the fundamental molecular and genetic basis of the disease. Despite these advancements, drug-screening methodologies have remained essentially unchanged since the introduction of the in vitro human cell line screen in 1990. Although the existing methods provide information on the overall effects of compounds on cell viability, they are restricted by bulk measurements, large sample sizes, and lack capability to measure proliferation kinetics at the individual cell level. To truly understand the nature of cancer cell proliferation and to develop personalized adjuvant therapies, there is a need for new methodologies that provide quantitative information to monitor the effect of drugs on cell growth as well as morphological and phenotypic changes at the single cell level. Here we show that a quantitative phase imaging modality known as spatial light interference microscopy (SLIM addresses these needs and provides additional advantages over existing proliferation assays. We demonstrate these capabilities through measurements on the effects of the hormone estradiol and the antiestrogen ICI182,780 (Faslodex on the growth of MCF-7 breast cancer cells. Along with providing information on changes in the overall growth, SLIM provides additional biologically relevant information. For example, we find that exposure to estradiol results in rapidly growing cells with lower dry mass than the control population. Subsequently blocking the estrogen receptor with ICI results in slower growing cells, with lower dry masses than the control. This ability to measure changes in growth kinetics in response to environmental conditions provides new insight on growth regulation mechanisms. Our results establish the capabilities of SLIM as an advanced drug screening technology that provides information on changes in proliferation

  11. Semiempirical Rules To Determine Drug Sensitivity and Ionization Efficiency in Secondary Ion Mass Spectrometry Using a Model Tissue Sample.

    Science.gov (United States)

    Vorng, Jean-Luc; Kotowska, Anna M; Passarelli, Melissa K; West, Andrew; Marshall, Peter S; Havelund, Rasmus; Seah, Martin P; Dollery, Colin T; Rakowska, Paulina D; Gilmore, Ian S

    2016-11-15

    There is an increasing need in the pharmaceutical industry to reduce drug failure at late stage and thus reduce the cost of developing a new medicine. Since most drug targets are intracellular, this requires a better understanding of the drug disposition within a cell. Secondary ion mass spectrometry has been identified as a potentially important technique to do this, as it is label-free and allows imaging in 3D with subcellular resolution and recent studies have shown promise for amiodarone. An important analytical parameter is sensitivity, and we measure this in a bovine liver homogenate reference sample for 20 drugs representing important class types relevant to the pharmaceutical industry. We also measure the sensitivity for pure drug and show, for the first time, that the secondary ion mass spectrometry (SIMS) positive ionization efficiency for small molecules is a simple power-law relationship to the log P value. This discovery will be important for advancing the understanding of the SIMS ionization process in small molecules that has, until now, been elusive. This simple relationship is found to hold true for drug doped in the bovine liver homogenate reference sample, except for fluticasone, nicardipine, and sorafenib which suffer from severe matrix suppression. This relationship provides a simple semiempirical method to determine drug sensitivity for positive secondary ions. Furthermore, we show, on chosen models, how the use of different solvents during sample preparation can affect the ionization of analytes.

  12. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Paula I. Moreira

    2009-12-01

    Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  13. The Role of More Sensitive Helminth Diagnostics in Mass Drug Administration Campaigns: Elimination and Health Impacts.

    Science.gov (United States)

    Medley, G F; Turner, H C; Baggaley, R F; Holland, C; Hollingsworth, T D

    2016-01-01

    Diagnostics play a crucial role in determining treatment protocols and evaluating success of mass drug administration (MDA) programmes used to control soil-transmitted helminths (STHs). The current diagnostic, Kato-Katz, relies on inexpensive, reusable materials and can be used in the field, but only trained microscopists can read slides. This diagnostic always underestimates the true prevalence of infection, and the accuracy worsens as the true prevalence falls. We investigate how more sensitive diagnostics would impact on the management and life cycle of MDA programmes, including number of mass treatment rounds, health impact, number of unnecessary treatments and probability of elimination. We use an individual-based model of STH transmission within the current World Health Organization (WHO) treatment guidelines which records individual disability-adjusted life years (DALY) lost. We focus on Ascaris lumbricoides due to the availability of high-quality data on existing diagnostics. We show that the effect of improving the sensitivity of diagnostics is principally determined by the precontrol prevalence in the community. Communities at low true prevalence (70%) do not benefit greatly from improved diagnostics. Communities with intermediate prevalence benefit greatly from increased chemotherapy application, both in terms of reduced DALY loss and increased probability of elimination. Our results suggest that programmes should be extended beyond school-age children, especially in high prevalence communities. Finally, we argue against using apparent or measured prevalence as an uncorrected proxy for true prevalence.

  14. Antiretroviral drug resistance mutations in the reverse transcriptase gene of HIV-1 isolates from Northern Indian patients: a follow-up study.

    Science.gov (United States)

    Dutta Choudhury, Shubhasree; Chaudhury, Alok K; Kalra, Rajesh; Andrabi, Raiees; Wig, Naveet; Biswas, Ashutosh; Bala, Manju; Luthra, Kalpana

    2010-04-01

    The viral reverse transcriptase gene was amplified from the plasma of 27 drug-naïve and five drug-experienced HIV patients in Northern India. Follow-up samples of naïve patients after antiretroviral therapy initiation were collected in six patients at 3 months and three patients at 6 months. Phylogenetic analysis revealed two new recombinant forms, CRF_CH and CRF_CK, and an accessory non-nucleoside reverse transcriptase inhibitor mutation E138A, not previously reported from India. The major DRMs found in two 6-month follow-up samples were absent in their baseline blood samples. This is the first follow-up study to determine anti-retroviral drug resistance mutations in Indian HIV patients.

  15. Novel multifunctional pH-sensitive nanoparticles loaded into microbubbles as drug delivery vehicles for enhanced tumor targeting.

    Science.gov (United States)

    Lv, Yongjiu; Hao, Lan; Hu, Wenjing; Ran, Ya; Bai, Yan; Zhang, Liangke

    2016-01-01

    This study fabricated novel multifunctional pH-sensitive nanoparticles loaded into microbubbles (PNP-MB) with the combined advantages of two excellent drug delivery vehicles, namely, pH-sensitive nanoparticles and microbubbles. As an antitumor drug, resveratrol (RES) was loaded into acetylated β-cyclodextrin nanoparticles (RES-PNP). The drug-loaded nanoparticles were then encapsulated into the internal space of the microbubbles. The characterization and morphology of this vehicle were investigated through dynamic light scattering and confocal laser scanning microscopy, respectively. In vitro drug release was performed to investigate the pH sensitivity of RES-PNP. The antitumor property of RES-loaded PNP-MB (RES-PNP-MB) was also analyzed in vivo to evaluate the antitumor effect of RES-PNP-MB. Results suggested that PNP exhibited pH sensitivity, and was successfully encapsulated into the microbubbles. RES-PNP-MB exhibit effective tumor growth suppressing in vivo. Therefore, such drug delivery vehicle should be of great attention in tumor therapy.

  16. Herceptin conjugated PLGA-PHis-PEG pH sensitive nanoparticles for targeted and controlled drug delivery.

    Science.gov (United States)

    Zhou, Zilan; Badkas, Apurva; Stevenson, Max; Lee, Joo-Youp; Leung, Yuet-Kin

    2015-06-20

    A dual functional nano-scaled drug carrier, comprising of a targeting ligand and pH sensitivity, has been made in order to increase the specificity and efficacy of the drug delivery system. The nanoparticles are made of a tri-block copolymer, poly(d,l lactide-co-glycolide) (PLGA)-b-poly(l-histidine) (PHis)-b-polyethylene glycol (PEG), via nano-precipitation. To provide the nanoparticle feature of endolysosomal escape and pH sensitivity, poly(l-histidine) was chosen as a proton sponge polymer. Herceptin, which specifically binds to HER2 antigen, was conjugated to the nanoparticles through click chemistry. The nanoparticles were characterized via dynamic light scattering (DLS) and transmission electron microscopy (TEM). Both methods showed the sizes of about 100nm with a uniform size distribution. The pH sensitivity was assessed by drug releases and size changes at different pH conditions. As pH decreased from 7.4 to 5.2, the drug release rate accelerated and the size significantly increased. During in vitro tests against human breast cancer cell lines, MCF-7 and SK-BR-3 showed significantly increased uptake for Herceptin-conjugated nanoparticles, as compared to non-targeted nanoparticles. Herceptin-conjugated pH-sensitive nanoparticles showed the highest therapeutic effect, and thus validated the efficacy of a combined approach of pH sensitivity and active targeting.

  17. Therapeutic drug monitoring of indinavir and nelfinavir to assess adherence to therapy in human immunodeficiency virus-infected children

    NARCIS (Netherlands)

    Van Rossum, AMC; Bergshoeff, AS; Fraaij, PLA; Hugen, PWH; Hartwig, NG; Geelen, SPM; Wolfs, TFW; Weemaes, CMR; De Groot, R; Burger, DM

    2002-01-01

    Introduction. Adherence to highly active anti-retroviral therapy is required to obtain an optimal long term virologic response rate of HIV-1-infected children. Plasma concentrations of protease inhibitors (PIs) outside the limits of the reference values indicate nonadherence to anti-retroviral thera

  18. Haemophilus paragallinarum in chickens in Indonesia: III. Antimicrobial drug sensitivity test ofHaemophilus paragallinarum from chickens suffering of coryza

    OpenAIRE

    1998-01-01

    An agar disc diffusion method was used to examine the sensitivity of 27 Haemophilus paragallinarum (Hpg) isolates consisted of 23 local isolates, 4 standard isolates (serotype A) and Escherichia coli ATCC 24922 as a control to eight antimicrobial drugs (ampicillin, erythromycin, oxytetracycline, doxycycline, neomycin, streptomycin, colistine and sulphanlethoxazole-trimethoprim) . Twenty one out of 23 local isolates of Hpg were sensitive to doxycycline, 19 isolates to ampsllin, 18 isolates to ...

  19. Functional Study of the P32T ITPA Variant Associated with Drug Sensitivity in Humans

    Science.gov (United States)

    Stepchenkova, Elena I.; Tarakhovskaya, Elena R.; Spitler, Kathryn; Frahm, Christin; Menezes, Miriam R.; Simone, Peter D.; Kolar, Carol; Marky, Luis A.; Borgstahl, Gloria E. O.; Pavlov, Youri I.

    2009-01-01

    Sanitization of the cellular nucleotide pools from mutagenic base analogs is necessary for the accuracy of transcription and replication of genetic material and plays a substantial role in cancer prevention. The undesirable mutagenic, recombinogenic and toxic incorporation of purine base analogs (i.e. ITP, dITP, XTP, dXTP or 6-hydroxyaminopurine (HAP) deoxynucleoside triphosphate) into nucleic acids is prevented by inosine triphosphate pyrophosphatase (ITPA). The ITPA gene is a highly conserved, moderately expressed gene. Defects in ITPA orthologs in model organisms cause severe sensitivity to HAP and chromosome fragmentation. A human polymorphic allele 94C->A encodes for the enzyme with a P32T amino acid change and leads to accumulation of non-hydrolyzed ITP. ITPase activity is not detected in erythrocytes of these patients. The P32T polymorphism has also been associated with adverse sensitivity to purine base analog drugs. We have found that the ITPA-P32T mutant is a dimer in solution, as is wild-type ITPA, and has normal ITPA activity in vitro, but the melting point of ITPA-P32T is 5 degrees C lower than that of wild-type. ITPA-P32T is also fully functional in vivo in model organisms as determined by a HAP mutagenesis assay and its complementation of a bacterial ITPA defect. The amount of ITPA protein detected by western blot is severely diminished in a human fibroblast cell line with the 94C->A change. We propose that the P32T mutation exerts its effect in certain human tissues by cumulative effects of destabilization of transcripts, protein stability and availability. PMID:19631656

  20. Imipramine is an orally active drug against both antimony sensitive and resistant Leishmania donovani clinical isolates in experimental infection.

    Directory of Open Access Journals (Sweden)

    Sandip Mukherjee

    Full Text Available BACKGROUND: In an endeavor to find an orally active and affordable antileishmanial drug, we tested the efficacy of a cationic amphiphilic drug, imipramine, commonly used for the treatment of depression in humans. The only available orally active antileishmanial drug is miltefosine with long half life and teratogenic potential limits patient compliance. Thus there is a genuine need for an orally active antileishmanial drug. Previously it was shown that imipramine, a tricyclic antidepressant alters the protonmotive force in promastigotes, but its in vivo efficacy was not reported. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the drug is highly active against antimony sensitive and resistant Leishmania donovani in both promastigotes and intracellular amastigotes and in LD infected hamster model. The drug was found to decrease the mitochondrial transmembrane potential of Leishmania donovani (LD promastigotes and purified amastigotes after 8 h of treatment, whereas miltefosine effected only a marginal change even after 24 h. The drug restores defective antigen presenting ability of the parasitized macrophages. The status of the host protective factors TNF α, IFN γ and iNOS activity increased with the concomitant decrease in IL 10 and TGF β level in imipramine treated infected hamsters and evolution of matured sterile hepatic granuloma. The 10-day therapeutic window as a monotherapy, showing about 90% clearance of organ parasites in infected hamsters regardless of their SSG sensitivity. CONCLUSIONS: This study showed that imipramine possibly qualifies for a new use of an old drug and can be used as an effective orally active drug for the treatment of Kala-azar.

  1. Aerosol-Assisted Fast Formulating Uniform Pharmaceutical Polymer Microparticles with Variable Properties toward pH-Sensitive Controlled Drug Release

    Directory of Open Access Journals (Sweden)

    Hong Lei

    2016-05-01

    Full Text Available Microencapsulation is highly attractive for oral drug delivery. Microparticles are a common form of drug carrier for this purpose. There is still a high demand on efficient methods to fabricate microparticles with uniform sizes and well-controlled particle properties. In this paper, uniform hydroxypropyl methylcellulose phthalate (HPMCP-based pharmaceutical microparticles loaded with either hydrophobic or hydrophilic model drugs have been directly formulated by using a unique aerosol technique, i.e., the microfluidic spray drying technology. A series of microparticles of controllable particle sizes, shapes, and structures are fabricated by tuning the solvent composition and drying temperature. It is found that a more volatile solvent and a higher drying temperature can result in fast evaporation rates to form microparticles of larger lateral size, more irregular shape, and denser matrix. The nature of the model drugs also plays an important role in determining particle properties. The drug release behaviors of the pharmaceutical microparticles are dependent on their structural properties and the nature of a specific drug, as well as sensitive to the pH value of the release medium. Most importantly, drugs in the microparticles obtained by using a more volatile solvent or a higher drying temperature can be well protected from degradation in harsh simulated gastric fluids due to the dense structures of the microparticles, while they can be fast-released in simulated intestinal fluids through particle dissolution. These pharmaceutical microparticles are potentially useful for site-specific (enteric delivery of orally-administered drugs.

  2. Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data

    Science.gov (United States)

    Nguyen, Linh; Dang, Cuong C; Ballester, Pedro J.

    2017-01-01

    Background: Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets, such as those by Genomics of Drug Sensitivity in Cancer (GDSC) consortium, were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single-gene markers based on genomics data. Methods: Here we present this systematic comparison using Random Forest (RF) classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC 50 measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than standard k-fold cross-validation. Results and Discussion: Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug). Regarding overall classification performance, about two thirds of the drugs are better predicted by the multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG. Conclusions: Thanks to this unbiased validation, we now know that this type of models can predict in vitro tumour response to some of these drugs. These models

  3. Investigation of thermo-sensitive amphiphilic micelles as drug carriers for chemotherapy in cholangiocarcinoma in vitro and in vivo.

    Science.gov (United States)

    Wang, Xuefeng; Li, Songgang; Wan, Ziwei; Quan, Zhiwei; Tan, Qinggang

    2014-03-10

    Cholangiocarcinoma is an epithelial cancer of the bile ducts with poor prognosis and, in recent years, a rapidly increasing incidence. In this study, nano-sized thermo-sensitive micelles were investigated as drug carriers to improve chemotherapy in cholangiocarcinoma. Thermo-sensitive amphiphilic block copolymer, P-(N,N-isopropylacrylamide-co-N-hydroxymethylacrylamide)-b-caprolactone [P-(NIPAAm-co-NHMAAm)-b-PCL] with lower critical solution temperature (LCST) at about 38°C was synthesized. Doxorubicin (DOX)-loaded micelles were prepared by dialysis method. The micelles exhibited a sustained and temperature-dependent DOX release. Toxicity of the blank micelles for human cholangiocarcinoma (QBC939) cells was minimal both in vitro and in vivo. In contrast, the DOX-loaded micelles effectively inhibited proliferation and induced apoptosis of QBC939 cells in vitro (pthermo-sensitive amphiphilic micelles are a promising and effective drug carrier, and show potential for improving chemotherapy for cholangiocarcinoma.

  4. In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity.

    Science.gov (United States)

    Lucchi, Naomi W; Komino, Franklin; Okoth, Sheila Akinyi; Goldman, Ira; Onyona, Philip; Wiegand, Ryan E; Juma, Elizabeth; Shi, Ya Ping; Barnwell, John W; Udhayakumar, Venkatachalam; Kariuki, Simon

    2015-12-01

    Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.

  5. New amphiphilic glycopolypeptide conjugate capable of self-assembly in water into reduction-sensitive micelles for triggered drug release

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Hui-Kang [DSAPM Lab and PCFM Lab, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275 (China); Zhang, Li-Ming, E-mail: ceszhlm@mail.sysu.edu.cn [DSAPM Lab and PCFM Lab, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275 (China); Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006 (China)

    2014-08-01

    For the development of biomimetic carriers for stimuli-sensitive delivery of anticancer drugs, a novel amphiphilic glycopolypeptide conjugate containing the disulfide bond was prepared for the first time by the ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of (propargyl carbamate)ethyl dithio ethylamine and then click conjugation with α-azido dextran. Its structure was characterized by Fourier-transform infrared spectroscopy and nuclear magnetic resonance analyses. Owing to its amphiphilic nature, such a conjugate could self assemble into nanosize micelles in aqueous medium, as confirmed by fluorometry, transmission electron microscopy and dynamic light scattering. For the resultant micelles, it was found to encapsulate poorly water-soluble anticancer drug (methotrexate, MTX) with the loading efficiency of 45.2%. By the in vitro drug release tests, the release rate of encapsulated MTX was observed to be accelerated significantly in the presence of 10 mM 1,4-dithio-DL-threitol (DTT), analogous to the intracellular redox potential. - Graphical abstract: New amphiphilic glycopolypeptide conjugate containing the disulfide bond could self-assemble in aqueous solution into reduction-sensitive micelles for triggered release of an anticancer drug (methotrexate, MTX) in the presence of 10 mM 1,4-dithio-DL-threitol (DTT). - Highlights: • Amphiphilic glycopolypeptide conjugate containing disulfide bond was prepared. • Such a conjugate self assembled in aqueous solution into nanosize micelles. • The resultant micelles could encapsulate effectively methotrexate drug. • The drug-loaded micelles showed a reduction-sensitive drug release behavior.

  6. Successful analysis of anticancer drug sensitivity by CD-DST using pleural fluid and ascites from patients with advanced ovarian cancer: case reports.

    Science.gov (United States)

    Kawaguchi, Makiko; Banno, Kouji; Susumu, Nobuyuki; Yanokura, Megumi; Kuwabara, Yoshiko; Hirao, Nobumaru; Tsukazaki, Katsumi; Nozawa, Shiro

    2005-01-01

    In vitro anticancer drug sensitivity tests have been performed for various types of cancers, and a relationship with clinical response has been observed. The collagen gel droplet-embedded culture drug sensitivity test (CD-DST) is a new in vitro anticancer drug sensitivity test by Yabushita et al., recently reported to be useful in ovarian cancer. CD-DST allows analysis of a small number of cells, compared to other anticancer drug sensitivity tests. Here, we report a successful analysis of anticancer drug sensitivity by CD-DST using cancerous ascites and pleural fluid samples from 2 patients with advanced ovarian cancer. To our knowledge, this is only the second report of the application of CD-DST in ovarian cancer, and our results suggest that CD-DST could be helpful in the selection of anticancer drugs for neoadjuvant chemotherapy in advanced ovarian cancer.

  7. Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development

    DEFF Research Database (Denmark)

    Imamovic, Lejla; Sommer, Morten

    2013-01-01

    New drug deployment strategies are imperative to address the problem of drug resistance, which is limiting the management of infectious diseases and cancers. We evolved resistance in Escherichia coli toward 23 drugs used clinically for treating bacterial infections and mapped the resulting...

  8. Temperature-sensitive polymer-coated magnetic nanoparticles as a potential drug delivery system for targeted therapy of thyroid cancer.

    Science.gov (United States)

    Koppolu, Bhanuprasanth; Bhavsar, Zarna; Wadajkar, Aniket S; Nattama, Sivaniarvindpriya; Rahimi, Maham; Nwariaku, Fiemu; Nguyen, Kytai T

    2012-12-01

    The objective of this work was to develop and investigate temperature-sensitive poly(N-isopropylacrylamide-acrylamide-allylamine)-coated iron oxide magnetic nanoparticles (TPMNPs) as possible targeted drug carriers for treatments of advanced thyroid cancer (ATC). These nanoparticles were prepared by free radical polymerization of monomers on the surface of silane-coupled iron oxide nanoparticles. In vitro studies demonstrated that TPMNPs were cytocompatible and effectively taken up by cancer cells in a dose-dependent manner. An external magnetic field significantly increased nanoparticle uptake, especially when cells were exposed to physiological flow conditions. Drug loading and release studies using doxorubicin confirmed the temperature-responsive release of drugs from nanoparticles. In addition, doxorubicin-loaded nanoparticles significantly killed ATC cells when compared to free doxorubicin. The in vitro results indicate that TPMNPs have potential as targeted and controlled drug carriers for thyroid cancer treatment.

  9. Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment.

    Science.gov (United States)

    Kosa, Peter; Ghazali, Danish; Tanigawa, Makoto; Barbour, Chris; Cortese, Irene; Kelley, William; Snyder, Blake; Ohayon, Joan; Fenton, Kaylan; Lehky, Tanya; Wu, Tianxia; Greenwood, Mark; Nair, Govind; Bielekova, Bibiana

    2016-01-01

    Therapeutic advance in progressive multiple sclerosis (MS) has been very slow. Based on the transformative role magnetic resonance imaging (MRI) contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for developing new treatments for progressive MS. The purpose of this study was to compare 58 prospectively acquired candidate outcomes in the real-world situation of progressive MS trials to select and validate the best-performing outcome. The 1-year pre-treatment period of adaptively designed IPPoMS (ClinicalTrials.gov #NCT00950248) and RIVITaLISe (ClinicalTrials.gov #NCT01212094) Phase II trials served to determine the primary outcome for the subsequent blinded treatment phase by comparing 8 clinical, 1 electrophysiological, 1 optical coherence tomography, 7 MRI volumetric, 9 quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over 1 year (Δ) in the predetermined analysis and seven out of these were validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratios (SNR) and recorded overlapping values between healthy subjects and MS patients with moderate-severe disability. Clinical measures correlated better, even though each reflects a somewhat different disability domain. Therefore, using machine-learning techniques, we developed a combinatorial weight-adjusted disability score (CombiWISE) that integrates four clinical scales: expanded disability status scale (EDSS), Scripps neurological rating scale, 25 foot walk and 9 hole peg test. CombiWISE outperformed all clinical scales (Δ = 9.10%; p = 0.0003) and all MRI outcomes. CombiWISE recorded no overlapping values between healthy subjects and disabled MS patients, had high SNR, and predicted changes in EDSS in a longitudinal assessment of 98 progressive MS

  10. Development of a sensitive outcome for economical drug screening for progressive multiple sclerosis treatment

    Directory of Open Access Journals (Sweden)

    Peter Kosa

    2016-08-01

    Full Text Available Therapeutic advance in progressive multiple sclerosis (MS has been very slow. Based on the transformative role magnetic resonance imaging (MRI contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for developing new treatments for progressive MS. The purpose of this study was to compare 58 prospectively-acquired candidate outcomes in the real-world situation of progressive MS trials, to select and validate the best-performing outcome.The one year pre-treatment period of adaptively-designed IPPoMS (ClinicalTrials.gov #NCT00950248 and RIVITaLISe (ClinicalTrials.gov #NCT01212094 Phase II trials served to determine the primary outcome for the subsequent blinded treatment phase by comparing eight clinical, one electrophysiological, one optical coherence tomography, seven MRI volumetric, nine quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over one year (Δ in the predetermined analysis and seven out of these were validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratios (SNR and recorded overlapping values between healthy subjects and MS patients with moderate-severe disability. Clinical measures correlated better, even though each reflects a somewhat different disability domain. Therefore, using machine-learning optimization, we developed a combinatorial weight-adjusted disability score (CombiWISE that integrates four clinical scales: expanded disability status scale (EDSS, Scripps neurological rating scale, 25 foot walk and nine hole peg test. CombiWISE outperformed all clinical scales (Δ=9.10%; p=0.0003 and all MRI outcomes. CombiWISE recorded no overlapping values between healthy subjects and disabled MS patients, had high SNR and predicted changes in EDSS in a longitudinal assessment of 98

  11. miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1.

    Science.gov (United States)

    Lu, Fei; Zhang, Jingru; Ji, Min; Li, Peng; Du, Yahui; Wang, Hongchun; Zang, Shaolei; Ma, Daoxin; Sun, Xiulian; Ji, Chunyan

    2014-07-01

    Multidrug resistance (MDR) remains the major cause of disease relapse and poor prognosis in adults with acute myeloid leukemia (AML). Emerging evidence shows that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to elucidate the mechanisms through which AML patients develop drug resistance. MicroRNAs have been shown to play an important role in regulating the chemotherapy resistance in AML. A detailed understanding of the mechanisms of microRNA that are clinically relevant in AML may enhance our ability to predict and overcome drug resistance. Here, we demonstrated, for the first time, that miR-181b was decreased significantly in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-181b increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents and promoted drug-induced apoptosis. Moreover, miR-181b inhibited HMGB1 and Mcl-1 expression by direct binding to their 3'-untranslated regions. In addition, HMGB1 was expressed at high levels in relapsed/refractory AML patients and suppression of HMGB1 via RNA interference sensitized multidrug-resistant leukemia cells to chemotherapy and induced apoptosis. In conclusion, these results provide a strong rationale for the development of miR-181b-based therapeutic strategies for the enhancement of efficacy in AML treatment.

  12. Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents.

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    Ryan J Mailloux

    Full Text Available Uncoupling protein-2 (UCP2 is known to suppress mitochondrial reactive oxygen species (ROS production and is employed by drug-resistant cancer cells to mitigate oxidative stress. Using the drug-sensitive HL-60 cells and the drug-resistant MX2 subline as model systems, we show that genipin, a UCP2 inhibitor, sensitizes drug-resistant cells to cytotoxic agents. Increased MX2 cell death was observed upon co-treatment with genipin and different doses of menadione, doxorubicin, and epirubicin. DCFH-DA fluorimetry revealed that the increase in MX2 cell death was accompanied by enhanced cellular ROS levels. The drug-induced increase in ROS was linked to genipin-mediated inhibition of mitochondrial proton leak. State 4 and resting cellular respiratory rates were higher in the MX2 cells in comparison to the HL-60 cells, and the increased respiration was readily suppressed by genipin in the MX2 cells. UCP2 accounted for a remarkable 37% of the resting cellular oxygen consumption indicating that the MX2 cells are functionally reliant on this protein. Higher amounts of UCP2 protein were detected in the MX2 versus the HL-60 mitochondria. The observed effects of genipin were absent in the HL-60 cells pointing to the selectivity of this natural product for drug-resistant cells. The specificity of genipin for UCP2 was confirmed using CHO cells stably expressing UCP2 in which genipin induced an ∼22% decrease in state 4 respiration. These effects were absent in empty vector CHO cells expressing no UCP2. Thus, the chemical inhibition of UCP2 with genipin sensitizes multidrug-resistant cancer cells to cytotoxic agents.

  13. Utilização de medicamentos por indivíduos HIV positivos: abordagem qualitativa Utilization of prescribed drugs by HIV infected individuals: qualitative approach

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    Francisco A. Acurcio

    1999-02-01

    Full Text Available OBJETIVO: Analisar, em sua dimensão qualitativa, a utilização de medicamentos por indivíduos infectados pelo HIV, durante o processo de procura e atendimento em serviços de saúde. MÉTODOS: Foram realizadas 52 entrevistas semi-estruturadas com pacientes, trabalhadores da saúde e voluntários de organizações não-governamentais, e revistos 1.079 prontuários médicos para obtenção de informações sobre a utilização de medicamentos por portadores do HIV, cuja primeira visita a um dos serviços públicos de referência estudados ocorreu entre janeiro de 1989 e dezembro de 1992. RESULTADOS: Os problemas relacionados à utilização de anti-retrovirais foram: recusa ao uso, dificuldade de obtenção e de cumprimento da prescrição. Outros problemas foram a auto-medicação, dificuldade de obter medicamentos para patologias associadas e de cumprimento da prescrição de sulfas. CONCLUSÕES: Os resultados permitiram compreender melhor os principais obstáculos e dificuldades vivenciados pelo usuário dos serviços, desde o ato da prescrição até a continuidade do tratamento.OBJECTIVE: The assessment, in its qualitative dimension, of the utilization - by HIV infected individuals - of selected prescribed drugs during the process of the search for and the obtaining of care in public health services in Belo Horizonte, Brazil. METHOD: Fifty two semi-structured interviews with patients, health care workers and non- governamental organizations volunteers were carried out and 1,079 medical records were reviewed. Data were obtained on the utilization of prescribed drugs by HIV infected individuals, whose first visit to one of the public services studied occurred between January 1989 and December 1992. Problems related to the use of anti-retroviral and/or opportunistic infection medication were identified and a qualitative description of their possible causes and consequences was commented on. RESULTS: Refusal to use, difficulty in obtaining and

  14. Haemophilus paragallinarum in chickens in Indonesia: III. Antimicrobial drug sensitivity test ofHaemophilus paragallinarum from chickens suffering of coryza

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    Sri Poernomo

    1998-12-01

    Full Text Available An agar disc diffusion method was used to examine the sensitivity of 27 Haemophilus paragallinarum (Hpg isolates consisted of 23 local isolates, 4 standard isolates (serotype A and Escherichia coli ATCC 24922 as a control to eight antimicrobial drugs (ampicillin, erythromycin, oxytetracycline, doxycycline, neomycin, streptomycin, colistine and sulphanlethoxazole-trimethoprim . Twenty one out of 23 local isolates of Hpg were sensitive to doxycycline, 19 isolates to ampsllin, 18 isolates to oxytetracycline, 17 isolates to sulphametoxazole-trimethoprim, 16 isolates to erythromycin, and 13 isolates to neomycin, while 13 isolates were resistance to colistine and 11 isolates were also resistance to streptomycin .

  15. Growth Hormone Receptor Knockdown Sensitizes Human Melanoma Cells to Chemotherapy by Attenuating Expression of ABC Drug Efflux Pumps.

    Science.gov (United States)

    Basu, Reetobrata; Baumgaertel, Nicholas; Wu, Shiyong; Kopchick, John J

    2017-03-14

    Melanoma remains one of the most therapy-resistant forms of human cancer despite recent introductions of highly efficacious targeted therapies. The intrinsic therapy resistance of human melanoma is largely due to abundant expression of a repertoire of xenobiotic efflux pumps of the ATP-binding cassette (ABC) transporter family. Here, we report that GH action is a key mediator of chemotherapeutic resistance in human melanoma cells. We investigated multiple ABC efflux pumps (ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, ABCG1, and ABCG2) reportedly associated with melanoma drug resistance in different human melanoma cells and tested the efficacy of five different anti-cancer compounds (cisplatin, doxorubicin, oridonin, paclitaxel, vemurafenib) with decreased GH action. We found that GH treatment of human melanoma cells upregulates expression of multiple ABC transporters and increases the EC50 of melanoma drug vemurafenib. Also, vemurafenib-resistant melanoma cells had upregulated levels of GH receptor (GHR) expression as well as ABC efflux pumps. GHR knockdown (KD) using siRNA in human melanoma cells treated with sub-EC50 doses of anti-tumor compounds resulted in significantly increased drug retention, decreased cell proliferation and increased drug efficacy, compared to mock-transfected controls. Our set of findings identify an unknown mechanism of GH regulation in mediating melanoma drug resistance and validates GHR as a unique therapeutic target for sensitizing highly therapy-resistant human melanoma cells to lower doses of anti-cancer drugs.

  16. In vitro sensitivities to antimicrobial drugs of ureaplasmas isolated from the bovine respiratory tract, genital tract and eye.

    Science.gov (United States)

    Kishima, M; Hashimoto, K

    1979-09-01

    The sensitivity to 18 antimicrobial drugs was examined for 66 strains of Ureaplasma sp isolated from respiratory tracts of calves suffering from enzootic pneumonia, urinary tracts of bulls and eyes of cows suffering from infectious bovine kerato-conjunctivitis. Furamizole, tiamulin fumarate, erythromycin lactobionate, malidomycin C, doxycycline hydrochloride, kitasamycin tartrate, tylosin tartrate, T-2636C, tetracycline hydrochloride, oxytetracycline hydrochloride, chlortetracycline hydrochloride, oleandomycin phosphate, furazolidone, spiramycin adipate, chloramphenicol and thiophenicol showed strong inhibiting activity on all the test strains. Among them, furamizole, tiamulin fumarate and erythromycin lactobionate were most active. Kanamycin sulphate showed weak activity on all the strains tested. The differences in origin of the test strains did not affect their sensitivity to any of the drugs.

  17. The absence of functional glucosylceramide synthase does not sensitize melanoma cells for anticancer drugs

    NARCIS (Netherlands)

    Veldman, RJ; Mita, A; Cuvillier, O; Garcia, [No Value; Klappe, K; Medin, JA; Campbell, JD; Carpentier, S; Kok, JW; Levade, T

    2003-01-01

    Conversion of ceramide, a putative mediator of anticancer drug-induced apoptosis, into glucosylceramide, by the action of glucosylceramide synthase (GCS), has been implicated in drug resistance. Herein, we compared GM95 mouse melanoma cells deficient in GCS activity, with cells stably transfected wi

  18. Rheology-sensitive response of zeolite-supported anti-inflammatory drug systems.

    Science.gov (United States)

    Pasquino, R; Di Domenico, M; Izzo, F; Gaudino, D; Vanzanella, V; Grizzuti, N; de Gennaro, B

    2016-10-01

    Drug release from inorganic supports is a challenge for the scientific community for various reasons, related to the low costs of the systems and the possibility of easily regulating the drug release. In the present work, surface-modified zeolite particles are used as carriers for non steroidal antiflammatory drugs (NSAIDs). The release of the drug has been studied in a solution that simulates the intestinal fluid as well as in a gel-like system, based on a surfactant and a binding salt. In the solution case, the quantity of drug released has been tracked via spectrophotometric assay. Release in the gel has been monitored by rheological methods. The molecular conformation of the NSAIDs is fundamental for the interaction with the zeolite surface, whose modified surface has a strong binding energy. It has been proven that the main mechanism for the drug release is anion exchange. It has been found that the NSAIDs, used in their sodic form, can act as binding salts by themselves in the gel-like system, thus changing the viscoelastic response of the overall solution. Drug release kinetics in the solution compare quantitatively well with the released drug in the gel-like fluid, as measured by rheometry.

  19. Apoptosis-related molecular differences for response to tyrosin kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells

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    Jixia Li

    2013-01-01

    Full Text Available Context: The epidermal growth factor receptor (EGFR family is reportedly overexpressed in bladder cancer, and tyrosine kinaseinhibitors (TKIs have been suggested as treatment. Gefitinib is a selective inhibitor of the EGFR and lapatinib is a dual inhibitor of both the EGFR and HER2 (human EGFR type 2 receptor. Both compounds compete with the binding of adenosine triphosphate (ATP to the tyrosine kinase domain of the respective receptors to inhibit receptor autophosphorylation causing suppression of signal transduction. Unfortunately, resistance to these inhibitors is a major clinical problem. Aims: To compare the apoptosis signaling pathway(s induced by gefitinib and lapatinib, in UM-UC-5 (drug-sensitive and UM-UC-14 (drug-resistant bladder cancer cells and to identify molecular differences that might be useful predictors of their efficacy. Materials and Methods: Cell proliferation, cell cycle and apoptosis assay were used to detect the effect of TKIs on UM-UC-5 and UM-UC-14 cells. Molecular differences for response to TKIs were examined by protein array. Results: TKIs strongly inhibited cell proliferation and induced cell cycle G1 arrest and apoptosis in UM-UC-5 cells. Most notable apoptosis molecular differences included decreased claspin, trail, and survivin by TKIs in the sensitive cells. In contrast, TKIs had no effect on resistant cells. Conclusions: Claspin, trail, and survivin might be used to determine the sensitivity of bladder cancers to TKIs.

  20. Characterization of drug release and diffusion mechanism through hydroxyethylmethacrylate/methacrylic acid pH-sensitive hydrogel.

    Science.gov (United States)

    Varshosaz, Jaleh; Hajian, Mahmood

    2004-01-01

    Hydroxyethylmethacrylate/methacrylic acid copolymer cross-linked with ethylenglycol dimethacrylate was prepared by a bulk free radical polymerization method. The permeability studies of this pH-sensitive hydrogel to drugs with different water solubilities showed a water-content dependent diffusion or pore mechanism for ephedrine HCl (water-soluble model drug), whereas, a partition or solute-diffusion mechanism for indomethacin (a water-insoluble drug) was seen. Data analysis of release tests, according to the swelling interface number and Peppas equation for ephedrine HCl in pH 7.4, showed a biexponential model kinetic, whereas in pH 1.2 a swelling-controlled mechanism was seen. Indomethacin was released by an anomalous or non-Fickian release kinetics.

  1. Alpinetin inhibits lung cancer progression and elevates sensitization drug-resistant lung cancer cells to cis-diammined dichloridoplatium

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    Wu L

    2015-11-01

    Full Text Available Lin Wu, Wei Yang, Su-ning Zhang, Ji-bin Lu Department of Thoracic Surgery, Sheng Jing Hospital of China Medical University, Shenyang, People’s Republic of China Objective: Alpinetin is a novel flavonoid that has demonstrated potent antitumor activity in previous studies. However, the efficacy and mechanism of alpinetin in treating lung cancer have not been determined. Methods: We evaluated the impact of different doses and durations of alpinetin treatment on the cell proliferation, the apoptosis of lung cancer cells, as well as the drug-resistant lung cancer cells. Results: This study showed that the alpinetin inhibited the cell proliferation, enhanced the apoptosis, and inhibited the PI3K/Akt signaling in lung cancer cells. Moreover, alpinetin significantly increased the sensitivity of drug-resistant lung cancer cells to the chemotherapeutic effect of cis-diammined dichloridoplatium. Taken together, this study demonstrated that alpinetin significantly suppressed the development of human lung cancer possibly by influencing mitochondria and the PI3K/Akt signaling pathway and sensitized drug-resistant lung cancer cells. Conclusion: Alpinetin may be used as a potential compound for combinatorial therapy or as a complement to other chemotherapeutic agents when multiple lines of treatments have failed to reduce lung cancer. Keywords: alpinetin, cell proliferation and apoptosis, drug resistance reversal, PI3K/Akt, lung cancer

  2. pH-sensitive nanomicelles for controlled and efficient drug delivery to human colorectal carcinoma LoVo cells.

    Directory of Open Access Journals (Sweden)

    Shi-Ting Feng

    Full Text Available BACKGROUND: The triblock copolymers PEG-P(Asp-DIP-P(Lys-Ca (PEALCa of polyethylene glycol (PEG, poly(N-(N',N'-diisopropylaminoethyl aspartamide (P(Asp-DIP, and poly (lysine-cholic acid (P(Lys-Ca were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES, and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments. METHODOLOGY/PRINCIPAL FINDINGS: The anticancer drug Paclitaxel (PTX and hydrophilic superparamagnetic iron oxide (SPIO were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIO-PEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells, and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated. CONCLUSIONS/SIGNIFICANCE: These results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRI-visible drug release system for colorectal cancer therapy.

  3. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaoguang [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Department of Medical Microbiology, Harbin Medical University, Harbin 150086 (China); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Qian, Hua [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Miyamoto, Fusako [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Naito, Takeshi [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Kawaji, Kumi [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Kajiwara, Kazumi [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); JST Innovation Plaza Kyoto, Japan Science and Technology Agency, Nishigyo-ku, Kyoto 615-8245 (Japan); Hattori, Toshio [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Matsuoka, Masao [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); and others

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.

  4. Analysis of Culture and Drug Sensitivity Tests of Mycoplasmas for 387 Patients with Nongonococcal Urethritis (Cervicitis) in Chongqing

    Institute of Scientific and Technical Information of China (English)

    翟志芳; 郝飞; 钟白玉; 黄秀英; 唐书谦; 刁庆春

    2004-01-01

    Objective: To investigate the prevalence of mycoplasma infections and the sensitivity to antibiotics among patients with nongonococcal urethritis or cervicitis (NGU) in Chongqing. Methods: 387 NGU cases with mycoplasma-positive results upon culture were analysed retrospectively. RESULTS: The majority of patients with mycoplasma infections were in the 20-40 year old age group. No significant difference was found between males and females. Ureaplasma urealyticum is the main pathogen of these NGU cases and no clear relationship between its concentration and pathogenic ability was noted. Drug sensitivity was tested against nine antibiotics; the sensitivity rates to josamycin, minocycline and doxycycline were 94.06%, 88.89% and 86.82% respectively, while the resistance rates to lincomycin, ofloxacin, azithromycin and roxthromycin were 74.94%, 42.12%, 41.60% and 40.31% in turn. Conclusions: Josamycin, minocycline and doxycycline could be used as the first choice to treat NGU with mycoplasma infections in Chongqing. It is important to select antibiotics for NGU treatment with mycoplasma infections based on the results of drug sensitivity tests.

  5. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.

    Science.gov (United States)

    Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah H; Bouyer, Guillaume; Moore, Catherine M; Daley, Daniel A; Hoke, Matthew J; Altenhofen, Lindsey M; Painter, Heather J; Mu, Jianbing; Ferguson, David J P; Llinás, Manuel; Martin, Rowena E; Fidock, David A; Cooper, Roland A; Krishna, Sanjeev

    2015-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.

  6. Graphene oxide-enhanced sol-gel transition sensitivity and drug release performance of an amphiphilic copolymer-based nanocomposite

    Science.gov (United States)

    Hu, Huawen; Wang, Xiaowen; Lee, Ka I.; Ma, Kaikai; Hu, Hong; Xin, John H.

    2016-08-01

    We report the fabrication of a highly sensitive amphiphilic copolymer-based nanocomposite incorporating with graphene oxide (GO), which exhibited a low-intensity UV light-triggered sol-gel transition. Non-cytotoxicity was observed for the composite gels after the GO incorporation. Of particular interest were the microchannels that were formed spontaneously within the GO-incorporated UV-gel, which expedited sustained drug release. Therefore, the present highly UV-sensitive, non-cytotoxic amphiphilic copolymer-based composites is expected to provide enhanced photothermal therapy and chemotherapy by means of GO’s unique photothermal properties, as well as through efficient passive targeting resulting from the sol-gel transition characteristic of the copolymer-based system with improved sensitivity, which thus promises the enhanced treatment of patients with cancer and other diseases.

  7. Graphene oxide-enhanced sol-gel transition sensitivity and drug release performance of an amphiphilic copolymer-based nanocomposite.

    Science.gov (United States)

    Hu, Huawen; Wang, Xiaowen; Lee, Ka I; Ma, Kaikai; Hu, Hong; Xin, John H

    2016-08-19

    We report the fabrication of a highly sensitive amphiphilic copolymer-based nanocomposite incorporating with graphene oxide (GO), which exhibited a low-intensity UV light-triggered sol-gel transition. Non-cytotoxicity was observed for the composite gels after the GO incorporation. Of particular interest were the microchannels that were formed spontaneously within the GO-incorporated UV-gel, which expedited sustained drug release. Therefore, the present highly UV-sensitive, non-cytotoxic amphiphilic copolymer-based composites is expected to provide enhanced photothermal therapy and chemotherapy by means of GO's unique photothermal properties, as well as through efficient passive targeting resulting from the sol-gel transition characteristic of the copolymer-based system with improved sensitivity, which thus promises the enhanced treatment of patients with cancer and other diseases.

  8. Synthesis of a novel thermo/pH sensitive nanogel based on salep modified graphene oxide for drug release.

    Science.gov (United States)

    Bardajee, Ghasem Rezanejade; Hooshyar, Zari; Farsi, Maryam; Mobini, Akram; Sang, Golnaz

    2017-03-01

    Nanogels (NGs) are three-dimensional water soluble cross-linked hydrogel materials in the nanoscale size range with a high loading capacity for guest molecules and act as drug carrier systems. In the present work, a new type of thermo/pH sensitive NG comprising salep modified graphene oxide (SMGO) with branched N-isopropylacrylamide (NIPAM) and acrylic acid (AA) was prepared. The SMGO/P(NIPAM-co-AA) NGs exhibited nanoporous structure and spherical particles with diameters about 82nm as characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The samples were also characterized by Fourier transform infrared spectroscopy (FT-IR) and thermo gravimetric analysis (TGA) to further confirm about the formation of NGs. Doxorubicin (DOX) loaded SMGO/P(NIPAM-co-AA) NGs showed thermo/pH dependent releasing behavior: slow drug release at neutral pH and lower temperature but increased significantly in acidic pH and higher temperature, without any burst release. In addition, the NGs exhibited no effect on the cell viability in the tested concentration range up to 410μg/mL and drug release systems enhanced toxicity to HeLa cells when compared to the equivalent dose of the free drug. Overall, our results put forth NGs as potential candidates in the development of a new nanocarrier for anti-cancer drug delivery.

  9. Sensitization of Candida albicans biofilms to various antifungal drugs by cyclosporine A

    Directory of Open Access Journals (Sweden)

    Shinde Ravikumar B

    2012-10-01

    Full Text Available Abstract Background Biofilms formed by Candida albicans are resistant towards most of the available antifungal drugs. Therefore, infections associated with Candida biofilms are considered as a threat to immunocompromised patients. Combinatorial drug therapy may be a good strategy to combat C. albicans biofilms. Methods Combinations of five antifungal drugs- fluconazole (FLC, voriconazole (VOR, caspofungin (CSP, amphotericin B (AmB and nystatin (NYT with cyclosporine A (CSA were tested in vitro against planktonic and biofilm growth of C. albicans. Standard broth micro dilution method was used to study planktonic growth, while biofilms were studied in an in vitro biofilm model. A chequerboard format was used to determine fractional inhibitory concentration indices (FICI of combination effects. Biofilm growth was analyzed using XTT-metabolic assay. Results MICs of various antifungal drugs for planktonic growth of C. albicans were lowered in combination with CSA by 2 to 16 fold. Activity against biofilm development with FIC indices of 0.26, 0.28, 0.31 and 0.25 indicated synergistic interactions between FLC-CSA, VOR-CSA, CSP-CSA and AmB-CSA, respectively. Increase in efficacy of the drugs FLC, VOR and CSP against mature biofilms after addition of 62.5 μg/ml of CSA was evident with FIC indices 0.06, 0.14 and 0.37, respectively. Conclusions The combinations with CSA resulted in increased susceptibility of biofilms to antifungal drugs. Combination of antifungal drugs with CSA would be an effective prophylactic and therapeutic strategy against biofilm associated C. albicans infections.

  10. Effect of all-trans retinoic acid 0n drug sensitivity and expression of survivin in LoVo cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background All-trans retinoic acid(ATRA)can influence the tumor cell proliferation cycle,and some chemotherapeutic drugs are cycle specific.In this study,we hypothesize that ATRA can enhance chemotherapeutic drug sensitivity by affecting the cell cycle of tumor cells.Methods The cell cycle of LoVo cells was evaluated using flow cytometry(FCM).Cell viability was analyzed using the MTT assay.The morphologic changes in the treated LoVo cells were measured with acridine orange (AO)/ethidium bromide(EB)staining.Expression of survivin in LoVo cells was analyzed by immunofluorescence assay.Results After LoVo cells were treated with ATRA,the G0/G1 ratio of the tumor cells increased and the cell ratio of Sand G2/M-phase decreased.Viability of the cells decreased significantly after combined treatment with ATRA and 5-fluorouracil(5-FU)or mitomycin c(MMC) and was evaluated by fluorescence microscopy.Expression level of survivin in the tumor cells decreased after ATRA combination treatment.Conclusions ATRA enhances drug sensitivity of the LoVo cell line to cell cycle-specific agents and inhibits the expression of survivin in LoVo cells.The combination of ATRA and 5-FU or MMC promoted cell apoptosis,and the mechanism involved in apoptosis may be related to inhibition of survivin gene expression.

  11. Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes.

    Science.gov (United States)

    Yudina, A; de Smet, M; Lepetit-Coiffé, M; Langereis, S; Van Ruijssevelt, L; Smirnov, P; Bouchaud, V; Voisin, P; Grüll, H; Moonen, C T W

    2011-11-01

    A novel two-step protocol for intracellular drug delivery has been evaluated in vitro. As a first step TO-PRO-3 (a cell-impermeable dye that displays a strong fluorescence enhancement upon binding to nucleic acids) encapsulated in thermosensitive liposomes was released after heating to 42°C. A second step consisted of ultrasound-mediated local permeabilization of cell membrane allowing TO-PRO-3 internalization observable as nuclear staining. Only the combination of two consecutive steps - heating and sonication in the presence of SonoVue microbubbles led to the model drug TO-PRO-3 release from the thermosensitive liposomes and its intracellular uptake. This protocol is potentially beneficial for the intracellular delivery of cell impermeable drugs that suffer from rapid clearance and/or degradation in blood and are not intrinsically taken up by cells.

  12. Regulation of Drug Sensitivity by Functional Status of p53 in Human Prostate Cancer

    Science.gov (United States)

    2005-01-01

    containing 5% C0 2/95% air. Cell lines were free of Mycoplasnma Received 6/24/02; accepted 4/2/03. and fungi and were discarded after 3 months; new cell...cells expressing the prostate cancer cells. J. Clin. Investig., 105: 1261-1267, 2000. multidrug resistance-associated protein MRP. Anticancer Drugs, 8... Anticancer Drugs, 8: 125-140, 1997. stimulates sulfated estrogen transport by multidrug resistance protein 1. J. Biol. 25. Hipfner, D. R., Deeley, R. G. and

  13. Development of Nano-Liposomal Formulations of Epidermal Growth Factor Receptor Inhibitors and their Pharmacological Interactions on Drug-Sensitive and Drug-Resistant Cancer Cell Lines

    Science.gov (United States)

    Trummer, Brian J.

    , due to leaky tumor vasculature and the resulting Enhanced Permeability and Retention (EPR) phenomenon. In Chapter 2 we report that both gefitinib and the structurally similar EGFR inhibitor erlotinib display environment-dependent fluorescence properties. Peak excitation was 345 nm, and the emission peak ranged from 365 to 476 nm, depending upon the polarity of the environment and physical state of the drug. The fluorescence was negligible in aqueous solution, but intense in organic solvents or membrane bilayers. The environment-sensitive fluorescence properties of these drugs enabled rapid evaluation of numerous parameters affecting liposomal drug incorporation and performance. Up to 4-6 mol% of gefitinib could be incorporated in the liposome bilayer, based upon hydrophobic interactions with membrane bilayers. In contrast, 40-60 mol% could be loaded into the aqueous core of pre-formed liposomes at high efficiency, using a remote loading procedure. A stable formulation consisting of distearoylphosphatidylcholine: polyethylene glycol-distereoylphosphatidylethanolamine: cholesterol (DSPC:PEGDSPE:Chol, 9:1:5 mol:mol:mol) and containing drug at 50-60 mol% gefitinib (L-GEF) showed minimal leakage in serum-containing medium over 24 h at 37°C, which should be sufficient to improve biodistribution in vivo. Chapter 3 investigated the pharmacological activity of liposome-encapsulated gefitinib, alone and in combination with several prevalent anticancer agents. Experiments with MCF7 breast cancer cell lines demonstrated that liposome encapsulated gefitinib formulation (L-GEF) had a 2-fold higher IC50 (concentration of drug resulting in half-maximal growth inhibition) than free gefitinib. Lower in vitro potency would be consistent with delayed drug release from the carrier. Therapeutic effects were investigated in combination with the cytotoxic agents paclitaxel and doxorubicin. The drug-resistant MCF7R cell line was 23-fold more resistant to paclitaxel than the parental, drug-sensitive

  14. Sensitivity to Lovastatin of Saccharomyces cerevisiae Strains Deleted for Pleiotropic Drug Resistance (PDR) Genes

    DEFF Research Database (Denmark)

    Formenti, Luca Riccardo; Kielland-Brandt, Morten

    2011-01-01

    based on the use of statins. We investigated the susceptibility to lovastatin of S. cerevisiae strains deleted for PDR genes, responsible for exporting hydrophobic and amphi-philic drugs, such as lovastatin. Strains deleted for the genes tested, PDR1, PDR3, PDR5 and SNQ2, exhibited remarkably different...

  15. Radiation synthesis of pH-sensitive hydrogels from {beta}-cyclodextrin-grafted PEG and acrylic acid for drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Chen Jie; Rong Liang [Department of Chemical Engineering and Technology, School of Environmental and Chemical Engineering, Shanghai University, Baoshan, Shanghai 200444 (China); Lin Han, E-mail: linhan1205@yahoo.com.cn [Department of Chemical Engineering and Technology, School of Environmental and Chemical Engineering, Shanghai University, Baoshan, Shanghai 200444 (China); Xiao Ruijia; Wu Huifeng [Department of Chemical Engineering and Technology, School of Environmental and Chemical Engineering, Shanghai University, Baoshan, Shanghai 200444 (China)

    2009-07-15

    A water-soluble macromonomer (PEG-{beta}-CD) was synthesised by reaction of {beta}-cyclodextrin with poly(ethylene glycol) diglycidyl ether. Then, a novel hydrogel with pH-sensitivity was prepared by irradiating the mixture of acrylic acid and PEG-{beta}-CD with electron beam. Compared with the normal PAAc hydrogel, this novel hydrogel had a higher swelling ratio at pH 3-8. 5-Fluorouracil (5-FU) was chosen as a model drug, and the kinetics of 5-FU releasing behavior was studied. Compared with the PAAc hydrogel, the results showed the release time of 5-FU from the cyclodextrin containing hydrogel was prolonged. It may be ascribed to the formation of inclusion complexes between the drug molecules and cyclodextrin groups.

  16. Simple and sensitive high performance liquid chromatography method with fluorescence detection for therapeutic drug monitoring of topiramate.

    Science.gov (United States)

    Milosheska, Daniela; Vovk, Tomaž; Grabnar, Iztok; Roškar, Robert

    2015-01-01

    A simple, sensitive, accurate, precise and inexpensive HPLC method with fluorescence detection, suitable for routine therapeutic drug monitoring (TDM) of an antiepileptic drug topiramate, was developed and validated. The determination of plasma topiramate concentration was carried out after precolumn derivatization, using 4-chloro-7-nitrobenzofurazan as a fluorescent labeling agent and bendroflumethiazide as an internal standard. The standard calibration curve was linear over the concentration range of 0.01-24 μg/mL (r² > 0.9998). The intra- and inter-day accuracies expressed as bias were from 1.4 to 9.9% and from 1.9 to 10.2%, respectively. The intra- and inter-day precisions were below 7.9% and 2.7%, respectively. The validated method was applied for the measurement of plasma topiramate concentrations in patients with epilepsy. The reported method is appropriate for TDM of topiramate as well as for pharmacokinetic and bioequivalence studies.

  17. Nationwide survey of the development of drug-resistant pathogens in the pediatric field in 2007 and 2010: drug sensitivity of Streptococcus pneumoniae in Japan (second report).

    Science.gov (United States)

    Tajima, Takeshi; Sato, Yoshitake; Toyonaga, Yoshikiyo; Hanaki, Hideaki; Sunakawa, Keisuke

    2013-06-01

    We previously conducted nationwide surveillance of Streptococcus pneumoniae in 2000-2001 (period 1) and 2004 (period 2) and reported the findings. Subsequent surveillance surveys conducted in 2007 (period 3) and 2010 (period 4) are now reported. Bacterial strains were clinically isolated from children with meningitis, sepsis, and respiratory tract infections at 27 hospitals participating in the Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. Twenty-one drugs were investigated for 283 isolated strains in period 3, and 24 drugs were investigated for 459 strains in period 4. In period 3, 43.8 % of strains were penicillin-susceptible S. pneumoniae (PSSP), 52.3 % were penicillin-intermediate S. pneumoniae (PISP), and 3.9 % were penicillin-resistant S. pneumoniae (PRSP). In period 4, the percentages were PSSP 23.1 %, PISP 49.9 %, and PRSP 27.0 %. The resistance rates were 56.2 % and 76.9 %, respectively. Drug sensitivity was best with panipenem, at a minimum inhibitory concentration (MIC)90 ≤0.063 μg/ml in period 3, and with tebipenem (MIC90 ≤ 0.063 μg/ml) in period 4. Patients' background factors related to increased bacterial resistance were investigated, and significant differences were found depending on whether a child had siblings (P = 0.0056) or was a daycare center attendee (P = 0.0195) in period 3, and age category (P = 0.0256) in period 4. No factors were common to both periods 3 and 4. Pneumococcus is a major causative organism of pediatric infectious disease, and we plan to continue conducting surveillance and providing information in the future.

  18. Changes in the sensitivity of GABAA current rundown to drug treatments in a model of temporal lobe epilepsy

    Directory of Open Access Journals (Sweden)

    Pierangelo eCifelli

    2013-07-01

    Full Text Available The pharmacological treatment of mesial temporal lobe epilepsy (mTLE, the most common epileptic syndrome in adults, is still unsatisfactory, as one third of the patients are or become refractory to antiepileptic agents. Refractoriness may depend upon drug-induced alterations, but the disease per se may also undergo a progressive evolution that affects the sensitivity to drugs. mTLE has been shown to be associated with a dysfunction of the inhibitory signaling mediated by GABAA receptors. In particular, the repetitive activation of GABAA receptors produces a use-dependent decrease (rundown of the evoked currents (IGABA, which is markedly enhanced in the hippocampus and cortex of drug-resistant mTLE patients. This phenomenon has been also observed in the pilocarpine model, where the increased IGABA rundown is observed in the hippocampus at the time of the first spontaneous seizure, then extends to the cortex and remains constant in the chronic phase of the disease. Here, we examined the sensitivity of IGABA to pharmacological modulation. We focused on the antiepileptic agent levetiracetam and on the neurotrophin BDNF, which were previously reported to attenuate mTLE-induced increased rundown in the chronic human tissue. In the pilocarpine model, BDNF displayed a paramount effect, decreasing rundown in the hippocampus at the time of the first seizure, as well as in the hippocampus and cortex in the chronic period. In contrast, levetiracetam did not affect rundown in the hippocampus, but attenuated it in the cortex. Interestingly, this effect of levetiracetam was also observed on the still unaltered rundown observed in the cortex at the time of the first spontaneous seizure. These data suggest that the sensitivity of GABAA receptors to pharmacological interventions undergoes changes during the natural history of mTLE, implicating that the site of seizure initiation and the timing of treatment may highly affect the therapeutic outcome.

  19. Development of Novel Polymeric Materials for Gene Therapy and pH-Sensitive Drug Delivery: Modeling, Synthesis, Characterization, and Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Anderson, Brian Curtis [Iowa State Univ., Ames, IA (United States)

    2002-01-01

    The underlying theme of this thesis is the use of polymeric materials in bioapplications. Chapters 2-5 either develop a fundamental understanding of current materials used for bioapplications or establish protocols and procedures used in characterizing and synthesizing novel materials. In chapters 6 and 7 these principles and procedures are applied to the development of materials to be used for gene therapy and drug delivery. Chapter one is an introduction to the ideas that will be necessary to understand the subsequent chapters, as well as a literature review of these topics. Chapter two is a paper that has been published in the ''Journal of Controlled Release'' that examines the mechanism of drug release from a polymer gel, as well as experimental design suggestions for the evaluation of water soluble drug delivery systems. Chapter three is a paper that has been published in the ''Journal of Pharmaceutical Sciences'' that discusses the effect ionic salts have on properties of the polymer systems examined in chapter two. Chapter four is a paper published in the Materials Research Society Fall 2000 Symposium Series dealing with the design and synthesis of a pH-sensitive polymeric drug delivery device. Chapter five is a paper that has been published in the journal ''Biomaterials'' proposing a novel polymer/metal composite for use as a biomaterial in hip arthroplasty surgery. Chapter six is a paper that will appear in an upcoming volume of the Journal ''Biomaterials'' dealing with the synthesis of a novel water soluble cationic polymer with possible applications in non-viral gene therapy. Chapter seven is a paper that has been submitted to ''Macromolecules'' discussing several novel block copolymers based on poly(ethylene glycol) and poly(diethylamino ethyl methacrylate) that possess both pH-sensitive and temperature sensitive properties. Chapter eight contains a

  20. Development of Novel Polymeric Materials for Gene Therapy and pH-Sensitive Drug Delivery: Modeling, Synthesis, Characterization, and Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Brian Curtis Anderson

    2002-08-27

    The underlying theme of this thesis is the use of polymeric materials in bioapplications. Chapters 2-5 either develop a fundamental understanding of current materials used for bioapplications or establish protocols and procedures used in characterizing and synthesizing novel materials. In chapters 6 and 7 these principles and procedures are applied to the development of materials to be used for gene therapy and drug delivery. Chapter one is an introduction to the ideas that will be necessary to understand the subsequent chapters, as well as a literature review of these topics. Chapter two is a paper that has been published in the ''Journal of Controlled Release'' that examines the mechanism of drug release from a polymer gel, as well as experimental design suggestions for the evaluation of water soluble drug delivery systems. Chapter three is a paper that has been published in the ''Journal of Pharmaceutical Sciences'' that discusses the effect ionic salts have on properties of the polymer systems examined in chapter two. Chapter four is a paper published in the Materials Research Society Fall 2000 Symposium Series dealing with the design and synthesis of a pH-sensitive polymeric drug delivery device. Chapter five is a paper that has been published in the journal ''Biomaterials'' proposing a novel polymer/metal composite for use as a biomaterial in hip arthroplasty surgery. Chapter six is a paper that will appear in an upcoming volume of the Journal ''Biomaterials'' dealing with the synthesis of a novel water soluble cationic polymer with possible applications in non-viral gene therapy. Chapter seven is a paper that has been submitted to ''Macromolecules'' discussing several novel block copolymers based on poly(ethylene glycol) and poly(diethylamino ethyl methacrylate) that possess both pH-sensitive and temperature sensitive properties. Chapter eight contains a

  1. Renal (tissue) kallikrein-kinin system in the kidney and novel potential drugs for salt-sensitive hypertension.

    Science.gov (United States)

    Katori, Makoto; Majima, Masataka

    2014-01-01

    A large variety of antihypertensive drugs, such as angiotensin converting enzyme inhibitors, diuretics, and others, are prescribed to hypertensive patients, with good control of the condition. In addition, all individuals are generally believed to be salt sensitive and, thus, severe restriction of salt intake is recommended to all. Nevertheless, the physiological defense mechanisms in the kidney against excess salt intake have not been well clarified. The present review article demonstrated that the renal (tissue) kallikrein-kinin system (KKS) is ideally situated within the nephrons of the kidney, where it functions to inhibit the reabsorption of NaCl through the activation of bradykinin (BK)-B2 receptors localized along the epithelial cells of the collecting ducts (CD). Kinins generated in the CD are immediately inactivated by two kidney-specific kinin-inactivating enzymes (kininases), carboxypeptidase Y-like exopeptidase (CPY), and neutral endopeptidase (NEP). Our work demonstrated that ebelactone B and poststatin are selective inhibitors of these kininases. The reduced secretion of the urinary kallikrein is linked to the development of salt-sensitive hypertension, whereas potassium ions and ATP-sensitive potassium channel blockers ameliorate salt-sensitive hypertension by accelerating the release of renal kallikrein. On the other hand, ebelactone B and poststatin prolong the life of kinins in the CD after excess salt intake, thereby leading to the augmentation of natriuresis and diuresis, and the ensuing suppression of salt-sensitive hypertension. In conclusion, accelerators of the renal kallikrein release and selective renal kininase inhibitors are both novel types of antihypertensive agents that may be useful for treatment of salt-sensitive hypertension.

  2. Development of pH sensitive polyacrylamide grafted pectin hydrogel for controlled drug delivery system.

    Science.gov (United States)

    Sutar, Prashant B; Mishra, Rakesh K; Pal, Kunal; Banthia, Ajit K

    2008-06-01

    In the present study an attempt was made to graft polyacrylamide on pectin. The grafted polymer was characterized by FTIR spectroscopy, differential scanning calorimetry and X-ray diffraction. Rheological property of pectin solution was compared with the product solution. The grafted polymer was cross-linked with varying amount of glutaraldehyde. The swelling properties of the cross-linked product were also studied. The salicylic acid, an antipyretic drug, was incorporated in the cross-linked gel as a model drug and the drug release studies were done in a modified Franz's diffusion cell. The effect of cross-linking density on the release property of salicylic acid was studied through the cross-linked product. The product showed better film forming property and gelling property than pectin. The comparative rheological properties of pectin and grafted copolymer indicated change in the property of the product. FTIR studies indicated incorporation of amide group. Differential scanning calorimetry and XRD suggested formation of a new polymer. Swelling study indicated pH dependent swelling of the cross-linked hydrogel. Salicylic acid release indicated pH dependent release from the hydrogel.

  3. Impact of highly active antiretroviral therapy (HAART on the incidence of opportunistic infections, hospitalizations and mortality among children and adolescents living with HIV/AIDS in Belo Horizonte, Minas Gerais State, Brazil Impacto da terapia anti-retroviral de alta potência (HAART na incidência de infecções oportunistas, hospitalização e mortalidade associadas em crianças e adolescentes vivendo com HIV/AIDS em Belo Horizonte, Minas Gerais, Brasil

    Directory of Open Access Journals (Sweden)

    Talitah M. S. Candiani

    2007-01-01

    Full Text Available The impact of highly active antiretroviral therapy (HAART can be evaluated using indicators, such as rates of opportunistic infections, hospitalizations by cause of infection, and associated death. This study aimed to estimate the impact of HAART on the incidence of these indicators, in children and adolescents with HIV/AIDS. It was a hybrid cohort study; 371 patients were followed from 1989 to 2003. In December 2003, 76% of the patients were still being followed, while 12.1% had died, 9.5% had dropped out, and 2.4% had been transferred. The overall rate of opportunistic infections was 18.32 infections/100 persons-year and 2.63 in the pre- and post-HAART periods, respectively. In the multivariate analysis, the risk of developing an opportunistic infection was 5.4 times greater and 3.3 times greater for hospitalization risk before HAART. Respiratory causes represented 65% of the hospitalizations and they were reduced by 44.6% with therapeutic intervention. The average hospital stay of 15 days was reduced to 9.There was a post-HAART decline in deaths of 38%. This study demonstrates the effectiveness of HAART in significantly reducing opportunistic infections, hospitalizations, and deaths in this Brazilian cohort.O impacto da terapia anti-retroviral de alta potência ativa (HAART pode ser avaliado utilizando-se indicadores, como taxas de incidências de infecções oportunistas, hospitalizações por causas infecciosas e mortalidade associada. O objetivo deste trabalho foi estimar o impacto da HAART na incidência desses indicadores em crianças e adolescentes com HIV/AIDS. Trata-se de uma coorte híbrida, na qual foram acompanhados 371 pacientes no período de 1989-2003. Em dezembro de 2003, 76% dos pacientes permaneciam em acompanhamento, 12,1% faleceram, 9,5% foram perda de seguimento e 2,4% transferidos. A taxa de incidência global de infecções oportunistas foi de 18,32 infecções/100 pessoas-ano e 2,63 nos períodos pré e p

  4. Drug-induced diseases (DIDs: An experience of a tertiary care teaching hospital from India

    Directory of Open Access Journals (Sweden)

    Vishal R Tandon

    2015-01-01

    Full Text Available Background & objectives: Drug-induced diseases (DIDs are well known but least studied. Data on DIDs from India are not available. Hence, this retrospective cross-sectional study was undertaken using suspected adverse drug reaction (ADR data collected form Pharmacovigilance Programme of India (PvPI to evaluate profile of DIDs over two years, in a tertiary care teaching hospital from north India. Methods: The suspected ADRs in the form of DID were evaluated for drug and disease related variables and were classified in terms of causality. Results: DID rate was 38.80 per cent. Mean duration of developing DIDs was 26.05 ± 9.6 days; 25.16 per cent had more than one co-morbid condition. Geriatric population (53.99% accounted for maximum DIDs followed by adult (37.79% and paediatric (8.21%. Maximum events were probable (93.98% followed by possible (6.04%. All DIDs required intervention. Gastritis (7.43%, diarrhoea (5.92%, anaemia (4.79%, hypotension (2.77%, hepatic dysfunction (2.69%, hypertension (1.51%, myalgia (1.05%, and renal dysfunction (1.01% were some of the DIDs. Anti-tubercular treatment (ATT, anti- retroviral treatment (ART, ceftriaxone injection, steroids, non-steroidal anti-inflammatory drugs, antimicrobials and anticancer drugs were found as commonly offending drugs. Interpretation & conclusions: Our findings show that DIDs are a significant health problem in our country, which need more attention.

  5. Properties of recombinant human N1-acetylpolyamine oxidase (hPAO): potential role in determining drug sensitivity.

    Science.gov (United States)

    Wang, Yanlin; Hacker, Amy; Murray-Stewart, Tracy; Frydman, Benjamin; Valasinas, Aldonia; Fraser, Alison V; Woster, Patrick M; Casero, Robert A

    2005-07-01

    The recent cloning of the mammalian gene coding for N(1)-acetylpolyamine oxidase (PAO) provides the opportunity to directly examine the role of human PAO (hPAO) in polyamine homeostasis as well as its potential role in determining cellular response to antitumor polyamine analogues. To facilitate the study of this enzyme, the production, purification, and characterization of the recombinant hPAO is reported. hPAO oxidizes N(1)-acetylspermidine (K(m)=2.1 microM, K(cat)=15.0 s(-1)) and has very high affinity for N(1)-acetylspermine (K(m)=0.85 microM, K(cat)=31.7 s(-1)). The recombinant hPAO does not efficiently oxidize spermine, thereby demonstrating a significant difference in substrate specificity from the previously described human spermine oxidase PAOh1/SMO. Importantly, hPAO demonstrates the ability to oxidize a subset of antitumor polyamine analogues, suggesting that this oxidase activity could have a significant effect on determining tumor sensitivity to these or similar agents. Transfection of A549 human lung cancer cells with an hPAO-expressing plasmid leads to a profound decrease in sensitivity to those analogues which act as substrates, confirming its potential to alter drug response. One similarity that hPAO shares with human PAOh1/SMO, is that certain oligoamine analogues are potent inhibitors of its oxidase activity. The results of these studies demonstrate how changes in polyamine catabolism may affect drug response.

  6. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    Science.gov (United States)

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-06-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

  7. pH-Sensitive, N-ethoxybenzylimidazole (NEBI) bifunctional crosslinkers enable triggered release of therapeutics from drug delivery carriers.

    Science.gov (United States)

    Luong, Alice; Issarapanichkit, Tawny; Kong, Seong Deok; Fong, Rina; Yang, Jerry

    2010-11-21

    This paper presents a pH-sensitive bifunctional crosslinker that enables facile conjugation of small molecule therapeutics to macromolecular carriers for use in drug delivery systems. This N-ethoxybenzylimidazole (NEBI) bifunctional crosslinker was designed to exploit mildly acidic, subcellular environments to trigger the release of therapeutics upon internalization in cells. We demonstrate that an analog of doxorubicin (a representative example of an anticancer therapeutic) conjugated to human serum albumin (HSA, a representative example of a macromolecular carrier) via this NEBI crosslinker can internalize and localize into acidic lysosomes of ovarian cancer cells. Fluorescence imaging and cell viability studies demonstrate that the HSA-NEBI-doxorubicin conjugate exhibited improved uptake and cytotoxic activity compared to the unconjugated doxorubicin analog. The pH-sensitive NEBI group was also shown to be relatively stable to biologically-relevant metal Lewis acids and to serum proteins, supporting that these bifunctional crosslinkers may be useful for constructing drug delivery systems that will be stable in biological fluids such as blood.

  8. Enhancement of neutrophil autophagy by an IVIG preparation against multidrug-resistant bacteria as well as drug-sensitive strains.

    Science.gov (United States)

    Itoh, Hiroshi; Matsuo, Hidemasa; Kitamura, Naoko; Yamamoto, Sho; Higuchi, Takeshi; Takematsu, Hiromu; Kamikubo, Yasuhiko; Kondo, Tadakazu; Yamashita, Kouhei; Sasada, Masataka; Takaori-Kondo, Akifumi; Adachi, Souichi

    2015-07-01

    Autophagy occurs in human neutrophils after the phagocytosis of multidrug-resistant bacteria and drug-sensitive strains, including Escherichia coli and Pseudomonas aeruginosa. The present study detected autophagy by immunoblot analysis of LC3B conversion, by confocal scanning microscopic examination of LC3B aggregate formation and by transmission electron microscopic examination of bacteria-containing autophagosomes. Patients with severe bacterial infections are often treated with IVIG alongside antimicrobial agents. Here, we showed that IVIG induced neutrophil-mediated phagocytosis of multidrug-resistant strains. Compared with untreated neutrophils, neutrophils exposed to IVIG showed increased levels of bacterial cell killing, phagocytosis, O(2)(-) release, MPO release, and NET formation. IVIG also increased autophagy in these cells. Inhibiting the late phase of autophagy (fusion of lysosomes with autophagosomes) with bafilomycin A1-reduced, neutrophil-mediated bactericidal activity. These findings indicate that autophagy plays a critical role in the bactericidal activity mediated by human neutrophils. Furthermore, the autophagosomes within the neutrophils contained bacteria only and their organelles only, or both bacteria and their organelles, a previously undocumented observation. Taken together, these results suggest that the contents of neutrophil autophagosomes may be derived from specific autophagic systems, which provide the neutrophil with an advantage. Thus, IVIG promotes the neutrophil-mediated killing of multidrug-resistant bacteria as well as drug-sensitive strains.

  9. Redox modulation of adjacent thiols in VLA-4 by AS101 converts myeloid leukemia cells from a drug-resistant to drug-sensitive state.

    Science.gov (United States)

    Layani-Bazar, Adi; Skornick, Itai; Berrebi, Alain; Pauker, Maor H; Noy, Elad; Silberman, Alon; Albeck, Michael; Longo, Dan L; Kalechman, Yona; Sredni, Benjamin

    2014-06-01

    Interaction between the integrin VLA-4 on acute myelogenous leukemia (AML) cells with stromal fibronectin is a decisive factor in chemotherapeutic resistance. In this study, we provide a rationale for a drug repositioning strategy to blunt integrin activation in AML cells and restore their sensitivity to chemotherapy. Specifically, we demonstrate that the nontoxic tellurium compound AS101, currently being evaluated in clinical trials, can abrogate the acquired resistance of AML. Mechanistic investigations revealed that AS101 caused redox inactivation of adjacent thiols in the exofacial domain of VLA-4 after its ligation to stromal fibronectin. This effect triggered cytoskeletal conformational changes that decreased PI3K/Akt/Bcl2 signaling, an obligatory step in chemosensitization by AS101. In a mouse xenograft of AML derived from patient leukemic cells with high VLA-4 expression and activity, we demonstrated that AS101 abrogated drug resistance and prolonged survival in mice receiving chemotherapy. Decreased integrin activity was confirmed on AML cells in vivo. The chemosensitizing activity of AS101 persisted in hosts with defective adaptive and innate immunity, consistent with evidence that integrin deactivation was not mediated by heightening immune attack. Our findings provide a mechanistic rationale to reposition the experimental clinical agent, AS101, to degrade VLA-4-mediated chemoresistance and improve clinical responses in patients with AML.

  10. A new disposable electrode for electrochemical study of leukemia K562 cells and anticancer drug sensitivity test.

    Science.gov (United States)

    Yu, Chunmei; Zhu, Zhenkun; Wang, Li; Wang, Qiuhong; Bao, Ning; Gu, Haiying

    2014-03-15

    Developing cost-effective and simple analysis tools is of vital importance for practical applications in bioanalysis. In this work, a new disposable electrochemical cell sensor with low cost and simple fabrication was proposed to study the electrochemical behavior of leukemia K562 cells and the effect of anticancer drugs on cell viability. The analytical device was integrated by using ITO glass as the substrate of working electrodes and paper as the electrolytic cell. The cyclic voltammetry of the K562 cells at the disposable electrode exhibited an irreversible anodic peak and the peak current is proportional to the cell number. This anodic peak is attributed to the oxidation of guanine in cells involving two protons per transfer of two electrons. For the drug sensitivity tests, arsenic trioxide and cyclophosphamide were added to cell culture media. As a result, the electrochemical responses of the K562 cells decreased significantly. The cytotoxicity curves and results obtained corresponded well with the results of CCK-8 assays. In comparison to conventional methods, the proposed method is simple, rapid and inexpensive. More importantly, the developed sensor is supposed to be a single-use disposable device and electrodes were prepared "as new" for each experiment. We think that such disposable electrodes with these characteristics are suitable for experimental study with cancer cells or other types of pathogens for disease diagnosis, drug selection and on-site monitoring.

  11. Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells From Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo.

    Science.gov (United States)

    Knorr, Katherine L B; Finn, Laura E; Smith, B Douglas; Hess, Allan D; Foran, James M; Karp, Judith E; Kaufmann, Scott H

    2016-11-07

    : Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting.

  12. Hypoxia-sensitive, Multifunctional Nanoparticles for Targeted Drug Delivery to Breast Cancer

    Science.gov (United States)

    2012-09-01

    solution containing tween 80 as a surfactant. The prepared polymeric nanoparticles was isolated by centrifugation, purified by rinsing with ionized water...polymer solution (25mg) in 0.5 mL dichloromethane was added to 9.4 mL of PBS containing 0.1 mL of tween 80 as a surfactant, while stirring at room...modified to the end carboxyl groups. Redox-sensitive polymeric nanoparticles were prepared from the synthesized polymer by an emulsion method.14 Tween

  13. Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

    Directory of Open Access Journals (Sweden)

    Jane Claire Munday

    2015-03-01

    Full Text Available Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (Berenil®, cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (MPXR is the result of loss of a separate High Affinity Pentamidine Transporter (HAPT1. A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the selectivity region of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this

  14. Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

    Science.gov (United States)

    Munday, Jane C.; Settimo, Luca; de Koning, Harry P.

    2015-01-01

    Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (DA; Berenil®), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (melarsoprol/pentamidine cross resistance, MPXR) is the result of loss of a separate high affinity pentamidine transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the “selectivity region” of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a

  15. Antibacterial effect of mango (Mangifera indica Linn.) leaf extract against antibiotic sensitive and multi-drug resistant Salmonella typhi.

    Science.gov (United States)

    Hannan, Abdul; Asghar, Samra; Naeem, Tahir; Ikram Ullah, Muhammad; Ahmed, Ijaz; Aneela, Syeda; Hussain, Shabbir

    2013-07-01

    Alternative herbal medicine has been used to treat various infections from centuries. Natural plants contain phytoconstituents having similar chemical properties as of synthetic antibiotics. Typhoid fever is a serious infection and failure of its treatment emerged multi-drug resistant (MDR) bugs of Salmonella typhi. Due to multiple and repeated issues with antibiotics efficacy, it became essential to evaluate biological properties of plants from different geographical origins. Mango leaves have been Reported for various medicinal effects like antioxidant, antimicrobial, antihelminthic, antidiabetic and antiallergic etc. Objective of present study was to investigate anti-typhoid properties of acetone mango leaf extract (AMLE) against antibiotic sensitive and MDR S. typhi isolates. A total of 50 isolates of S. typhi including MDR (n=30) and antibiotic sensitive (n=20) were investigated. Staphylococcus aureus (ATCC 25923) and Salmonella typhimurium (ATCC14028) were used as quality control strains. AMLE was prepared and its antibacterial activity was evaluated by agar well diffusion screening method and minimum inhibitory concentration (MIC), by agar dilution technique. Zone of inhibition (mm) of AMLE against MDR and antibiotic sensitive isolates was 18±1.5mm (Mean±S.D). Zone of S. aureus (ATCC 25923) and S. typhimurium (ATCC14028) was 20±1.5mm (Mean±S.D). MIC of AMLE was Reported in range from 10-50 mg/ml. The present study described the inhibitory effects of mango leaves against S. typhi.

  16. Self-assembled nanocomplexes of anionic pullulan and polyallylamine for DNA and pH-sensitive intracellular drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Vora, Lalit [University under Sect. 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, Center for Novel Drug Delivery Systems, Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (India); Tyagi, Monica [Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Gupta Lab, Cancer Research Institute (India); Patel, Ketan [University under Sect. 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, Center for Novel Drug Delivery Systems, Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (India); Gupta, Sanjay [Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Gupta Lab, Cancer Research Institute (India); Vavia, Pradeep, E-mail: vaviapradeep@yahoo.com [University under Sect. 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, Center for Novel Drug Delivery Systems, Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology (India)

    2014-12-15

    The amalgamation of chemotherapy and gene therapy is promising treatment option for cancer. In this study, novel biocompatible self-assembled nanocomplexes (NCs) between carboxylmethylated pullulan t335 (CMP) with polyallylamine (CMP–PAA NCs) were developed for plasmid DNA (pDNA) and pH-sensitive doxorubicin (DOX) delivery. DOX was conjugated to CMP (DOX–CMP) via hydrazone and confirmed by FTIR and {sup 1}H-NMR. In vitro release studies of pH-sensitive DOX–CMP conjugate showed 23 and 85 % release after 48 h at pH 7.4 (physiological pH) and pH 5 (intracellular/tumoral pH), respectively. The CMP–PAA NCs or DOX–CMP–PAA NCs self-assembled into a nanosized (<250 nm) spherical shape as confirmed by DLS and TEM. The hemolysis and cytotoxicity study indicated that the CMP–PAA NCs did not show cytotoxicity in comparison with plain polyallylamine. Gel retardation assay showed complete binding of pDNA with CMP–PAA NCs at 1:2 weight ratio. CMP–PAA NCs/pDNA showed significantly higher transfection in HEK293 cells compared to PAA/pDNA complexes. Confocal imaging demonstrated successful cellular uptake of DOX–CMP–PAA NCs in HEK293 cells. Thus, NCs hold great potential for targeted pDNA and pH-sensitive intratumoral drug delivery.

  17. In situ gelling pH- and temperature-sensitive biodegradable block copolymer hydrogels for drug delivery.

    Science.gov (United States)

    Singh, Narendra K; Lee, Doo Sung

    2014-11-10

    Stimuli-sensitive injectable polymeric hydrogels have been extensively investigated during the past decade as bioactive agent delivery vehicles and for tissue engineering applications. An aqueous solution of these polymers undergoes a sol-to-gel phase transition in response to external stimuli such as pH, temperature, salt, light, biomolecules, electromagnetic field, etc. Bioactive molecules or cells can be mixed into the low-viscosity state of the polymer solution and injected into the body at a target site, forming an in situ hydrogel depot, which can then serve as bioactive-molecule-releasing carriers or a cell-growing microenvironment. This review systematically summarizes the recent progress in biodegradable and injectable block copolymer hydrogels, giving special attention to the novel and promising pH- and temperature-sensitive injectable block copolymer hydrogels for biomedical applications. The gelation mechanism, formation of ionic complexes, and biodegradation are highlighted as key factors responsible for controlled protein/drug delivery. The advantages and perspectives of pH- and temperature-sensitive injectable block copolymer hydrogels are also highlighted.

  18. Facile synthesis of glucose-sensitive chitosan-poly(vinyl alcohol) hydrogel: Drug release optimization and swelling properties.

    Science.gov (United States)

    Abureesh, Mosab Ali; Oladipo, Akeem Adeyemi; Gazi, Mustafa

    2016-09-01

    The study describes the development of glucose-sensitive hydrogel and optimization of bovine serum albumin release profile from the hydrogel. To enhance the glucose sensitivity and improve the swelling behaviors of the hydrogel system, boric acid crosslinking, and freeze-thawing cycle techniques were used to prepare chitosan-poly(vinyl alcohol) hydrogel. The structure of the resultant hydrogel was confirmed by scanning electron microscopy and Fourier transform infrared spectroscopy. The experimental results revealed that the swelling of the hydrogel was influenced by the pH of the medium, and the hydrogel displayed explicit glucose-sensitivity under physiological conditions. The values of the diffusion exponent range between 0.34 and 0.44 and the diffusion of water into the gel system are assumed to be pseudo-Fickian in nature. Under optimized conditions, the cumulative Bovine serum albumin (BSA) drug releases ranged between 69.33±1.95% and 86.45±1.16% at 37°C in the presence of glucose and pH 7.4, respectively.

  19. Hyaluronic acid nanogels with enzyme-sensitive cross-linking group for drug delivery.

    Science.gov (United States)

    Yang, Chenchen; Wang, Xin; Yao, Xikuang; Zhang, Yajun; Wu, Wei; Jiang, Xiqun

    2015-05-10

    A methacrylation strategy was employed to functionalize hyaluronic acid and prepare hyaluronic acid (HA) nanogels. Dynamic light scattering, zeta potential analyzer and electron microscopy were utilized to characterize the nanogels and their enzyme-degradability in vitro. It was found that these nanogels had a spherical morphology with the diameter of about 70nm, and negative surface potential. When doxorubicin (DOX) was loaded into the nanogels, the diameter decreased to approximately 50nm with a drug loading content of 16% and encapsulation efficiency of 62%. Cellular uptake examinations showed that HA nanogels could be preferentially internalized by two-dimensional (2D) cells and three-dimensional (3D) multicellular spheroids (MCs) which both overexpress CD44 receptor. Near-infrared fluorescence imaging, biodistribution and penetration examinations in tumor tissue indicated that the HA nanogels could efficiently accumulate and penetrate the tumor matrix. In vivo antitumor evaluation found that DOX-loaded HA nanogels exhibited a significantly superior antitumor effect.

  20. PEG-SS-PPS: reduction-sensitive disulfide block copolymer vesicles for intracellular drug delivery.

    Science.gov (United States)

    Cerritelli, Simona; Velluto, Diana; Hubbell, Jeffrey A

    2007-06-01

    Under appropriate conditions, block copolymeric macroamphiphiles will self-assemble in water to form vesicles, referred to as polymersomes. We report here polymersomes that can protect biomolecules in the extracellular environment, are taken up by endocytosis, and then suddenly burst within the early endosome, releasing their contents prior to exposure to the harsh conditions encountered after lysosomal fusion. Specifically, block copolymers of the hydrophile poly(ethylene glycol) (PEG) and the hydrophobe poly(propylene sulfide) (PPS) were synthesized with an intervening disulfide, PEG17-SS-PPS30. Polymersomes formed from this block copolymer were demonstrated to disrupt in the presence of intracellular concentrations of cysteine. In cellular experiments, uptake, disruption, and release were observed within 10 min of exposure to cells, well within the time frame of the early endosome of endolysosomal processing. This system may be useful in cytoplasmic delivery of biomolecular drugs such as peptides, proteins, oligonucleotides, and DNA.

  1. Approaches of Novel drug delivery systems for Anti-HIV agents

    Directory of Open Access Journals (Sweden)

    Vedha Hari B. N

    2013-12-01

    Full Text Available The Human Immunodeficiency Virus (HIV is a pandemic disease spreading very rapidly all over the world, causing approximately 15,000 or more new infections every day and the community acquiring sexually transmitted infections (STIs is prone to easily acquire this HIV infections. The objective of the current review is to describe the comprehensiveness of the various advanced anti-HIV drug delivery systems and compounds that have been developed for targeting drugs to the macrophages, gastric mucosa and brain. Novel drug delivery system gives an opportunity to bypass the shortcomings related to the anti-retroviral treatment. It helps in addressing towards the complexity of dosage form development such as instability, insolubility and limited entrapment of the drugs. Several optional routes have been identified for the management of the ARV therapy which includes transdermal, mucosal (vaginal, rectal, buccal, etc. and also lymphatic delivery, with the application of novel systems like nanoparticles, vesicular systems (liposomes, niosomes, ethosomes, emulsomes, micellar assemblies, etc. This review spotlights the prospectives of novel drug release systems used in preventing the transmission and treatment of retroviral infections.

  2. Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy.

    Directory of Open Access Journals (Sweden)

    Adam Szulkin

    Full Text Available BACKGROUND: Malignant mesothelioma cells have an epithelioid or sarcomatoid morphology, both of which may be present in the same tumor. The sarcomatoid phenotype is associated with worse prognosis and heterogeneity of mesothelioma cells may contribute to therapy resistance, which is often seen in mesothelioma. This study aimed to investigate differences in sensitivity between mesothelioma cell lines to anti-cancer drugs. We studied two novel drugs, selenite and bortezomib and compared their effect to four conventional drugs. We also investigated the immunoreactivity of potential predictive markers for drug sensitivity; Pgp, MRP-1, ERCC1, RRM1, TS, xCT and proteasome 20S subunit. MATERIALS AND METHODS: We treated six mesothelioma cell lines with selenite, bortezomib, carboplatin, pemetrexed, doxorubicin or gemcitabine as single agents and in combinations. Viability was measured after 24 and 48 hours. Immunocytochemistry was used to detect predictive markers. RESULTS: As a single agent, selenite was effective on four out of six cell lines, and in combination with bortezomib yielded the greatest response in the studied mesothelioma cell lines. Cells with an epithelioid phenotype were generally more sensitive to the different drugs than the sarcomatoid cells. Extensive S-phase arrest was seen in pemetrexed-sensitive cell lines. MRP-1 predicted sensitivity of cell lines to treatment with carboplatin and xCT predicted pemetrexed effect. CONCLUSIONS: The observed heterogeneity in sensitivity of mesothelioma cell lines with different morphology highlights the need for more individualized therapy, requiring development of methods to predict drug sensitivity of individual tumors. Selenite and bortezomib showed a superior effect compared to conventional drugs, motivating clinical testing of these agents as future treatment regime components for patients with malignant mesothelioma.

  3. Highly sensitive dendrimer-based nanoplasmonic biosensor for drug allergy diagnosis.

    Science.gov (United States)

    Soler, Maria; Mesa-Antunez, Pablo; Estevez, M-Carmen; Ruiz-Sanchez, Antonio Jesus; Otte, Marinus A; Sepulveda, Borja; Collado, Daniel; Mayorga, Cristobalina; Torres, Maria Jose; Perez-Inestrosa, Ezequiel; Lechuga, Laura M

    2015-04-15

    A label-free biosensing strategy for amoxicillin (AX) allergy diagnosis based on the combination of novel dendrimer-based conjugates and a recently developed nanoplasmonic sensor technology is reported. Gold nanodisks were functionalized with a custom-designed thiol-ending-polyamido-based dendron (d-BAPAD) peripherally decorated with amoxicilloyl (AXO) groups (d-BAPAD-AXO) in order to detect specific IgE generated in patient's serum against this antibiotic during an allergy outbreak. This innovative strategy, which follows a simple one-step immobilization procedure, shows exceptional results in terms of sensitivity and robustness, leading to a highly-reproducible and long-term stable surface which allows achieving extremely low limits of detection. Moreover, the viability of this biosensor approach to analyze human biological samples has been demonstrated by directly analyzing and quantifying specific anti-AX antibodies in patient's serum without any sample pretreatment. An excellent limit of detection (LoD) of 0.6ng/mL (i.e. 0.25kU/L) has been achieved in the evaluation of clinical samples evidencing the potential of our nanoplasmonic biosensor as an advanced diagnostic tool to quickly identify allergic patients. The results have been compared and validated with a conventional clinical immunofluorescence assay (ImmunoCAP test), confirming an excellent correlation between both techniques. The combination of a novel compact nanoplasmonic platform and a dendrimer-based strategy provides a highly sensitive label free biosensor approach with over two times better detectability than conventional SPR. Both the biosensor device and the carrier structure hold great potential in clinical diagnosis for biomarker analysis in whole serum samples and other human biological samples.

  4. PES1 regulates sensitivity of colorectal cancer cells to anticancer drugs

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Wei [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China); Qu, Like, E-mail: qulike@bjcancer.org [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China); Meng, Lin; Liu, Caiyun; Wu, Jian [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China); Shou, Chengchao, E-mail: scc@bjcancer.org [Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital and Institute, Beijing 100142 (China)

    2013-02-15

    Highlights: ► PES1 was overexpressed in diverse cancer cell lines. ► PES1-ablation enhances DNA damage response by decreasing DNA repair. ► PES1-ablation increases the sensitivity of HCT116 cells to chemotherapeutic agents. ► PES1-ablation is associated with diminished nuclear entry of RAD51. -- Abstract: PES1 (also known as Pescadillo), a nucleolar protein, was involved in biogenesis of ribosomal RNA. Up-regulation of PES1 has been documented in some human cancers, indicating that PES1 may play some crucial roles in tumorigenesis. In our previous study, it was found that silencing of PES1 resulted in decreased proliferation of colorectal cancer cells. We also noticed that depletion of PES1 altered expression profiles of diverse genes. In the present study, we validated the expression changes of a subset of genotoxic stress-related genes in PES1-silenced HCT116 cells by quantitative RT-PCR. The steady and etoposide-induced phosphorylated H2AX (γ-H2AX) were higher in PES1-silenced cells than in control cells. Besides, etoposide-induced γ-H2AX persisted longer in PES1-silenced cells after removing the etoposide. Next, results of comet assay revealed decreased DNA repair after PES1-ablation. PES1-ablated cells were more sensitive to chemotherapeutic agents, which could be reversed by reconstitution with exogenous PES1. Furthermore, deletion of PES1 diminished steady and DNA damage-induced levels of nuclear RAD51. Our results uncover a potential role of PES1 in chemoresistance by regulating DNA damage response in colorectal cancer cells.

  5. The drug sensitivity and transmission dynamics of human malaria on Nias Island, North Sumatra, Indonesia.

    Science.gov (United States)

    Fryauff, D J; Leksana, B; Masbar, S; Wiady, I; Sismadi, P; Susanti, A I; Nagesha, H S; Syafruddin; Atmosoedjono, S; Bangs, M J; Baird, J K

    2002-07-01

    Nias Island, off the north-western coast of Sumatra, Indonesia, was one of the first locations in which chloroquine-resistant Plasmodium vivax malaria was reported. This resistance is of particular concern because its ancient megalithic culture and the outstanding surfing conditions make the island a popular tourist destination. International travel to and from the island could rapidly spread chloroquine-resistant strains of P. vivax across the planet. The threat posed by such strains, locally and internationally, has led to the routine and periodic re-assessment of the efficacy of antimalarial drugs and transmission potential on the island. Active case detection identified malaria in 124 (17%) of 710 local residents whereas passive case detection, at the central health clinic, confirmed malaria in 77 (44%) of 173 cases of presumed 'clinical malaria'. Informed consenting volunteers who had malarial parasitaemias were treated, according to the Indonesian Ministry of Health's recommendations, with sulfadoxine-pyrimethamine (SP) on day 0 (for P. falciparum) or with chloroquine (CQ) on days 0, 1 and 2 (for P. vivax). Each volunteer was then monitored for clinical and parasite response until day 28. Recurrent parasitaemia by day 28 treatment was seen in 29 (83%) of the 35 P. falciparum cases given SP (14, 11 and four cases showing RI, RII and RIII resistance, respectively). Recurrent parasitaemia was also observed, between day 11 and day 21, in six (21%) of the 28 P. vivax cases given CQ. Although the results of quantitative analysis confirmed only low prevalences of CQ-resistant P. vivax malaria, the prevalence of SP resistance among the P. falciparum cases was among the highest seen in Indonesia. When the parasites present in the volunteers with P. falciparum infections were genotyped, mutations associated with pyrimethamine resistance were found at high frequency in the dhfr gene but there was no evidence of selection for sulfadoxine resistance in the dhps gene

  6. B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides.

    Science.gov (United States)

    Schwamb, Janine; Feldhaus, Valeska; Baumann, Michael; Patz, Michaela; Brodesser, Susanne; Brinker, Reinhild; Claasen, Julia; Pallasch, Christian P; Hallek, Michael; Wendtner, Clemens-Martin; Frenzel, Lukas P

    2012-11-08

    Survival of chronic lymphocytic leukemia (CLL) cells is triggered by several stimuli, such as the B-cell receptor (BCR), CD40 ligand (CD40L), or interleukin-4 (IL-4). We identified that these stimuli regulate apoptosis resistance by modulating sphingolipid metabolism. Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of proapoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared with untreated controls. Antiapoptotic glucosylceramide levels were significantly increased after BCR cross-linking. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via UDP-glucose ceramide glucosyltransferase (UGCG). Besides specific UGCG inhibitors, our data demonstrate that IgM-mediated UGCG expression was inhibited by the novel and highly effective PI3Kδ and BTK inhibitors CAL-101 and PCI-32765, which reverted IgM-induced resistance toward apoptosis of CLL cells. Sphingolipids were recently shown to be crucial for mediation of apoptosis via mitochondria. Our data reveal ABT-737, a mitochondria-targeting drug, as interesting candidate partner for PI3Kδ and BTK inhibition, resulting in synergistic apoptosis, even under protection by the BCR. In summary, we identified the mode of action of novel kinase inhibitors CAL-101 and PCI-32765 by controlling the UGCG-mediated ceramide/glucosylceramide equilibrium as a downstream molecular switch of BCR signaling, also providing novel targeted treatment options beyond current chemotherapy-based regimens.

  7. A drug-sensitive genetic network masks fungi from the immune system.

    Directory of Open Access Journals (Sweden)

    Robert T Wheeler

    2006-04-01

    Full Text Available Fungal pathogens can be recognized by the immune system via their beta-glucan, a potent proinflammatory molecule that is present at high levels but is predominantly buried beneath a mannoprotein coat and invisible to the host. To investigate the nature and significance of "masking" this molecule, we characterized the mechanism of masking and consequences of unmasking for immune recognition. We found that the underlying beta-glucan in the cell wall of Candida albicans is unmasked by subinhibitory doses of the antifungal drug caspofungin, causing the exposed fungi to elicit a stronger immune response. Using a library of bakers' yeast (Saccharomyces cerevisiae mutants, we uncovered a conserved genetic network that is required for concealing beta-glucan from the immune system and limiting the host response. Perturbation of parts of this network in the pathogen C. albicans caused unmasking of its beta-glucan, leading to increased beta-glucan receptor-dependent elicitation of key proinflammatory cytokines from primary mouse macrophages. By creating an anti-inflammatory barrier to mask beta-glucan, opportunistic fungi may promote commensal colonization and have an increased propensity for causing disease. Targeting the widely conserved gene network required for creating and maintaining this barrier may lead to novel broad-spectrum antimycotics.

  8. Cell Line Derived 5-FU and Irinotecan Drug-Sensitivity Profiles Evaluated in Adjuvant Colon Cancer Trial Data

    DEFF Research Database (Denmark)

    Buhl, Ida Kappel; Gerster, Sarah; Delorenzi, Mauro

    2016-01-01

    PURPOSE: This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. METHODS: To test if an irinotecan signature and a SN-38 signature could identify...... patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer...... patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy. RESULTS: There was no statistically...

  9. Assessment of the Worldwide Antimalarial Resistance Network Standardized Procedure for In Vitro Malaria Drug Sensitivity Testing Using SYBR Green Assay for Field Samples with Various Initial Parasitemia Levels.

    Science.gov (United States)

    Cheruiyot, Agnes C; Auschwitz, Jennifer M; Lee, Patricia J; Yeda, Redemptah A; Okello, Charles O; Leed, Susan E; Talwar, Mayank; Murthy, Tushar; Gaona, Heather W; Hickman, Mark R; Akala, Hoseah M; Kamau, Edwin; Johnson, Jacob D

    2016-04-01

    The malaria SYBR green assay, which is used to profilein vitrodrug susceptibility ofPlasmodium falciparum, is a reliable drug screening and surveillance tool. Malaria field surveillance efforts provide isolates with various low levels of parasitemia. To be advantageous, malaria drug sensitivity assays should perform reproducibly among various starting parasitemia levels rather than at one fixed initial value. We examined the SYBR green assay standardized procedure developed by the Worldwide Antimalarial Resistance Network (WWARN) for its sensitivity and ability to accurately determine the drug concentration that inhibits parasite growth by 50% (IC50) in samples with a range of initial parasitemia levels. The initial sensitivity determination of the WWARN procedure yielded a detection limit of 0.019% parasitemia.P. falciparumlaboratory strains and field isolates with various levels of initial parasitemia were then subjected to a range of doses of common antimalarials. The IC50s were comparable for laboratory strains with between 0.0375% and 0.6% parasitemia and for field isolates with between 0.075% and 0.6% parasitemia for all drugs tested. Furthermore, assay quality (Z') analysis indicated that the WWARN procedure displays high robustness, allowing for drug testing of malaria field samples within the derived range of initial parasitemia. The use of the WWARN procedure should allow for the inclusion of more malaria field samples in malaria drug sensitivity screens that would have otherwise been excluded due to low initial parasitemia levels.

  10. Radiological Findings of Extensively Drug-Resistant Pulmonary Tuberculosis in Non-AIDS Adults: Comparisons with Findings of Multidrug-Resistant and Drug-Sensitive Tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Ji Hoon; Lee, Ho Yun; Lee, Kyung Soo; Koh, Won Jung; Kwon, O Jung; Yi, Chin A; Kim, Tae Sung; Chung, Myung Jin [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2009-06-15

    This study was designed to describe the radiological findings of extensively drug-resistant (XDR) pulmonary tuberculosis (TB) and to compare the observed findings with findings of drug-sensitive (DS) and non-XDR multidrug- resistant (MDR) TB in non-AIDS patients. From September 1994 to December 2007, 53 MDR TB patients (M:F = 32:21; mean age, 38 years) and 15 XDR TB non-AIDS patients (M:F = 8:7; mean age, 36 years) were enrolled in the study. All of the MDR TB patients had received no treatment or less than one month of anti-TB treatment. In addition, all XDR TB patients received either no anti-TB treatment or only first-line anti-TB drugs. In addition, 141 consecutive DS TB patients (M:F = 79:62; mean age, 51 years) were also enrolled in the study for comparison. Chest radiograph, CT and demographic findings were reviewed and were compared among the three patient groups. For patients with XDR TB, the most frequent radiographic abnormalities were nodules (15 of 15 patients, 100%), reticulo-nodular densities (11 of 15, 73%), consolidation (9 of 15, 60%) and cavities (7 of 15, 47%) that were located mainly in the upper and middle lung zones. As seen on radiographs, significant differences were found for the frequency of nodules and ground-glass opacity lesions (all p < 0.001) (more frequent in DS TB patients than in MDR and XDR TB patients). For the use of CT, significant differences (more frequent in MDR and XDR TB patients) were found for the frequency of multiple cavities, nodules and bronchial dilatation (p = 0.001 or p < 0.001). Patients with MDR TB and XDR TB were younger as compared to patients with DS TB (p < 0.001). Imaging findings were not different between patients with MDR TB and XDR TB. By observation of multiple cavities, nodules and bronchial dilatation as depicted on CT in young patients with acid-fast bacilli (AFB) positive sputum, the presence of MDR TB or XDR TB rather than DS TB can be suggested. There is no significant difference in imaging

  11. The CYP3A4 inhibitor intraconazole does not affect the pharmacokinetics of a new calcium-sensitizing drug levosimendan.

    Science.gov (United States)

    Antila, S; Honkanen, T; Lehtonen, L; Neuvonen, P J

    1998-08-01

    Itraconazole is a potent inhibitor of CYP3A4 isoenzyme and it can cause clinically significant interactions with some other drugs. Levosimendan is a new calcium-sensitizing drug intended for congestive heart failure. We aimed to study possible interactions of itraconazole with levosimendan in healthy volunteers. Twelve healthy male volunteers were included into a randomized, double-blind, two-phase crossover study. A wash-out period of 4 weeks was held between the phases. The subjects were given orally itraconazole 200 mg or placebo daily for 5 days. On the fifth day, they received a single oral dose of 2 mg of levosimendan. Levosimendan plasma concentrations were determined up to 12 hours and ECG, heart rate, and blood pressure followed-up to 8 hours after intake of levosimendan. Itraconazole had no significant effects on the pharmacokinetic parameters of levosimendan. Neither were there any differences in heart rate, PQ-, QTc- or QRS intervals between the placebo and itraconazole phases. The systolic blood pressure was decreased slightly more (p < 0.05) during the itraconazole phase than during the placebo phase. In conclusion, because the potent CYP3A4 inhibitor itraconazole had no significant pharmacokinetic interaction with levosimendan, interactions with CYP3A4 inhibitor, and oral levosimendan are unlikely.

  12. MSH3 mismatch repair protein regulates sensitivity to cytotoxic drugs and a histone deacetylase inhibitor in human colon carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Jae Myung Park

    Full Text Available BACKGROUND: MSH3 is a DNA mismatch repair (MMR gene that undergoes frequent somatic mutation in colorectal cancers (CRCs with MMR deficiency. MSH3, together with MSH2, forms the MutSβ heteroduplex that interacts with interstrand cross-links induced by drugs such as cisplatin. To date, the impact of MSH3 on chemosensitivity is unknown. METHODS: We utilized isogenic HCT116 (MLH1-/MSH3- cells where MLH1 is restored by transfer of chromosome 3 (HCT116+ch3 and also MSH3 by chromosome 5 (HCT116+3+5. We generated HCT116+3+5, SW480 (MLH1+/MSH3+ and SW48 (MLH1-/MSH3+ cells with shRNA knockdown of MSH3. Cells were treated with 5-fluorouracil (5-FU, SN-38, oxaliplatin, or the histone deacetylase (HDAC inhibitor PCI-24781 and cell viability, clonogenic survival, DNA damage and apoptosis were analyzed. RESULTS: MSH3-deficient vs proficient CRC cells showed increased sensitivity to the irinotecan metabolite SN-38 and to oxaliplatin, but not 5-FU, as shown in assays for apoptosis and clonogenic survival. In contrast, suppression of MLH1 attenuated the cytotoxic effect of 5-FU, but did not alter sensitivity to SN-38 or oxaliplatin. The impact of MSH3 knockdown on chemosensitivity to SN-38 and oxaliplatin was maintained independent of MLH1 status. In MSH3-deficient vs proficient cells, SN-38 and oxaliplatin induced higher levels of phosphorylated histone H2AX and Chk2, and similar results were found in MLH1-proficient SW480 cells. MSH3-deficient vs proficient cells showed increased 53BP1 nuclear foci after irradiation, suggesting that MSH3 can regulate DNA double strand break (DSB repair. We then utilized PCI-24781 that interferes with homologous recombination (HR indicated by a reduction in Rad51 expression. The addition of PCI-24781 to oxaliplatin enhanced cytotoxicity to a greater extent compared to either drug alone. CONCLUSION: MSH3 status can regulate the DNA damage response and extent of apoptosis induced by chemotherapy. The ability of MSH3 to regulate

  13. Restoration of sensitivity to salinomycin in Eimeria following 5 flocks of broiler chickens reared in floor-pens using drug programs and vaccination to control coccidiosis.

    Science.gov (United States)

    Chapman, H D; Jeffers, T K

    2015-05-01

    Five successive flocks of broilers were reared in floor-pens and given different drug programs or were vaccinated against coccidiosis. Oocysts of Eimeria were isolated from the litter of pens during the fifth flock and their sensitivity to salinomycin (Sal) investigated by measuring new oocyst production following infection of medicated and unmedicated birds. Parasites obtained following 5 flocks given Sal were not well-controlled and it was concluded that they were partially resistant to the drug. Parasites obtained following 4 unmedicated flocks and one medicated flock were better controlled by Sal and it was concluded that in the absence of continuous medication there had been an improvement in drug efficacy. Sal almost completely suppressed oocyst production of isolates from treatments in which medication was followed by vaccination, indicating that when a drug program is followed by vaccination, restoration of sensitivity to Sal had occurred.

  14. Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty

    OpenAIRE

    Verheij, Michel M. M.; Veenvliet, Jesse V.; Groot Kormelink, Tom; Steenhof, Maaike; Cools, Alexander R.

    2009-01-01

    Rationale The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences. Objectives A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment. Methods Low responders (LR) and high responders (HR) to nove...

  15. 人类免疫缺陷病毒感染者混合感染丙型和乙型肝炎病毒后对高效抗逆转录病毒治疗疗效的影响%The influence of human immunodeficiency virus co-infection with hepatitis C virus and hepatitis B virus on the efficacy of high active anti-retroviral therapy

    Institute of Scientific and Technical Information of China (English)

    李晓菲; 阚全程; 何云; 余祖江; 李志勤; 梁红霞

    2010-01-01

    Objective To evaluate the impact of HIV co-infection with HCV or HBV on the efficacy of highly active anti-retroviral therapy (HARRT). Methods The patients were divided into three groups: HIV + HBV + HCV co-infection group ( 23 patients), HIV + HCV co-infection group ( 166 patients), and HIV-only group (178 patients). HIV RNA, HCV RNA or HBV DNA were detected by real time PCR before treatment and 1,3,6,9 and 12 monthes after treatment, meanwhile the counts of CD4+ T lymphocyte and liver function including ALT, AST and TBil were tested. Results During one-year HAART, HIV RNA of HIV-only group, HIV + HBV + HCV co-infection group and HIV + HCV co-infection group decreased significantly from (6.78 ± 1.08), (6.23 ± 1.34), (6.54 ± 1.23) lg copies/ml to (0.53 ±0.15), (0.67 ±0.16),(0.43 ±0.11 ) lg copies/ml respectively (P<.001 ). And CD4+ T lymphocyte counts of the three groups elevated significantly from ( 197 ± 127), (184 ± 113), (213 ± 143) cells/μl to (382 ±74), (383 ±70),(378 ±76) cells/μl respectively (P <0.001 ). However there were no differences among the three groups in HIV RNA and CD4+ T lymphocyte counts. There were no differences in liver functions including ALT,AST and TBil among the three groups. Conclusiom HIV co-infected with HBV and/or HCV does not impact on the efficacy of HAART. What more, HAART does not impact HCV replication.%目的 观察HIV感染者合并HCV和HBV感染后对高效抗逆转录病毒治疗(HAART)疗效的影响.方法 对某地区HIV、HCV共感染患者166例(HIV+HCV组),HIV、HCV和HBV混合感染患者23例(H1V+HCV+HBV组)及单纯HIV感染者178例,给予1年的HAART治疗,观察3组患者病毒学反应、免疫学反应和肝功能动态变化.以流式细胞仪检测外周血CD4+T淋巴细胞;实时PCR定量检测HCV、HIV和HBV病毒载量.结果 单纯HIV感染组、HIV+HCV+HBV组和HIV+HCV组经HAART 1年后,HIV病毒载量分别由治疗前(6.78±1.08)、(6.23±1.34)、(6.54±1.23)lg拷贝/ml下降至(0

  16. Driving HIV-1 into a Vulnerable Corner by Taking Advantage of Viral Adaptation and Evolution

    Science.gov (United States)

    Harada, Shigeyoshi; Yoshimura, Kazuhisa

    2017-01-01

    Anti-retroviral therapy (ART) is crucial for controlling human immunodeficiency virus type-1 (HIV-1) infection. Recently, progress in identifying and characterizing highly potent broadly neutralizing antibodies has provided valuable templates for HIV-1 therapy and vaccine design. Nevertheless, HIV-1, like many RNA viruses, exhibits genetically diverse populations known as quasispecies. Evolution of quasispecies can occur rapidly in response to selective pressures, such as that exerted by ART and the immune system. Hence, rapid viral evolution leading to drug resistance and/or immune evasion is a significant barrier to the development of effective HIV-1 treatments and vaccines. Here, we describe our recent investigations into evolutionary pressure exerted by anti-retroviral drugs and monoclonal neutralizing antibodies (NAbs) on HIV-1 envelope sequences. We also discuss sensitivities of HIV-1 escape mutants to maraviroc, a CCR5 inhibitor, and HIV-1 sensitized to NAbs by small-molecule CD4-mimetic compounds. These studies help to develop an understanding of viral evolution and escape from both anti-retroviral drugs and the immune system, and also provide fundamental insights into the combined use of NAbs and entry inhibitors. These findings of the adaptation and evolution of HIV in response to drug and immune pressure will inform the development of more effective antiviral therapeutic strategies. PMID:28360890

  17. Controlled release from thermo-sensitive PNVCL-co-MAA electrospun nanofibers: The effects of hydrophilicity/hydrophobicity of a drug.

    Science.gov (United States)

    Liu, Lin; Bai, Shaoqing; Yang, Huiqin; Li, Shubai; Quan, Jing; Zhu, Limin; Nie, Huali

    2016-10-01

    The thermo-sensitive copolymer poly(N-vinylcaprolactam-co-methacrylic acid) (PNVCL-co-MAA) was synthesized by free radical polymerization and the resulting nanofibers were fabricated using an electrospinning process. The molecular weight of the copolymer was adjusted by varying the content of methacrylic acid (MAA) while keeping that of N-vinylcaprolactam (NVCL) constant. Hydrophilic captopril and hydrophobic ketoprofen were used as model drugs, and PNVCL-co-MAA nanofibers were used as the drug carrier to investigate the effects of drug on its release properties from nanofibers at different temperatures. The results showed that slow release over several hours was observed at 40°C (above the lower critical solution temperature (LCST) of PNVCL-co-MAA), while the drugs exhibited a burst release of several seconds at 20°C (below the LCST). Drug release slowed with increasing content of the hydrophobic monomer NVCL. The hydrophilic captopril was released at a higher rate than the hydrophobic ketoprofen. The drug release characteristics were dependent on the temperature, the portion of hydrophilic groups and hydrophobic groups in the copolymer and hydrophilicity/hydrophobicity of drug. Study on the mechanism of release showed that Korsmeyer-Peppas model as a major drug release mechanism. Given these results, the PNVCL-co-MAA copolymers are proposed to have useful applications in intellectual drug delivery systems.

  18. FORMULATION AND EVALUATION OF GASTRO RETENTIVE DRUG DELIVERY SYSTEM OF STAVUDINE

    Directory of Open Access Journals (Sweden)

    Voleti. Vijaya Kumar

    2011-02-01

    Full Text Available The present study was designed to formulate and evaluate hydro dynamically balanced Floating Drug Delivery Systems as controlled release modules, which prolongs the release rate of the drugs. Stavudine is an anti- retroviral, reverse transcriptase inhibitor (Nucleoside. Stavudine triphosphate inhibits the HIV reverse transcriptase by competing with natural substrate, thymidine triphosphate. It also causes termination of DNA synthesis by incorporating into it. Formulation of Stavudine as gastro retentive drug delivery systems (GRDDS is especially advantageous over other prolonged type drug delivery systems and conventional tablets because the drug is having absorption window in the duodenum and jejunum level and having relatively short half life. Stavudine was taken as the model drug to optimized formulations was prepared. The floating ability of lipoidal fatty polymers Gelucire 13/01, Gelucire 43/ 01 is compared over various polymers like HPMC, HPMC K4M, Ethocel, Sodium carboxy methyl cellulose. The drug: polymer ratios used to prepare the different formulations were 1:0.5 and 1:1. Blend of all the formulations are prepared by melt granulation technique. All the tablets were subjected for dissolution study using USP dissolution apparatus (USP XXIII paddle method and data were analyzed at 265nm. The drug release of Stavudine from all the formulations followed zero order kinetics. According to the dissolution profiles of formulations drug retardation was enhanced in 1:1 Drug: Polymer proportion than 1:0.5 proportions. Of all the formulations in which Gelucire 13/01 is used as a floating polymer, has retarded the drug successfully upto 12 hours.

  19. Controlling the chemical stability of a moisture-sensitive drug product through monitoring and identification of coating process microenvironment.

    Science.gov (United States)

    Kestur, Umesh; Pandey, Preetanshu; Badawy, Sherif; Lin, Judy; Desai, Divyakant

    2014-12-10

    The objective of this work was to monitor and identify the impact of coating microenvironment, as measured by PyroButtons(®) data loggers, on the chemical stability of a moisture-sensitive drug molecule brivanib alaninate (BA). BA tablets were coated at two different scales (15 and 24 in pan). PyroButtons(®) data loggers were allowed to move freely within the tablet bed to record the temperature and relative humidity conditions of the tablet bed. The tablet moisture content at the end of the coating runs, and the rate of hydrolysis of the BA tablets based on HPLC analysis was found to be a function of the coating thermodynamic microenvironment. Wetter coating conditions resulted in tablets with higher water content and showed greater degradation upon storage. The coating process which yielded acceptable stability in a 15 in coater was transferred to a 24 in coater by maintaining similar tablet-bed relative humidity and temperature conditions. This was compared to a traditional scale-up approach where the environmental equivalency factor (EEF) was matched between scales during coating. The moisture content observed across the two scales indicated that maintaining a similar tablet-bed microenvironment ensured consistent results between scales.

  20. High sensitive and selective HPTLC method assisted by digital image processing for simultaneous determination of catecholamines and related drugs.

    Science.gov (United States)

    Sima Tuhuţiu, Ioana Anamaria; Casoni, Dorina; Sârbu, Costel

    2013-09-30

    A highly sensitive and selective thin layer chromatographic (TLC) method was developed for simultaneous determination of catecholamines and their related drugs using a new detection method and digital image processing of chromatographic plates. For the quantitative evaluation of the investigated compounds, the chromatographic separation was followed by spraying the plate with 0.02% solution of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) in ethanol. The BioDit Thin Layer Chromatography (TLC) Scanner device and advanced specific software (ImageDecipher-TLC, Sorbfil TLC Videodensitometer and JustTLC) were used for the detection and quantification of chromatographic spots. For an accurate determination, the RGB colored images of the bright-white spots detected against a purple background were inverted and processed after their conversion into green scale. The results showed a strongly linear correlation between area (R(2)>0.99) and volume (R(2)>0.99) of spots and concentration of investigated compounds in all cases. The limit of detection (LOD) and the limit of quantification (LOQ) were below 49.3 ng/spot and 69.6 ng/spot respectively in all cases. The evaluation of the method was performed using different pharmaceutical samples spiked with the investigated amines and validated with respect to accuracy and precision.

  1. Confocal fluorescence microscopy: An ultra-sensitive tool used to evaluate intracellular antiretroviral nano-drug delivery in HeLa cells

    Directory of Open Access Journals (Sweden)

    Subhra Mandal

    2015-08-01

    Full Text Available In the last decade, confocal fluorescence microscopy has emerged as an ultra-sensitive tool for real-time study of nanoparticles (NPs fate at the cellular-level. According to WHO 2007 report, Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS is still one of the world’s major health threats by claiming approximately 7,000 new infections daily worldwide. Although combination antiretroviral drugs (cARV therapy has improved the life-expectancy of HIV-infected patients, routine use of high doses of cARV has serious health consequences and requires complete adherence to the regimen for success. Thus, our research goal is to fabricate long-acting novel cARV loaded poly(lactide-co-glycolic acid (PLGA nanoparticles (cARV-NPs as drug delivery system. However, important aspects of cARV-NPs that require special emphasis are their cellular-uptake, potency, and sustained drug release efficiency over-time. In this article, ultra-sensitive confocal microscopy is been used to evaluate the uptake and sustained drug release kinetics of cARV-NPs in HeLa cells. To evaluate with the above goal, instead of cARV-drug, Rhodamine6G dye (fluorescent dye loaded NPs (Rho6G NPs have been formulated. To correlate the Rhodamin6G release kinetics with the ARV release from NPs, a parallel HPLC study was also performed. The results obtained indicate that Rho6G NPs were efficiently taken up at low concentration (<500 ng/ml and that release was sustained for a minimum of 4 days of treatment. Therefore, high drug assimilation and sustained release properties of PLGA-NPs make them an attractive vehicle for cARV nano-drug delivery with the potential to reduce drug dosage as well as the number of drug administrations per month.

  2. Confocal fluorescence microscopy: An ultra-sensitive tool used to evaluate intracellular antiretroviral nano-drug delivery in HeLa cells

    Science.gov (United States)

    Mandal, Subhra; Zhou, You; Shibata, Annemarie; Destache, Christopher J.

    2015-08-01

    In the last decade, confocal fluorescence microscopy has emerged as an ultra-sensitive tool for real-time study of nanoparticles (NPs) fate at the cellular-level. According to WHO 2007 report, Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) is still one of the world's major health threats by claiming approximately 7,000 new infections daily worldwide. Although combination antiretroviral drugs (cARV) therapy has improved the life-expectancy of HIV-infected patients, routine use of high doses of cARV has serious health consequences and requires complete adherence to the regimen for success. Thus, our research goal is to fabricate long-acting novel cARV loaded poly(lactide-co-glycolic acid) (PLGA) nanoparticles (cARV-NPs) as drug delivery system. However, important aspects of cARV-NPs that require special emphasis are their cellular-uptake, potency, and sustained drug release efficiency over-time. In this article, ultra-sensitive confocal microscopy is been used to evaluate the uptake and sustained drug release kinetics of cARV-NPs in HeLa cells. To evaluate with the above goal, instead of cARV-drug, Rhodamine6G dye (fluorescent dye) loaded NPs (Rho6G NPs) have been formulated. To correlate the Rhodamin6G release kinetics with the ARV release from NPs, a parallel HPLC study was also performed. The results obtained indicate that Rho6G NPs were efficiently taken up at low concentration (<500 ng/ml) and that release was sustained for a minimum of 4 days of treatment. Therefore, high drug assimilation and sustained release properties of PLGA-NPs make them an attractive vehicle for cARV nano-drug delivery with the potential to reduce drug dosage as well as the number of drug administrations per month.

  3. Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single-walled carbon nanotubes as tumor-targeting drug delivery system.

    Science.gov (United States)

    Zhu, Xiali; Xie, Yingxia; Zhang, Yingjie; Huang, Heqing; Huang, Shengnan; Hou, Lin; Zhang, Huijuan; Li, Zhi; Shi, Jinjin; Zhang, Zhenzhong

    2014-11-01

    This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 ± 5.6 nm, and drug entrapment efficiency was 86.5 ± 3.7%. The drug release test showed that doxorubicin released more quickly at 42℃ than at 37℃. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs.

  4. Solid-state probe based electrochemical aptasensor for cocaine: a potentially convenient, sensitive, repeatable, and integrated sensing platform for drugs.

    Science.gov (United States)

    Du, Yan; Chen, Chaogui; Yin, Jianyuan; Li, Bingling; Zhou, Ming; Dong, Shaojun; Wang, Erkang

    2010-02-15

    Aptamers, which are artificial oligonucleotides selected in vitro, have been employed to design novel biosensors (i.e., aptasensors). In this work, we first constructed a label-free electrochemical aptasensor introducing a probe immobilization technique by the use of a layer-by-layer (LBL) self-assembled multilayer with ferrocene-appended poly(ethyleneimine) (Fc-PEI) on an indium tin oxide (ITO) array electrode for detection of cocaine. The Fc-PEI and gold nanoparticles (AuNPs) were LBL assembled on the electrode surface via electrostatic interaction. Then, cocaine aptamer fragments, SH-C2, were covalently labeled onto the outermost AuNP layer. When the target cocaine and cocaine aptamer C1 were present simultaneously, the SH-C2 layer hybridized partly with C1 to bind the cocaine, which led to a decreased differential pulse voltammetry (DPV) signal of Fc-PEI. This DPV signal change could be used to sensitively detect cocaine with the lowest detectable concentration down to 0.1 microM and the detection range up to 38.8 microM, which falls in the the expected range for medical use of detecting drug abuse involving cocaine. Meanwhile, the sensor was specific to cocaine in complex biologic fluids such as human plasma, human saliva, etc. The sensing strategy had general applicability, and the detection of thrombin could also be realized, displayed a low detection limit, and exhibited worthiness to other analytes. The aptasensor based on the array electrode held promising potential for integration of the sensing ability in multianalysis for simultaneous detection.

  5. Novel pH-sensitive IPNs of polyacrylamide-g-gum ghatti and sodium alginate for gastro-protective drug delivery.

    Science.gov (United States)

    Boppana, Rashmi; Krishna Mohan, G; Nayak, Usha; Mutalik, Srinivas; Sa, Biswanath; Kulkarni, Raghavendra V

    2015-04-01

    This article reports the development of pH-sensitive interpenetrating polymer network (IPN) microbeads using polyacrylamide-grafted-gum ghatti (PAAm-g-GG) and sodium alginate (SA) for gastro-protective controlled delivery of ketoprofen. We have synthesized PAAm-grafted-GG copolymer under microwave irradiation using cerric ammonium nitrate as reaction initiator; further, the PAAm-g-GG was converted to pH-sensitive copolymer through alkaline hydrolysis. Sophisticated instrumentation techniques were used to characterize PAAm-g-GG. The IPN microbeads of PAAm-g-GG and SA, pre-loaded with ketoprofen were prepared by dual crosslinking using Ca(2+) ions and glutaraldehyde (GA). The IPN microbeads demonstrated excellent pH-sensitive behavior as noted in the pulsatile swelling test and scanning electron microscopy. IPN microbeads also showed larger amount of drug release in buffer solution of pH 7.4 as compared to drug release in solution of pH 1.2. The in vivo pharmacokinetic, pharmacodynamic and stomach histopathology studies conducted on wistar rats confirmed the pH-sensitive controlled release of ketoprofen; IPN microbeads retarded the drug release in stomach resulting in reduced adverse effects of ketoprofen.

  6. Synthesis and Properties of pH-, Thermo-, and Salt-Sensitive Modified Poly(aspartic acid/Poly(vinyl alcohol IPN Hydrogel and Its Drug Controlled Release

    Directory of Open Access Journals (Sweden)

    Jingqiong Lu

    2015-01-01

    Full Text Available Modified poly(aspartic acid/poly(vinyl alcohol interpenetrating polymer network (KPAsp/PVA IPN hydrogel for drug controlled release was synthesized by a simple one-step method in aqueous system using poly(aspartic acid grafting 3-aminopropyltriethoxysilane (KH-550 and poly(vinyl alcohol (PVA as materials. The hydrogel surface morphology and composition were characterized by Fourier transform infrared spectroscopy (FTIR and scanning electron microscopy (SEM. The thermal stability was analyzed by thermogravimetric analysis (TGA. The swelling properties and pH, temperature, and salt sensitivities of KPAsp, KPAsp/PVA semi-interpenetrating polymer network (semi-IPN, and KPAsp/PVA IPN hydrogels were also investigated. All of the three hydrogels showed ampholytic pH-responsive properties, and swelling behavior was also extremely sensitive to the temperature, ionic strength, and cationic species. Finally, the drug controlled release properties of the three hydrogels were evaluated and results indicated that three hydrogels could control drug release by external surroundings stimuli. The drug controlled release properties of KPAsp/PVA IPN hydrogel are the most outstanding, and the correlative measured release profiles of salicylic acid at 37°C were 32.6 wt% at pH = 1.2 (simulated gastric fluid and 62.5 wt% at pH = 7.4 (simulated intestinal fluid, respectively. These results indicated that KPAsp/PVA IPN hydrogels are a promising carrier system for controlled drug delivery.

  7. Synthesis and Properties of pH-, Thermo-, and Salt-Sensitive Modified Poly(aspartic acid)/Poly(vinyl alcohol) IPN Hydrogel and Its Drug Controlled Release.

    Science.gov (United States)

    Lu, Jingqiong; Li, Yinhui; Hu, Deng; Chen, Xiaoling; Liu, Yongmei; Wang, Liping; Zhao, Yansheng

    2015-01-01

    Modified poly(aspartic acid)/poly(vinyl alcohol) interpenetrating polymer network (KPAsp/PVA IPN) hydrogel for drug controlled release was synthesized by a simple one-step method in aqueous system using poly(aspartic acid) grafting 3-aminopropyltriethoxysilane (KH-550) and poly(vinyl alcohol) (PVA) as materials. The hydrogel surface morphology and composition were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The thermal stability was analyzed by thermogravimetric analysis (TGA). The swelling properties and pH, temperature, and salt sensitivities of KPAsp, KPAsp/PVA semi-interpenetrating polymer network (semi-IPN), and KPAsp/PVA IPN hydrogels were also investigated. All of the three hydrogels showed ampholytic pH-responsive properties, and swelling behavior was also extremely sensitive to the temperature, ionic strength, and cationic species. Finally, the drug controlled release properties of the three hydrogels were evaluated and results indicated that three hydrogels could control drug release by external surroundings stimuli. The drug controlled release properties of KPAsp/PVA IPN hydrogel are the most outstanding, and the correlative measured release profiles of salicylic acid at 37°C were 32.6 wt% at pH = 1.2 (simulated gastric fluid) and 62.5 wt% at pH = 7.4 (simulated intestinal fluid), respectively. These results indicated that KPAsp/PVA IPN hydrogels are a promising carrier system for controlled drug delivery.

  8. Drug induced linear IgA disease with unusual features: Koebner phenomenon, local insulin sensitivity and annular blister of the nipples.

    Science.gov (United States)

    Rashid Dar, Nasser; Raza, Naeem

    2008-01-01

    Linear IgA disease is an autoimmune subepidermal bullous disease in which linear IgA deposits are found at the basement membrane zone. It is classically idiopathic but may be drug induced. We report on a patient with drug induced linear IgA disease who exhibited certain unusual and interesting clinical features including isomorphic Koebner response, annular blister of the nipples and local insulin sensitivity. To the best of our knowledge, these clinical features have not yet been reported in linear IgA disease.

  9. Ex Vivo Drug Sensitivity Profiles of Plasmodium falciparum Field Isolates from Cambodia and Thailand, 2005 to 2010, Determined by a Histidine-Rich Protein-2 Assay

    Science.gov (United States)

    2012-06-13

    01 JUN 2012 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Ex vivo drug sensitivity profiles of Plasmodium falciparum field...PCR (RT-PCR) targeting the 18 s rRNA gene. Specimens with a microscopically or RT-PCR confirmed malaria co- infection at time zero, Plasmodium vivax...one week. Drug solutions were stored at 2 – 8°C and used within 1 week of preparation. Plasmodium falciparum W2 reference clone and quality control W2

  10. Highly sensitive LC-MS/MS methods for the determination of seven human CYP450 activities using small oral doses of probe-drugs in human.

    Science.gov (United States)

    Grangeon, Alexia; Gravel, Sophie; Gaudette, Fleur; Turgeon, Jacques; Michaud, Veronique

    2017-01-01

    Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC-MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe-drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively. Serial plasma and urine samples were collected over an 8h period. The probe-drugs and their respective metabolites were measured in both human plasma and urine, except for omeprazole (plasma only) and chlorzoxazone (urine only). Samples were analyzed by high performance liquid chromatography with heated electrospray ionization tandem mass spectrometry (HPLC-HESI-MS/MS) using a Phenomenex Luna PFP (2) analytical column (3μm PFP(2) 150×3mm) for chromatographic separation. Optimal detection was achieved based on 3 different analytical methods; (1) isocratic elution with a mobile phase consisting of acetonitrile and water both fortified with 0.01% formic acid for the analysis of bupropion, tolbutamide, chlorzoxazone and their respective metabolites; (2) isocratic elution with a mobile phase composed of acetonitrile and ammonium formate (pH 3; 10mM) for omeprazole, dextromethorphan, midazolam and their metabolites; (3) for caffeine and paraxanthine, gradient elution using acetonitrile and 0.01% formic acid in water was used. All calibration functions were linear for all probe drugs and metabolites in both matrices over wide analytical ranges. The main advantages of our methods are the use of specific probe drugs available in most countries, the administration of small doses of probe drugs, small

  11. Amphiphilic polymer-mediated formation of laponite-based nanohybrids with robust stability and pH sensitivity for anticancer drug delivery.

    Science.gov (United States)

    Wang, Guoying; Maciel, Dina; Wu, Yilun; Rodrigues, João; Shi, Xiangyang; Yuan, Yuan; Liu, Changsheng; Tomás, Helena; Li, Yulin

    2014-10-08

    The development of pH-sensitive drug delivery nanosystems that present a low drug release at the physiological pH and are able to increase the extent of the release at a lower pH value (like those existent in the interstitial space of solid tumors (pH 6.5) and in the intracellular endolysosomal compartments (pH 5.0)) is very important for an efficient and safe cancer therapy. Laponite (LP) is a synthetic silicate nanoparticle with a nanodisk structure (25 nm in diameter and 0.92 nm in thickness) and negative-charged surface, which can be used for the encapsulation of doxorubicin (DOX, a cationic drug) through electrostatic interactions and exhibit good pH sensitivity in drug delivery. However, the colloidal instability of LP still limits its potential clinical applications. In this study, we demonstrate an elegant strategy to develop stable Laponite-based nanohybrids through the functionalization of its surface with an amphiphile PEG-PLA copolymer by a self-assembly process. The hydrophobic block of PEG-PLA acts as an anchor that binds to the surface of drug-loaded LP nanodisks, maintaining the core structure, whereas the hydrophilic PEG part serves as a protective stealth shell that improves the whole stability of the nanohybrids under physiological conditions. The resulting nanocarriers can effectively load the DOX drug (the encapsulation efficiency is 85%), and display a pH-enhanced drug release behavior in a sustained way. In vitro biological evaluation indicated that the DOX-loaded nanocarriers can be effectively internalized by CAL-72 cells (an osteosarcoma cell line), and exhibit a remarkable higher anticancer cytotoxicity than free DOX. The merits of Laponite/PEG-PLA nanohybrids, such as good cytocompatibility, excellent physiological stability, sustained pH-responsive release properties, and improved anticancer activity, make them a promising platform for the delivery of other therapeutic agents beyond DOX.

  12. A simultaneous determination of related substances by high performance liquid chromatography in a drug product using quality by design approach.

    Science.gov (United States)

    Tol, Trupti; Kadam, Nilesh; Raotole, Nilesh; Desai, Anita; Samanta, Gautam

    2016-02-05

    The combination of Abacavir, Lamivudine and Dolutegravir is an anti-retroviral formulation that displays high efficacy and superiority in comparison to other anti-retroviral combinations. Analysis of related substances in this combination drug product was very challenging due to the presence of nearly thirty peaks including the three active pharmaceutical ingredients (APIs), eleven known impurities and other pharmaceutical excipients. Objective of this study was to develop a single, selective, and robust high performance liquid chromatography method for the efficient separation of all peaks. Initially, one-factor-at-a-time (OFAT) approach was adopted to develop the method. But, it could not resolve all the critical peaks in such complex matrix. This led to the advent of two different HPLC methods for the determination of related substances, one for Abacavir and Lamivudine and the other for Dolutegravir. But, since analysis of a single sample using two methods instead of one is time and resource consuming and thus expensive, an attempt was made to develop a single and robust method by adopting quality by design (QbD) principles. Design of Experiments (DoE) was applied as a tool to achieve the optimum conditions through Response surface methodology with three method variables, pH, temperature, and mobile phase composition. As the study progressed, it was discovered that establishment of the design space was not viable due to the completely distant pH requirements of the two responses, i.e. (i) retention time for Lamivudine carboxylic acid and (ii) resolution between Abacavir impurity B and unknown impurity. Eventually, neglecting one of these two responses each time, two distinguished design spaces have been established and verified. Edge of failures at both design spaces indicate high probability of failure. It therefore, becomes very important to identify the most robust zone or normal operating range (NOR) within the design space with low risk of failure and high

  13. Toll-like receptor 7 controls the anti-retroviral germinal center response.

    Directory of Open Access Journals (Sweden)

    Edward P Browne

    2011-10-01

    Full Text Available The development of vaccines that can enhance immunity to viral pathogens is an important goal. However, the innate molecular pathways that regulate the strength and quality of the immune response remain largely uncharacterized. To define the role of Toll-like receptor (TLR signaling in control of a model retroviral pathogen, Friend virus (FV, I generated mice in which the TLR signaling adapter Myd88 was selectively deleted in dendritic cell (DC or in B cell lineages. Deletion of Myd88 in DCs had little effect on immune control of FV, while B cell specific deletion of Myd88 caused a dramatic increase in viral infectious centers and a significantly reduced antibody response, indicating that B cell-intrinsic TLR signaling plays a crucial role, while TLR signaling in DCs is less important. I then identified the single-stranded RNA sensing protein TLR7 as being required for antibody-mediated control of FV by analyzing mice deficient in TLR7. Remarkably, B cells in infected TLR7-deficient mice upregulated CD69 and CD86 early in infection, but failed to develop into germinal center B cells. CD4 T cell responses were also attenuated in the absence of TLR7, but CD8 responses were TLR7 independent, suggesting the existence of additional pathways for detection of retroviral particles. Together these results demonstrate that the vertebrate immune system detects retroviruses in vivo via TLR7 and that this pathway regulates a key checkpoint controlling development of germinal center B cells.

  14. Who is utilizing anti-retroviral therapy in Ghana: An analysis of ART service utilization

    Directory of Open Access Journals (Sweden)

    Dako-Gyeke Phyllis

    2012-10-01

    Full Text Available Abstract Introduction The global scale-up of antiretroviral therapy (ART for HIV patients has led to concerns regarding inequities in utilization of ART services in resource-limited contexts. In this paper, we describe regional and sex differentials in the distribution of ART among adult HIV patients in Ghana. We highlight the need for interventions to address the gender-based and geographic inequities related to the utilization of ART services in Ghana. Methods We reviewed National AIDS/STIs Control Program’s ART service provision records from January 2003 through December 2010, extracting data on adults aged 15+ who initiated ART in Ghana over a period of eight years. Data on the number of patients on treatment, year of enrollment, sex, and region were obtained and compared. Results The number of HIV patients receiving ART in Ghana increased more than 200-fold from 197 in 2003, to over 45,000 in 2010. However, for each of six continuous years (2005-2010 males comprised approximately one-third of adults newly enrolled on ART. As ART coverage has expanded in Ghana, the proportion of males receiving ART declined from 41.7% in 2004 to 30.1% in 2008 and to 27.6% in 2010. Also, there is disproportionate regional ART utilization across the country. Some regions report ART enrollment lower than their percent share of number of HIV infected persons in the country. Conclusions Attention to the comparatively fewer males initiating ART, as well as disproportionate regional ART utilization is urgently needed. All forms of gender-based inequities in relation to HIV care must be addressed in order for Ghana to realize successful outcomes at the population level. Policy makers in Ghana and elsewhere need to understand how gender-based health inequities in relation to HIV care affect both men and women and begin to design appropriate interventions.

  15. Late Reporting Among Newly Registered Patients for Anti Retroviral Therapy in a Central District Ujjain, India

    Directory of Open Access Journals (Sweden)

    Vidit Khandelwal, Yogesh D Sabde, Riddhi Pradhan, Mehta Chandra Sathsh

    2013-01-01

    Conclusion: Late reporting at the initiation of ART was reported in about one third of the patients which could adversely affect effectiveness of ART. Efforts to investigate lesser representation of women and rural people are indicated. The study raised concerns about the possible routes of transmission need more investigation.

  16. Ex vivo cultures of glioblastoma in three-dimensional hydrogel maintain the original tumor growth behavior and are suitable for preclinical drug and radiation sensitivity screening

    Energy Technology Data Exchange (ETDEWEB)

    Jiguet Jiglaire, Carine, E-mail: carine.jiguet-jiglaire@univ-amu.fr [Aix Marseille Université, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille (France); CRO2, UMR 911, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille Cedex (France); INSERM, U911, 13005 Marseille (France); Baeza-Kallee, Nathalie; Denicolaï, Emilie; Barets, Doriane [Aix Marseille Université, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille (France); CRO2, UMR 911, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille Cedex (France); INSERM, U911, 13005 Marseille (France); Metellus, Philippe [Aix Marseille Université, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille (France); CRO2, UMR 911, Faculté de Médecine de la Timone, 27 boulevard Jean Moulin, 13284 Marseille Cedex (France); INSERM, U911, 13005 Marseille (France); APHM, Timone Hospital, Department of Neurosurgery, 13005 Marseille (France); Timone Hospital, 264 Rue Saint Pierre, 13385 Marseille Cedex 5 (France); and others

    2014-02-15

    Identification of new drugs and predicting drug response are major challenges in oncology, especially for brain tumors, because total surgical resection is difficult and radiation therapy or chemotherapy is often ineffective. With the aim of developing a culture system close to in vivo conditions for testing new drugs, we characterized an ex vivo three-dimensional culture system based on a hyaluronic acid-rich hydrogel and compared it with classical two-dimensional culture conditions. U87-MG glioblastoma cells and seven primary cell cultures of human glioblastomas were subjected to radiation therapy and chemotherapy drugs. It appears that 3D hydrogel preserves the original cancer growth behavior and enables assessment of the sensitivity of malignant gliomas to radiation and drugs with regard to inter-tumoral heterogeneity of therapeutic response. It could be used for preclinical assessment of new therapies. - Highlights: • We have compared primary glioblastoma cell culture in a 2D versus 3D-matrix system. • In 3D morphology, organization and markers better recapitulate the original tumor. • 3D-matrix culture might represent a relevant system for more accurate drug screening.

  17. Assessment of a five-layer laminate technique to measure the saturation solubility of drug in pressure-sensitive adhesive film.

    Science.gov (United States)

    Reismann, Simone; Lee, Geoffrey

    2012-07-01

    A five-layer laminate technique is used to determine the saturation solubility of a drug in a thin polymer film, c(p)(s), of pressure-sensitive adhesive (PSA) used to prepare transdermal patches. A drug-loaded donor polymer film is attached via a separating membrane to an initially drug-free acceptor polymer film. Diffusion of drug occurs into the acceptor up to saturation solubility equilibrium. This systematic study of the technique using the drug tamsulosin and the PSA Duro Tak 87-4098 was a kinetic analysis of the diffusion process. It was found that the technique gives an equilibrium value for c(p)(s) in a PSA polymer film in the presence of crystalline phase of the drug in the donor. A highly permeable Perthese-separating membrane caused overshoot in the acceptor, most likely induced by initial supersaturation of the donor. Change to a less-permeable ethylene-vinyl-acetate-separating membrane avoided overshoot, but gave a prolonged time, >300 days, to equilibrium. Preloading the acceptor accelerated the equilibration process to approximately 50 days with the Perthese. Suitable experimental conditions are identified that, if performed correctly, allow the technique to give an equilibrium value for c(p)(s).

  18. Simple flow cytometric detection of haemozoin containing leukocytes and erythrocytes for research on diagnosis, immunology and drug sensitivity testing

    Directory of Open Access Journals (Sweden)

    Grobusch Martin P

    2011-03-01

    . Conclusions A simple modification of a flow cytometer allows for rapid and reliable detection and quantification of Hz-containing leukocytes and the analysis of differential surface marker expression in the same sample of Hz-containing versus non-Hz-containing leukocytes. Importantly, it distinguishes different maturation stages of parasitized RBC and may be the basis of a rapid no-added-reagent drug sensitivity assay.

  19. Balancing the stability and drug release of polymer micelles by the coordination of dual-sensitive cleavable bonds in cross-linked core.

    Science.gov (United States)

    Deng, Hongzhang; Zhang, Yumin; Wang, Xue; Jianhuazhang; Cao, Yan; Liu, Jinjian; Liu, Jianfeng; Deng, Liandong; Dong, Anjie

    2015-01-01

    The optimal structure design of nanocarriers to inhibit premature release of anticancer drugs from nanocarriers during blood circulation and improve drug release inside tumor cells is still a significant issue for polymer micelles applied to antitumor drug delivery. Herein, in order to balance the contradiction between polymer micellar stability and drug release, dual-sensitive cleavable cross-linkages of benzoic imine conjugated disulfide bonds were introduced into the core of the amphiphilic copolymer micelles to form core-cross-linked micelles. First, biodegradable poly(ethylene glycol)-b-(polycaprolactone-g-poly(methacrylic acid-p-hydroxy benzaldehyde-cystamine)), i.e. mPEG-b-(PCL-g-P(MAA-Hy-Cys)) (PECMHC) copolymers were synthesized and assembled into PECMHC micelles (PECMHC Ms). Then, simply by introducing H2O2 to the PECMHC Ms dispersions to oxidate the thiol groups of cystamine moieties in the core, core-cross-linked PECMHC micelles (cc-PECMHC Ms) ∼100 nm in size were readily obtained in water. In vitro studies of doxorubicin (DOX)-loaded cc-PECMHC Ms show that the cross-linked core impeded the drug release in the physical conditions, owing to the high stability of the micelles against both extensive dilution and salt concentration, while it greatly accelerated DOX release in mildly acidic (pH ∼5.0-6.0) medium with glutathione, owing to the coordination of the pH-sensitive cleaving of benzoic imine bonds and the reduction-sensitive cleaving of disulfide bonds. The in vivo tissue distribution and tumor accumulation of the DOX-loaded cc-PECMHC Ms were monitored via fluorescence images of DOX. DOX-loaded cc-PECMHC Ms exhibited enhanced tumor accumulation because of their high stability in blood circulation and less DOX premature release. Therefore, the cc-PECMHC Ms with dual-sensitive cleavable bonds in the cross-linked core were of excellent biocompatibility, high extracellular stability and had intelligent intracellular drug release properties

  20. Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry

    OpenAIRE

    Yong HUANG; Gandhi, Monica; Greenblatt, Ruth M.; Gee, Winnie; Lin, Emil T.; Messenkoff, Nicholas

    2008-01-01

    A highly sensitive and selective method using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) was developed and validated for the measurement of three antiretroviral agents, efavirenz, lopinavir and ritonavir, in human hair. Hair samples from adherent HIV-infected patients on antiretroviral therapies were cut into about 1 mm length segments and drugs were extracted by first shaking the samples with methanol in a 37°C water bath overnight (>14 h), followed by methyl tert...

  1. Radiation survival parameters of antineoplastic drug-sensitive and -resistant human ovarian cancer cell lines and their modification by buthionine sulfoximine

    Energy Technology Data Exchange (ETDEWEB)

    Louie, K.G.; Behrens, B.C.; Kinsella, T.J.; Hamilton, T.C.; Grotzinger, K.R.; McKoy, W.M.; Winker, M.A.; Ozols, R.F.

    1985-05-01

    The optimum integration of chemotherapy and irradiation is of potential clinical significance in the treatment of ovarian cancer. A series of human ovarian cancer cell lines have been developed in which dose-response relationships to standard anticancer drugs have been determined, and the patterns of cross-resistance between these drugs and irradiation have been established. By stepwise incubation with drugs, sublines of A2780, a drug-sensitive cell line, have been made 100-fold, 10-fold, and 10-fold more resistant to Adriamycin (2780AD), melphalan (2780ME), and cisplatin (2780CP). Two additional cell lines, NIH:OVCAR-3nu(Ag+) and NIH:OVCAR-4(Ag+), were established from drug-refractory patients. 2780ME, 2780CP, OVCAR-3nu(Ag+), and OVCAR-4(Ag+) are all cross-resistant to irradiation, with DOS of 146, 187, 143, and 203, respectively. However, 2780AD remains sensitive to radiation, with a DO of 111, which is similar to that of A2780 (101). Glutathione (GSH) levels are elevated in 2780ME, 2780CP, OVCAR-3nu(Ag+), and OVCAR-4(Ag+) to 4.58, 6.13, 12.10, and 15.14 nmol/10(6) cells as compared to A2780, with 1.89 nmol/10(6) cells. However, the GSH level in 2780AD is only minimally higher than that in A2780 (2.94 nmol/10(6) cells). Buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly increases the radiation sensitivity of 2780ME (changing the DO from 143 to 95) and 2780CP to a lesser extent, suggesting that intracellular GSH levels may play an important role in the radiation response of certain neoplastic cells.

  2. TIMP-1 overexpression does not affect sensitivity to HER2-targeting drugs in the HER2-gene-amplified SK-BR-3 human breast cancer cell line.

    Science.gov (United States)

    Deng, Xiaohong; Fogh, Louise; Lademann, Ulrik; Jensen, Vibeke; Stenvang, Jan; Yang, Huanming; Brünner, Nils; Schrohl, Anne-Sofie

    2013-04-01

    Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested as a marker of prognosis and response to treatment in breast cancer. In vitro, TIMP-1 can regulate shedding of the extracellular domain of HER2 and signalling via the Akt pathway, and we hypothesize that TIMP-1 therefore can affect sensitivity to the HER2-targeting drugs trastuzumab and lapatinib. SK-BR-3 human breast cancer cells were stably transfected with TIMP-1, characterized with regard to TIMP-1 protein expression, proliferation, and functionality of the secreted TIMP-1, and the sensitivity to trastuzumab and lapatinib was studied in five selected single-cell subclones expressing TIMP-1 protein at various levels plus the parental SK-BR-3 cell line. Both trastuzumab and lapatinib reduced cell viability, as determined by MTT assay, but the sensitivity to the drugs was not associated with the expression level of TIMP-1 protein. Western blotting showed that the activation of Akt, PTEN, and HER2 as well as ADAM10 was similar in all clones. In conclusion, in this model, TIMP-1 overexpression does not affect HER2 cleavage by ADAM10 or signalling via the Akt pathway, and TIMP-1 does not influence sensitivity to trastuzumab and lapatinib.

  3. Development and qualification of a high sensitivity, high throughput Q-PCR assay for quantitation of residual host cell DNA in purification process intermediate and drug substance samples.

    Science.gov (United States)

    Zhang, Wei; Wu, Meng; Menesale, Emily; Lu, Tongjun; Magliola, Aeona; Bergelson, Svetlana

    2014-11-01

    Methods of high sensitivity, accuracy and throughput are needed for quantitation of low level residual host cell DNA in purification process intermediates and drug substances of therapeutic proteins. In this study, we designed primer/probe sets targeting repetitive Alu repeats or Alu-equivalent sequences in the human, Chinese hamster and murine genomes. When used in quantitative polymerase chain reactions (Q-PCRs), these primer/probe sets showed high species specificity and gave significantly higher sensitivity compared to those targeting the low copy number GAPDH gene. This allowed for detection of residual host cell DNA of much lower concentrations and, for some samples, eliminated the need for DNA extraction. By combining the high sensitivity Alu Q-PCR with high throughput automated DNA extraction using an automated MagMAX magnetic particle processor, we successfully developed and qualified a highly accurate, specific, sensitive and efficient method for the quantitation of residual host cell DNA in process intermediates and drug substances of multiple therapeutic proteins purified from cells of multiple species. Compared to the previous method using manual DNA extraction and primer/probe sets targeting the GAPDH gene, this new method increased our DNA extraction throughput by over sevenfold, and lowered the lower limit of quantitation by up to eightfold.

  4. Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus

    DEFF Research Database (Denmark)

    de Evgrafov, Mari Cristina Rodriguez; Gumpert, Heidi; Munck, Christian

    2015-01-01

    revealed that resistance to drug combinations was mediated largely by mutations in the same genes as single-drug-evolved lineages highlighting the importance of the component drugs in determining the rate of resistance evolution. Results of this work suggest that the mechanisms of resistance to constituent......As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations......, and the scientific model emerging from in vitro experimental work, which maintains that this interaction provides greater selective pressure toward resistance development than other interaction types. We sought to extend the current paradigm, based on work below or near minimum inhibitory concentration levels...

  5. Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs.

    Directory of Open Access Journals (Sweden)

    Karolin Hijazi

    Full Text Available Anti-retroviral (ARV -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on

  6. Nationwide survey of the development of drug resistance in the pediatric field in 2007 and 2010: drug sensitivity of Haemophilus influenzae in Japan (second report)

    OpenAIRE

    Hoshino, Tadashi; Sato, Yoshitake; Toyonaga, Yoshikiyo; Hanaki, Hideaki; Sunakawa, Keisuke; ,

    2013-01-01

    The Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease conducted national surveillance for Haemophilus influenzae in 2007 (phase 3) and 2010 (phase 4), following the previous surveillance conducted from 2000 to 2001 (phase 1) and in 2004 (phase 2). We examined the antimicrobial susceptibility for H. influenzae derived from clinical specimens of pediatric patients collected nationwide from 27 institutions during phases 3 (386 strains) and 4 (484 strains). The frequency ...

  7. A comprehensive and sensitive method for hair analysis in drug-facilitated crimes and incorporation of zolazepam and tiletamine into hair after a single exposure.

    Science.gov (United States)

    Kim, Jihyun; Yum, Hyesun; Jang, Moonhee; Shin, Ilchung; Yang, Wonkyung; Baeck, Seungkyung; Suh, Joon Hyuk; Lee, Sooyeun; Han, Sang Beom

    2016-01-01

    Hair is a highly relevant specimen that is used to verify drug exposure in victims of drug-facilitated crime (DFC) cases. In the present study, a new analytical method involving ultrahigh-performance liquid chromatography-tandem mass spectrometry was developed for determining the presence of model drugs, including zolazepam and tiletamine and their metabolites in hair specimens from DFCs. The incorporation of zolazepam and tiletamine into hair after a single exposure was investigated in Long-Evans rats with the ratio of the hair concentration to the area under the curve. For rapid and simple sample preparation, methanol extraction and protein precipitation were performed for hair and plasma, respectively. No interference was observed in drug-free hair or plasma, except for hair-derived diphenhydramine in blank hair. The coefficients of variance of the matrix effects were below 12%, and the recoveries of the analytes exceeded 70% in all of the matrices. The precision and accuracy results were satisfactory. The limits of quantification ranged from 20 to 50 pg in 10 mg of hair. The drug incorporation rates were 0.03 ± 0.01% for zolazepam and 2.09 ± 0.51% for tiletamine in pigmented hair. We applied the present method to real hair samples in order to determine the drug that was used in seven cases. These results suggest that this comprehensive and sensitive hair analysis method can successfully verify a drug after a single exposure in crimes and can be applied in forensic and clinical toxicology laboratories.

  8. Population structure and circulating genotypes of drug-sensitive and drug-resistant Mycobacterium tuberculosis clinical isolates in São Paulo state, Brazil.

    Science.gov (United States)

    Martins, Maria Conceição; Giampaglia, Carmen M Saraiva; Oliveira, Rosângela S; Simonsen, Vera; Latrilha, Fábio Oliveira; Moniz, Letícia Lisboa; Couvin, David; Rastogi, Nalin; Ferrazoli, Lucilaine

    2013-03-01

    São Paulo is the most populous Brazilian state and reports the largest number of tuberculosis cases in the country annually (over 18,500). This study included 193 isolates obtained during the 2nd Nationwide Survey on Mycobacterium tuberculosis Drug Resistance that was conducted in São Paulo state and 547 isolates from a laboratory based study of drug resistance that were analyzed by the Mycobacteria Reference Laboratory at the Institute Adolfo Lutz. Both studies were conducted from 2006 to 2008 and sought to determine the genetic diversity and pattern of drug resistance of M. tuberculosis isolates (MTC) circulating in São Paulo. The patterns obtained from the spoligotyping analysis demonstrated that 51/740 (6.9%) of the isolates corresponded to orphan patterns and that 689 (93.1%) of the isolates distributed into 144 shared types, including 119 that matched a preexisting shared type in the SITVIT2 database and 25 that were new isolates. A total of 77/144 patterns corresponded to unique isolates, while the remaining 67 corresponded to clustered patterns (n=612 isolates clustered into groups of 2-84 isolates each). The evolutionarily ancient PGG1 lineages (Beijing, CAS1-DEL, EAI3-IND, and PINI2) were rarely detected in São Paulo and comprised only 13/740, or 1.76%, of the total isolates; all of the remaining 727/740, or 98.24%, of the MTC isolates from São Paulo state were from the recent PGG2/3 evolutionary isolates belonging to the LAM, T, S, X, and Haarlem lineages, i.e., the Euro-American group. This study provides the first overview of circulating genotypes of M. tuberculosis in São Paulo state and demonstrates that the clustered shared types containing seven or more M. tuberculosis isolates that are spread in São Paulo state included both resistant and susceptible isolates.

  9. Self-assembly of pH-sensitive fluorinated peptide dendron functionalized dextran nanoparticles for on-demand intracellular drug delivery.

    Science.gov (United States)

    Ma, Shengnan; Zhou, Jie; Wali, Aisha Roshan Mohamed; He, Yiyan; Xu, Xianghui; Tang, James Zhenggui; Gu, Zhongwei

    2015-08-01

    In this study, the amphiphilic fluorinated peptide dendrons functionalized dextran (FPD-HZN-Dex) via an acid-sensitive hydrazone linkage was successfully designed and prepared for the first time. We demonstrated a spontaneous self-assembly of amphiphilic FPD-HZN-Dex into the well-defined nanoparticles with the core-shell architecture in aqueous media, which is attributed to the efficient amphiphilic functionalization of dextran by the hydrophobic fluorinated peptide dendrons. The spherical morphology, uniform particle size and good storage stability of the prepared FPD-HZN-Dex nanoparticles were characterized by dynamic light scattering and transmission electron microscopy, respectively. In vitro drug release studies showed a controlled and pH dependent hydrophobic drug release profile. The cell viability assays show excellent biocompatibility of the FPD-HZN-Dex nanoparticles for both normal cells and tumor cells. Moreover, the FPD-HZN-Dex self-assembled systems based on pH-sensitive hydrazone linkage also can serve as stimulus bioresponsive carriers for on-demand intracellular drug delivery. These self-assembled nanoparticles exhibit a stimulus-induced response to endo/lysosome pH (pH 5.0) that causes their disassembly over time, enabling controlled release of encapsulated DOX. This work has unveiled a unique non-covalent interaction useful for engineering amphiphilic dendrons or dendrimers self-assembled systems.

  10. Antagonistic changes in sensitivity to antifungal drugs by mutations of an important ABC transporter gene in a fungal pathogen.

    Directory of Open Access Journals (Sweden)

    Wenjun Guan

    Full Text Available Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.

  11. Highly fluorescent and morphology-controllable graphene quantum dots-chitosan hybrid xerogels for in vivo imaging and pH-sensitive drug carrier

    Energy Technology Data Exchange (ETDEWEB)

    Lv, Ouyang; Tao, Yongxin; Qin, Yong [Advanced Catalysis and Green Manufacturing Collaborative Innovation Center, School of Petrochemical Engineering, Changzhou University, Changzhou 213164 (China); Chen, Chuanxiang [School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003 (China); Pan, Yan; Deng, Linhong [Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou 213164 (China); Liu, Li [School of pharmaceutical Engineering & Life Science, Changzhou University, Changzhou 213164 (China); Kong, Yong, E-mail: yzkongyong@126.com [Advanced Catalysis and Green Manufacturing Collaborative Innovation Center, School of Petrochemical Engineering, Changzhou University, Changzhou 213164 (China)

    2016-10-01

    Highly fluorescent graphene quantum dots (GQDs)-chitosan (CS) hybrid xerogels (GQDs-CS) were facilely synthesized, and the morphology of GQDs-CS was controllable by varying the content of GQDs in the xerogel. The GQDs-CS exhibited a porous and three-dimensional (3D) network structure when the content of GQDs reached 43% (wt%) in the xerogel, which was beneficial for drug loading and sustained release. The as-prepared GQDs-CS could also be applied for in vivo imaging since it showed strong blue, green and red luminescence under excitation of varying wavelengths. Moreover, the pH-induced protonation/deprotonation of the –NH{sub 2} groups on CS chains can result in a pH-dependent drug delivery behavior of the GQDs-CS hybrid xerogel. - Graphical abstract: Highly fluorescent and morphology-controllable graphene quantum dots-chitosan hybrid xerogels for in vivo imaging and pH-sensitive drug carrier. Display Omitted - Highlights: • Highly fluorescent GQDs-CS hybrid xerogels were facilely synthesized. • The as-made xerogels exhibited various morphologies with different GQDs contents. • The GQDs-CS exhibited a porous and 3D network when the content of GQDs reached 43%. • The GQDs-CS could be applied for in vivo imaging since it showed strong luminescence. • The protonation/deprotonation of –NH{sub 2} on CS result in a pH-dependent drug delivery.

  12. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  13. 沙门菌感染血清型及药敏分析%Analysis of Salmonella serotypes and drug sensitivity

    Institute of Scientific and Technical Information of China (English)

    廖晓林

    2013-01-01

    Objective To study the characteristics of the serotype distribution of Salmonella infection and drug resistance in the region, and provide reference for clinical rational drug use. Methods 163 cases of clinical specimens were isolated and cultured, and identified Salmonella serotype. drug sensitivity was measured. Results 163 strains of Salmonella included 80 strains of Salmonella paratyphi(49. 1%), 17strains of Salmonella typhi(10. 4%), 40 strains of Salmonella typhimurium(24. 5%), 19 strains of Salmonella enteritidis(l0. 4%)and 4 strains of Salmonella choleraesuis (2. 4%). Salmonella paratyphi A, Salmonella, Salmonella typhimurium and Salmonella enteritidis were seriously resistanta to ciprofloxacin, levofloxacin, ceftriaxone, cefotaxime, imipenem sensitive,, ampicillin, compound sulfamethoxazole, streptomycin and chloramphenicol. Conclusion Clinical use of antibiotics should be based on the drug sensitive test, minimize the emergence of drug-resistant strains.%目的 研究沙门菌感染的血清型分布特点及耐药情况,为临床合理用药提供参考.方法 对收集到的163例临床标本进行沙门茵分离培养、血清分型鉴定和药敏试验.结果 163株沙门茵中甲型副伤寒沙门茵80株(49.1%),伤寒沙门茵17株(10.4%),鼠伤寒沙门茵40株(24.5%),肠炎沙门茵19株(10.4%),猪霍乱沙门茵4株(2.4%);甲型副伤寒沙门茵、伤寒沙门菌、鼠伤寒沙门茵、肠炎沙门茵以环丙沙星、左氧氟沙星、头孢噻肟、头孢曲松、亚胺培南比较敏感,氨苄西林、复方磺胺甲噁唑、链霉素、氯霉素的耐药现象比较严重.结论 临床应根据药敏试验合理使用抗生素,尽量减少耐药菌株的产生.

  14. A sensitive enzyme-linked immunosorbent assay amplified by biotin-streptavidin system for detecting non-steroidal anti-inflammatory drug ketoprofen.

    Science.gov (United States)

    Bu, Dan; Zhuang, Hui S; Yang, Guang X

    2014-01-01

    A sensitive biotin-streptavidin-amplified enzyme-linked immunosorbent assay (BA-ELISA) method was developed for detecting non-steroidal anti-inflammatory drug ketoprofen. Compared with traditional ELISA method, the sensitivity of proposed immunoassay was enhanced by the biotin-streptavidin system. Under the optimal condition, the median inhibitory concentration (IC50) was 0.25 ng mL(-1), with minor cross-reactivity to a number of structural analogs. This developed assay was successfully applied to detect the ketoprofen residues in different fish samples, and good recoveries (72.6-105.5%) were obtained. The results indicated that this immunoassay method could specifically detect trace ketoprofen residues and could be widely used for routine monitoring of food samples.

  15. Evaluation of pH-sensitive poly(2-hydroxyethyl methacrylate-co-2-(diisopropylaminoethyl methacrylate copolymers as drug delivery systems for potential applications in ophthalmic therapies/ocular delivery of drugs

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    P. A. Faccia

    2015-06-01

    Full Text Available Smart polymers like pH sensitive systems can improve different pharmacological treatment. In this work the behavior of copolymers containing 2-hydroxyethyl methacrylate (HEMA with different proportions of 2-(diisopropylamino ethyl methacrylate (DPA and different amounts of cross-linker agent, ethylene glycol dimethacrylate (EGDMA are evaluated as pH-sensitive drug delivery systems for potential application in ophthalmic therapies. A detailed characterization of the pH-responsive behavior was performed by swelling studies and scanning electron microscopy (SEM analysis. Drug loading and release studies at different pH values were evaluated using Rhodamine 6G (Rh6G as a model drug. The interaction between Rh6G and hydrogels was studied by Fourier Transform Infrared (FTIR spectroscopy and scanning electron microscopy (SEM. The results show that the presence of DPA in the copolymers confers pH-responsive properties to the polymer, as noted in swelling and SEM studies, when the pH decreases below 7.40 the swelling degree increases and a porous morphology is observed. The apparent pKa of copolymers was estimated between 6.80 and 7.17 depending on the composition. The amount of Rh6G loaded depends mainly on the medium pH and the interaction between the drug and the copolymers, observed by SEM and FTIR spectrum. The release of Rh6G of copolymers p(HEMA/DPA show a normal Fickian or anomalous diffusion behavior at different pH values, depending on the HEMA/DPA ratio.

  16. In vitro Plasmodium falciparum drug sensitivity assay: inhibition of parasite growth by incorporation of stomatocytogenic amphiphiles into the erythrocyte membrane

    DEFF Research Database (Denmark)

    Ziegler, Hanne L; Staerk, Dan; Christensen, Jette

    2002-01-01

    culture continued to grow well in untreated erythrocytes. Thus, the antiplasmodial activity of lupeol appears to be indirect, being due to stomatocytic transformation of the host cell membrane and not to toxic effects via action on a drug target within the parasite. A number of amphiphiles that cause...... stomatocyte formation, but not those causing echinocyte formation, were shown to inhibit growth of the parasites, apparently via a mechanism similar to that of lupeol. Since antiplasmodial agents that inhibit parasite growth through erythrocyte membrane modifications must be regarded as unsuitable as leads...... for development of new antimalarial drugs, care must be exercised in the interpretation of results of screening of plant extracts and natural product libraries by an in vitro Plasmodium toxicity assay....

  17. Assessing spatiotemporal patterns of multidrug-resistant and drug-sensitive tuberculosis in a South American setting

    Science.gov (United States)

    Lin, H.; Shin, S.; Blaya, J. A.; Zhang, Z.; Cegielski, P.; Contreras, C.; Asencios, L.; Bonilla, C.; Bayona, J.; Paciorek, C. J.; Cohen, T.

    2011-01-01

    Summary We examined the spatiotemporal distribution of laboratory-confirmed multidrug-resistant tuberculosis (MDR TB) cases and that of other TB cases in Lima, Peru with the aim of identifying mechanisms responsible for the rise of MDR TB in an urban setting. All incident cases of TB in two districts of Lima, Peru during 2005–2007 were included. The spatiotemporal distributions of MDR cases and other TB cases were compared with Ripley's K statistic. Of 11 711 notified cases, 1187 received drug susceptibility testing and 376 were found to be MDR. Spatial aggregation of patients with confirmed MDR disease appeared similar to that of other patients in 2005 and 2006; however, in 2007, cases with confirmed MDR disease were found to be more tightly grouped. Subgroup analysis suggests the appearance of resistance may be driven by increased transmission. Interventions should aim to reduce the infectious duration for those with drug-resistant disease and improve infection control. PMID:21205434

  18. 鲍曼不动杆菌的临床分布与药敏分析%Clinical distribution and drug sensitivity analysis of Acinetobacter baumannii

    Institute of Scientific and Technical Information of China (English)

    秦攀; 裴保香

    2011-01-01

    To understand clinical distribution and drug-resistance features of Acinetobacter baumannii. Methods We analysed the treatment of Acinetobacter baumannii from venous blood specimen of the hospitalized patients in our hospital from February 2008 to October 2009 and the distribution of department and pathogen of Acinetobacter baumannii statistically. As the empirical treatment coincided with drug sensitivity results or not, specimen were divided into 2 groups and the cure rate was compared. Results The positive rates of specimen from intensive care unit and department of hepatobiliary surgery were 40.91% and 22.73% respectively. The drug sensitive test showed the resistance rates of Cefoperazone/Sulbactam, Ampicillin/Sullbactam, lmipenem and Meropenem to Acinetobacter baumannii were 47.6%, 72.7% and 81.8% separately. 7 empirical treatment agreed with drug sensitivity results and the effective rate was 85.71%; 7 empirical treatment didn't agree with drug sensitivity results and the effective rate was 57.14%. Conclusion Acinetobacter baumannii was common in intensive care unit. If treatment was on the basis of drug sensitivity results, it was of significance to the clinical treatment of Acinetobacter baumannii.%目的 了解鲍曼不动杆菌的临床分布情况及耐药特点.方法 分析我院2008年2月-2009年10月静脉血标本中检出鲍曼不动杆菌的住院患者治疗情况,对鲍曼不动杆菌的科室分布、伴发病原菌情况进行统计学分析;并按临床经验用药与药敏结果是否相符分为两组,各7例;比较两组的治疗有效率.结果 重症监护室送检标本阳性率占40.91%,肝胆外科占22.73%;药敏试验显示,鲍曼不动杆菌对头孢哌酮,舒巴坦耐药率最低(47.6%),其次是氨苄西林/舒巴坦(72.7%)、亚胺培南和美罗培南(81.8%).相符组有效率85.71%;不符组有效率57.14%.结论 鲍曼不动杆菌感染常见于重症监护室;根据药敏结果用药,对指导临床治疗鲍曼不动杆菌具有重要意义.

  19. Nanoparticle induced cell magneto-rotation: monitoring morphology, stress and drug sensitivity of a suspended single cancer cell.

    Directory of Open Access Journals (Sweden)

    Remy Elbez

    Full Text Available Single cell analysis has allowed critical discoveries in drug testing, immunobiology and stem cell research. In addition, a change from two to three dimensional growth conditions radically affects cell behavior. This already resulted in new observations on gene expression and communication networks and in better predictions of cell responses to their environment. However, it is still difficult to study the size and shape of single cells that are freely suspended, where morphological changes are highly significant. Described here is a new method for quantitative real time monitoring of cell size and morphology, on single live suspended cancer cells, unconfined in three dimensions. The precision is comparable to that of the best optical microscopes, but, in contrast, there is no need for confining the cell to the imaging plane. The here first introduced cell magnetorotation (CM method is made possible by nanoparticle induced cell magnetization. By using a rotating magnetic field, the magnetically labeled cell is actively rotated, and the rotational period is measured in real-time. A change in morphology induces a change in the rotational period of the suspended cell (e.g. when the cell gets bigger it rotates slower. The ability to monitor, in real time, cell swelling or death, at the single cell level, is demonstrated. This method could thus be used for multiplexed real time single cell morphology analysis, with implications for drug testing, drug discovery, genomics and three-dimensional culturing.

  20. MicroRNA-133b targets glutathione S-transferase π expression to increase ovarian cancer cell sensitivity to chemotherapy drugs

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    Chen S

    2015-09-01

    Full Text Available Shuo Chen,1 Jin-Wen Jiao,2 Kai-Xuan Sun,1 Zhi-Hong Zong,3 Yang Zhao1 1Department of Gynecology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Gynecology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, People’s Republic of China Background: Accumulating studies reveal that aberrant microRNA (miRNA expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. The aim of this study was to investigate the role of miR-133b in the development of drug resistance in ovarian cancer cells. Methods: We examined the levels of miR-133b expression in ovarian carcinoma tissues and the human ovarian carcinoma cell lines (A2780, A2780/DDP and A2780/Taxol, respectively. We determined the cell viability of these cell lines treated with cisplatin or paclitaxel in the presence or absence of miR-133b or anti-miR-133b transfection using the MTT assay. Reverse transcription polymerase chain reaction and Western blotting were used to assess the mRNA and protein expression levels of two drug-resistance-related genes: glutathione S-transferase (GST-π and multidrug resistance protein 1 (MDR1. The dual-luciferase reporter assay was used to detect the promoter activity of GST-π in the presence and absence of miR-133b. Results: The expression of miR-133b was significantly lower in primary resistant ovarian carcinomas than in the chemotherapy-sensitive carcinomas (P<0.05, and the same results were found in primary resistant ovarian cell lines (A2780/Taxol and A2780/DDP compared to the chemotherapy-sensitive cell line (A2780; P<0.05. Following miR-133b transfection, four cell lines showed increased sensitivity to paclitaxel and cisplatin, while anti-miR-133b transfection

  1. Opiate drug use and the pathophysiology of neuroAIDS.

    Science.gov (United States)

    Hauser, Kurt F; Fitting, Sylvia; Dever, Seth M; Podhaizer, Elizabeth M; Knapp, Pamela E

    2012-07-01

    Opiate abuse and HIV-1 have been described as interrelated epidemics, and even in the advent of combined anti-retroviral therapy, the additional abuse of opiates appears to result in greater neurologic and cognitive deficits. The central nervous system (CNS) is particularly vulnerable to interactive opiate-HIV-1 effects, in part because of the unique responses of microglia and astroglia. Although neurons are principally responsible for behavior and cognition, HIV-1 infection and replication in the brain is largely limited to microglia, while astroglia and perhaps glial progenitors can be latently infected. Thus, neuronal dysfunction and injury result from cellular and viral toxins originating from HIV-1 infected/exposed glia. Importantly, subsets of glial cells including oligodendrocytes, as well as neurons, express µ-opioid receptors and therefore can be direct targets for heroin and morphine (the major metabolite of heroin in the CNS), which preferentially activate µ-opioid receptors. This review highlights findings that neuroAIDS is a glially driven disease, and that opiate abuse may act at multiple glial-cell types to further compromise neuron function and survival. The ongoing, reactive cross-talk between opiate drug and HIV-1 co-exposed microglia and astroglia appears to exacerbate critical proinflammatory and excitotoxic events leading to neuron dysfunction, injury, and potentially death. Opiates enhance synaptodendritic damage and a loss of synaptic connectivity, which is viewed as the substrate of cognitive deficits. We especially emphasize that opioid signaling and interactions with HIV-1 are contextual, differing among cell types, and even within subsets of the same cell type. For example, astroglia even within a single brain region are heterogeneous in their expression of µ-, δ-, and κ-opioid receptors, as well as CXCR4 and CCR5, and Toll-like receptors. Thus, defining the distinct targets engaged by opiates in each cell type, and among brain

  2. Assessing the HIV-1 Epidemic in Brazilian Drug Users: A Molecular Epidemiology Approach.

    Directory of Open Access Journals (Sweden)

    Monick Lindenmeyer Guimarães

    Full Text Available Person who inject illicit substances have an important role in HIV-1 blood and sexual transmission and together with person who uses heavy non-injecting drugs may have less than optimal adherence to anti-retroviral treatment and eventually could transmit resistant HIV variants. Unfortunately, molecular biology data on such key population remain fragmentary in most low and middle-income countries. The aim of the present study was to assess HIV infection rates, evaluate HIV-1 genetic diversity, drug resistance, and to identify HIV transmission clusters in heavy drug users (DUs. For this purpose, DUs were recruited in the context of a Respondent-Driven Sampling (RDS study in different Brazilian cities during 2009. Overall, 2,812 individuals were tested for HIV, and 168 (6% of them were positive, of which 19 (11.3% were classified as recent seroconverters, corresponding to an estimated incidence rate of 1.58%/year (95% CI 0.92-2.43%. Neighbor joining phylogenetic trees from env and pol regions and bootscan analyses were employed to subtype the virus from132 HIV-1-infected individuals. HIV-1 subtype B was prevalent in most of the cities under analysis, followed by BF recombinants (9%-35%. HIV-1 subtype C was the most prevalent in Curitiba (46% and Itajaí (86% and was also detected in Brasília (9% and Campo Grande (20%. Pure HIV-1F infections were detected in Rio de Janeiro (9%, Recife (6%, Salvador (6% and Brasília (9%. Clusters of HIV transmission were assessed by Maximum likelihood analyses and were cross-compared with the RDS network structure. Drug resistance mutations were verified in 12.2% of DUs. Our findings reinforce the importance of the permanent HIV-1 surveillance in distinct Brazilian cities due to viral resistance and increasing subtype heterogeneity all over Brazil, with relevant implications in terms of treatment monitoring, prophylaxis and vaccine development.

  3. Interaction between Tat and Drugs of Abuse during HIV-1 Infection and Central Nervous System Disease

    Directory of Open Access Journals (Sweden)

    Monique E Maubert

    2016-01-01

    Full Text Available In many individuals, drug abuse is intimately linked with HIV-1 infection. In addition to being associated with one-third of all HIV-1 infections in the United States, drug abuse also plays a role in disease progression and severity in HIV-1-infected patients, including adverse effects on the central nervous system (CNS. Specific systems within the brain are known to be damaged in HIV-1-infected individuals and this damage is similar to that observed in drug abuse. Even in the era of anti-retroviral therapy (ART, CNS pathogenesis occurs with HIV-1 infection, with a broad range of cognitive impairment observed, collectively referred to as HIV-1-associated neurocognitive disorders (HAND. A number of HIV-1 proteins (Tat, gp120, Nef, Vpr have been implicated in the etiology of pathogenesis and disease as a result of the biologic activity of the extracellular form of each of the proteins in a number of tissues, including the CNS, even in ART-suppressed patients. In this review, we have made Tat the center of attention for a number of reasons. First, it has been shown to be synthesized and secreted by HIV-1-infected cells in the CNS, despite the most effective suppression therapies available to date. Second, Tat has been shown to alter the functions of several host factors, disrupting the molecular and biochemical balance of numerous pathways contributing to cellular toxicity, dysfunction, and death. In addition, the advantages and disadvantages of ART suppression with regard to controlling the genesis and progression of neurocognitive impairment are currently under debate in the field and are yet to be fully determined. In this review, we discuss the individual and concerted contributions of HIV-1 Tat, drug abuse, and ART with respect to damage in the CNS, and how these factors contribute to the development of HAND in HIV-1-infected patients.

  4. Nationwide survey of the development of drug resistance in the pediatric field in 2007 and 2010: drug sensitivity of Haemophilus influenzae in Japan (second report).

    Science.gov (United States)

    Hoshino, Tadashi; Sato, Yoshitake; Toyonaga, Yoshikiyo; Hanaki, Hideaki; Sunakawa, Keisuke

    2013-06-01

    The Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease conducted national surveillance for Haemophilus influenzae in 2007 (phase 3) and 2010 (phase 4), following the previous surveillance conducted from 2000 to 2001 (phase 1) and in 2004 (phase 2). We examined the antimicrobial susceptibility for H. influenzae derived from clinical specimens of pediatric patients collected nationwide from 27 institutions during phases 3 (386 strains) and 4 (484 strains). The frequency of β-lactamase-nonproducing ampicillin (ABPC)-resistant (BLNAR) strains, which rapidly increased from 11.4 % in phase 1 to 43.4 % in phase 2, has gradually decreased from 38.3 % in phase 3 to 37.8 % in phase 4. In contrast, On the other hand, the frequency of β-lactamase-producing strains, which continuously decreased from 8.3 % in phase 1 to 4.4 % in phase 3, has increased to 8.7 % in phase 4. Prevalence of β-lactamase-producing clavulanic acid/amoxicillin-resistant (BLPACR) strains, especially, has increased from 1.6 % in phase 3 to 4.8 % in phase 4. The oral antimicrobial agents with the lowest MIC90 were levofloxacin in both phases, and tosufloxacin in phase 4 (≤0.063 μg/ml), whereas for intravenous use the corresponding agent was tazobactam/piperacillin in both phases (0.125 μg/ml). There was no increase in the MIC90 of most β-lactams between phase 3 and phase 4. In relationship to sex, age, presence of siblings, attendance at a daycare center, siblings' attendance at a daycare center, and prior administration of antimicrobial agents within 1 month, the frequency of β-lactamase-nonproducing ABPC-intermediately resistant (BLNAI) strains + BLNAR strains was high (P = 0.005) in cases with prior administration of antimicrobial agents in phase 3.

  5. [Drug sensitivity in Mycobacterium tuberculosis versus its viability, cytotoxicity, genotype, and the course of the process in patients with pulmonary tuberculosis].

    Science.gov (United States)

    Manicheva, O A; Lasunskaia, E B; Zhuravlev, V Iu; Otten, T F; Barnaulov, A O; Mokrousov, I V; Pavlova, M V; Vishnevskiĭ, B I; Narvskaia, O V

    2008-01-01

    The authors studied drug sensitivity, mutations in the katG, in-hA, alpC, rpoB genes, virulence via the cytotoxicity test on THP-1 cells, and the viability and genetic affiliation of 53 clinical M. tuberculosis isolates versus data on the form and dynamics of a process. Sensitive and resistant strains did not significantly differ in viability and cytotoxicity. The highest death of infected macrophages was observed was seen with infection of M. tuberculosis of the Beijing B0 genotype, the least one seen with that of LAM with the similar rate of multiple drug resistance. There was a correlation of the changes in the count of lymphocytes in patients with the genetic affiliation of a causative agent. The severest course of the tuberculous process was observed in baseline lymphopenia (before treatment) in combination with multidrug resistance of mycobacteria, high and moderate cytotoxicity and high viability. Ser-Leu 531 mutation resulted in cross resistance to rifampicin and mycobutin in most cases.

  6. Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

    Directory of Open Access Journals (Sweden)

    Zhang CY

    2014-10-01

    Full Text Available Can Yang Zhang, Di Xiong, Yao Sun, Bin Zhao, Wen Jing Lin, Li Juan Zhang School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong Province, People’s Republic of China Abstract: A novel amphiphilic triblock pH-sensitive poly(ß-amino ester-g-poly(ethylene glycol methyl ether-cholesterol (PAE-g-MPEG-Chol was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation–deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy. Keywords: micelle, pH-sensitive, cholesterol, poly(ß-amino ester, drug delivery

  7. Computer simulations on the pH-sensitive tri-block copolymer containing zwitterionic sulfobetaine as a novel anti-cancer drug carrier.

    Science.gov (United States)

    Min, Wenfeng; Zhao, Daohui; Quan, Xuebo; Sun, Delin; Li, Libo; Zhou, Jian

    2017-04-01

    In this work, dissipative particle dynamics (DPD) simulations were performed to study the self-assembled microstructures and doxorubicin (DOX) loading/release properties of pH-sensitive amphiphilic triblock copolymer: poly(ε-caprolactone)-b-poly(diethylaminoethyl methacrylate)-b-poly(sulfobetaine methacrylate) or poly (ethylene glycol methacrylate) (PCL-PDEA-PSBMA/PEGMA). Our results show that both copolymers can self-assemble into core-shell-corona micelles in aqueous environment. However, the corona structures are quite different for the two copolymer micelles. The shell layers formed by PEGMA have heterogeneous sizes while the shell layers in PCL-PDEA-PSBMA micelles are homogenous. This is mainly attributed to the stronger hydrophilicity of PSBMA than PEGMA. As the mole concentration of copolymer is increased from 10% to 50%, the microstructures formed by PCL-PDEA-PSBMA and DOX remains spherical micelles whereas PCL-PDEA-PEGMA undergoes structural transition from spherical to cylindrical and finally to lamellar micelles. Interestingly, the studied micelles have a pH-responsive drug release property, owing to the protonation of the PDEA block. The drug release process follows a "swelling-demicellization-release" mode. The multi-scale simulations demonstrate an avenue to the optimal design of nanomaterials for drug delivery with desired properties.

  8. pH-sensitive drug loading/releasing in amphiphilic copolymer PAE-PEG: integrating molecular dynamics and dissipative particle dynamics simulations.

    Science.gov (United States)

    Luo, Zhonglin; Jiang, Jianwen

    2012-08-20

    Molecular dynamics (MD) and dissipative particle dynamics (DPD) simulations are integrated to investigate the loading/releasing of anti-cancer drug camptothecin (CPT) in pH-sensitive amphiphilic copolymer, composed of hydrophobic poly(β-amino ester) (PAE) and hydrophilic methyl ether-capped poly(ethylene glycol) (PEG). MD simulation is used to estimate the Flory-Huggins interaction parameters and miscibility of binary components. On this basis, DPD simulation is applied to examine the micellization of PAE-PEG, CPT loading in PAE-PEG, and CPT releasing in PAEH-PEG. With increasing concentration, PAE-PEG forms spherical then disk-like micelles and finally vesicles, as a competitive counterbalance of free energies for the formation of shell, interface and core. CPT loading in PAE-PEG micelles/vesicles is governed by adsorption-growth-micellization mechanism, and CPT is loaded into both hydrophobic core and interface of hydrophobic core/hydrophilic shell. The predicted loading efficiency is close to experimental value. Similar to literature reports, the loading of high concentration of CPT is observed to cause morphology transition from micelles to vesicles. Upon protonation, CPT is released from micelles/vesicles by swelling-demicellization-releasing mechanism. This multi-scale simulation study provides microscopic insight into the mechanisms of drug loading and releasing, and might be useful for the design of new materials for high-efficacy drug delivery.

  9. Enhanced sensitivity of A549 cells to the cytotoxic action of anticancer drugs via suppression of Nrf2 by procyanidins from Cinnamomi Cortex extract

    Energy Technology Data Exchange (ETDEWEB)

    Ohnuma, Tomokazu; Matsumoto, Takashi; Itoi, Ayano; Kawana, Ayako; Nishiyama, Takahito; Ogura, Kenichiro [Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392 (Japan); Hiratsuka, Akira, E-mail: hiratuka@toyaku.ac.jp [Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392 (Japan)

    2011-10-07

    Highlights: {yields} We found a novel inhibitor of Nrf2 known as a chemoresistance factor. {yields} Overexpressed Nrf2 in lung cancer cells was suppressed by Cinnamomi Cortex extract. {yields} Cytotoxic action of anticancer drugs in cells treated with the extract was enhanced. {yields} Procyanidin tetramers and pentamers were active components in suppressing Nrf2. -- Abstract: Nuclear factor-E2-related factor 2 (Nrf2) is an important cytoprotective transcription factor because Nrf2-regulated enzymes play a key role in antioxidant and detoxification processes. Recent studies have reported that lung cancer cells overexpressing Nrf2 exhibit increased resistance to chemotherapy. Suppression of overexpressed Nrf2 is needed for a new therapeutic approach against lung cancers. In the present study, we found that Cinnamomi Cortex extract (CCE) has an ability to suppress Nrf2-regulated enzyme activity and Nrf2 expression in human lung cancer A549 cells with high Nrf2 activity. Moreover, we demonstrated that CCE significantly enhances sensitivity of A549 cells to the cytotoxic action of doxorubicin and etoposide as well as increasing the intracellular accumulation of both drugs. These results suggest that CCE might be an effective concomitant agent to reduce anticancer drug resistance derived from Nrf2 overexpression. Bioactivity-guided fractionation revealed that procyanidin tetramers and pentamers contained in CCE were active components in suppressing Nrf2.

  10. Spectrofluorometric determination of intracellular levels of reactive oxygen species in drug-sensitive and drug-resistant cancer cells using the 2‧,7‧-dichlorofluorescein diacetate assay

    Science.gov (United States)

    Loetchutinat, Chatchanok; Kothan, Suchart; Dechsupa, Samarn; Meesungnoen, Jintana; Jay-Gerin, Jean-Paul; Mankhetkorn, Samlee

    2005-02-01

    This article examines a non-invasive spectrofluorometric method using the 2',7'-dichlorofluorescein diacetate (DCHF-DA) assay for quantifying the intracellular reactive oxygen species (ROS i) produced in four cultured cancer cell lines: drug-sensitive (K562) and drug-resistant (K562/ adr) human erythromyelogenous leukemia cell lines, and drug-sensitive (GLC4) and drug-resistant (GLC4/ adr) human small cell lung carcinoma cell lines. The oxidation of the probe to the fluorescent dichlorofluorescein (DCF) was continuously monitored by following the DCF fluorescence intensity as a function of time using a standard spectrofluorometer in the presence of an extracellular DCF fluorescence quencher (Co 2+). By fitting the spectrofluorometric data to a kinetic model based on the following two reactions: (i) deacetylation of DCHF-DA to the oxidant-sensitive compound 2',7'-dichlorofluorescein (DCHF) by cellular esterase enzymes (pseudo-first-order rate constant: ke) and (ii) oxidation of DCHF by ROS i (second-order rate constant: k2), the parameters intervening in DCF formation, ke and the product of k2 by the ROS i concentration, were quantitatively determined for the different cell lines studied. The results revealed that the intracellular esterase content or activity is similar in K562, K562/ adr, and GLC4 cells, but 5-fold higher in GLC4/ adr cells. The product k2[ROS i] was found to be similar in the four cell lines considered, with a mean value of (5.3±0.9)×10 -7 cell -1 s -1. Assuming that H 2O 2 (in combination with peroxidases) is the primary responsible species for DCHF oxidation in intact cells, and using the rate constant value k2=790±62 M s established in our laboratory for the reaction of DCHF with H 2O 2 in the presence of horseradish peroxidase, the mean value of the intracellular levels of ROS i in those cells was estimated to be 0.67±0.16 nM per cell. Such a value compares favorably to H 2O 2 intracellular steady-state concentrations that have been

  11. The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms.

    Science.gov (United States)

    Beranova, Lenka; Pombinho, Antonio R; Spegarova, Jarmila; Koc, Michal; Klanova, Magdalena; Molinsky, Jan; Klener, Pavel; Bartunek, Petr; Andera, Ladislav

    2013-06-01

    TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co-treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT-29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL-based, anti-cancer combination therapy.

  12. Preparation, characterization, and in vitro drug release behavior of glutathione-sensitive long-circulation micelles based on polyethylene glycol prodrug.

    Science.gov (United States)

    Shi, Liyan; Ding, Kaikai; Sun, Xin; Zhang, Ling; Zeng, Tian; Yin, Yihua; Zheng, Hua

    2016-01-01

    In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH)-sensitive strategy is based on a Michael addition-elimination reaction, that is the amphiphilic polymeric prodrug which contains α, β-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile - glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 ± 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days. In vitro drug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV-vis spectrophotometer. In vitro macrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs.

  13. Yolk-shell hybrid nanoparticles with magnetic and pH-sensitive properties for controlled anticancer drug delivery

    Science.gov (United States)

    Li, Shunxing; Zheng, Jianzhong; Chen, Dejian; Wu, Yijin; Zhang, Wuxiang; Zheng, Fengying; Cao, Jing; Ma, Heran; Liu, Yaling

    2013-11-01

    A facile and effective way for the preparation of nano-sized Fe3O4@graphene yolk-shell nanoparticles via a hydrothermal method is developed. Moreover, the targeting properties of the materials for anticancer drug (doxorubicin hydrochloride) delivery are investigated. Excitingly, these hybrid materials possess favorable dispersibility, good superparamagnetism (the magnetic saturation value is 45.740 emu g-1), high saturated loading capacity (2.65 mg mg-1), and effective loading (88.3%). More importantly, the composites exhibit strong pH-triggered drug release response (at the pH value of 5.6 and 7.4, the release rate was 24.86% and 10.28%, respectively) and good biocompatibility over a broad concentration range of 0.25-100 μg mL-1 (the cell viability was 98.52% even at a high concentration of 100 μg mL-1) which sheds light on their potentially bright future for bio-related applications.

  14. MiR-122 increases sensitivity of drug-resistant BEL-7402/5-FU cells to 5-fluorouracil via down-regulation of bcl-2 family proteins.

    Science.gov (United States)

    Yin, Jie; Tang, Hui Fang; Xiang, Qiong; Yu, Jia; Yang, Xiao Yang; Hu, Nan; Lei, Xiao Yong

    2011-12-01

    To investigate the changes in drug sensitivity of miR-122 transfected BEL-7402/5-FU cells. MiR-122 and negative miRNA expression vectors were constructed and stably transfected into BEL-7402/5-FU cells. Real-time RT-PCR was used to detect the level of miR-122, Bcl-XL, Bcl-2 and P53 mRNA. Western Blotting was used to detect Bcl-2, Bcl-XL and P53 protein expression. Drug sensitivity of the cells to 5-fluorouracil (5-FU) was analyzed with MTT and flow cytometry. Compared with negative miRNA transfectants or untreated cells, mRNA and protein expression level of Bcl-2, Bcl-XL in stable miR-122 transfectants were decreased. Accordingly, P53 protein expression showed a significant up-regulation; MTT results showed that after incubation with 5-FU, miR-122 transfectants had higher cell inhibitory rates than negative miRNA or untreated cells; flow cytometry results demonstrated that apoptosis rate increased in miR-122 transfected cells, compared with negative miRNA or untreated cells. After addition of 5-FU (10 and 100 micromol/I), miR-122 transfected cells showed higher apoptosis rate than negative miRNA or untreated cells. MiR-122 can specifically down-regulate the expression of Bcl-2 and Bcl-XL, and increase P53 activity in BEL-7402/5-FU cells, which increased cells spontaneous apoptosis and sensitize cells to 5-FU. Therefore, MiR-122 can be used as a potential therapy agent against human hepatoblastoma.

  15. Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery.

    Science.gov (United States)

    Zhang, Can Yang; Xiong, Di; Sun, Yao; Zhao, Bin; Lin, Wen Jing; Zhang, Li Juan

    2014-01-01

    A novel amphiphilic triblock pH-sensitive poly(β-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation-deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy.

  16. Monitoring the drug-sensitivity of Plasmodium falciparum in coastal towns in Madagascar by use of in vitro chemosensitivity and mutation detection tests

    Directory of Open Access Journals (Sweden)

    Rason M.A.

    2002-09-01

    Full Text Available The dissemination of mutant and resistant strains of Plasmodium falciparum makes a considerable contribution to the spread of drug-resistant malaria. Populations around harbours and airports could be particularly exposed to Plasmodium isolates introduced with imported cases of malaria. The use of chloroquine as well as the use of and sulfadoxine/pyrimethamine is currently an effective method for treating uncomplicated cases of malaria in Madagascar. As part of a monitoring programme, in vitro methods were used to assess the sensitivity of P. falciparum isolates in two coastal towns in Madagascar: Mahajanga on the west coast and Toamasina on the east coast. All of the isolates from both sites were sensitive to amodiaquine, quinine, pyrimethamine and cycloguanil. All of the isolates from Mahajanga were sensitive to chloroquine (n = 25; mean IC50 = 22.6 nM, 95 % confidence interval: 16.8-28.7 nM, whereas three of the isolates from Toamasina were resistant to chloroquine (n = 18; mean IC50 = 66.3 nM; 95 % confidence interval : 42.6-90 nM, The frequency of the Pfcrt Thr-76 and the dhfr Asn- 108 mutations was estimated by PCR/RFLP. The 43 P. falciparum isolates examined, including the three in vitro chloroquine-resistant isolates from Toamasina were all wild-type (Lys-76. Phenotyping and genotyping studies suggested that the prevalence of chloroquine- and pyrimethamine-resistant isolates and of mutant strains of P. falciparum is very low. These results showed that in vitro test and genotyping of resistance markers approaches could be successfully used to monitor the emergence of drug-resistant malaria and to try to alleviate the lack of medical teams able to carry out in vivo test. The possible hazard/risk associated with imported cases of malaria is discussed.

  17. Are standard tests sensitive enough to evaluate effects of human pharmaceuticals in aquatic biota? Facing changes in research approaches when performing risk assessment of drugs.

    Science.gov (United States)

    Aguirre-Martínez, G V; Owuor, M A; Garrido-Pérez, C; Salamanca, M J; Del Valls, T A; Martín-Díaz, M L

    2015-02-01

    Nowadays, the presence of pharmaceutical products in aquatic environments is not only common, but is also of significant concern regarding the adverse effect they may produce to aquatic biota. In order to determine the adverse effects of caffeine (CAF), ibuprofen (IBU), carbamazepine (CBZ) and novobiocin (NOV), at environmental occurring concentrations, standardized endpoints applied in current guidelines were evaluated in four organisms including bioluminescence response in Vibrio fischeri, growth inhibition in Isochrysis galbana (marine water) and Pseudokirchneriella subcapitata (fresh water) and fertilization and embryo-larval development in Paracentrotus lividus. To reach this aim bioassays were implemented by exposing organisms to water spiked with drugs dissolved in DMSO (0.001% v/v). Risk characterization was performed, calculating the environmental impact of drugs by calculating environmental concentration and predicted no effect concentration ratio (MEC/PNEC). Results indicate that acute toxicity was found above environmental concentrations in the order of mg L(-1) for bacteria bioluminescence, microalgae growth inhibition and sea urchin fertilization. However, teratogenicity was observed on sea urchin after exposure to environmental concentrations of drugs at 0.00001 mg L(-1); at this concentration CBZ and IBU were found to reduce significantly the embryo-larval development compared to controls (p<0.01). The risk calculated for selected drugs suggested they are harmless for aquatic environment except when applying the embryo-larval development endpoint. Endpoints applied in this study showed the necessity of using more sensitive responses, when assessing risk of pharmaceuticals in aquatic environments, since endpoints applied in current guidelines may not be suitable.

  18. TOP1 gene copy numbers in colorectal cancer samples and cell lines and their association to in vitro drug sensitivity

    DEFF Research Database (Denmark)

    Rømer, Maria Unni; Jensen, Niels Frank; Nielsen, Signe Lykke;

    2012-01-01

    Background and aims: A positive relationship between topoisomerase-1 (TOP1) protein and sensitivity towards the TOP1 inhibitor irinotecan has been reported in patients with metastatic colorectal cancer (mCRC). The aim of this study was to analyse TOP1 gene copy number variation in tumor tissue from...... epithelium 84% of the samples demonstrated an increased TOP1 gene copy number and 66% had an increased TOP1/CEN-20 ratio compared to the non-affected mucosa. Sixteen (32%) of the tumors had a ratio = 1.5 and 9 of these had a ratio of = 2.0. A positive association was observed between the TOP1 gene copy...... CRC patients and CRC cell lines with different sensitivities to the TOP1 inhibitor SN-38 and oxaliplatin. Methods: A TOP1 gene probe with a chromosome 20 centromere (CEN-20) reference probe was tested on tumor tissue from 50 stage III CRC patients. Additionally, associations between TOP1/CEN-20 ratio...

  19. In-vitro sensitivity of Pakistani Leishmania tropica field isolate against buparvaquone in comparison to standard anti-leishmanial drugs.

    Science.gov (United States)

    Jamal, Qaisar; Khan, Nazma Habib; Wahid, Sobia; Awan, Mahwish Mustafa; Sutherland, Colin; Shah, Akram

    2015-07-01

    In this study, in vitro anti-leishmanial activity of buparvaquone was evaluated against promastigotes and intracellular amastigotes of Pakistani Leishmania tropica isolate KWH23 in relation to the current standard chemotherapy for leishmaniasis (sodium stibogluconate, sodium stibogluconate, amphotericin B and miltefosine). For buparvaquone, mean % inhibition in intracellular amastigotes at four different concentrations (1.35 µM, 0.51 µM, 0.17 µM and 0.057 µM) was 78%, 44%, 20% and 14% respectively, whereas, against promastigotes it was 89%, 77%, 45% and 35% respectively. IC50 values calculated to estimate the anti-leishmanial activity of buparvaquone against intra-cellular amastigotes and promastigotes was 0.53 µM (95% C.I. = 0.32-0.89) and 0.15 µM (95% C.I. = 0.01-1.84) respectively. Amphotericin B was the most potent in-vitro drug tested, with an IC50 of 0.075 µM (95% C.I. = 0.006-0.907) against promastigotes, and 0.065 µM (95% C.I. = 0.048-0.089) against intra-cellular amastigotes. Amphotericin B was more cytotoxic against THP1 cells, with an IC50 of 0.15 µM (95% C.I. = 0.01-0.95) and an apparent in-vitro therapeutic index of 2.0, than was buparvaquone, with an IC50 of 12.03 µM (95% C.I. = 5.36-26.96) against THP1 cells and a therapeutic index of 80.2. The study proposes that buparvaquone may be further investigated as a candidate drug for treatment of cutaneous leishmaniasis.

  20. The effects of cold atmospheric plasma on cell adhesion, differentiation, migration, apoptosis and drug sensitivity of multiple myeloma.

    Science.gov (United States)

    Xu, Dehui; Luo, Xiaohui; Xu, Yujing; Cui, Qingjie; Yang, Yanjie; Liu, Dingxin; Chen, Hailan; Kong, Michael G

    2016-05-13

    Cold atmospheric plasma was shown to induce cell apoptosis in numerous tumor cells. Recently, some other biological effects, such as induction of membrane permeation and suppression of migration, were discovered by plasma treatment in some types of tumor cells. In this study, we investigated the biological effects of plasma treatment on multiple myeloma cells. We detected the detachment of adherent myeloma cells by plasma, and the detachment area was correlated with higher density of hydroxyl radical in the gas phase of the plasma. Meanwhile, plasma could promote myeloma differentiation by up-regulating Blimp-1 and XBP-1 expression. The migration ability was suppressed by plasma treatment through decreasing of MMP-2 and MMP-9 secretion. In addition, plasma could increase bortezomib sensitivity and induce myeloma cell apoptosis. Taking together, combination with plasma treatment may enhance current chemotherapy and probably improve the outcomes.

  1. Sensitive spectrophotometric determination of ascorbic acid in drugs and foods using surface plasmon resonance band of silver nanoparticles

    Directory of Open Access Journals (Sweden)

    Kobra Zarei

    2015-12-01

    Full Text Available A simple and sensitive procedure was proposed for spectrophotometric determination of ascorbic acid. It was found that the reduction of Ag+ to silver nanoparticles (Ag-NPs by ascorbic acid in the presence of polyvinylpyrrolidone (PVP as a stabilizing agent produce very intense surface plasmon resonance peak of Ag-NPs. The plasmon absorbance of the Ag-NPs at λ = 440 nm allows the quantitative spectrophotometric detection of the ascorbic acid. The calibration curve was linear with concentration of ascorbic acid in the range of 0.5–60 μM. The detection limit was obtained as 0.08 μM. The influence of potential interfering substances on the determination of ascorbic acid was studied. The proposed method was successfully applied for the determination of ascorbic acid in some powdered drink mixtures, commercial orange juice, natural orange juice, vitamin C injection, effervescent tablet, and multivitamin tablet.

  2. Evaluation of adverse drug reactions in HIV positive patients in a tertiary care hospital

    Directory of Open Access Journals (Sweden)

    Anshu Kumar Jha

    2015-01-01

    Full Text Available Context: The advancement and development of new drugs and treatment strategies increase the risk of unusual Adverse Events (AEs in HIV patients. Aims: The objective of our study was to assess the incidence, types and nature of AEs in HIV positive subjects. Settings and Design: Patients with WHO stage IV disease irrespective of the CD4 cell count, or WHO stage III disease with a CD4 cell count <350 cell/cu. Mm, or, WHO stage I or II disease with a CD4 cell count of <200 cells/cu. mm, and on prior anti-retroviral therapy for not more than six months preceding the observation date, were included in the study. After initiation of therapy, the patients were examined for the occurrence any adverse events including the type and severity, or any other abnormal laboratory findings. Causality assessment of the adverse events was done using the Naranjo′s scale. Results: Out of 327 patients studied prospectively, 43 patients developed AEs. Out of these, 23 (53.5% were males and 20 (46.5% were females. A total of 53 (16.21% AEs were reported. Antitubercular drugs caused the maximum AEs (28.3% followed by zidovudine (20.7%, nevirapine (15.0% and efavirenz (5.6%. Stavudine, ethambutol, sulfamethoxazole and trimethoprim, and atazanavir were also responsible for 3.7% of AEs individually. Causality assessment done according to the Naranjo′s scale revealed that 66.04% AEs were ′probable′ and 33.96% were ′possible′. Conclusions: Anemia, hepatitis and dermatological adverse effects are the most common AEs. Antitubercular drugs contributed significantly for the incidence of AEs in these patients. Frequency of AEs was slightly more in males compared to females.

  3. Formulation, characterization and tissue distribution of a novel pH-sensitive long-circulating liposome-based theranostic suitable for molecular imaging and drug delivery

    Science.gov (United States)

    Duan, Yin; Wei, Lihui; Petryk, Julia; Ruddy, Terrence D

    2016-01-01

    Purpose When designing liposome formulas for treatment and diagnostic purposes, two of the most common challenges are 1) the lack of a specific release mechanism for the encapsulated contents and 2) a short circulation time due to poor resistance to biological fluids. This study aimed to create a liposome formula with prolonged in vivo longevity and pH-sensitivity for cytoplasmic drug delivery. Materials and methods Liposomal particles were generated using hydrogenated soy (HS) phosphatidylcholine, cholesteryl hemisuccinate (CHEM), polyethylene glycol (PEG) and diethylenetriaminepentaacetic acid-modified phosphatidylethanolamine with film hydration and extrusion methods. The physicochemical properties of the different formulas were characterized. pH-sensitivity was evaluated through monitoring release of encapsulated calcein. Stability of the radiolabeled liposomes was assessed in vitro through incubation with human serum. The best formula was selected and injected into healthy rats to assess tissue uptake and pharmacokinetics. Results Liposomal particles were between 88 and 102 nm in diameter and negatively charged on the surface. Radiolabeling of all formulas with indium-111 was successful with good efficiency. 1%PEG-HS-CHEM not only responded to acidification very quickly but also underwent heavy degradation with serum. The 4%PEG-HS-CHEM, which exhibited both comparatively good pH-sensitivity (up to 20% release) and satisfactory stability (stability >70% after 24 h), was considered the best candidate for in vivo evaluation. Tissue distribution of 4%PEG-HS-CHEM was comparable to that of 4%PEG-HS-Chol, a long-circulating but pH-insensitive control, showing major accumulation in liver, spleen, intestine and kidneys. Analysis of blood clearance showed favorable half-life values: 0.6 and 14 h in fast and slow clearance phases, respectively. Conclusion 4%PEG-HS-CHEM showed promising results in pH-sensitivity, serum stability, tissue uptake and kinetics and is a novel

  4. The reliability of sensitive information provided by injecting drug users in a clinical setting: clinician-administered versus audio computer-assisted self-interviewing (ACASI).

    Science.gov (United States)

    Islam, M Mofizul; Topp, Libby; Conigrave, Katherine M; van Beek, Ingrid; Maher, Lisa; White, Ann; Rodgers, Craig; Day, Carolyn A

    2012-01-01

    Research with injecting drug users (IDUs) suggests greater willingness to report sensitive and stigmatised behaviour via audio computer-assisted self-interviewing (ACASI) methods than during face-to-face interviews (FFIs); however, previous studies were limited in verifying this within the same individuals at the same time point. This study examines the relative willingness of IDUs to report sensitive information via ACASI and during a face-to-face clinical assessment administered in health services for IDUs. During recruitment for a randomised controlled trial undertaken at two IDU-targeted health services, assessments were undertaken as per clinical protocols, followed by referral of eligible clients to the trial, in which baseline self-report data were collected via ACASI. Five questions about sensitive injecting and sexual risk behaviours were administered to participants during both clinical interviews and baseline research data collection. "Percentage agreement" determined the magnitude of concordance/discordance in responses across interview methods, while tests appropriate to data format assessed the statistical significance of this variation. Results for all five variables suggest that, relative to ACASI, FFI elicited responses that may be perceived as more socially desirable. Discordance was statistically significant for four of the five variables examined. Participants who reported a history of sex work were more likely to provide discordant responses to at least one socially sensitive item. In health services for IDUs, information collection via ACASI may elicit more reliable and valid responses than FFI. Adoption of a universal precautionary approach to complement individually tailored assessment of and advice regarding health risk behaviours for IDUs may address this issue.

  5. Dopamine D3 receptor knock-out mice exhibit increased behavioral sensitivity to the anxiolytic drug diazepam.

    Science.gov (United States)

    Leggio, Gian Marco; Micale, Vincenzo; Le Foll, Bernard; Mazzola, Carmen; Nobrega, José N; Drago, Filippo

    2011-04-01

    Dopamine D(3) receptors (DRsD3) seem to have a pivotal role in mood disorders. Using the elevated plus maze (EPM) and the novelty-induced grooming test (NGT), we assessed the responses of DRD3-deficient (D(3)(-/-)) mice to the acute treatment (different testing time) with the anxiolytic drug, diazepam. D(3)(-/-) mice treated with diazepam (0.1 or 0.5mg/kg) exhibited a better behavioral response in the EPM than their wild type (WT). Furthermore, in D(3)(-/-) mice, but not in WT, 1mg/kg diazepam induced anxiolytic effects at all testing times. The contribution of DRsD3 in the anxiolytic effects of diazepam was confirmed by similar results obtained in EPM by using the selective DRD3 antagonist U99194A (10mg/kg) in combination with diazepam, in WT animals. D(3)(-/-) mice treated with diazepam (all doses), also showed a decrease in grooming behavior. However, the [(3)H]flunitrazepam autoradiographic analysis revealed no significant changes in D(3)(-/-) mice compared to WT, suggesting that if γ-aminobutyric acid receptor GABA(A) changes are involved, they do not occur at the level of binding to benzodiazepine site. These data suggest that D(3)(-/-) mice exhibit low baseline anxiety levels and provide the evidence that the DRD3 is involved in the modulation of benzodiazepine anxiolytic effects.

  6. Role of MRP transporters in regulating antimicrobial drug inefficacy and oxidative stress-induced pathogenesis during HIV-1 and TB infections.

    Science.gov (United States)

    Roy, Upal; Barber, Paul; Tse-Dinh, Yuk-Ching; Batrakova, Elena V; Mondal, Debasis; Nair, Madhavan

    2015-01-01

    Multi-Drug Resistance Proteins (MRPs) are members of the ATP binding cassette (ABC) drug-efflux transporter superfamily. MRPs are known to regulate the efficacy of a broad range of anti-retroviral drugs (ARV) used in highly active antiretroviral therapy (HAART) and antibacterial agents used in Tuberculus Bacilli (TB) therapy. Due to their role in efflux of glutathione (GSH) conjugated drugs, MRPs can also regulate cellular oxidative stress, which may contribute to both HIV and/or TB pathogenesis. This review focuses on the characteristics, functional expression, and modulation of known members of the MRP family in HIV infected cells exposed to ARV drugs and discusses their known role in drug-inefficacy in HIV/TB-induced dysfunctions. Currently, nine members of the MRP family (MRP1-MRP9) have been identified, with MRP1 and MRP2 being the most extensively studied. Details of the other members of this family have not been known until recently, but differential expression has been documented in inflammatory tissues. Researchers have found that the distribution, function, and reactivity of members of MRP family vary in different types of lymphocytes and macrophages, and are differentially expressed at the basal and apical surfaces of both endothelial and epithelial cells. Therefore, the prime objective of this review is to delineate the role of MRP transporters in HAART and TB therapy and their potential in precipitating cellular dysfunctions manifested in these chronic infectious diseases. We also provide an overview of different available options and novel experimental strategies that are being utilized to overcome the drug resistance and disease pathogenesis mediated by these membrane transporters.

  7. Role of MRP Transporters in Regulating Antimicrobial Drug Inefficacy and Oxidative Stress-induced Pathogenesis during HIV-1 and TB Infections

    Directory of Open Access Journals (Sweden)

    Upal eRoy

    2015-09-01

    Full Text Available Multi-Drug Resistance Proteins (MRPs are members of the ATP binding cassette (ABC drug-efflux transporter superfamily. MRPs are known to regulate the efficacy of a broad range of anti-retroviral drugs (ARV used in highly active antiretroviral therapy (HAART and antibacterial agents used in Tuberculus Bacilli (TB therapy. Due to their role in efflux of glutathione (GSH conjugated drugs, MRPs can also regulate cellular oxidative stress, which may contribute to both HIV and/or TB pathogenesis. This review focuses on the characteristics, functional expression, and modulation of known members of the MRP family in HIV infected cells exposed to ARV drugs and discusses their known role in drug-inefficacy in HIV/TB-induced dysfunctions. Currently, nine members of the MRP family (MRP1-MRP9 have been identified, with MRP1 and MRP2 being the most extensively studied. Details of the other members of this family have not been known until recently, but differential expression has been documented in inflammatory tissues. Researchers have found that the distribution, function and reactivity of members of MRP family vary in different types of lymphocytes and macrophages, and are differentially expressed at the basal and apical surfaces of both endothelial and epithelial cells. Therefore, the prime objective of this review is to delineate the role of MRP transporters in HAART and TB therapy and their potential in precipitating cellular dysfunctions manifested in these chronic infectious diseases. We also provide an overview of different available options and novel experimental strategies that are being utilized to overcome the drug resistance and disease pathogenesis mediated by these membrane transporters.

  8. A novel application of maleimide for advanced drug delivery: in vitro and in vivo evaluation of maleimide-modified pH-sensitive liposomes

    Directory of Open Access Journals (Sweden)

    Li T

    2013-10-01

    Full Text Available Tianshu Li, Shinji TakeokaDepartment of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns, Shinjuku-ku, Tokyo, JapanAbstract: Maleimide is a stable and easy-to-handle moiety that rapidly and covalently conjugates thiol groups of cysteine residues in proteins or peptides. Herein, we use maleimide to modify the surface of liposomes in order to obtain an advanced drug delivery system. Employing a small amount (0.3 mol% of maleimide-polyethylene glycol (PEG to modify the surface of the liposomes M-GGLG-liposomes, composed of 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (GGLG/cholesterol/poly(ethylene glycol 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG5000-DSPE/maleimide-PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03, drug delivery efficiency was remarkably improved both in vitro and in vivo compared to unmodified liposomes (GGLG-liposomes, composed of GGLG/cholesterol/PEG5000-DSPE/PEG5000-Glu2C18 at a molar ratio of 5:5:0.03:0.03. Moreover, this modification did not elicit any detectable increase in cytotoxicity. The maleimide-modification did not alter the physical characteristics of the liposomes such as size, zeta potential, pH sensitivity, dispersibility and drug encapsulation efficiency. However, M-GGLG-liposomes were more rapidly (≥2-fold internalized into HeLa, HCC1954, and MDA-MB-468 cells compared to GGLG-liposomes. In vivo, M-GGLG-liposomes encapsulating doxorubicin (M-GGLG-DOX-liposomes also showed a more potent antitumor effect than GGLG-DOX-liposomes and the widely used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC-DOX-liposomes after two subcutaneous injections around breast cancer tissue in mice. The biodistribution of liposomes in this model was observed using an in vivo imaging system, which showed that M-GGLG-liposomes were present for significantly longer at the injection site compared to GGLG-liposomes. The outstanding biological functions of

  9. The molecular epidemiological study of colistin-only-sensitive strains in multi-drug resistant Acinetobacter baumannii

    Institute of Scientific and Technical Information of China (English)

    YANG Li; HAN Lizhong; SUN Jingyong; YU Yunsong; NI Yuxing

    2007-01-01

    This paper reported the epidemiology of the colistin-only-sensitive Acinetobacter baumannii(COS-AB)in a tertiary teaching hospital in China.We analyzed the clinical data of 136 COS-AB isolates from June 2004 to May 2005 and collected 66 A.baumannii isolates in which 33 strains were COS-AB,and the rest were non-COS-AB.Random amplified polymorphic DNA(RAPD)analysis (primer ERIC2 and 272)showed that all COS-AB were identical,while pulsed-field gel electrophotesis(PFGE)analysis showed two separate genotypes of these COS-ABwhich were distinctly different from that of non-COS-AB.The COS-AB from burn wards showed the identical PFGE pattern which was distinguished from the genotype of COS-AB in other departments,mainly surgical systems.The cross-infection was severe and strict methods of disinfection and sterilization should be implemented.Meanwhile,the epidemiology of COS-AB in environment and patients should be closely monitored.The PFGE analysis is a reliable method of A.baumannii typing.

  10. Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Eric W Fish

    Full Text Available Fragile X syndrome (FXS is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y mice with intracranial self-stimulation (ICSS and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynylpyridine (MPEP, was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.

  11. Methylphenidate enhances the abuse-related behavioral effects of nicotine in rats: intravenous self-administration, drug discrimination, and locomotor cross-sensitization.

    Science.gov (United States)

    Wooters, Thomas E; Neugebauer, Nichole M; Rush, Craig R; Bardo, Michael T

    2008-04-01

    Stimulant drugs, including D-amphetamine, cocaine, and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination, and locomotor cross-sensitization procedures. Adult male Sprague-Dawley rats were trained to respond for intravenous nicotine (0.01 or 0.03 mg/kg/infusion) or sucrose, and the acute effects of methylphenidate (1.25-10 mg/kg) were determined; in addition, separate groups of rats were treated with methylphenidate (2.5 mg/kg) or saline before 12 consecutive nicotine (0.03 mg/kg/infusion) self-administration sessions. Next, the discriminative stimulus effects of nicotine (0.03-0.3 mg/kg) and methylphenidate (1.25-10 mg/kg), alone and in combination with a low nicotine dose (0.056 mg/kg), were tested in nicotine-trained rats. Finally, the locomotor effect of repeated methylphenidate (2.5 mg/kg) was tested in rats previously treated with nicotine (0.2-0.8 mg/kg). Results indicated that acute methylphenidate increased the rate of nicotine self-administration at doses that reduced sucrose-maintained responding; furthermore, tolerance to this effect was not apparent following repeated methylphenidate. Methylphenidate, while not substituting for nicotine alone, dose-dependently enhanced the discriminative stimulus effect of a low nicotine dose. In addition, repeated nicotine exposure promoted the development of locomotor sensitization to methylphenidate. Taken together with recent clinical findings, these results suggest that methylphenidate may enhance the abuse-related behavioral effects of nicotine, perhaps increasing vulnerability to tobacco dependence.

  12. Novel pH sensitive ferrogels as new approach in cancer treatment: Effect of the magnetic field on swelling and drug delivery.

    Science.gov (United States)

    Muzzalupo, Rita; Tavano, Lorena; Rossi, Cesare Oliviero; Picci, Nevio; Ranieri, Giuseppe Antonio

    2015-10-01

    Ferrogels (or magnetic hydrogels) are cross-linked polymer networks containing magnetic nanoparticles: they are mechanically soft and highly elastic and at the same time they exhibit a strong magnetic response. Our work focuses on an combinatorial strategy to improve the efficacy of 5-Fluorouracil (5-FU) assisted chemotherapy, by developing novel multifunctional pH-sensitive ferrogels. We designed gels based on N,N'-dimethylacrylamide monomers polymerized in presence of methacrylic acid or 2-aminoethyl methacrylate hydrochloride, containing ferro-nanoparticles. The influence of polymeric matrix composition and exposition to magnetic field (MF) on swelling behavior and drugs release were investigated at pH 7.4 and 5. In particular, the magnetic field was obtained by using permanent magnetic bar (0.25 T) or electromagnet (0.5 and 1.2 T), with the aim to analyze quantitatively the magnetic effects. A strong influence of the magnetic field on ferrogels properties have been observed. Swelling analysis indicated a dependence on both pH and network composition, reaching a maximum at pH 7.4, for formulations containing methacrylic acid, while the application of MF appeared to decrease the swelling percentages. Release profiles of 5-FU showed effective modulation in release by application of MF: drug release is always higher in the presence of a magnetic field and generally increases with its intensity. The combining effect of pH sensitive properties and application of MF improved the performance of the systems. Results showed that our ferrogels may be technologically applicable as devices for delivery of 5-FU in a controllable manner.

  13. Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1.

    Science.gov (United States)

    Heredia, Alonso; Latinovic, Olga; Gallo, Robert C; Melikyan, Gregory; Reitz, Marv; Le, Nhut; Redfield, Robert R

    2008-12-23

    Vicriviroc (VCV) is a chemokine (C-C motif) receptor 5 (CCR5) antagonist with potent anti-HIV activity that currently is being evaluated in phase III clinical trials. In the present study, donor CCR5 density (CCR5 receptors/CD4 lymphocytes) inversely correlated with VCV antiviral activity (Spearman's correlation test; r = 0.746, P = 0.0034). Low doses of the transplant drug rapamycin (RAPA) reduced CCR5 density and enhanced VCV antiviral activity. In drug interaction studies, the RAPA/VCV combination had considerable antiviral synergy (combination indexes of 0.1-0.04) in both multicycle and single-cycle infection of lymphocytes. The synergy between RAPA and VCV translated into dose reduction indexes of 8- to 41-fold reductions for RAPA and 19- to 658-fold reductions for VCV. RAPA enhanced VCV antiviral activity against both B and non-B clade isolates, potently suppressing clade G viruses with reported reduced sensitivities to VCV and to the licensed CCR5 antagonist maraviroc. Importantly, RAPA reduction of CCR5 density in lymphocytes sensitized VCV-resistant strains to VCV, inhibiting virus production by approximately 90%. We further demonstrated the role of CCR5 density on VCV activity against resistant virus in donor lymphocytes and in cell lines expressing varying CCR5 densities. Together, these results suggest that low doses of RAPA may increase the durability of VCV-containing regimens in patients by enhancing VCV viral suppression, by allowing the use of lower doses of VCV with reduced potential for toxicity, and by controlling emerging VCV-resistant variants.

  14. Simple and sensitive stability-indicating ion chromatography method for the determination of cyclopropylamine in nevirapine and moxifloxacin hydrochloride drug substances.

    Science.gov (United States)

    Kothapalli, Pavan Kumar S R; Khagga, Mukkanti; Mekala, Nageswara Rao; Sigamani, John Prasanna; Vundavilli, Jagadeesh Kumar; Masani, Narendra Kumar; Sharma, Hemant Kumar

    2012-01-01

    A simple and sensitive ion chromatography method has been developed for the determination of cyclopropylamine (CPA) in nevirapine (NEV) and moxifloxacin HCl (MOX) pharmaceutical drug substances. Efficient chromatographic separation was achieved on a Metrosep C4, 5 μm (250 mm × 4.0 mm) column. The mobile phase consists of 5 mM hydrochloric acid containing 10% (v/v) acetonitrile and was delivered in an isocratic mode at a flow rate of 0.9 mL min(-1) at 27°C. A conductometric detector was used for the detection of the analyte. The drug substances were subjected to stress conditions including oxidation, thermal, photolytic and humidity for the evaluation of the stability-indicating nature of the method. The method was validated for specificity, precision, linearity, accuracy and solution stability. The limit of detection (LOD) and limit of quantification (LOQ) values are 0.10 μg mL(-1) and 0.37 μg mL(-1) respectively. The linearity range of the method is between 0.37 μg mL(-1) and 1.5 μg mL(-1) and the correlation coefficient is found to be 0.9971. The average recoveries of CPA in NEV and MOX are 97.0% and 98.0%, respectively.

  15. Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1

    Directory of Open Access Journals (Sweden)

    Zantl Niko

    2010-06-01

    Full Text Available Abstract Background Human renal cell carcinoma (RCC is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c. Conclusions Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.

  16. pH-sensitive nanoparticles of poly(L-histidine)-poly(lactide-co-glycolide)-tocopheryl polyethylene glycol succinate for anti-tumor drug delivery.

    Science.gov (United States)

    Li, Zhen; Qiu, Lipeng; Chen, Qing; Hao, Tangna; Qiao, Mingxi; Zhao, Haixia; Zhang, Jie; Hu, Haiyang; Zhao, Xiuli; Chen, Dawei; Mei, Lin

    2015-01-01

    A novel pH-sensitive polymer, poly(L-histidine)-poly(lactide-co-glycolide)-tocopheryl polyethylene glycol succinate (PLH-PLGA-TPGS), was synthesized to design a biocompatible drug delivery system for cancer chemotherapy. The structure of the PLH-PLGA-TPGS copolymer was confirmed by (1)H-NMR, FTIR and GPC. The apparent pKa of the PLH-PLGA-TPGS copolymer was calculated to be 6.33 according to the acid-base titration curve. The doxorubicin (DOX)-loaded nanoparticles (PLH-PLGA-TPGS nanoparticles and PLGA-TPGS nanoparticles) and corresponding blank nanoparticles were prepared by a co-solvent evaporation method. The blank PLH-PLGA-TPGS nanoparticles showed an acidic pH-induced increase in particle size. The DOX-loaded nanoparticles based on PLH-PLGA-TPGS showed a pH-triggered drug-release behavior under acidic conditions. The results of in vitro cytotoxicity experiment on MCF-7 and MCF-7/ADR cells showed that the DOX-loaded PLH-PLGA-TPGS nanoparticles resulted in lower cell viability versus the PLGA-TPGS nanoparticles and free DOX solution. Confocal laser scanning microscopy images showed that DOX-loaded PLH-PLGA-TPGS nanoparticles were internalized by MCF-7/ADR cells after 1 and 4h incubation and most of them accumulated in lysosomes to accelerate DOX release under acidic conditions. In summary, the PLH-PLGA-TPGS nanoparticles have great potential to be used as carriers for anti-tumor drug delivery.

  17. A mini-electrochemical system integrated micropipet tip and pencil graphite electrode for detection of anticancer drug sensitivity in vitro.

    Science.gov (United States)

    Guo, Xiaoling; Wang, Qian; Li, Jinlian; Cui, Jiwen; Zhou, Shi; Hao, Sue; Wu, Dongmei

    2015-02-15

    Developing a reliable and cost-effective miniaturized electroanalysis tool is of vital importance for cell electrochemical analysis. In this work, a novel mini-electrochemical system has been constructed for trace detection of cell samples. The mini-electrochemical system was constructed by integrating a pencil graphite modified by threonine (PT/PGE) as working electrode, an Ag/AgCl (Sat'd) as reference electrode, platinum wire as counter electrode and a micropipet tip as electrochemical cell. The mini-electrochemical system not only saved dramatically usage of samples from 500 μL in traditional electrochemical system to 10 μL, but also possessed an adjustable active surface area by changing the length of PT/PGE immersed into the cell suspension from 3mm to 15 mm, and the linear equation was ipa = 2.25 l-2.64 (R(2) = 0.990). The system was successfully used in detection of MCF-7 cells, and a nonlinear exponent relationship between peak current and the cell number range from 3.0 × l0(3) to 7.0 × l0(6) cells mL(-1) was established firstly with the index equation ipa = 59.557 e (-C/1.709)-71.486 (R(2) = 0.954). Finally, the system was used for evaluating the sensitivity of cyclophosphamide on MCF-7 cell, and the result was corresponded well with that of MTT assay. The proposed system is sufficiently simple, cheap and easy operated, and could be applied in electrochemical detection of other biological samples.

  18. The anti-obesity drug orlistat promotes sensitivity to TRAIL by two different pathways in hormone-refractory prostate cancer cells.

    Science.gov (United States)

    Fujiwara, Jun; Sowa, Yoshihiro; Horinaka, Mano; Koyama, Makoto; Wakada, Miki; Miki, Tsuneharu; Sakai, Toshiyuki

    2012-05-01

    The administration of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the expected cancer therapeutics. However, improvements are required in therapies against TRAIL-resistant tumor cells. We report, here, that the anti-obesity drug orlistat enhances the sensitivity to TRAIL in hormone-refractory prostate cancer (HRPC) cells through two different pathways. The combination of orlistat and TRAIL remarkably induced apoptosis in TRAIL-resistant HRPC, DU145 and PC3 cells. Orlistat induced the expression of death receptor (DR) 5, which is one of the TRAIL receptors, at both the mRNA and protein levels. The suppression of DR5 with siRNA reduced the apoptosis induced by the combination of orlistat and TRAIL, suggesting that the apoptosis was at least partially due to the upregulation of DR5. Although the upregulation by orlistat of CHOP at both mRNA and protein levels was observed in both cell lines, the activation of the DR5 promoter in DU145 cells was CHOP-dependent, but that in PC3 cells was CHOP-independent. Moreover, orlistat induced reactive oxygen species (ROS), and a ROS scavenger diminished the sensitivity to TRAIL through the suppression of CHOP and DR5 expression in both cell lines. These results suggest that there are two pathways of upregulation of DR5 by orlistat, which are the ROS-CHOP pathway and the ROS-direct pathway. In conclusion, orlistat promotes the sensitivity to TRAIL by ROS-mediated pathways in prostate cancer cells, especially in TRAIL-resistant cells. We believe that the combination of orlistat and TRAIL in HRPC is promising as a new chemotherapeutic strategy.

  19. Drug mules” as a radiological challenge: Sensitivity and specificity in identifying internal cocaine in body packers, body pushers and body stuffers by computed tomography, plain radiography and Lodox

    Energy Technology Data Exchange (ETDEWEB)

    Flach, Patricia M., E-mail: patricia.flach@irm.uzh.ch [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Department of Neuroradiology, Inselspital Bern, University of Bern, 3010 Bern (Switzerland); Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich (Switzerland); Department of Radiology, University Hospital USZ, University of Zurich, Raemistrasse 100, 8091 Zurich (Switzerland); Ross, Steffen G. [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Ampanozi, Garyfalia; Ebert, Lars [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich (Switzerland); Germerott, Tanja; Hatch, Gary M. [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Thali, Michael J. [Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Bern, Buehlstrasse 20, 3012 Bern (Switzerland); Centre for Forensic Imaging and Virtopsy, Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich (Switzerland); Patak, Michael A. [Department of Radiology, Inselspital Bern, University of Bern, 3010 Bern (Switzerland); Department of Radiology, University Hospital USZ, University of Zurich, Raemistrasse 100, 8091 Zurich (Switzerland)

    2012-10-15

    Purpose: The purpose of our study was to retrospectively evaluate the specificity, sensitivity and accuracy of computed tomography (CT), digital radiography (DR) and low-dose linear slit digital radiography (LSDR, Lodox{sup ®}) in the detection of internal cocaine containers. Methods: Institutional review board approval was obtained. The study collectively consisted of 83 patients (76 males, 7 females, 16–45 years) suspected of having incorporated cocaine drug containers. All underwent radiological imaging; a total of 135 exams were performed: nCT = 35, nDR = 70, nLSDR = 30. An overall calculation of all “drug mules” and a specific evaluation of body packers, pushers and stuffers were performed. The gold standard was stool examination in a dedicated holding cell equipped with a drug toilet. Results: There were 54 drug mules identified in this study. CT of all drug carriers showed the highest diagnostic accuracy 97.1%, sensitivity 100% and specificity 94.1%. DR in all cases was 71.4% accurate, 58.3% sensitive and 85.3% specific. LSDR of all patients with internal cocaine was 60% accurate, 57.9% sensitive and 63.4% specific. Conclusions: CT was the most accurate test studied. Therefore, the detection of internal cocaine drug packs should be performed by CT, rather than by conventional X-ray, in order to apply the most sensitive exam in the medico-legal investigation of suspected drug carriers. Nevertheless, the higher radiation applied by CT than by DR or LSDR needs to be considered. Future studies should include evaluation of low dose CT protocols in order to address germane issues and to reduce dosage.

  20. Analysis of drug sensitivity and drug resistance of 303 strains of clinically isolated Klebsiella pneumoniae%303株肺炎克雷伯杆菌的药敏结果及耐药性分析

    Institute of Scientific and Technical Information of China (English)

    赖秀花; 邹汉良; 钟彦云; 魏晟潇

    2016-01-01

    Objective To investigate the drug sensitivity and clinical commonly used drugs resistance of Klebsi-ella pneumoniae, and provide reference for using the medicine rationally. Methods The number of Klebsiella pneumoniae isolated from outpatients and inpatients in our hospital from January 2011 to November 2014, extended spectrum beta lac-tamases (ESBLs) detection rate and drug resistant spectrum were retrospective analyzed. Results A total of 303 strains of Klebsiella pneumoniae was isolated from 1 327 sputum samples with detection rate of 22.8%, of which 137 strains pro-duced extended spectrum beta lactamases (ESBLs), accounting for 45.2%. ESBLs producing Klebsiella pneumoniae has 100%resistance to penicillin, and 78.8%or more resistance to cephalosporins, which mainly isolated from the adult group. Aminoglycosides ESBLs producing Klebsiella pneumonia had the lowest resistance to Amikacin with 31.4%, which had 35.1%~43.8% resistance to beta lactamase inhibitor and 46.7% resistance to primaquine ketones. Conclusion The long-term dynamic monitoring of drug sensitivity and drug resistance tendency of Klebsiella pneumoniae, and regularly screening of ESBLs producing Klebsiella pneumoniae are very important to reasonable use of antibiotics.%目的:探讨肺炎克雷伯杆菌的药敏结果及其对临床常用药物的耐药性,为合理用药提供依据。方法回顾性分析2011年1月至2014年11月我院门诊和住院患者送检的痰标本中分离出的非重复性肺炎克雷伯杆菌的数量以及产超广谱β-内酰胺酶(ESBLs)检出率和耐药谱。结果1327份痰标本中分离出303株肺炎克雷伯杆菌,检出率为22.8%,其中产ESBLs检出137株,占45.2%。产ESBLs肺炎克雷伯菌青霉素类100%耐药,头孢类78.8%以上耐药,且以成人组居多,而氨基糖苷类在产ESBLs肺炎克雷伯菌中耐药性最低的是阿米卡星,占31.4%。β-内酰胺酶抑制剂占35.1%~43.8%、喹若酮类耐药率占46.7%

  1. 酸敏释药胶束肿瘤靶向给药系统的研究进展%Progress in the study of acid-sensitive micelles for the targeting drug delivery system

    Institute of Scientific and Technical Information of China (English)

    黄榕彬; 唐国涛

    2012-01-01

    As a novel targeting drug delivery system, acid-sensitive micelles have many advantages, such as increasing solubility of lipophilic drugs, acid-sensitive release, high drug loading, etc. They can load drugs though non-covalent encapsulation and covalent conjugation methods. In tumor tissues, drugs are released quickly from the depolymerized micelles with lipophilic copolymer protonation or lypohydrophilic copolymer hydrolysis and covalent conjugated drugs are released when the acid-sensitive covalent linkage breaks. This review mainly advances acid-sensitive micelles for the tumor targeting drug delivery systems from drug-loaded methods and release mechanisms.%酸敏释药胶束作为一种新型的靶向给药系统,具有增溶疏水性药物、载药量高,酸敏感释药等优势.可通过物理包埋或酸敏感键共价连接药物的方式包载药物.在肿瘤组织的偏酸环境下,物理包埋载药胶束由于共聚物亲脂嵌段质子化或亲水亲脂嵌段水解分离、共聚物失去两亲性,胶束解聚释药;而以共价连接方式包载的药物经酸敏键断裂释放.现主要从载药方式及释药机制方面探讨酸敏释药胶束作为肿瘤靶向给药系统的研究进展.

  2. Analysis on Clinical Distribution and Drug Sensitivity of 435 Strains of Fungi%435株真菌的临床分布及药敏分析

    Institute of Scientific and Technical Information of China (English)

    付祖姣; 禹凯琼; 李红卫; 彭怀燕

    2011-01-01

    目的 了解临床分离的真菌分布,分析其药敏性,为临床感染性疾病提供病原学诊断和合理使用抗真菌药物的依据.方法 收集2010年1 - 12月中南大学湘雅三医院住院患者送检标本,经血培养基或沙保罗培养基培养后,挑取酵母样菌落,进行菌种鉴定和药敏试验.结果 分离到435株真菌,居前三位者分别为白色念珠菌(54.9%),近平滑念珠菌(20.5%),葡萄牙念珠菌(11.3%).这些真菌主要来自重症监护室(ICU)(32.6%)和痰标本中(74.8%).药敏结果显示,分离的酵母样真菌对5氟胞嘧啶、两性霉素B和酮康唑敏感性较高,分别为97.5%、96.8%和95.8%.对氟康唑、伊曲康唑和益康唑耐药性较高,分别为47.4%、43.0%和21.2%.结论 真菌临床分离菌株以白色念珠菌和近平滑念珠菌为主,临床真菌对5-氟胞嘧啶、两性霉素B和酮康唑具有较高的敏感性.%Objective To investigate the distribution and drug sensitivity of fungi isolated from clinical specimens, and to provide the evidence for etiologic diagnosis and suitable antifungal management of clinical infective diseases. Methods Specimens from inpatients of the Third Xiangya Hospital of Central South University from January to December 2010 were collected and cultured on blood culture medium and Sabourand's medium. After detecting by microscope, the yeast- like strains were selected and identified. Then the drug sensitivity tests of these strains were conducted. Results Among the selected 435 strains, the top three types of strains were Candida albicans (54.9%), Candida parepsilosis (20.5%) and Candida lus-itaniae (11.3%). Most of the strains came from intensive care unit (32.6%) and sputum samples (74.8%). Susceptibility results showed that yeast- like fungi were highly sensitive to 5 - fluorocytosine, amphotericin B and ketoconazole, with the sensitivity rates of 97.5%, 96.8%, and 95.8% respectively, but highly resistant to fluconazole

  3. Formulation, characterization and tissue distribution of a novel pH-sensitive long-circulating liposome-based theranostic suitable for molecular imaging and drug delivery

    Directory of Open Access Journals (Sweden)

    Duan Y

    2016-11-01

    Full Text Available Yin Duan,1,2 Lihui Wei,1–3 Julia Petryk,2,3 Terrence D Ruddy2,3 1Nordion Inc., 2Cardiac Positron Emission Tomography (PET Radiochemistry Research Core Laboratory, Canadian Molecular Imaging Center of Excellence, University of Ottawa Heart Institute, 3Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada Purpose: When designing liposome formulas for treatment and diagnostic purposes, two of the most common challenges are 1 the lack of a specific release mechanism for the encapsulated contents and 2 a short circulation time due to poor resistance to biological fluids. This study aimed to create a liposome formula with prolonged in vivo longevity and pH-sensitivity for cytoplasmic drug delivery. Materials and methods: Liposomal particles were generated using hydrogenated soy (HS phosphatidylcholine, cholesteryl hemisuccinate (CHEM, polyethylene glycol (PEG and diethylenetriaminepentaacetic acid-modified phosphatidylethanolamine with film hydration and extrusion methods. The physicochemical properties of the different formulas were characterized. pH-sensitivity was evaluated through monitoring release of encapsulated calcein. Stability of the radiolabeled liposomes was assessed in vitro through incubation with human serum. The best formula was selected and injected into healthy rats to assess tissue uptake and pharmacokinetics. Results: Liposomal particles were between 88 and 102 nm in diameter and negatively charged on the surface. Radiolabeling of all formulas with indium-111 was successful with good efficiency. 1%PEG-HS-CHEM not only responded to acidification very quickly but also underwent heavy degradation with serum. The 4%PEG-HS-CHEM, which exhibited both comparatively good pH-sensitivity (up to 20% release and s.tisfactory stability (stability >70% after 24 h, was considered the best candidate for in vivo evaluation. Tissue distribution of 4%PEG-HS-CHEM was comparable to that of 4%PEG-HS-Chol, a long

  4. Clinical Correlates and Drug Resistance in HIV-Infected and -Uninfected Pulmonary Tuberculosis Patients in South India

    Science.gov (United States)

    Sara, Chandy; Elsa, Heylen; Baijayanti, Mishra; Lennartsdotter, Ekstrand Maria

    2016-01-01

    Objectives To examine demographics, clinical correlates, sputum AFB (acid fast bacilli) smear grading DOTS (Directly Observed Therapy Short Course) uptake, and drug resistance in a cohort of newly-diagnosed, smear positive pulmonary tuberculosis (TB) patients with respect to HIV status at baseline, and compare smear conversion rates, side effects and mortality after two months. Design A prospective study among 54 HIV positive and 41 HIV negative pulmonary TB patients. Data were collected via face-to-face interviews, review of medical records, and lab tests. Results HIVTB co-infected patients, though more symptomatic at baseline, showed more improvement in their symptoms compared to HIV-uninfected TB patients at follow-up. The HIV co-infected group had more prevalent perceived side effects, and sputum smear positivity was marginally higher compared to the HIV negative group at follow-up. Mortality was higher among the HIV-infected group. Both groups had high rates of resistance to first-line anti-tubercular drugs, particularly isoniazid. There was no significant difference in the drug resistance patterns between the groups. Conclusions Prompt initiation and provision of daily regimens of ATT (Anti-Tubercular treatment) along with ART (Anti-Retroviral treatment) via ART centers is urgently needed in India. As resistance to ART and/or ATT is directly linked to medication non-adherence, the use of counseling, regular reinforcement, early detection and appropriate intervention strategies to tackle this complex issue could help prevent premature mortality and development of resistance in HIV-TB co-infected patients. The high rate of isoniazid resistance might preclude its use in India as prophylaxis for latent TB in HIV infected persons as per the World Health Organization (WHO) guideline. PMID:27708985

  5. 尿液标本中的病原菌分布及药敏结果分析%Bacterial Distribution and Drug Sensitivity Analysis in Urine Specimens

    Institute of Scientific and Technical Information of China (English)

    周锦绣; 银振华

    2014-01-01

    目的:探讨尿路感染患者尿液标本中病原菌的分布及其耐药状况,为临床抗感染治疗提供参考依据。方法:采用细菌培养鉴定及药敏试验卡试验。结果:尿路感染患者尿液标本中共检出479株病原菌。其中,G-杆菌281株,占58.66%,以大肠埃希菌为主,其次为肺炎克雷伯菌;G+球菌122株,占25.47%,以凝固酶阴性葡萄球菌(CNS)和鹑鸡肠球菌为主;真菌74株,占15.45%,以白假丝酵母菌居多;G+杆菌2株,占0.42%。大肠埃希菌和肺炎克雷伯菌对亚胺培南、美罗培南和阿米卡星都有高度的敏感率;CNS和鹑鸡肠球菌对多种抗生素的敏感率都很低,CNS 对万古霉素的敏感率为100%,鹑鸡肠球菌对复方磺胺的敏感率较高;真菌感染呈上升趋势,对两性霉素B高度敏感。结论:治疗尿路感染应根据药敏结果合理选择抗生素。%Objective:To provide information to clinicians on the anti-infective therapy,a retrospective analysis was performed on the distribution and drug resistance of pathogens of urine specimens.Methods:Identification of bacterial culture and sensitivity test pilot plate were taken.Results:Totally 479 strains of pathogenic bacteria in urine specimens of the patients with urinary tract infections were detected.Of 479 clinical strains,Gram-negative bacillus accounted for 58.66%(281/479)and Escherichia coli was the most prevalent species,followed by Klebsiella pneumoniae,Gram-positive Cocci accounted for 25.47% (122/479)and the predominant pathogens were Coagulase negative Staphylococci (CNS)and Enterococcus gallinarum,Fungu accounted for 15.45%(74/479)and Candida albican was the most prevalent species,Gram-positive rods accounted for 0.42%(2/479).Susceptibility results reveled that Escherichia coli and Klebsiella pneumoniae were highly sensitive to imipenem,meropenem and amikacin.The sensitive rates of CNS and Enterococcus gallinarum to various antibiotics were low.The sensitive rates of CNS

  6. A pleiotropic drug resistance transporter is involved in reduced sensitivity to multiple fungicide classes in Sclerotinia homoeocarpa (F.T. Bennett).

    Science.gov (United States)

    Sang, Hyunkyu; Hulvey, Jon; Popko, James T; Lopes, John; Swaminathan, Aishwarya; Chang, Taehyun; Jung, Geunhwa

    2015-04-01

    Dollar spot, caused by Sclerotinia homoeocarpa, is a prevalent turfgrass disease, and the fungus exhibits widespread fungicide resistance in North America. In a previous study, an ABC-G transporter, ShatrD, was associated with practical field resistance to demethylation inhibitor (DMI) fungicides. Mining of ABC-G transporters, also known as pleiotropic drug resistance (PDR) transporters, from RNA-Seq data gave an assortment of transcripts, several with high sequence similarity to functionally characterized transporters from Botrytis cinerea, and others with closest blastx hits from Aspergillus and Monilinia. In addition to ShatrD, another PDR transporter showed significant over-expression in replicated RNA-Seq data, and in a collection of field-resistant isolates, as measured by quantitative polymerase chain reaction. These isolates also showed reduced sensitivity to unrelated fungicide classes. Using a yeast complementation system, we sought to test the hypothesis that this PDR transporter effluxes DMI as well as chemically unrelated fungicides. The transporter (ShPDR1) was cloned into the Gal1 expression vector and transformed into a yeast PDR transporter deletion mutant, AD12345678. Complementation assays indicated that ShPDR1 complemented the mutant in the presence of propiconazole (DMI), iprodione (dicarboximide) and boscalid (SDHI, succinate dehydrogenase inhibitor). Our results indicate that the over-expression of ShPDR1 is correlated with practical field resistance to DMI fungicides and reduced sensitivity to dicarboximide and SDHI fungicides. These findings highlight the potential for the eventual development of a multidrug resistance phenotype in this pathogen. In addition, this study presents a pipeline for the discovery and validation of fungicide resistance genes using de novo next-generation sequencing and molecular biology techniques in an unsequenced plant pathogenic fungus.

  7. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines.

    Science.gov (United States)

    Scudiero, D A; Shoemaker, R H; Paull, K D; Monks, A; Tierney, S; Nofziger, T H; Currens, M J; Seniff, D; Boyd, M R

    1988-09-01

    We have previously described the application of an automated microculture tetrazolium assay (MTA) involving dimethyl sulfoxide solubilization of cellular-generated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-formazan to the in vitro assessment of drug effects on cell growth (M.C. Alley et al., Proc. Am. Assoc. Cancer Res., 27:389, 1986; M.C. Alley et al., Cancer Res. 48:589-601, 1988). There are several inherent disadvantages of this assay, including the safety hazard of personnel exposure to large quantities of dimethyl sulfoxide, the deleterious effects of this solvent on laboratory equipment, and the inefficient metabolism of MTT by some human cell lines. Recognition of these limitations prompted development of possible alternative MTAs utilizing a different tetrazolium reagent, 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl] -2H- tetrazolium hydroxide (XTT), which is metabolically reduced in viable cells to a water-soluble formazan product. This reagent allows direct absorbance readings, therefore eliminating a solubilization step and shortening the microculture growth assay procedure. Most human tumor cell lines examined metabolized XTT less efficiently than MTT; however, the addition of phenazine methosulfate (PMS) markedly enhanced cellular reduction of XTT. In the presence of PMS, the XTT reagent yielded usable absorbance values for growth and drug sensitivity evaluations with a variety of cell lines. Depending on the metabolic reductive capacity of a given cell line, the optimal conditions for a 4-h XTT incubation assay were 50 micrograms of XTT and 0.15 to 0.4 microgram of PMS per well. Drug profiles obtained with representative human tumor cell lines for several standard compounds utilizing the XTT-PMS methodology were similar to the profiles obtained with MTT. Addition of PMS appeared to have little effect on the metabolism of MTT. The new XTT reagent thus provides for a simplified, in vitro cell growth assay

  8. Microwave drying of granules containing a moisture-sensitive drug: a promising alternative to fluid bed and hot air oven drying.

    Science.gov (United States)

    Chee, Sze Nam; Johansen, Anne Lene; Gu, Li; Karlsen, Jan; Heng, Paul Wan Sia

    2005-07-01

    The impact of microwave drying and binders (copolyvidone and povidone) on the degradation of acetylsalicylic acid (ASA) and physical properties of granules were compared with conventional drying methods. Moist granules containing ASA were prepared using a high shear granulator and dried with hot air oven, fluid bed or microwave (static or dynamic bed) dryers. Percent ASA degradation, size and size distribution, friability and flow properties of the granules were determined. Granules dried with the dynamic bed microwave dryer showed the least amount of ASA degradation, followed by fluid bed dryer, static bed microwave oven and hot air oven. The use of microwave drying with a static granular bed adversely affected ASA degradation and drying capability. Dynamic bed microwave dryer had the highest drying capability followed by fluid bed, static bed microwave dryer and conventional hot air oven. The intensity of microwave did not affect ASA degradation, size distribution, friability and flow properties of the granules. Mixing/agitating of granules during drying affected the granular physical properties studied. Copolyvidone resulted in lower amount of granular residual moisture content and ASA degradation on storage than povidone, especially for static bed microwave drying. In conclusion, microwave drying technology has been shown to be a promising alternative for drying granules containing a moisture-sensitive drug.

  9. 鸭疫里氏杆菌的分离鉴定及药敏试验%Isolation, Identification and Drug-sensitivity Tests of Riemerella anatipestifer Isolates

    Institute of Scientific and Technical Information of China (English)

    潘淑惠; 王璇; 郭光容; 徐景峨; 吴位珩; 杨莉; 余波

    2011-01-01

    为鸭疫里氏杆菌病的防治提供参考,2009年5月,对贵州某肉鸭养殖场送检病鸭进行了剖检病变观察、细菌分离鉴定,并进行了药敏试验.结果表明,分离细菌通过细菌形态、染色特性、生化试验、培养特征鉴定为鸭疫里氏杆菌,7株菌对头孢拉定、头孢曲松钠、头孢噻肟和氟苯尼考高度敏感,对庆大霉素、新霉素、青霉素、多粘菌素B、氟哌酸、复方新诺明、链霉素和卡那霉素耐药.%To make references for prevention and treatment of Riemerella anatipestifer, in May 2009, pathological changes of sick duck was observed, bacteria were isolated and identified and drug-sensitivity tests were carried out in Guizhou meat duck farm. The results showed that the isolated bacteria were identified as Riemerella anatipestifer by bacterium form, biochemistry and cultured characteristics. The seven strains were highly susceptible to cefradine, ceftriaxone sodium, cefotaxime, florfenicol, not susceptible to gentamicin, neomycin, penicillin, polymyxin B, norfloxacin, sinomin compositea, streptomycin and kanamycin.

  10. The influence of excipients on the stability of the moisture sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose monohydrate with tablets containing anhydrous lactose.

    Science.gov (United States)

    Du, J; Hoag, S W

    2001-01-01

    The purpose of this study is to test the hypothesis that in tablet formulations, moisture-sensitive drugs formulated with lactose monohydrate have the same stability as formulations containing anhydrous lactose, and to characterize the kinetics of niacinamide degradation in the solid state. Aspirin and niacinamide decomposition were used as indicators of stability. Aspirin and niacinamide tablets containing either lactose monohydrate or anhydrous lactose were separately investigated at different temperatures and relative humidities; the stability tests were done at 25 degrees C--60% RH, 40 degrees C--80% RH, 60 degrees C--60% RH, 60 degrees C--80% RH, and 80 degrees C--80% RH. Official U.S. Pharmacopeia methods were used for the aspirin and niacinamide assays. Statistical analysis showed that tablets containing lactose monohydrate have the same stability as tablets containing anhydrous lactose, which means that even though water is present in the crystal structure, the bound water does not influence the reaction rate. In addition, niacinamide degradation in the solid-state can be described by a third order rate equation.

  11. Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

    Science.gov (United States)

    Bianco, R; Garofalo, S; Rosa, R; Damiano, V; Gelardi, T; Daniele, G; Marciano, R; Ciardiello, F; Tortora, G

    2008-01-01

    Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo. We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting. PMID:18319715

  12. Drug-sensitive tuberculosis, multidrug-resistant tuberculosis, and nontuberculous mycobacterial pulmonary disease in nonAIDS adults: comparisons of thin-section CT findings

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Myung Jin; Lee, Kyung Soo; Kim, Tae Sung; Kim, Sung Mok [Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Seoul (Korea); Koh, Won-Jung; Kwon, O Jung [Sungkyunkwan University School of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Seoul (Korea); Kang, Eun Young [Korea University Guro Hospital, Department of Diagnostic Radiology, Korea University College of Medicine, Seoul (Korea); Kim, Seonwoo [Sungkyunkwan University School of Medicine, Biostatistics Unit of the Samsung Biomedical Research Institute, Samsung Medical Center, Seoul (Korea)

    2006-09-15

    The aim of this work was to compare thin-section CT (TSCT) findings of drug-sensitive (DS) tuberculosis (TB), multidrug-resistant (MDR) TB, and nontuberculous mycobacterial (NTM) pulmonary disease in nonAIDS adults. During 2003, 216 (113 DS TB, 35 MDR TB, and 68 NTM) patients with smear-positive sputum for acid-fast bacilli (AFB), and who were subsequently confirmed to have mycobacterial pulmonary disease, underwent thoracic TSCT. The frequency of lung lesion patterns on TSCT and patients' demographic data were compared. The commonest TSCT findings were tree-in-bud opacities and nodules. On a per-person basis, significant differences were found in the frequency of multiple cavities and bronchiectasis (P<0.001, chi-square test and multiple logistic regression analysis). Multiple cavities were more frequent in MDR TB than in the other two groups and extensive bronchiectasis in NTM disease (multiple logistic regression analysis). Patients with MDR TB were younger than those with DS TB or NTM disease (P<0.001, multiple logistic regression analysis). Previous tuberculosis treatment history was significantly more frequent in patients with MDR TB or NTM disease (P<0.001, chi-square test and multiple logistic regression analysis). In patients with positive sputum AFB, multiple cavities, young age, and previous tuberculosis treatment history imply MDR TB, whereas extensive bronchiectasis, old age, and previous tuberculosis treatment history NTM disease. (orig.)

  13. Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry.

    Science.gov (United States)

    Huang, Yong; Gandhi, Monica; Greenblatt, Ruth M; Gee, Winnie; Lin, Emil T; Messenkoff, Nicholas

    2008-11-01

    A highly sensitive and selective method using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) was developed and validated for the measurement of three antiretroviral agents, efavirenz, lopinavir and ritonavir, in human hair. Hair samples from adherent HIV-infected patients on antiretroviral therapies were cut into about 1 mm length segments and drugs were extracted by first shaking the samples with methanol in a 37 degrees C water bath overnight (>14 h), followed by methyl tert-butyl ether/ethyl acetate (1:1) extraction under weak alkaline conditions. The extracted lopinavir and ritonavir were separated by reversed-phase chromatography and detected by tandem mass spectrometry in electrospray positive ionization mode with multiple reaction monitoring (MRM), while efavirenz was monitored in negative ionization MRM mode. This method was validated from 0.01 to 4.0 ng/mg hair for ritonavir and 0.05-20 ng/mg hair for lopinavir and efavirenz by using 2 mg of a human hair sample. The interday and intraday assay precision (coefficients of variation, CV) for spiked quality control (QC) samples at low, medium and high concentrations were within 15% and accuracy ranged from 89% to 110%. Assay reproducibility was also demonstrated by analysis of incurred hair QC samples (CV hair samples of HIV-infected women on antiretroviral therapy in an observational study using small amounts of hair.

  14. 假丝酵母菌属对氟康唑药敏分析%Analysis of distribution of Candida and its drug sensitivity to fluconazole

    Institute of Scientific and Technical Information of China (English)

    王德; 徐红; 黄欣; 叶元康

    2015-01-01

    目的:探析医院假丝酵母菌属的分布及对氟康唑的敏感性,为防范重点科室患者假丝酵母菌属感染及提高治疗效果提供依据。方法选取医院2012年7月-2013年7月从真菌室分离到的假丝酵母菌属178株作为鉴定对象,采用科玛嘉假丝酵母菌属显色培养基鉴定菌种分布,以及微量稀释法检测对氟康唑的敏感性,采用SPSS 16.0进行统计分析。结果178株假丝酵母菌属中以白色假绿酵母菌为主,共140株占78.7%;白色假丝酵母菌对氟康唑的敏感率最高,敏感率为97.9%,其次为伏立康唑96.4%,伊曲康唑敏感率最低为82.1%,其他假绿酵母菌属也对氟康唑的敏感率最高。结论医院分离的假丝酵母菌属以白色假丝酵母菌为主,对氟康唑敏感。%OBJECTIVE To discuss and analyze the Candida distribution and drug sensitivity to fluconazole in the hospital so as to provide basis for preventing Candida infections in key departments in the hospital and improving clinical efficacy .METHODS Totally 178 strains of Candida were separated in fungi room from Jul .2012 to Jul . 2013 in the hospital .They were chosen as research objects .CHROMagar Candida chromogenic medium was ap‐plied to identify species distribution and microdilution method was applied to test sensibility to fluconazole .All da‐ta were analyzed by SPSS 16 .0 software .RESULTS Among 178 strains of Candida ,there were 78 .7% (140/178) Candida albicans .Drug sensibility rate of C .albicans to fluconazole was the highest of 97 .9% (137/140) ,sec‐ond by voriconazole with the rate of 96 .4% and least by itraconazole with the rate of 82 .1% .Other Candida was also the most sensitive to fluconazole .CONCLUSION Candida separated in our hospital are mainly C . albicans , and they are sensitive to fluconazole .

  15. Establishment of Drug Sensitive Model for Radial Artery ill vitro%桡动脉体外药物敏感模型的建立

    Institute of Scientific and Technical Information of China (English)

    祝岩; 王辉山; 李新民; 汪曾炜

    2011-01-01

    目的 利用组织浴槽的方法 体外模拟在体桡动脉,摸索建立体外桥血管药物敏感模型,研究单一因素改变对血管舒缩状态的影响.方法 取成年男性桡动脉,4℃Krebs-Ringer保存液中切割成3~4 mm宽、内膜完好的血管环,两端分别牵引,在10 ml麦式组织浴槽中水浴,并连接至换能器、生理记录仪和适度的前负荷上,待血管环状态稳定后记录初长度及静息张力.分别用终浓度为0.06 mol/L的K+和20 μmol/L的乙酰胆碱评估内膜组织的完整性和证实血管环舒张、收缩活性.取内膜完整且舒缩活性良好的血管环分别用不同终浓度的苯肾上腺素作用作为刺激因素,观测血管环收缩程度的变化.绘制在不同半对数克分子浓度苯肾上腺素作用下,血管环收缩静息张力变化曲线.结果 所有血管环在水浴槽中均能很快达到稳定状态.对KCl和乙酰胆碱的反应敏感,提示血管环内膜完整及收缩、舒张功能良好.苯肾上腺素半对数克分子浓度与血管环静息张力呈正相关.结论 利用组织浴槽建立药物敏感模型在方法 上是可行的.血管环可以很好的模拟桥血管在体内的状态,可将实验所得苯肾上腺素浓度一静息张力曲线中的半对数克分子浓度作为后续实验中刺激血管收缩的标准浓度.%Objective To establish a drug sensitive model for radial artery in vitro by utilizing the organ bath to mimic radial artery in vivo, and to study the unifactor which affects the systolic and diastolic state of the radial artery. Methods The radial arteries were harvested from adult male and cut into 3 to 4 mm vessel rings with intima intact in the Krebs-Rubger hquid at 4 ℃. The vessel ring was pulled with proper preload at both ends and connected to the pressure transducer and physilogical recorder in the organ bath. The initial length and resting tension were recorded after stabilization of the radial artery. The 0.06 mol/L KCL

  16. Investigation and drug sensitivity analysis of urinary tract fungal infections in hospital%尿路真菌感染调查与药敏分析

    Institute of Scientific and Technical Information of China (English)

    胡跃世; 李鹏; 曹志华; 刘磊; 王阳

    2016-01-01

    -ry medicine ,the total rate was 83 .12% in the hospital .C .albicans ,C .glabrata and Canadida tropioale were all sensitive to amphotericin B and 5-flucytosine ,their drug resistance rates were as follows :0 and 0 .88% ,1 .27%and 0 ,0 and 0 ,while the drug resistance rates of C .albicans to fluconazole ,itraconazole and voriconazole were lower than 10 .00% ,and the other two kinds of fungi were higher than 10 .00% .Candida krusei was only sensi-tive to 5-flucytosine .The drug resistance rate of C .krusei was 38 .4% to itraconazole and 30 .7% to voriconazole . CONCLUSION C .albicans ,C .glabrata and C .tropioale are the main pathogenic bacteria causing urinary tract fungal infections in hospital .They have good susceptibility to 5-flucytosine and amphotericin B .

  17. Fasciola hepatica: Histology of the Reproductive Organs and Differential Effects of Triclabendazole on Drug-Sensitive and Drug-Resistant Fluke Isolates and on Flukes from Selected Field Cases.

    Science.gov (United States)

    Hanna, Robert

    2015-06-26

    This review summarises the findings of a series of studies in which the histological changes, induced in the reproductive system of Fasciola hepatica following treatment of the ovine host with the anthelmintic triclabendazole (TCBZ), were examined. A detailed description of the normal macroscopic arrangement and histological features of the testes, ovary, vitelline tissue, Mehlis' gland and uterus is provided to aid recognition of the drug-induced lesions, and to provide a basic model to inform similar toxicological studies on F. hepatica in the future. The production of spermatozoa and egg components represents the main energy consuming activity of the adult fluke. Thus the reproductive organs, with their high turnover of cells and secretory products, are uniquely sensitive to metabolic inhibition and sub-cellular disorganisation induced by extraneous toxic compounds. The flukes chosen for study were derived from TCBZ-sensitive (TCBZ-S) and TCBZ-resistant (TCBZ-R) isolates, the status of which had previously been proven in controlled clinical trials. For comparison, flukes collected from flocks where TCBZ resistance had been diagnosed by coprological methods, and from a dairy farm with no history of TCBZ use, were also examined. The macroscopic arrangement of the reproductive system in flukes was studied using catechol/carmine stained whole mounts, and the histology of the main organs was examined using conventional haematoxylin-eosin stained sections. Validation of apoptosis in the fluke sections was carried out using an in situ hybridisation method designed to label endonuclease-induced DNA strand breaks. In TCBZ-S flukes exposed to TCBZ metabolites for 24-96 h in vivo, but not in TCBZ-R flukes, those tissues where active meiosis and/or mitosis occurred (testis, ovary, and vitelline follicles), were found to display progressive loss of cell content. This was due to apparent failure of cell division to keep pace with expulsion of the mature or effete products

  18. Fasciola hepatica: Histology of the Reproductive Organs and Differential Effects of Triclabendazole on Drug-Sensitive and Drug-Resistant Fluke Isolates and on Flukes from Selected Field Cases

    Directory of Open Access Journals (Sweden)

    Robert Hanna

    2015-06-01

    Full Text Available This review summarises the findings of a series of studies in which the histological changes, induced in the reproductive system of Fasciola hepatica following treatment of the ovine host with the anthelmintic triclabendazole (TCBZ, were examined. A detailed description of the normal macroscopic arrangement and histological features of the testes, ovary, vitelline tissue, Mehlis’ gland and uterus is provided to aid recognition of the drug-induced lesions, and to provide a basic model to inform similar toxicological studies on F. hepatica in the future. The production of spermatozoa and egg components represents the main energy consuming activity of the adult fluke. Thus the reproductive organs, with their high turnover of cells and secretory products, are uniquely sensitive to metabolic inhibition and sub-cellular disorganisation induced by extraneous toxic compounds. The flukes chosen for study were derived from TCBZ-sensitive (TCBZ-S and TCBZ-resistant (TCBZ-R isolates, the status of which had previously been proven in controlled clinical trials. For comparison, flukes collected from flocks where TCBZ resistance had been diagnosed by coprological methods, and from a dairy farm with no history of TCBZ use, were also examined. The macroscopic arrangement of the reproductive system in flukes was studied using catechol/carmine stained whole mounts, and the histology of the main organs was examined using conventional haematoxylin-eosin stained sections. Validation of apoptosis in the fluke sections was carried out using an in situ hybridisation method designed to label endonuclease-induced DNA strand breaks. In TCBZ-S flukes exposed to TCBZ metabolites for 24–96 h in vivo, but not in TCBZ-R flukes, those tissues where active meiosis and/or mitosis occurred (testis, ovary, and vitelline follicles, were found to display progressive loss of cell content. This was due to apparent failure of cell division to keep pace with expulsion of the mature or

  19. Increased Sensitivity to Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats.

    Science.gov (United States)

    Banerjee, Atrayee; Abdelmegeed, Mohamed A; Jang, Sehwan; Song, Byoung-Joon

    2015-01-01

    The mechanisms of alcohol-mediated advanced liver injury in HIV-infected individuals are poorly understood. Thus, this study was aimed to investigate the effect of binge alcohol on the inflammatory liver disease in HIV transgenic rats as a model for simulating human conditions. Female wild-type (WT) or HIV transgenic rats were treated with three consecutive doses of binge ethanol (EtOH) (3.5 g/kg/dose oral gavages at 12-h intervals) or dextrose (Control). Blood and liver tissues were collected at 1 or 6-h following the last dose of ethanol or dextrose for the measurements of serum endotoxin and liver pathology, respectively. Compared to the WT, the HIV rats showed increased sensitivity to alcohol-mediated gut leakiness, hepatic steatosis and inflammation, as evidenced with the significantly elevated levels of serum endotoxin, hepatic triglycerides, histological fat accumulation and F4/80 staining. Real-time PCR analysis revealed that hepatic levels of toll-like receptor-4 (TLR4), leptin and the downstream target monocyte chemoattractant protein-1 (MCP-1) were significantly up-regulated in the HIV-EtOH rats, compared to all other groups. Subsequent experiments with primary cultured cells showed that both hepatocytes and hepatic Kupffer cells were the sources of the elevated MCP-1 in HIV-EtOH rats. Further, TLR4 and MCP-1 were found to be upregulated by leptin. Collectively, these results show that HIV rats, similar to HIV-infected people being treated with the highly active anti-retroviral therapy (HAART), are more susceptible to binge alcohol-induced gut leakiness and inflammatory liver disease than the corresponding WT, possibly due to additive or synergistic interaction between binge alcohol exposure and HIV infection. Based on these results, HIV transgenic rats can be used as a surrogate model to study the molecular mechanisms of many disease states caused by heavy alcohol intake in HIV-infected people on HAART.

  20. Increased Sensitivity to Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats.

    Directory of Open Access Journals (Sweden)

    Atrayee Banerjee

    Full Text Available The mechanisms of alcohol-mediated advanced liver injury in HIV-infected individuals are poorly understood. Thus, this study was aimed to investigate the effect of binge alcohol on the inflammatory liver disease in HIV transgenic rats as a model for simulating human conditions. Female wild-type (WT or HIV transgenic rats were treated with three consecutive doses of binge ethanol (EtOH (3.5 g/kg/dose oral gavages at 12-h intervals or dextrose (Control. Blood and liver tissues were collected at 1 or 6-h following the last dose of ethanol or dextrose for the measurements of serum endotoxin and liver pathology, respectively. Compared to the WT, the HIV rats showed increased sensitivity to alcohol-mediated gut leakiness, hepatic steatosis and inflammation, as evidenced with the significantly elevated levels of serum endotoxin, hepatic triglycerides, histological fat accumulation and F4/80 staining. Real-time PCR analysis revealed that hepatic levels of toll-like receptor-4 (TLR4, leptin and the downstream target monocyte chemoattractant protein-1 (MCP-1 were significantly up-regulated in the HIV-EtOH rats, compared to all other groups. Subsequent experiments with primary cultured cells showed that both hepatocytes and hepatic Kupffer cells were the sources of the elevated MCP-1 in HIV-EtOH rats. Further, TLR4 and MCP-1 were found to be upregulated by leptin. Collectively, these results show that HIV rats, similar to HIV-infected people being treated with the highly active anti-retroviral therapy (HAART, are more susceptible to binge alcohol-induced gut leakiness and inflammatory liver disease than the corresponding WT, possibly due to additive or synergistic interaction between binge alcohol exposure and HIV infection. Based on these results, HIV transgenic rats can be used as a surrogate model to study the molecular mechanisms of many disease states caused by heavy alcohol intake in HIV-infected people on HAART.

  1. HIV Clinical Pathway: A New Approach to Combine Guidelines and Sustainability of Anti-Retroviral Treatment in Italy

    Science.gov (United States)

    Croce, Davide; Lazzarin, Adriano; Rizzardini, Giuliano; Gianotti, Nicola; Scolari, Francesca; Foglia, Emanuela; Garagiola, Elisabetta; Ricci, Elena; Bini, Teresa; Quirino, Tiziana; Viganò, Paolo; Re, Tiziana; D’Arminio Monforte, Antonella; Bonfanti, Paolo

    2016-01-01

    The present article describes the case study of a “real world” HIV practice within the debate concerning the strategic role of Clinical Governance (CG) tools in the management of a National Healthcare System’s sustainability. The study aimed at assessing the impact of a Clinical Pathway (CP) implementation, required by the Regional Healthcare Service, in terms of effectiveness (virological and immunological conditions) and efficiency (economic resources absorption), from the budget holder perspective. Data derived from a multi-centre cohort of patients treated in 6 Hospitals that provided care to approximately 42% of the total HIV+ patients, in Lombardy Region, Italy. Two phases were compared: Pre-CP (2009–2010) vs. Post-CP implementation (2011–2012). All HIV infected adults, observed in the participating hospitals during the study periods, were enrolled and stratified into the 3 categories defined by the Regional CP: first-line, switch for toxicity/other, and switch for failure. The study population was composed of 1,284 patients (Pre-CP phase) and 1,135 patients (Post-CP phase). The results showed that the same level of virological and immunological effectiveness was guaranteed to HIV+ patients: 81.2% of Pre-CP phase population and 83.2% of Post-CP phase population had undetectable HIV-RNA (defined as management of the HIV disease (ART, hospital admission and laboratory tests) decreased (-8.60%) in the Post-CP phase (p-value < 0.0001). Results confirmed that the CP provided appropriateness and quality of care, with a cost reduction for the budget holder. PMID:28030621

  2. Incubation periods under various anti-retroviral therapies in homogeneous mixing and age-structured dynamical models: A theoretical approach

    CERN Document Server

    Rao, Arni S R Srinivasa

    2008-01-01

    Abstract. We consider previously well-known models in epidemiology where the parameter for incubation period is used as one of the important components to explain the dynamics of the variables. Such models are extended here to explain the dynamics with respect to a given therapy that prolongs the incubation period. A deconvolution method is demonstrated for estimation of parameters in the situations when no-therapy and multiple therapies are given to the infected population. The models and deconvolution method are extended in order to study the impact of therapy in age-structured populations. A generalisation for a situation when n-types of therapies are available is given.

  3. Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human

    Directory of Open Access Journals (Sweden)

    Burny Arsène

    2007-03-01

    Full Text Available Abstract In 1871, the observation of yellowish nodules in the enlarged spleen of a cow was considered to be the first reported case of bovine leukemia. The etiological agent of this lymphoproliferative disease, bovine leukemia virus (BLV, belongs to the deltaretrovirus genus which also includes the related human T-lymphotropic virus type 1 (HTLV-1. This review summarizes current knowledge of this viral system, which is important as a model for leukemogenesis. Recently, the BLV model has also cast light onto novel prospects for therapies of HTLV induced diseases, for which no satisfactory treatment exists so far.

  4. Intestinal Parasitosis in Relation to Anti-Retroviral Therapy, CD4(+) T-cell Count and Diarrhea in HIV Patients.

    Science.gov (United States)

    Khalil, Shehla; Mirdha, Bijay Ranjan; Sinha, Sanjeev; Panda, Ashutosh; Singh, Yogita; Joseph, Anju; Deb, Manorama

    2015-12-01

    Intestinal parasitic infections are one of the major causes of diarrhea in human immunodeficiency virus (HIV) seropositive individuals. Antiretroviral therapy has markedly reduced the incidence of many opportunistic infections, but parasite-related diarrhea still remains frequent and often underestimated especially in developing countries. The present hospital-based study was conducted to determine the spectrum of intestinal parasitosis in adult HIV/AIDS (acquired immunodeficiency syndrome) patients with or without diarrhea with the levels of CD4(+) T-cell counts. A total of 400 individuals were enrolled and were screened for intestinal parasitosis. Of these study population, 200 were HIV seropositives, and the remaining 200 were HIV uninfected individuals with or without diarrhea. Intestinal parasites were identified by using microscopy as well as PCR assay. A total of 130 (32.5%) out of 400 patients were positive for any kinds of intestinal parasites. The cumulative number of parasite positive patients was 152 due to multiple infections. A significant association of Cryptosporidium (P<0.001) was detected among individuals with CD4(+) T-cell counts less than 200 cells/μl.

  5. Who has access to counseling and testing and anti-retroviral therapy in Malawi – an equity analysis

    Directory of Open Access Journals (Sweden)

    Banda Talumba

    2009-05-01

    Full Text Available Abstract Background The HIV and AIDS epidemic in Malawi poses multiple challenges from an equity perspective. It is estimated that 12% of Malawians are living with HIV or AIDS among the 15-49 age group. This paper synthesises available information to bring an equity lens on Counselling and Testing (CT and Antiretroviral Therapy (ART policy, practice and provision in Malawi. Methods A synthesis of a wide range of published and unpublished reports and studies using a variety of methodological approaches was undertaken. The analysis and recommendations were developed, through consultation with key stakeholders in Malawi. Findings At the policy level Malawi is unique in having an equity in access to ART policy, and equity considerations are also included in key CT documents. The number of people accessing CT has increased considerably from 149,540 in 2002 to 482,364 in 2005. There is urban bias in provision of CT and more women than men access CT. ART has been provided free since June 2004 and scale up of ART provision is gathering pace. By end December 2006, there were 85,168 patients who had ever started on ART in both the public and private health sector, 39% of the patients were male while 61% were female. The majority of patients were adults, and 7% were children, aged 14 years or below. Despite free ART services, patients, especially poor rural patients face significant barriers in access and adherence to services. There are missed opportunities in strengthening integration between CT and ART and TB, Sexually Transmitted Infections (STI and maternal health services. Conclusion To promote equitable access for CT and ART in Malawi there is need to further invest in human resources for health, and seize opportunities to integrate CT and ART services with tuberculosis, sexually transmitted infections and maternal health services. This should not only promote access to services but also ensure that resources available for CT and ART strengthen rather than undermine the provision of the essential health package in Malawi. Ongoing equity analysis of services is important in analyzing which groups are unrepresented in services and developing initiatives to address these. Creative models of decentralization, whilst maintaining quality of services are needed to further enhance access of poor rural women, men, girls and boys.

  6. Cognitive and psychosocial development of HIV pediatric patients receiving highly active anti-retroviral therapy: a case-control study

    Directory of Open Access Journals (Sweden)

    Theodoridou Maria

    2010-12-01

    Full Text Available Abstract Background The psychosocial development of pediatric HIV patients has not been extensively evaluated. The study objectives were to evaluate whether emotional and social functions are differentially associated with HIV-related complications. Methods A matched case-control study design was conducted. The case group (n = 20 consisted of vertically infected children with HIV (aged 3-18 years receiving HAART in Greece. Each case was matched with two randomly selected healthy controls from a school-based population. CNS imaging and clinical findings were used to identify patients with HIV-related neuroimaging abnormalities. The Wechsler Intelligence Scale III and Griffiths Mental Abilities Scales were applied to assess cognitive abilities. The age specific Strengths and Difficulties Questionnaire was used to evaluate emotional adjustment and social skills. The Fisher's exact test, student's t-test, and Wilcoxon rank sum test were used to compare categorical, continuous, and ordinal scores, respectively, of the above scales between groups. Results HIV patients without neuroimaging abnormalities did not differ from patients with neuroimaging abnormalities with respect to either age at HAART initiation (p = 0.306 or months of HAART treatment (p = 0.964. While HIV patients without neuroimaging abnormalities had similar cognitive development with their healthy peers, patients with neuroimaging abnormalities had lower mean General (p = 0.027 and Practical (p = 0.042 Intelligence Quotient scores. HIV patients without neuroimaging abnormalities had an increased likelihood of both Abnormal Emotional Symptoms (p = 0.047 and Hyperactivity scores (p = 0.0009. In contrast, HIV patients with neuroimaging abnormalities had an increased likelihood of presenting with Abnormal Peer Problems (p = 0.033. Conclusions HIV patients without neuroimaging abnormalities are more likely to experience maladjustment with respect to their emotional and activity spheres, while HIV patients with neuroimaging abnormalities are more likely to present with compromised social skills. Due to the limited sample size and age distribution of the study population, further studies should investigate the psychosocial development of pediatric HIV patients following the disclosure of their condition.

  7. Effect of micronutrient and probiotic fortified yogurt on immune-function of anti-retroviral therapy naive HIV patients

    NARCIS (Netherlands)

    R.B.S. Hummelen (Ruben); J. Hemsworth (Jaimie); J. Changalucha (John); N.L. Butamanya (Nicodemus); S. Hekmat (Sharareh); J.D.F. Habbema (Dik); G. Reid (Gregor)

    2011-01-01

    textabstractBackground: Micronutrient supplementation has been shown to reduce the progression of HIV but does not have an effect on the intestinal barrier or the intestinal microbiota of HIV patients. Studies have suggested that probiotics could potentially complement micronutrients in preserving t

  8. Image guided drug release from pH-sensitive Ion channel-functionalized stealth liposomes into an in vivo glioblastoma model

    NARCIS (Netherlands)

    Pacheco-Torres, Jesus; Mukherjee, Nobina; Walko, Martin; Lopez-Larrubia, Pilar; Ballesteros, Paloma; Cerdan, Sebastian; Kocer, Armagan

    2015-01-01

    Liposomal drug delivery vehicles are promising nanomedicine tools for bringing cytotoxic drugs to cancerous tissues selectively. However, the triggered cargo release from liposomes in response to a target-specific stimulus has remained elusive. We report on functionalizing stealth-liposomes with an

  9. Analysis of pathogens and drug sensitivity on 87 cases of chronic suppurative osteomyelitis%87例慢性化脓性骨髓炎病原菌构成及药敏分析

    Institute of Scientific and Technical Information of China (English)

    陈爱宝; 龚琦; 宋建辉; 曾国庆

    2012-01-01

    Objective To analyse constitutes strains of pathogenic bacteria and drug sensitivity test of 87 cases of chronic suppurative osteomyelitis. Methods Bacteria culture and drug sensitive test were performed by taking sinus secretions or tissue in deep focus of infection from patients with chronic suppurative osteomyelitis. Results A total of 120 strains of pathogenic bacteria were isolated. From high to low infection rate the top 3 bacteria as Staphylococcus aureus ( 30% ), Pseudomonas aeruginosa (25% ), Escherichia coli ( 14.2% ). Vancomycin, imipenem were the highest rate of sensitive drug. Conclusion The main pathogens of chronic suppurative osteomyelitis were composed with Staphylococcus aureus, Pseudomonas aeruginosa. Drug sensitive test is the important basis for selection of antibiotics.%目的 分析87 例慢性化脓性骨髓炎的病原菌菌种构成、药敏实验结果.方法 取慢性化脓性骨髓炎患者窦道深部分泌物或病灶组织做细菌培养及药敏试验.结果 共培养出病原菌120 株,感染率由高到低前三位菌为金黄色葡萄球菌(占30%)、铜绿假单胞菌(占25%)、大肠埃希菌(占14.2%).万古霉素、亚胺培南是敏感率最高药物.结论 慢性化脓性骨髓炎的病原菌构成以金黄色葡萄球菌、铜绿假单胞菌为主,药敏试验是选用抗菌药物的重要依据.

  10. Direct Comparison of the Histidine-rich Protein-2 Enzyme-linked Immunosorbent Assay (HRP-2 ELISA) and Malaria SYBR Green I Fluorescence (MSF) Drug Sensitivity Tests in Plasmodium falciparum Reference Clones and Fresh ex vivo Field Isolates from Cambodia

    Science.gov (United States)

    2013-07-12

    RESEARCH Open Access Direct comparison of the histidine -rich protein-2 enzyme-linked immunosorbent assay (HRP-2 ELISA) and malaria SYBR green I...Walsh1, David L Saunders1 and Charlotte A Lanteri1* Abstract Background: Performance of the histidine -rich protein-2 enzyme-linked immunosorbent... histidine -rich protein-2 enzyme-linked immunosorbent assay (HRP-2 ELISA) and malaria SYBR green I fluorescence (MSF) drug sensitivity tests in

  11. IN VITRO EFFECT OF VITAMIN C ON THE LABORATORY ISOLATES OF MYCOBACTERIUM TUBERCULOSIS WITH KNOWN SENSITIVITY AND RESISTANCE TO THE FIRST LINE ANTI TUBERCULAR DRUGS: AN EXPERIMENTAL PILOT STUDY

    Directory of Open Access Journals (Sweden)

    Talaulikar Nikita.S , Dsouza Delia.B , Rodrigues Savio , Kulkarni MS

    2015-04-01

    Full Text Available Background and Objectives: Globally, 3.5% of new cases of Tuberculosis (TB and 20.5% of previously treated cases are estimated to have multidrug- resistant tuberculosis, the corresponding estimates for India are 2.2%, and 15% respectively. Progress has been made in research and development of new drugs for TB over the last decade, thus fuelling the need for more innovative options. Recent in-vitro studies that claim Vitamin C to have an inhibitory effect on Mycobacterium tuberculosis could possibly prove to be a major breakthrough in Medicine. Hence this experimental study was conducted on a pilot basis with the objective of studying the in -vitro effect of the active ingredient of vitamin C on the laboratory isolates of Mycobacterium tuberculosis that were known to be sensitive and resistant to the first line anti tubercular drugs (Isoniazid, Rifampicin, Pyrazinamide and Ethambutol and to compare the dose related response of both sensitive and resistant strains of Mycobacterium tuberculosis to varying concentrations of Vitamin C. Materials and Methods: Using a Completely Randomized Design, a total of 17 viable Mycobacterium tuberculosis strains, 10 of which were sensitive to all first line anti-TB drugs (Isoniazid, Rifampicin, Pyrazinamide and Ethambutol and seven strains resistant to all first line Anti-TB drugs were experimented upon. Proportion method was used to determine drug susceptibility of Mycobacterium tuberculosis to Ascorbic acid. Data is presented in a summary table. Results: With 1mM (millimole concentration of Ascorbic acid, growth of Mycobacterium tuberculosis was observed on both drug containing as well as control media, but with higher concentration of Ascorbic acid (10 mM and 100mM, no growth was observed on Ascorbic acid containing Lowenstein Jenson media. Conclusion: Although the findings of this pilot study add to the supportive evidence of an in- vitro susceptibility of Mycobacterium tuberculosis to Vitamin C, the authors

  12. Occurrence of intestinal parasites amongst persons on highly active antiretroviral drug therapy in Calabar, Cross River State, Nigeria

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    Paul C. Inyang-Etoh

    2015-02-01

    Full Text Available Opportunistic and intestinal parasite infections are common health problem among HIV/AIDS patients. Early detection and treatment of these parasites are important to improve the quality of life of this category of patients. The occurrence of intestinal parasites among 400 patients on highly active anti-retroviral drug therapy (HAART aged 11-60 years was investigated. Standard parasitological techniques like direct microscopy, formol ether concentration and modified Ziehl- Neelsen staining techniques were used to analyze the stool samples. Intestinal parasite infections were positive in 116 (29% of the subjects on HAART while control subjects had 12 (12% and the difference was statistically significant (P<0.05. Subjects in the age group 21-30 years had the highest infection rate 54 (35.1%. There was no statistically significant difference in infection according to age (P>0.05. Females 76 (32.5% had a higher prevalence rate than males 40 (24.1%. But there was no statistically significant difference in infection according to gender (P<0.05. Patients with CD4 count of less than 200 cells/mm3 were observed to be more infected than those with CD4 count of more than 200 cells/mm3. There was a strong positive correlation (r=0.94 between CD4 count and the occurrence of intestinal parasite infection. Protozoan parasites 84 (21.0% accounted for a higher prevalence rate than helminthic parasites 32 (8.0%. These findings has revealed a high prevalence of intestinal parasite infection among patients on HAART thus the routine screening of stool samples from these category of patients for intestinal parasites is advocated for effective management of the disease.

  13. A Recombinant Human Pluripotent Stem Cell Line Stably Expressing Halide-Sensitive YFP-I152L for GABAAR and GlyR-Targeted High-Throughput Drug Screening and Toxicity Testing

    Science.gov (United States)

    Kuenzel, Katharina; Friedrich, Oliver; Gilbert, Daniel F.

    2016-01-01

    GABAARs and GlyRs are considered attractive drug targets for therapeutic intervention and are also increasingly recognized in the context of in vitro neurotoxicity (NT) and developmental neurotoxicity (DNT) testing. However, systematic human-specific GABAAR and GlyR-targeted drug screening and toxicity testing is hampered due to lack of appropriate in vitro models that express native GABAARs and GlyRs. We have established a human pluripotent stem cell line (NT2) stably expressing YFP-I152L, a halide-sensitive variant of yellow fluorescent protein (YFP), allowing for fluorescence-based functional analysis of chloride channels. Upon stimulation with retinoic acid, NT2 cells undergo neuronal differentiation and allow pharmacological and toxicological evaluation of native GABAARs and GlyRs at different stages of brain maturation. We applied the cell line in concentration-response experiments with the neurotransmitters GABA and glycine as well as with the drugs strychnine, picrotoxin, fipronil, lindane, bicuculline, and zinc and demonstrate that the established in vitro model is applicable to GABAAR and GlyR-targeted pharmacological and toxicological profiling. We quantified the proportion of GABAAR and GlyR-sensitive cells, respectively, and identified percentages of approximately 20% each within the overall populations, rendering the cells a suitable model for systematic in vitro GABAAR and GlyR-targeted screening in the context of drug development and NT/DNT testing. PMID:27445687

  14. The Analysis Results of Detection and Drug Sensitivity Test of Pathogens in 183 Cases of Children with Diarrhea%183例腹泻儿童病原学检测及药敏试验结果分析

    Institute of Scientific and Technical Information of China (English)

    王文雅; 张秀敏; 杜会双

    2016-01-01

    目的:腹泻儿童病原学检测及药敏试验结果分析。方法对我院183例腹泻儿童进行病原学检测和药物敏感试验,分析结果。结果腹泻患儿大便病原菌主要有G+菌、大肠埃希菌、志贺菌、沙门菌等。药敏试验结果显示金黄色葡萄球菌、大肠埃希菌、志贺菌和沙门菌对左氧氟沙星、亚胺培南、阿米卡星敏感度较高,而对传统的一线抗生素阿莫西林、头孢噻肟和红霉素类抗菌药敏感度较低。结论腹泻儿童在治疗中最好根据病原学诊断和病原菌,选择合理的抗生素。%Objective To analyze children with diarrhea pathogen detection and drug sensitivity test.Methods 183 cases of children with diarrhea pathogen detection and drug sensitivity test results.Results diarrhea stool pathogens are mainly G+ bacteria, Escherichia coli, Shigella, Salmonella etc. Drug sensitivity test showed that Staphylococcus aureus, Escherichia coli, Shigella and Salmonella of levolfoxacin, imipenem, amikacin sensitivity higher, while to the traditional ifrst-line antibiotics amoxicillin, cefotaxime and erythromycin antibiotics sensitivity is low.Conclusion In the treatment of children with diarrhea in the best according to the etiological diagnosis and pathogenic bacteria, reasonable selection of antibiotics.

  15. Pectin-HPMC E15LV Vs pH sensitive polymer coating films for delayed drug delivery to colon: a comparison of two dissolution models to assess colonic targeting performance in-vitro

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    A. Maria John Newton

    2012-08-01

    Full Text Available Summary.The study was designed to evaluate the in vitro dissolution characteristics comparatively between pH sensitive polymer coated tablets and natural polymer coated tablets in a various simulated fluids (pH values 1.2, 6, 6.8, 7.2, 5. The fabricated Mesalamine tablets were coated with pectin-HPMC(Hydroxy propyl methyl cellulose E15LV (FC1-FC5 in combination and with Eudragit L100 ( FC6-FC10separately. Different buffer conditions were chosen to mimic the pH changes of the terminal part of the ileum as well as the colon.  Two in vitro studies were conducted separately in all the formulations. The impact of the pH changes on the coated tablets in normal pH condition and reduced pH condition (which occurs during inflammation in the colon were compared. The results showed that the impact of pH changes on the release profile of Eudragit L100  coated tablets was significant in reduced pH condition. In pH sensitive polymer coated tablets, drug release characteristics and the rate were affected when compared to the pectin coated tablets.  This study indicates that poly methacrylate polymers could not release the drug in predetermined rate in a variety of pH conditions. The present treatment methods of inflammatory bowel disease (IBD mostly depend on pH sensitive polymers. These pH sensitive polymers based colonic devices may not serve the patient need successfully because the influence of colonic pH on pH sensitive polymers plays an important role in drug release. The lowered pH condition in diseased state could not trigger the drug release, as it was not the threshold pH of the particular coated polymer. Therefore, in such diseased conditions natural polymer (pectinbased devices serve better for the objective of the therapy. The study on the effect of pH changes on the drug release profile of natural polymer-based colonic devices revealed that there was no impact by pH changes on the devices since they release the drug by the effect of colonic

  16. Numerical solution for 5-layer laminate technique to determine saturation solubility of a drug in a thin film of pressure sensitive adhesive.

    Science.gov (United States)

    Bänsch, Eberhard; Reismann, Simone; Lee, Geoffrey

    2014-08-01

    A numerical solution of the one-dimensional diffusion equation is presented to describe the 5-layer laminate technique for estimating the saturation solubility of a drug in a thin polymer film. The boundary and initial conditions encompass a donor layer, a separating membrane, and an acceptor layer. Alteration of the drug's partition coefficient between donor and separating membrane has little influence on drug accumulation with the acceptor. The diffusivity in the separating membrane should be high to promote a short experimental time to achieve saturation equilibrium in the acceptor layer. The essential parameter to give rapid equilibrium is the thickness of the acceptor polymer film. For values of diffusivity typical for drugs of molecular weight around 500 an acceptor layer thickness of 10 µm-20 µm is required to achieve equilibrium within less than 10 d. These simulations allow the selection of suitable experimental conditions to make the 5-layer laminate technique a viable method for routine use.

  17. Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [{sup 11}C]methamphetamine in methamphetamine sensitized dog: Application of PET to drug pharmacokinetic study

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Hitoshi; Hishinuma, Takanori; Tomioka, Yoshihisa; Ishiwata, Shunji; Ido, Tatsuo; Iwata, Ren; Funaki, Yoshihito; Itoh, Masatoshi; Fujiwara, Takehiko; Yanai, Kazuhiko; Sato, Mitsumoto; Numachi, Yohtaro; Yoshida, Sumiko; Mizugaki, Michinao

    1997-02-01

    Repeated administration of methamphetamine (MAP) causes behavioral sensitization in animals. We previously reported that the maximum accumulation level of [{sup 11}C]MAP in the MAP-sensitized dog brain was 1.4 times higher than that in the control. In behavioral studies, haloperidol (a dopamine D{sub 2} receptor antagonist) prevents MAP-induced behavioral sensitization, and cocaine (a dopamine reuptake blocker) has the cross-behavioral sensitization with MAP. In the present study, to elucidate the relation between the MAP-induced behavioral sensitization and the pharmacokinetics of MAP, we investigated the effects of haloperidol and cocaine pretreatments on brain regional distribution and kinetics of [{sup 11}C]MAP using positron emission tomography (PET). A significant increase of [{sup 11}C]MAP uptake into the sensitized dog brain was prevented by haloperidol and cocaine pretreatments. These pharmacokinetic changes were not due to the changes in the rate of MAP metabolism. These results suggest haloperidol and cocaine can change the cerebral pharmacokinetic profile of MAP in the behavioral-sensitized dog. The variations of MAP-accumulation may affect the development or expression of MAP-induced behavioral sensitization.

  18. METHYLPHENIDATE ENHANCES THE ABUSE-RELATED BEHAVIORAL EFFECTS OF NICOTINE IN RATS: INTRAVENOUS SELF-ADMINISTRATION, DRUG DISCRIMINATION AND LOCOMOTOR CROSS-SENSITIZATION

    OpenAIRE

    Wooters, Thomas E.; Neugebauer, Nichole M.; Rush, Craig R.; Bardo, Michael T.

    2007-01-01

    Stimulant drugs, including d-amphetamine, cocaine and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination and locomotor cross-se...

  19. Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs.

    Science.gov (United States)

    Fouquet, Grégory; Debuysscher, Véronique; Ouled-Haddou, Hakim; Eugenio, Mélanie Simoes; Demey, Baptiste; Singh, Amrathlal Rabbind; Ossart, Christèle; Al Bagami, Mohammed; Regimbeau, Jean-Marc; Nguyen-Khac, Eric; Naassila, Mickael; Marcq, Ingrid; Bouhlal, Hicham

    2016-05-31

    Multidrug resistance MDR proteins (MRPs) are members of the C family of a group of proteins named ATP binding cassette (ABC) transporters. MRPs can transport drugs including anticancer drugs, nucleoside analogs, antimetabolites and tyrosine kinase inhibitors. Drugs used in HCC therapy, such as tyrosine kinase inhibitor sorafenib, are substrates of uptake and/or efflux transporters. Variable expression of MRPs at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. Recently, we reported that the hepatocyte SLAMF3 expression (Signaling Lymphocytic Activation Molecule Family member 3) was reduced in tumor cells from hepatocellular carcinoma (HCC) compared to its high expression in adjacent tissues. In the present study, we make a strong correlation between induced SLAMF3 overexpression and the specific loss of MRP-1 expression and its functionalities as a drugs resistance transporter. No changes were observed on expression of ABCG2 and MDR. More importantly, we highlight a strong inverse correlation between MRP-1 and SLAMF3 expression in patients with HCC. We propose that the SLAMF3 overexpression in cancerous cells could represent a potential therapeutic strategy to improve the drugs sensibility of resistant cells and thus control the therapeutic failure in HCC patients.

  20. Mangiferin enhances the sensitivity of human multiple myeloma cells to anticancer drugs through suppression of the nuclear factor κB pathway.

    Science.gov (United States)

    Takeda, Tomoya; Tsubaki, Masanobu; Kino, Toshiki; Kawamura, Ayako; Isoyama, Shota; Itoh, Tatsuki; Imano, Motohiro; Tanabe, Genzoh; Muraoka, Osamu; Matsuda, Hideaki; Satou, Takao; Nishida, Shozo

    2016-06-01

    Multiple myeloma (MM) is still an incurable hematological malignancy with a 5-year survival rate of ~35%, despite the use of various treatment options. The nuclear factor κB (NF-κB) pathway plays a crucial role in the pathogenesis of MM. Thus, inhibition of the NF-κB pathway is a potential target for the treatment of MM. In a previous study, we showed that mangiferin suppressed the nuclear translocation of NF-κB. However, the treatment of MM involves a combination of two or three drugs. In this study, we examined the effect of the combination of mangiferin and conventional anticancer drugs in an MM cell line. We showed that the combination of mangiferin and an anticancer drug decreased the viability of MM cell lines in comparison with each drug used separately. The decrease in the combination of mangiferin and an anticancer drug induced cell viability was attributed to increase the expression of p53 and Noxa and decreases the expression of XIAP, survivin, and Bcl-xL proteins via inhibition of NF-κB pathway. In addition, the combination treatment caused the induction of apoptosis, activation of caspase-3 and the accumulation of the cells in the sub-G1 phase of the cell cycle. Our findings suggest that the combination of mangiferin and an anticancer drug could be used as a new regime for the treatment of MM.

  1. 溶血性葡萄球菌前列腺炎细菌鉴定及药敏试验%Bacterial identity and drug sensitivity of hemolytic staphylococcus in chronic prostatitis

    Institute of Scientific and Technical Information of China (English)

    宋国章; 董进浪; 崔勇

    2001-01-01

    目的:给溶血性葡萄球菌引起的慢性细菌性前列腺炎患者治疗提供病原学诊断及用药依据。方法:采用MicroScan自动微生物鉴定/药敏测定系统及PosCombo Panel Type9板型,对36例溶血性葡萄球菌前列腺炎患者进行了细菌鉴定和药敏试验。结果:溶血性葡萄球菌对氨苄青霉素、环丙氟哌酸、红霉素、青霉素、呋喃坦啶、氟哌酸及氟嗪酸呈完全耐药,对万古霉素呈高度敏感,对利福平、氯林克霉素、复方新诺明、庆大霉素呈多数或大多数敏感。结论:在选用抗生素时,应以药敏测定结果为依据。%Purpose:To provide evidence of et iology and drug selection forpatients having chronic prostatitis,caused by hemo lytic staphylococcus.Method:Of 36 patients we have bacterial identity and drug -sensitivity test using Micro Scan auto Microbial identification drug sensitivi ty testing system and Pos Combo Panel(type 9).Result:Hemolytic staphylococcus is completely resistant to Ampicillin,Chloramphenicol,Erythromycin,Penicillin,Nitrofurantoin,Norfloxacin and Ofloxacin;to Vancomycin it is hypersensitive,and sensitive to Rifampin,Clinda mycin,SMZ co,Gentamicin.Conclusion:We should choose antibiotics according to drug -sensitivity test to these patients.

  2. Cinnamaldehyde Derivative (CB-PIC Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling

    Directory of Open Access Journals (Sweden)

    Jianzhong Xi

    2015-03-01

    Full Text Available Background/Aims: Our group reported that cinnamaldehyde derivative, (E-4-((2-(3-oxopop-1-enylphenoxymethylpyridinium malonic acid (CB-PIC induced apoptosis in hypoxic SW620 colorectal cancer cells via activation of AMP-activated protein kinase (AMPK and extracellular signal regulated kinase (ERK. Herein, sensitizing effect of CB-PIC was investigated in resistant cancer cells such as paclitaxel (PT resistant lung cancer cells (H460/PT, and Adriamycin (Adr resistant breast cancer (MCF7/Adr and colon cancer (HCT15/cos cells. Methods: Various drug resistant cell lines were treated with CB-PIC, and the signalling pathway and functional assay were explored by Western blot, Rhodamine assay, FACS, RT-PCR and MTT assay. Results: We found that CB-PIC effectively exerted cytotoxicity, increased sub G1 population and the cleaved form of poly (ADP-ribose polymerase (PARP and caspase 9 in drug resistant cancer cells. Furthermore, CB-PIC sensitized resistant cancer cells to adriamycin via downregulation of survival proteins such as survivin, Bcl-xL and Bcl-2, along with MDR1 suppression leading to accumulation of drug in the intracellular region. Of note, CB-PIC transcriptionally decreased MDR1 expression via suppression of STAT3 and AKT signalling in three resistant cancer cells with highly expressed P-glycoprotein. Nonetheless, CB-PIC did not affect transport activity of P-glycoprotein in a short time efflux assay, while epigallocatechin gallate (EGCG accumulated Rhodamine 123 into intracellular region of cell by direct inhibition of MDR1 transport activity. Conclusions: These data demonstrate that CB-PIC suppresses the P-glycoprotein expression through inhibition of STAT3 and AKT signalling to overcome drug resistance in chemo-resistant cancer cells as a potent chemotherapeutic sensitizer.

  3. Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology.

    Science.gov (United States)

    Benson, Neil; Matsuura, Tomomi; Smirnov, Sergey; Demin, Oleg; Jones, Hannah M; Dua, Pinky; van der Graaf, Piet H

    2013-04-06

    The nerve growth factor (NGF) pathway is of great interest as a potential source of drug targets, for example in the management of certain types of pain. However, selecting targets from this pathway either by intuition or by non-contextual measures is likely to be challenging. An alternative approach is to construct a mathematical model of the system and via sensitivity analysis rank order the targets in the known pathway, with respect to an endpoint such as the diphosphorylated extracellular signal-regulated kinase concentration in the nucleus. Using the published literature, a model was created and, via sensitivity analysis, it was concluded that, after NGF itself, tropomyosin receptor kinase A (TrkA) was one of the most sensitive druggable targets. This initial model was subsequently used to develop a further model incorporating physiological and pharmacological parameters. This allowed the exploration of the characteristics required for a successful hypothetical TrkA inhibitor. Using these systems models, we were able to identify candidates for the optimal drug targets in the known pathway. These conclusions were consistent with clinical and human genetic data. We also found that incorporating appropriate physiological context was essential to drawing accurate conclusions about important parameters such as the drug dose required to give pathway inhibition. Furthermore, the importance of the concentration of key reactants such as TrkA kinase means that appropriate contextual data are required before clear conclusions can be drawn. Such models could be of great utility in selecting optimal targets and in the clinical evaluation of novel drugs.

  4. Preparation of multilocation reduction-sensitive core crosslinked folate-PEG-coated micelles for rapid release of doxorubicin and tariquidar to overcome drug resistance

    Science.gov (United States)

    Yi, Xiaoqing; Zhao, Dan; Zhang, Quan; Xu, Jiaqi; Yuan, Gongdao; Zhuo, Renxi; Li, Feng

    2017-02-01

    Herein, we prepared folate-targeting core crosslinked polymeric micelles (CCL/FA) containing multiple disulfide bonds located at the interface and core of the micelles to co-deliver doxorubicin (DOX) and the P-glycoprotein (P-gp) inhibitor tariquidar (TQR) for reversing drug resistance. The stability and redox-responsive behavior of the CCL/FA micelles was evaluated through the changes in morphology, molecular weight and hydrodynamic size. On the one hand, the micelles possessed good stability, which led to the suppression of drug release from the CCL micelles in the physiological environment. On the other hand, under reductive conditions, the CCL micelles collapsed rapidly and accelerated drug release markedly. In vitro cytotoxicity measurements, combined with confocal laser scanning microscopy (CLSM) and flow cytometry, confirmed that the dual-drug-loaded micelles exhibited obviously higher cytotoxicity to MCF-7/ADR-resistant cells than free DOX · HCl, single-drug loaded CCL micelles and nontargeted CCL micelles. The results imply that co-delivering DOX and TQR by CCL/FA micelles may be a promising way of overcoming multidrug resistance in tumor treatments.

  5. 神经内科重症监护病房病原菌分布及药敏分析%Characteristic Description and Drug Sensitivity Testing of Pathogenic Bacteria in Neurological Intensive Care Unit

    Institute of Scientific and Technical Information of China (English)

    李海英; 李淑娟; 胡文立; 秦伟

    2011-01-01

    Objective The characteristic of infection strains and the changes in antibiotic-resistance in neurological intensive care unit(NICU) were investigated to direct the antibiotics clinical application, and to reduce the hospital infection incidence rates. Methods From Sep. 2008 to May 2010,451 species from 216 patients in N1CU, including sputum, urine, stools, and blood, were cultured for bacteria identification and drug sensitivity testing. Results Among the isolated 399 strains of pathogenic bacteria,Gram-negative bacilli,Gram-positive cocci and fungi, were 140,73 and 186, respectively. The pathogens were mainly from respiratory tract. As the major pathogens, Candida albicans and Staphylococcus aureu accounted for 49.9% of all pathogens. The results of drug sensitivity testing showed that fungi had great clinical drug resistance; MRSA showed high sensitivity to Glyco-peptides-type drugs;and Gram-negative bacilli showed sensitivity to Carbapenem-type drugs. Cephalosporin-type and Penicillin-type drugs showed different sensitivities to the Gram-negative bacilli. Conclusion The main pathogenic bacteria of NICU were fungi and Gram-negative bacilli, which might be the contribution of extensive use of broad-spectrum antibiotics. The doctors should pay attention to reduce the use of broad-spectrum antibiotics,appropriately increase the use of Glycopeptides-type and Carbapenem-type drugs. Cefoperazone/sulbactam or ceftazidime was suggested as the conventional antiseptic drug.%目的 调查神经内科重症监护病房(NICU)感染患者的病原菌分布及耐药情况,以指导临床抗菌药物的应用,降低医院感染率.方法 对2008年9月-2010年5月期间入住NICU的216例患者送检的痰、尿、便、血等451份标本进行病原菌鉴定和体外药敏试验.结果检出的399株病原菌中,G-杆菌140株,G+球菌73株,真菌186株.病原菌主要采自于呼吸道.致病菌简单且集中,白色念珠菌和MRSA占所有致病菌的49.9%.药敏结果

  6. A Simple and Sensitive RP-UPLC Method for the Simultaneous Determination of N-Hydroxybenzotriazole, Cinchonidine and 1,3-Dicyclohexyl Urea Contents in Fosinopril Sodium Drug Substance

    Directory of Open Access Journals (Sweden)

    M. Narendra Kumar

    2012-01-01

    Full Text Available A simple and sensitive reverse phase ultra performance liquid chromatography (RP-UPLC method has been developed, optimized and validated for the simultaneous determination of N-Hydroxybenzotriazole (HOBt, Cinchonidine and 1,3-Dicyclohexyl urea (DCU contents at low levels in fosinopril sodium drug substance. Efficient chromatographic separation was achieved on Acquity UPLC HSS C18 column, 100 mm long with 2.1 mm i.d., 1.8 µm particle diameter, thermo stated at 30°C. Gradient elution involving binary mixture of potassium dihydrogen orthophosphate (0.01M, pH:3.0±0.05 with ortho-phosphoric acid and acetonitrile at a flow rate of 0.10 mL min-1 has been used. The analytes were monitored by photodiode array (PDA detector set at 205 nm. The drug substance was subjected to stress conditions of hydrolysis, oxidation, photolysis, thermal and humidity degradation. The method was validated for specificity, sensitivity, linearity, precision, accuracy and solution stability. The limit of detection (LOD and limit of quantification (LOQ for HOBt, Cinchonidine and DCU were in the range of 0.85-3.52 ppm and 2.57-10.67 ppm, respectively. The average recoveries for HOBt, Cinchonidine and DCU are in the range of 98.1% to 102.6%. The method can be used for the routine quality control analysis of fosinopril sodium drug substance.

  7. Drug sensitivity analysis of type 2 diabetes complicated with urinary tract infection in Handan City%邯郸市2型糖尿病伴尿路感染的药敏分析

    Institute of Scientific and Technical Information of China (English)

    高玉梅; 韩永霞; 冯采兰

    2013-01-01

    目的 分析2型糖尿病伴尿路感染病例药敏试验结果,以指导临床合理选择抗生素.方法 取糖尿病伴尿路感染患者的清洁中段尿进行培养,采用配套的药敏卡进行药敏试验;按糖尿病伴尿路感染和非糖尿病伴尿路感染分组进行分析.结果 糖尿病伴尿路感染组患者感染的菌种存在多样性,糖尿病伴尿路感染组比非糖尿病伴尿路感染组对亚胺培南(敏感率91.49%)、阿米卡星(敏感率53.19%)敏感率高,且两组比较,差异有统计学意义(P<0.05).两组对头孢哌酮/舒巴坦、哌拉西林/他唑巴坦敏感率均>60%,所有菌株均对亚胺培南、阿米卡星敏感;糖尿病伴尿路感染阳性组有4例合并肠球菌感染.结论 糖尿病伴尿路感染患者应根据药敏试验结果合理使用抗生素,亚胺培南、阿米卡星、头孢哌酮/舒巴坦、哌拉西林/他唑巴坦为敏感药物.%[Objective] To analyze the results of drug sensitive test of type 2 diabetes complicated with urinary tract infection cases, guide reasonable choice of antibiotics in clinic. [ Methods] The samples of clean midstream urine from patients with diabetes and u-rinary tract infection were cultured, and the drug sensitive test was conducted with targeted drug sensitivity cards. Two groups, which included the diabetes with urinary tract infection group and the non-diabetes with urinary tract infection group, were analyzed. [ Results] The patients in the diabetes with urinary tract infection group were infected with a variety of bacteria. The sensitivity to imipenem (91.49% ) and amikacin (53.19% ) of the diabetes with urinary tract infection group was higher than that of the non-diabetes with urinary tract infection group, and the differences were significant (P < 0. 05). The sensitivity to cefoperazone/ sulbactam and piperacillin/tazobactam of both two groups were higher than 60% , while all strains were sensitive to imipenem and amikacin. 4 cases were

  8. Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

    OpenAIRE

    2008-01-01

    Vicriviroc (VCV) is a chemokine (C-C motif) receptor 5 (CCR5) antagonist with potent anti-HIV activity that currently is being evaluated in phase III clinical trials. In the present study, donor CCR5 density (CCR5 receptors/CD4 lymphocytes) inversely correlated with VCV antiviral activity (Spearman's correlation test; r = 0.746, P = 0.0034). Low doses of the transplant drug rapamycin (RAPA) reduced CCR5 density and enhanced VCV antiviral activity. In drug interaction studies, the RAPA/VCV com...

  9. Isolation Identification and Drug Sensitive Test of Avian Escherichia coli in the Area of Jinzhou%锦州地区鸡大肠杆菌的分离鉴定及耐药性分析

    Institute of Scientific and Technical Information of China (English)

    李冰; 唐峰; 马鸣潇

    2011-01-01

    Samples were collected from the chiken that suspected as colibacillosis in Jinzhou district, 15 strains of Avian E.coli were isolated. They were belonged to 14 serotypes, Serotype O15, O35 constituted a majority of the isolates. Drug sensitive test were carried out on the 10 strains, the result showed that drug resistance and multi-drug resistant was serious. The sistant rate were 46.67%-100%, about 86.67% strains resist to more than 5 drugs in the test.%由锦州地区不同类型鸡场采集疑似大肠杆菌病病料,分离出大肠杆菌15株.血清型鉴定试验确定14株的血清型,优势血清型为O15,O35.并选择10种抗生素进行药敏试验,结果表明实验菌株耐药程度和多重耐药较为严重,耐药率在46.67%~100%,对5种以上抗生素耐药的菌株共有13株,占86.67%.

  10. A cross-sectional study of self-reported chemical-related sensitivity is associated with gene variants of drug-metabolizing enzymes

    Directory of Open Access Journals (Sweden)

    Fabig Nathalie

    2007-02-01

    Full Text Available Abstract Background N-acetyltransferases (NAT and glutathione S-transferases (GST are involved in the metabolism of several ubiquitous chemical substances leading to the activation and detoxification of carcinogenic heterocyclic and aromatic amines. Since polymorphisms within these genes are described to influence the metabolism of ubiquitous chemicals, we conducted the present study to determine if individuals with self-reported chemical-related sensitivity differed from controls without self-reported chemical-related sensitivity with regard to the distribution of genotype frequencies of NAT2, GSTM1, GSTT1, and GSTP1 polymorphisms. Methods Out of 800 subjects who answered a questionnaire of ten items with regard to their severity of chemical sensitivity 521 unrelated individuals agreed to participate in the study. Subsequently, genetic variants of the NAT2, GSTM1, GSTT1, and GSTP1 genes were analyzed. Results The results show significant differences between individuals with and without self-reported chemical-related sensitivity with regard to the distribution of NAT2, GSTM1, and GSTT1 gene variants. Cases with self-reported chemical-related sensitivity were significantly more frequently NAT2 slow acetylators (controlled OR = 1.81, 95% CI = 1.27–2.59, P = 0.001. GSTM1 and GSTT1 genes were significantly more often homozygously deleted in those individuals reporting sensitivity to chemicals compared to controls (GSTM1: controlled OR 2.08, 95% CI = 1.46–2.96, P = 0.0001; GSTT1: controlled OR = 2.80, 95% CI = 1.65–4.75, P = 0.0001. Effects for GSTP1 gene variants were observed in conjunction with GSTM1, GSTT1 and NAT2 gene. Conclusion The results from our study population show that individuals being slow acetylators and/or harbouring a homozygous GSTM1 and/or GSTT1 deletion reported chemical-related hypersensitivity more frequently.

  11. The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells

    DEFF Research Database (Denmark)

    Yde, Christina Westmose; Clausen, Mathias Porsmose; Bennetzen, Martin

    2009-01-01

    -glycoprotein in cancer cells. In this study, we have investigated the effect of chlorpromazine on tamoxifen response of human breast cancer cells. We found that chlorpromazine worked synergistically together with tamoxifen with respect to reduction of cell growth and metabolic activity, both in the antiestrogen......-sensitive breast cancer cell line, MCF-7, and in a tamoxifen-resistant cell line, established from the MCF-7 cells. Tamoxifen-sensitive and tamoxifen-resistant cells were killed equally well by combined treatment with chlorpromazine and tamoxifen. This synergistic effect could be prevented by addition of estrogen...

  12. HIV quasispecies dynamics during pro-active treatment switching: impact on multi-drug resistance and resistance archiving in latent reservoirs.

    Directory of Open Access Journals (Sweden)

    Max von Kleist

    Full Text Available The human immunodeficiency virus (HIV can be suppressed by highly active anti-retroviral therapy (HAART in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after

  13. Pharmacodynamics of cisplatin in human head and neck cancer : correlation between platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo

    NARCIS (Netherlands)

    Welters, M.J.P.; Fichtinger-Schepman, A.M.J.; Baan, R.A.; Jacobs-Bergmans, A.J.; Kegel, A.; Vijgh, W.J.F. van der; Braakhuis, B.J.M.

    1999-01-01

    Total platinum contents and cisplatin-DNA adduct levels were determined in vivo in xenografted tumour tissues in mice and in vitro in cultured tumour cells of head and neck squamous cell carcinoma (HNSCC), and correlated with sensitivity to cisplatin. In vivo, a panel of five HNSCC tumour lines grow

  14. Nationwide survey of the development of drug resistance in the pediatric field in 2000-2001, 2004, 2007, 2010, and 2012: evaluation of the changes in drug sensitivity of Haemophilus influenzae and patients' background factors.

    Science.gov (United States)

    Shiro, Hiroyuki; Sato, Yoshitake; Toyonaga, Yoshikiyo; Hanaki, Hideaki; Sunakawa, Keisuke

    2015-04-01

    The Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease has conducted surveillance of pediatric patients with respiratory tract infections, meningitis, and sepsis five times (in 2000-2001 [period 1], 2004 [period 2], 2007 [period 3], 2010 [period 4], and 2012 [period 5]). With respect to the clinically isolated Haemophilus influenzae, the drug susceptibility, the frequency of drug-resistant strains, and patients' background factors in each period have already been reported. Here we evaluate trends in the development of drug resistance in H. influenzae, and the relationship between the development of drug resistance and patients' background factors in the aforementioned five periods. H. influenzae derived from pediatric patients with respiratory tract infections that had been previously collected (period 1, 448 isolates; period 2, 376 isolates; period 3, 386 isolates; period 4, 484 isolates; and period 5, 411 isolates) were analyzed. The proportions of ß-lactamase-nonproducing ampicillin (ABPC)-intermediate resistant (BLNAI) strains + β-lactamase-nonproducing ABPC-resistant (BLNAR) strains were 28.8% in period 1, 59.3% in period 2, 61.1% in period 3, 58.1% in period 4, and 63.5% in period 5, showing a rapid increase from period 1 to period 2 followed by an almost constant rate of approximately 60%. The proportion of ß-lactamase-producing ABPC-resistant (BLPAR) strains + ß-lactamase-producing clavulanic acid/amoxicillin-resistant (BLPACR) strains was 4.4% in period 3, which was somewhat low; however, there were no significant changes in the proportions of these strains, which ranged between 6.4% and 8.7% throughout the surveillance period except for period 3. The drugs whose MIC90 values against BLNAR strains were low throughout the surveillance included piperacillin (0.25 μg/mL) and tazobactam/piperacillin (0.125-0.25 μg/mL) in the penicillins; cefditoren and ceftriaxone (0.25-0.5 μg/mL for both) in the cephems; meropenem (0.5-1

  15. Analysis on drug sensitivity of ESBL-producing Escherichia coli%产超广谱β-内酰胺酶大肠埃希菌药敏情况分析

    Institute of Scientific and Technical Information of China (English)

    孙午; 熊莺

    2013-01-01

    目的 分析产ESBLs大肠埃希菌的临床分离和药敏情况,并与不产酶的大肠埃希菌的情况进行比较.方法 回顾性分析198株产ESBLs大肠埃希菌和287株不产ESBLs大肠埃希菌的耐药情况,采用x2检验分析耐药株和敏感株的来源差异和对常用抗菌药物的敏感性差异.结果 药敏实验证实产ESBLs大肠埃希菌和不产ESBLs大肠埃希菌除对亚胺培南、美洛培南和阿米卡星的敏感性差异无统计学意义外(P>0.05),对其他抗菌药物的敏感性差异都有统计学意义(P<0.05),产ESBLs大肠埃希菌对这些抗菌药物的耐药率相对于不产ESBLs大肠埃希菌都有不同程度的提高.结论 由于产ESBLs大肠埃希菌耐药机制的多样性和存在多重耐药情况,在临床确诊产ESBLs大肠埃希菌株感染时应根据药敏结果合理使用抗菌药物,同时应该珍惜使用对产ESBLs大肠埃希菌和不产ESBLs大肠埃希菌治疗无显著差异的碳青霉烯类以及阿米卡星等抗菌药物.%OBJECTIVE To analyze drug sensitivity of ESBL-producing Escherichia coli and compare with non-ESBL-produc-ing Escherichia coli. METHODS We got 198 ESBL-producing Escherichia coli and 287 non-ESBL-producing Escherichia coli. The results of ESBL-producing Escherichia coli and non-ESBL-producing Escherichia coli were analysed by χ2 test. RESULTS There were no significant differences in drug sensitivity of ESBL-producing Escherichia coli and Non-ESBL-producing Escherichia coli to imipenem, meropenem and amikacin (P> 0.05). Drug sensitive test discovered that there were significant differences in drug sensitivity of ESBL-producing Escherichia coli and non-ESBL-producing Escherichia coli to other antibiotics (P> 0.05), and drug sensitivity of ESBL-producing Escherichia coli was higher than non-ESBL-producing Escherichia coli. CONCLUSION We should use drug to treat patients in time and reasonably when the patient is diagnosed as infection by ESBL

  16. The pus bacterial cultivation and drug sensitive test analysis of chronic suppurative otitis media in 81 cases%81例慢性化脓性中耳炎脓液细菌培养及药敏分析

    Institute of Scientific and Technical Information of China (English)

    胡春梅; 陈德珍; 何刚

    2015-01-01

    目的:分析入院拟手术的慢性化脓性中耳炎患者耳部感染的菌群分布及药敏结果,寻找敏感的抗生素,指导临床合理用药。方法81例诊断慢性化脓性中耳炎入院拟行手术的患者耳道分泌物进行细菌培养及药敏试验,对培养阳性菌株的种类以及药物敏感试验结果进行统计分析。结果81份标本中分离出致病菌43株,阳性率53%,革兰氏阳性球菌24株(55.8%),以金黄色葡萄球菌及星座链球菌为主;革兰氏阴性杆菌17株(39.5%),以铜绿假单胞菌,肺炎克雷伯菌,大肠埃希菌为主,真菌2株(4.6%)。革兰氏阳性菌普遍对碳青霉烯,万古霉素类抗生素敏感,革兰氏阴性菌普遍对莫西沙星,碳氢霉烯类,万古霉素等抗生素敏感,结论革兰氏阳性菌是本地区慢性化脓性中耳炎的主要致病菌,临床需根据药敏结果选择安全有效的药物治疗。%Objective Analysis of the distribution of pathogenic bacteria and its drug sensitivity of chronic suppurative otitis media in patients to be operated ,searching for sensitive antibiotics and guiding clinical rational drug use .Methods The bacterial culture and drug sensitivity test were carried out on the patient's ear canal secretion with chronic suppurative otitis media admitted to be treated with surgery ,and the type of positive strains and drug sensitivity test results were statistically analyzed .the results were statisticallyanalyzed.Results 43strainspathogenicbacteriaweredetectedin81samples,andthepositive rate was 53% .Gram positive bacteria were 24 (55 .8% ) ,mainly staphylococcus aureus and streptococcus constellation ;.gram negative bacilli were 17 (39 .5% ) ,mainly pseudomonas aeruginosa ,klebsiella pneumoniae ,escherichia coli;Fungi were 2 strains (4 .6% ) .Gram positive bacteria were sensitivated to carbapenems and vancomycin ,while gram negative bacteria generally to moxifloxacin ,carbapenems and

  17. Study on in vitro drug release behavior P (EG-MAA-MEG) pH sensitive hydrogels%P(CE-MAA-MEG)pH敏感性水凝胶的体外释放药物行为考察

    Institute of Scientific and Technical Information of China (English)

    郑施施; 王增寿

    2012-01-01

    目的:研究一种P(EG-MAA-MEG) pH敏感性水凝胶在口服药物传输体系中的应用.方法:本文采用自由基聚合方法制备一种具有良好pH响应性能的水凝胶,并对其pH响应性能进行相关的表征.以维生素B12(VB12)为模型药物,考察载药水凝胶在不同pH环境条件下(pH 1.2和pH 7.4)的药物释放行为.结果:P(EG-MAA-MEG) pH敏感水凝胶具有明显的孔洞结构和良好的pH响应性能,在中性磷酸盐缓冲溶液(pH 7.4)中吸水率显著大于在酸性溶液(pH 1.2)中的吸水率.装载维生素B12的pH敏感水凝胶在中性磷酸盐缓冲溶液(pH 7.4)中的8h的药物累计释放率达到50%,而在酸性溶液(pH1.2)中的8h的药物累计释放率只有30%左右.结论:可生物降解P(EG-MAA-MEG) pH敏感性水凝胶具有良好的pH敏感性和药物缓控释性能,在口服结肠靶向给药体系中有一定的应用前景.%OBJECTIVE To study of the P (EG-MAA-MEG) pH sensitive hydrogels for the application in oral drug delivery system. METHODS Using free radical polymerization method to develop a good pH response properties of the hydrogel, and the pH response performance were characterized. Using vitamin B12 as a model drug, the dnug release behavior of hydrogel at different pH conditions (pH I. 2 and pH 7. 4) was examined. RESULTS P (EG-MAA-MEG) pH sensitive hydrogels with visible hole structure and good pH response performance,in neutral phosphate buffer solution (pH 7. 4) in water absorption rate was significantly higher than that in acidic solution ( pH I, 2) in the rate of water absorption . Containing vitamin B12 pH sensitive hydrogels in neutral phosphate buffer solution ( pH 7. 4) ,the 8 h drug accumulative release rate reached 50%,m an acidic solution ( pH 1. 2),the 8 h drug accumulative release rate of only about 30% . CONCLUSION Biodegradable P (EG-MAA-MEG) pH sensitive hydrogel has good pH sensitivity and controlled drug release properties, in oral drug delivery system it has

  18. The transition of drug sensitivity of neonatal gonococcal conjunctivitis in recent 10 years%新生儿淋菌性结膜炎致病菌10年药物敏感性的变迁

    Institute of Scientific and Technical Information of China (English)

    黎明; 姚晓明; 聂丹瑶; 曹端荣; 林宝涛; 诸凤娇

    2011-01-01

    Objective To study the results of drug sensitivity of Neisseria gonorrhoeae from the inferior palpebral conjunctival surface of neonate with gonocaceal cterial conjunctivitis and research the transition of drug sensitivity in recent 10 years. For clinical treatment and rational drug use, provide the hasis. Methods Neisseria gonorrhoeae cultivated of conjunctival secretions of 78 cases with neonatal gonococcal conjunctivitis were drug sensitivity testing, and data analysis. Results The drug sensitivity of neonatal gonococcal conjunctivitis pathogens-Neisseria gonorrhoeae was high to cefoperazone, cefazolin, ciprofloxacin and tobramycin in recent 10 years. The resistance of that was strong to rifampin, neomycin, Chloramphenicol. Conclusions Neonatal gonocorcal conjunctivitis can be the first choice of Ciprofloxacin eye drops or tobramycin eye drops for treatment. For children with severe combined we can combine with Cefazolin or Cefoperazone. At the same time should try to take samples of bacterial culture and drug sensitivity tests to the test results came out in time to modify treatment in order to obtain better clinical results.%目的:对2001年至2010年临床确诊的新生儿淋菌性结膜炎的病人结膜囊分泌物进行细菌培养和药物敏感性试验,探讨其致病菌药物敏感性10年的变迁,为临床合理用药提供依据.方法:对78例临床诊断为新生儿淋菌性结膜炎患儿的结膜囊分泌物标本进行细菌培养,对培养出的淋球菌进行药物敏感性试验,并对数据进行分析.结果:10年来,新生儿淋菌性结膜炎的致病菌--淋球菌对头孢哌酮、头孢唑啉、环丙沙星和妥布霉素的药物敏感性高,对利福平、新霉素、氯霉素的耐药性强.结论:新生儿淋菌性结膜炎首选环丙沙星眼药水和妥布霉素眼药水.病情严重者可以联合头孢哌酮或者头孢唑啉类的药物,同时应及早取标本进行细菌培养和药物敏感试验,以便在试验结果

  19. Self-assembly of BODIPY based pH-sensitive near-infrared polymeric micelles for drug controlled delivery and fluorescence imaging applications.

    Science.gov (United States)

    Liu, Xiaodong; Chen, Bizheng; Li, Xiaojun; Zhang, Lifen; Xu, Yujie; Liu, Zhuang; Cheng, Zhenping; Zhu, Xiulin

    2015-10-21

    Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (∼7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells.

  20. [The drug sensitivity of enterohemorragic Escherichia coli and antibiotics treatment for hemorrhagic enterocolitis--from an outbreak of enterocolitis in Sakai city].

    Science.gov (United States)

    Moriguchi, N; Yagi, K; Yamamoto, T; Yoshioka, K; Kubo, S

    1997-07-01

    In July, 1996, a massive outbreak of hemorrhagic enterocolitis involving more than 5,000 people was caused by enterohemorragic Escherichia coli (EHEC) O157:H7 occurred mainly among elementary school children of Sakai City, Japan. The antibacterial activities in vitro against EHEC from stool specimens were determined. Norfloxacin showed the highest antibacterial activity, and fosfomycin, kanamycin, ampicillin, cefaclor were considered as effective drugs. But doxycycline showed lower antibacterial activities compared to other examined drugs, and it appears necessary to take antibiotic resistance of Escherichia coli into consideration when a treatment regimen is determined. As a result of the oral administration of fosfomycin to 95 patients of hemorrhagic enterocolitis and carrier, no patients developed complications with hemolytic uremic syndrome (HUS). However, a study of 17 patients with HUS demonstrated the fact that most of them were subjected to intravenous administration of fosfomycin. It may be needed to consider oral administration route of effective antibiotics in the treatment of enterocolitis in order to maintain high concentrations of a drug in the intestine.

  1. 儿童假丝酵母感染状况分析及药物敏感性研究%Analysis on the infection status of Candida in children and the drug sensitive test

    Institute of Scientific and Technical Information of China (English)

    王长嘉; 孙晓红; 贺丹; 李广泉; 高磊; 高嵩; 王丽

    2012-01-01

    目的:探讨儿童假丝酵母的感染情况,分析其对常用抗真菌药物的敏感性,为真菌感染的治疗和预防提供依据.方法:收集临床假丝酵母感染患儿标本77例,进行菌株的分离、鉴定.并从患儿年龄、基础疾病及标本来源、检出病原菌种类、菌株药物敏感性等方面进行分析.结果:真菌感染患儿的平均年龄为6岁.标本主要来源于咽拭子,白假丝酵母的分离率最高(63.6%),其次为光滑假丝酵母、热带假丝酵母、克柔假丝酵母和其他假丝酵母.药物敏感性实验结果表明,假丝酵母对两性霉素B (AmB)、5-氟胞嘧啶(5- FC)的敏感性较高.其中,白假丝酵母对AmB、5- FC、氟康唑(FCZ)及伊曲康唑(ICZ)的敏感率依次为100.0%、91.9%、83.7%、69.4%;对ICZ、FCZ、5- FC的耐药率依次为4.1%、2.0%、2.0%.结论:儿童真菌感染以白假丝酵母最多见,分离菌株对FCZ和ICZ的耐药性较高,临床医生应高度重视,并根据药物敏感性实验结果进行治疗和预防.%Objective: To explore the infection status of Candida in children, analyze its sensitivity to antibiotics commonly used in clinic, provide a basis for the treatment and prevention of fungal infection. Methods; A total of 77 specimens of clinical infection of Candida in children were collected, then isolation and identification of bacterial strains were conducted, then the results were analyzed from the aspects of age, basic diseases, source of specimens, types of pathogens detected , and drug sensitivity of bacterial strains. Results -. The average age of the children with fungal infection was six years. The specimens were mainly from nasopharyngeal swabs. The isolation rate of Candida albicans was the highest (63. 6% ) , followed by Candida glabrata, Candida tropicalis, Candida krusei, and other Candida. The results of drug sensitive test showed that the sensitivities of Candida to amphoteriein B and 5 - fluorouracil were high. The

  2. 4-IBP, a σ1 Receptor Agonist, Decreases the Migration of Human Cancer Cells, Including Glioblastoma Cells, In Vitro and Sensitizes Them In Vitro and In Vivo to Cytotoxic Insults of Proapoptotic and Proautophagic Drugs

    Directory of Open Access Journals (Sweden)

    Veronique Mégalizzi

    2007-05-01

    Full Text Available Although the molecular function of cr receptors has not been fully defined and the natural ligand(s is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-tibenzylpiperidin-4-yl-4iodobenzamide (4-IBP, a selective σ1, agonist, has been used to investigate whether this compound is able to modify: 1 in vitro the migration and proliferation of human cancer cells; 2 in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3 in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC models the survival of mice coadministered cytotoxic agents. 4-IBP has revealed weak anti proliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.

  3. Self-assembly of BODIPY based pH-sensitive near-infrared polymeric micelles for drug controlled delivery and fluorescence imaging applications

    Science.gov (United States)

    Liu, Xiaodong; Chen, Bizheng; Li, Xiaojun; Zhang, Lifen; Xu, Yujie; Liu, Zhuang; Cheng, Zhenping; Zhu, Xiulin

    2015-10-01

    Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (~7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells.Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR

  4. Differential sensitivity to JAK inhibitory drugs by isogenic human erythroblasts and hematopoietic progenitors generated from patient-specific induced pluripotent stem cells.

    Science.gov (United States)

    Ye, Zhaohui; Liu, Cyndi F; Lanikova, Lucie; Dowey, Sarah N; He, Chaoxia; Huang, Xiaosong; Brodsky, Robert A; Spivak, Jerry L; Prchal, Josef T; Cheng, Linzhao

    2014-01-01

    Disease-specific induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity to establish novel disease models and accelerate drug development using distinct tissue target cells generated from isogenic iPSC lines with and without disease-causing mutations. To realize the potential of iPSCs in modeling acquired diseases which are usually heterogeneous, we have generated multiple iPSC lines including two lines that are JAK2-wild-type and four lines homozygous for JAK2-V617F somatic mutation from a single polycythemia vera (PV) patient blood. In vitro differentiation of the same patient-derived iPSC lines have demonstrated the differential contributions of their parental hematopoietic clones to the abnormal erythropoiesis including the formation of endogenous erythroid colonies. This iPSC approach thus may provide unique and valuable insights into the genetic events responsible for disease development. To examine the potential of iPSCs in drug testing, we generated isogenic hematopoietic progenitors and erythroblasts from the same iPSC lines derived from PV patients and normal donors. Their response to three clinical JAK inhibitors, INCB018424 (Ruxolitinib), TG101348 (SAR302503), and the more recent CYT387 was evaluated. All three drugs similarly inhibited erythropoiesis from normal and PV iPSC lines containing the wild-type JAK2 genotype, as well as those containing a homozygous or heterozygous JAK2-V617F activating mutation that showed increased erythropoiesis without a JAK inhibitor. However, the JAK inhibitors had less inhibitory effect on the self-renewal of CD34+ hematopoietic progenitors. The iPSC-mediated disease modeling thus underlies the ineffectiveness of the current JAK inhibitors and provides a modeling system to develop better targeted therapies for the JAK2 mutated hematopoiesis.

  5. TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases

    Directory of Open Access Journals (Sweden)

    Kim Dong-Wan

    2010-07-01

    Full Text Available Abstract Background The development of new modulator possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcome P-glycoprotein (P-gp mediated multidrug resistance (MDR in cancer treatment. In this study, we suggest a new molecular mechanism that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand down-regulates P-glycoprotein (P-gp through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases and thereby sensitize MDR cells to MDR-related drugs. Results MDR variants, CEM/VLB10-2, CEM/VLB55-8 and CEM/VLB100 cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3β and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB100 cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3β pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5. Conclusion This study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by

  6. Fungal distribution and drug sensitivity analysis of cancer patients with oral infection%肿瘤患者口腔感染真菌分布与药敏分析

    Institute of Scientific and Technical Information of China (English)

    李玲; 徐峰; 鞠博; 高振; 李伟

    2016-01-01

    目的:研究肿瘤患者口腔感染真菌分布及敏感性,为临床抗真菌药物的选择提供依据。方法选取2014年12月-2015年12月医院口腔科诊治82例肿瘤真菌感染患者临床资料,采集患者标本,分析肿瘤患者口腔感染真菌分布及其对抗真菌药物的敏感性,数据采用SPSS 18.0软件进行统计分析。结果82例口腔真菌感染肿瘤患者的科室分布相对较广,排前3位的科室分别为老年科、IC U 及内分泌科,分别占31.71%、28.05%及12.20%;肿瘤口腔感染患者中共分离出真菌103株,排在前3位的分别为白色假丝酵母菌、热带假丝酵母菌以及光滑假丝酵母菌,分别占50.49%、20.39%以及12.62%;白色假丝酵母菌、热带假丝酵母菌及光滑假丝酵母菌对两性霉素B敏感率均为100.00%。结论肿瘤患者口腔感染的真菌相对复杂,应加强真菌的分离、鉴定,并根据真菌类型进行药敏试验,选择敏感抗菌药物。%OBJECTIVE To study fungal distribution and sensitivity to drugs of cancer patients with oral infection , so as to provide reference about how to choose antifungal drugs in clinic .METHODS A total of 82 cases of cancer patients with fungal infections got treatment from department of stomatology in our hospital during Dec .2014 to Dec .2015 were selected and samples of these patients were collected to analyze fungal distribution and sensitivity to antifungal drugs by using SPSS 18 .0 to give statistic analysis .RESULTS The departments of 82 cancer patients with oral infection were distributed widely ,and the top three were department of geriatrics ,ICU and endocrinolo‐gy ,accounting for 31 .71% ,28 .05 and 12 .20% respectively .A total of 103 strains of fungi were isolated from the cancer patients with oral infection ,and the top three were Candida ,Candida tropicalis and Candida glabrata , accounting for 50 .49% ,20 .39% and 12 .62% ,respectively .Drug

  7. Research Incidence and Drug Sensitivity on Thrush of Different Ages Children%不同年龄段儿童鹅口疮发病情况和药物敏感性调查

    Institute of Scientific and Technical Information of China (English)

    冯冬菲; 江华; 刘枫; 田素宝; 路风; 郅媛媛; 李威; 王春雨

    2014-01-01

    目的:调查儿童各年龄段鹅口疮发病情况和各类抗真菌药物的敏感性。方法:收集2012年到哈尔滨市儿童医院口腔科就诊的655例鹅口疮患儿,划分为新生儿组、婴儿组和幼儿组,分析各年龄段的疾病分布。其中241例用棉拭子法采集患者口腔粘膜病变部位的白念菌进行细菌培养,选取制霉菌素、酮康唑、伊曲康唑和氟康唑,进行体外抗真菌药敏敏感度试验,各年龄段进行对比。结果:新生儿组和婴儿组患病率相似,幼儿组患病率最低。婴儿组大多数患儿单纯患鹅口疮,而幼儿组患儿多合并其他疾病。药物有效率(敏感和中介例数所占的比例)最高的药物分别是:新生儿组:氟康唑,婴儿组:酮康唑,幼儿组:酮康唑和氟康唑。结论:各年龄段鹅口疮发病情况有差异,治疗敏感药物不同,临床用药应参考药敏结果进行选择。%Objective:To discuss incidence and all kinds of antifungal drugs sensitivity on thrush of different ages children . Methods:Selected 655 children with thrush who visited the Department of Stomatology in Harbin Children's Hospital in 2012.Di-vided them into neonatal group, Infants group and young children group.241 cases of different groups accepted the test of antifungal drug sensitivity in vitro with nystatin, ketoconazole, itraconazole and fluconazolein respectively.Results:Prevalence rate in neonatal group is similar to which in infants group.It is the lowest in young children group.Most children in infant group uncomplicated thrush, while the children in young children group were the opposite.Drug with the highest efficiency( the proportion of sensitivity and intermediate cases) is:fluconazole in neonatal group, ketoconazole in infant group, ketoconazole and fluconazole in young chil-dren group.Conclusion:The incidence and drug sensitive of thrush is different among three groups.Clinical medical selection should refer

  8. 暹罗斗鱼致病性嗜水气单胞菌的分离·鉴定及药敏试验%Isolation, Identification and Drug Sensitivity Test of Pathogenic Aeromonas hydrophila from Betta splendens Regan

    Institute of Scientific and Technical Information of China (English)

    杨宁; 黄海; 张希; 魏赟; 巫火连

    2012-01-01

    [Objective] The research aimed to discuss the disease cause of Betta splcnders Regan and the prevention and control methods of its diseases and pests. [Method] The pathogenic bacteria of B, splenders were isolated and identified by determining die physiological and biochemical indices and 16 S rDNA sequencing. And the drug sensitivity test was made. [Result] Strain DY001 was the pathogenic bacteria that caused Aeromonas hydrophila disease of B. splenders. Strain DY001 was identified as Aeromonas hydrophila. The median lethal dose (LD50) of this pathogeny to B. splenders was 0. 04 × 106 CFU/g. The results of drug sensitivity test showed that this pathogenic bacteria was sensitive to azithromycin, ofloxacin, norfloxacin, compound sinomin, ceftriaxone, trimethoprim, chloramphenicol and other antibiotics. [Conclusion] Aeromonas hydropkila was the pathogenic bacteria that caused the disease incidence of B. splenders. The results of drug sensitivity test could provide references for the disease prevention and control of B. splenders.%[目的]探讨暹罗斗鱼的发病原因和病害防治方法.[方法]对暹罗斗鱼的病原菌进行分离,并通过生理生化指标测定和16S rDNA测序对其鉴定,同时进行药敏试验.[结果]菌株DY001为暹罗斗鱼嗜水气单胞菌病的病原菌.经鉴定,确定菌株DY001为嗜水气单胞菌(Aeromonas hydrophila).该病原菌对暹罗斗鱼的半致死量(LD50)为0.04×106 CFU/g.药敏试验结果表明,病原菌对阿奇霉素、奥复星、氟哌酸、复方新诺明、菌必治、甲氧苄啶和氯霉素等抗生素敏感.[结论]嗜水气单胞菌是引起此次暹罗斗鱼发病的病原菌,而药敏试验结果将为其防治提供参考.

  9. Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer.

    Science.gov (United States)

    Li, Wei-Ming; Chiang, Chih-Sheng; Huang, Wei-Chen; Su, Chia-Wei; Chiang, Min-Yu; Chen, Jian-Yi; Chen, San-Yuan

    2015-12-28

    We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers.

  10. Evolution of systemic treatment for hormone-sensitive breast cancer: from sequential use of single agents to the upfront administration of drug combinations

    Directory of Open Access Journals (Sweden)

    E. N. Imyanitov

    2016-01-01

    Full Text Available Current standards of treatment of endocrine-dependent cancers (breast cancer (BC, prostate cancer imply sequential use of endocrine therapy and cytotoxic agents: it is believed, that steroid hormone antagonists cease the division of transformed cells and therefore make them resistant to other therapeutic modalities. It is important to recognize that conceptual investigations in this field were carried out dozens of years ago, and often involved relatively non-efficient drugs, imperfect laboratory tests, etc. There are several recent examples of combined use of endocrine therapy and other compounds. The addition of docetaxel (6 cycles to androgen deprivation resulted in significant improvement of overall survival in men with metastatic prostate cancer. Clinical trial involving the combined use of exemestane and everolimus demonstrated promising results. There are ongoing studies on inhibitors of cycline-dependent kinases. Use of these drugs in the beginning of endocrine therapy may significantly delay resistance to the antagonists of estrogen signaling.

  11. Anthelminthic drug niclosamide sensitizes the responsiveness of cervical cancer cells to paclitaxel via oxidative stress-mediated mTOR inhibition.

    Science.gov (United States)

    Chen, Liping; Wang, Li; Shen, Haibin; Lin, Hui; Li, Dan

    2017-03-04

    Drug repurposing represents an alternative therapeutic strategy to cancer treatment. The potent anti-cancer activities of a FDA-approved anthelminthic drug niclosamide have been demonstrated in various cancers. However, whether niclosamide is active against cervical cancer is unknown. In this study, we investigated the effects of niclosamide alone and its combination with paclitaxel in cervical cancer in vitro and in vivo. We found that niclosamide significantly inhibited proliferation and induced apoptosis of a panel of cervical cancer cell lines, regardless of their cellular origin and genetic pattern. Niclosamide also inhibited tumor growth in cervical cancer xenograft mouse model. Importantly, niclosamide significantly enhanced the responsiveness of cervical cancer cell to paclitaxel. We further found that niclosamide induced mitochondrial dysfunctions via inhibiting mitochondrial respiration, complex I activity and ATP generation, which led to oxidative stress. ROS scavenge agent N-acetyl-l-cysteine (NAC) completely reversed the effects of niclosamide in increasing cellular ROS, inhibiting proliferation and inducing apoptosis, suggesting that oxidative stress induction is the mechanism of action of niclosamide in cervical cancer cells. In addition, niclosamide significantly inhibited mammalian target of rapamycin (mTOR) signaling pathway in cervical cancer cells and its inhibitory effect on mTOR is modulated by oxidative stress. Our work suggests that niclosamide is a useful addition to the treatment armamentarium for cervical cancer and induction of oxidative stress may be a potential therapeutic strategy in cervical cancer.

  12. Noscapine Increases the Sensitivity of Drug-Resistant Ovarian Cancer Cell Line SKOV3/DDP to Cisplatin by Regulating Cell Cycle and Activating Apoptotic Pathways.

    Science.gov (United States)

    Shen, Wei; Liang, Bingfeng; Yin, Jie; Li, Xiurong; Cheng, Jianxin

    2015-05-01

    Cisplatin is a first-line chemotherapy drug against ovarian cancer. However, its strong toxic side effects and the development of cisplatin resistance in human cancer cells seriously influence the effects of chemotherapy and quality of life in patients. Noscapine (Nos), a non-toxic benzylisoquinoline alkaloid extracted from opium, has been recently reported to have anti-cancer activity, but the mechanism of that effect has not been clearly established. In the present study, we investigated cytotoxicity of Nos in combination with cisplatin (DDP) in drug-resistant human ovarian cancer cell line SKOV3/DDP in vitro and in vivo null mice xenograft model. Cell proliferation was measured by MTT assay, flow cytometry was used to analyze cell cycle and apoptosis, protein expression of several apoptotic factors was investigated by flow cytometry and immunohistochemical method, and their mRNA expression levels were determined by real-time PCR. In vitro experiments showed that Nos significantly inhibited proliferation of SKOV3/DDP cells. DDP/Nos-combined treatment notably enhanced DDP-induced inhibition of cell proliferation and increased the pro-apoptotic effect of DDP in SKOV3/DDP cells. DDP/Nos administration increased the proportion of G2/M cells, reduced both protein and mRNA expression of anti-apoptotic factors XIAP, surviving and NF-kB, and augmented protein and mRNA levels of pro-apoptotic caspase-3. In vivo experiments revealed that Nos/DDP treatment increased the apoptotic rate of xenograft tumors in null mice. Tumor volume decreased from 1.733 ± 0.155 g in mice treated with DDP alone to 1.191 ± 0.106 g in animals treated with Nos/DDP. These observations suggest that Nos increases the anti-cancer activity of DDP against the drug-resistant ovarian cancer cell line SKOV3/DDP by modulating the cell cycle and activating apoptotic pathways. The study provides a new chemotherapy strategy for the treatment of DDP-resistant human ovarian cancer.

  13. 白龙合剂对肉鸡大肠杆菌病药敏性试验研究%Effects of Bailong Mixture on Drug Sensitivity to Colibacillosis of Broiler

    Institute of Scientific and Technical Information of China (English)

    何二国; 赵凤玲; 刘二花; 孙春峰; 孙海军; 杨建红

    2012-01-01

    为研究白龙合剂对肉鸡大肠杆菌病的药敏性,采