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Sample records for isoniazid preventive therapy

  1. Eligibility for Isoniazid Preventive Therapy in South African Gold Mines

    PubMed Central

    Lewis, James J.; Fielding, Katherine L.; Grant, Alison D.; Chihota, Violet N.; Popane, Flora; Luttig, Mariette; Muller, Dorothy; Coetzee, Leonie; Churchyard, Gavin J.

    2013-01-01

    Setting The “Thibela TB” cluster randomised trial of community-wide isoniazid preventive therapy (IPT) to reduce tuberculosis incidence in the South African gold mines. Objectives To determine the proportion of participants eligible for IPT and the reasons and risk factors for ineligibility, to inform the scale-up of IPT. Design Cross-sectional survey of participants in intervention clusters (mine shafts) consenting to tuberculosis screening and assessment for eligibility to start IPT. Results Among 27,126 consenting participants, 94.7% were male, the median age was 41 years, 12.2% reported previous tuberculosis, 0.6% reported ever taking IPT and 2.5% reported currently taking antiretroviral therapy. There were 24,430 (90.1%) assessed as eligible to start IPT, of whom 23,659 started IPT. The most common reasons for ineligibility were having suspected tuberculosis that was subsequently confirmed by a positive smear and/or culture (n=705), excessive alcohol consumption (n=427) and being on tuberculosis treatment at time of initial screen (n=241). Ineligibility was associated with factors including older age, female gender, prior history of tuberculosis and being in “HIV care”. However, at least 78% were eligible for IPT in all of these sub-groups. Conclusions The vast majority of participants in this community-wide intervention were eligible for IPT. PMID:24244741

  2. Interventions to improve delivery of isoniazid preventive therapy: an overview of systematic reviews

    PubMed Central

    2014-01-01

    Background Uptake of isoniazid preventive therapy (IPT) to prevent tuberculosis has been poor, particularly in the highest risk populations. Interventions to improve IPT delivery could promote implementation. The large number of existing systematic reviews on treatment adherence has made drawing conclusions a challenge. To provide decision makers with the evidence they need, we performed an overview of systematic reviews to compare different organizational interventions to improve IPT delivery as measured by treatment completion among those at highest risk for the development of TB disease, namely child contacts or HIV-infected individuals. Methods We searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), and MEDLINE up to August 15, 2012. Two authors used a standardized data extraction form and the AMSTAR instrument to independently assess each review. Results Six reviews met inclusion criteria. Interventions included changes in the setting/site of IPT delivery, use of quality monitoring mechanisms (e.g., directly observed therapy), IPT delivery integration into other healthcare services, and use of lay health workers. Most reviews reported a combination of outcomes related to IPT adherence and treatment completion rate but without a baseline or comparison rate. Generally, we found limited evidence to demonstrate that the studied interventions improved treatment completion. Conclusions While most of the interventions were not shown to improve IPT completion, integration of tuberculosis and HIV services yielded high treatment completion rates in some settings. The lack of data from high burden TB settings limits applicability. Further research to assess different IPT delivery interventions, including those that address barriers to care in at-risk populations, is urgently needed to identify the most effective practices for IPT delivery and TB control in high TB burden settings. PMID:24886159

  3. MODS for Tuberculosis Screening Prior to Isoniazid Preventive Therapy in HIV-Infected Persons

    PubMed Central

    Reddy, Krishna P.; Brady, Mark F.; Gilman, Robert H.; Coronel, Jorge; Ñavincopa, Marcos; Ticona, Eduardo; Chavez, Gonzalo; Sánchez, Eduardo; Rojas, Christian; Solari, Lely; Valencia, Jorge; Pinedo, Yvett; Benites, Carlos; Friedland, Jon S.; Moore, David A.J.

    2010-01-01

    Background Active tuberculosis (TB) must be excluded before initiating isoniazid preventive therapy (IPT) in HIV-infected persons, but currently used screening strategies suffer from poor sensitivity and specificity and high patient attrition rates. Liquid TB culture is now recommended for the detection of Mycobacterium tuberculosis in TB suspects. This study compared the efficacy, effectiveness and speed of the microscopic-observation drug-susceptibility (MODS) assay with currently used strategies for tuberculosis screening prior to IPT in HIV-infected persons. Methods 471 HIV-infected IPT candidates at three hospitals in Lima, Peru, were enrolled into a prospective comparison of tuberculosis screening strategies, including laboratory, clinical and radiographic assessments. Results Of 435 patients who provided two sputum samples, M. tuberculosis was detected in 27 (6.2%) by MODS, 22 (5.1%) by Lowenstein-Jensen culture and 7 (1.6%) by smear. Of patients with any positive microbiological test, a MODS culture was positive in 96% by 14 days and 100% by 21 days. MODS simultaneously detected multidrug-resistant tuberculosis in two patients. Screening strategies involving combinations of clinical assessment, chest radiograph and sputum smear were less effective than two liquid TB cultures in accurately diagnosing and excluding tuberculosis (p<0.01). Screening strategies that included non-culture tests had poor sensitivity and specificity. Conclusions MODS identified, and reliably excluded, cases of pulmonary tuberculosis more accurately than other screening strategies, while providing results significantly faster than Lowenstein-Jensen culture. The streamlining of TB rule-out through the use of liquid culture-based strategies could help facilitate the massive upscaling of IPT required to reduce HIV and TB morbidity and mortality. PMID:20192727

  4. Tuberculosis Control in South African Gold Mines: Mathematical Modeling of a Trial of Community-Wide Isoniazid Preventive Therapy

    PubMed Central

    Vynnycky, Emilia; Sumner, Tom; Fielding, Katherine L.; Lewis, James J.; Cox, Andrew P.; Hayes, Richard J.; Corbett, Elizabeth L.; Churchyard, Gavin J.; Grant, Alison D.; White, Richard G.

    2015-01-01

    A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006–2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial (“optimized intervention”), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus–positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus–positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens. PMID:25792607

  5. Tuberculosis control in South African gold mines: mathematical modeling of a trial of community-wide isoniazid preventive therapy.

    PubMed

    Vynnycky, Emilia; Sumner, Tom; Fielding, Katherine L; Lewis, James J; Cox, Andrew P; Hayes, Richard J; Corbett, Elizabeth L; Churchyard, Gavin J; Grant, Alison D; White, Richard G

    2015-04-15

    A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006-2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial ("optimized intervention"), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus-positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus-positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens.

  6. Implementation and evaluation of an isoniazid preventive therapy pilot program among HIV-infected patients in Vietnam, 2008–2010

    PubMed Central

    Trinh, Thuy T.; Han, Dien T.; Bloss, Emily; Le, Thai H.; Vu, Tung T.; Mai, Anh H.; Nguyen, Nhung V.; Nguyen, Long T.; Dinh, Sy N.; Whitehead, Sara

    2016-01-01

    Background WHO recommends screening for TB and evaluation for isoniazid preventive therapy (IPT) based on evidence that they reduce TB-related morbidity and mortality among HIV-infected persons. In Vietnam, an IPT pilot was implemented in two provinces; TB screening, treatment and outcomes were evaluated to inform the adoption and scale-up of IPT. Methods During April 2008 to March 2010, eligible HIV-infected persons aged >15 years, with no previous or current TB treatment, alcohol abuse or liver disease were screened for TB. If TB disease was ruled out based on symptoms, chest x-rays and sputum smears, isoniazid was administered for 9 months. Results Among 1281 HIV-infected persons who received initial eligibility screening, 520 were referred to and evaluated at district TB clinics for TB disease or IPT eligibility. Active TB was diagnosed in 17 patients and all were started on treatment. Of 520 patients evaluated, 416 (80.0%) initiated IPT: 382 (91.8%) completed IPT, 17 (4.1%) stopped treatment, 8 (1.9%) died, 3 (0.7%) developed TB during IPT and 6 (1.4%) had unknown outcomes. No severe adverse events were reported. Conclusions IPT treatment completion was high; no serious complications occurred. Improving and expanding intensified case-finding and IPT should be considered in Vietnam. PMID:26385936

  7. Uptake of Isoniazid Preventive Therapy among Under-Five Children: TB Contact Investigation as an Entry Point.

    PubMed

    Tadesse, Yared; Gebre, Nigussie; Daba, Shallo; Gashu, Zewdu; Habte, Dereje; Hiruy, Nebiyu; Negash, Solomon; Melkieneh, Kassahun; Jerene, Degu; K Haile, Yared; Kassie, Yewulsew; Melese, Muluken; G Suarez, Pedro

    2016-01-01

    A child's risk of developing tuberculosis (TB) can be reduced by nearly 60% with administration of 6 months course of isoniazid preventive therapy (IPT). However, uptake of IPT by national TB programs is low, and IPT delivery is a challenge in many resource-limited high TB-burden settings. Routinely collected program data was analyzed to determine the coverage and outcome of implementation of IPT for eligible under-five year old children in 28 health facilities in two regions of Ethiopia. A total of 504 index smear-positive pulmonary TB (SS+) cases were reported between October 2013 and June 2014 in the 28 health facilities. There were 282 under-five children registered as household contacts of these SS+ TB index cases, accounting for 17.9% of all household contacts. Of these, 237 (84%) were screened for TB symptoms, and presumptive TB was identified in 16 (6.8%) children. TB was confirmed in 5 children, producing an overall yield of 2.11% (95% confidence interval, 0.76-4.08%). Of 221 children eligible for IPT, 64.3% (142) received IPT, 80.3% (114) of whom successfully completed six months of therapy. No child developed active TB while on IPT. Contact screening is a good entry point for delivery of IPT to at risk children and should be routine practice as recommended by the WHO despite the implementation challenges. PMID:27196627

  8. Uptake of Isoniazid Preventive Therapy among Under-Five Children: TB Contact Investigation as an Entry Point

    PubMed Central

    Gebre, Nigussie; Daba, Shallo; Gashu, Zewdu; Habte, Dereje; Hiruy, Nebiyu; Negash, Solomon; Melkieneh, Kassahun; Jerene, Degu; K. Haile, Yared; Kassie, Yewulsew; Melese, Muluken; G. Suarez, Pedro

    2016-01-01

    A child’s risk of developing tuberculosis (TB) can be reduced by nearly 60% with administration of 6 months course of isoniazid preventive therapy (IPT). However, uptake of IPT by national TB programs is low, and IPT delivery is a challenge in many resource-limited high TB-burden settings. Routinely collected program data was analyzed to determine the coverage and outcome of implementation of IPT for eligible under-five year old children in 28 health facilities in two regions of Ethiopia. A total of 504 index smear-positive pulmonary TB (SS+) cases were reported between October 2013 and June 2014 in the 28 health facilities. There were 282 under-five children registered as household contacts of these SS+ TB index cases, accounting for 17.9% of all household contacts. Of these, 237 (84%) were screened for TB symptoms, and presumptive TB was identified in 16 (6.8%) children. TB was confirmed in 5 children, producing an overall yield of 2.11% (95% confidence interval, 0.76–4.08%). Of 221 children eligible for IPT, 64.3% (142) received IPT, 80.3% (114) of whom successfully completed six months of therapy. No child developed active TB while on IPT. Contact screening is a good entry point for delivery of IPT to at risk children and should be routine practice as recommended by the WHO despite the implementation challenges. PMID:27196627

  9. Uptake of Isoniazid Preventive Therapy among Under-Five Children: TB Contact Investigation as an Entry Point.

    PubMed

    Tadesse, Yared; Gebre, Nigussie; Daba, Shallo; Gashu, Zewdu; Habte, Dereje; Hiruy, Nebiyu; Negash, Solomon; Melkieneh, Kassahun; Jerene, Degu; K Haile, Yared; Kassie, Yewulsew; Melese, Muluken; G Suarez, Pedro

    2016-01-01

    A child's risk of developing tuberculosis (TB) can be reduced by nearly 60% with administration of 6 months course of isoniazid preventive therapy (IPT). However, uptake of IPT by national TB programs is low, and IPT delivery is a challenge in many resource-limited high TB-burden settings. Routinely collected program data was analyzed to determine the coverage and outcome of implementation of IPT for eligible under-five year old children in 28 health facilities in two regions of Ethiopia. A total of 504 index smear-positive pulmonary TB (SS+) cases were reported between October 2013 and June 2014 in the 28 health facilities. There were 282 under-five children registered as household contacts of these SS+ TB index cases, accounting for 17.9% of all household contacts. Of these, 237 (84%) were screened for TB symptoms, and presumptive TB was identified in 16 (6.8%) children. TB was confirmed in 5 children, producing an overall yield of 2.11% (95% confidence interval, 0.76-4.08%). Of 221 children eligible for IPT, 64.3% (142) received IPT, 80.3% (114) of whom successfully completed six months of therapy. No child developed active TB while on IPT. Contact screening is a good entry point for delivery of IPT to at risk children and should be routine practice as recommended by the WHO despite the implementation challenges.

  10. Benefits of combined preventive therapy with co-trimoxazole and isoniazid in adults living with HIV: time to consider a fixed-dose, single tablet coformulation.

    PubMed

    Harries, Anthony D; Lawn, Stephen D; Suthar, Amitabh B; Granich, Reuben

    2015-12-01

    Antiretroviral therapy (ART) is the main intervention needed to reduce morbidity and mortality and to prevent tuberculosis in adults living with HIV. However, in most resource-limited countries, especially in sub-Saharan Africa, ART is started too late to have an effect with substantial early morbidity and mortality, and in high tuberculosis burden settings ART does not reduce the tuberculosis risk to that reported in individuals not infected with HIV. Co-trimoxazole preventive therapy started before or with ART, irrespective of CD4 cell count, reduces morbidity and mortality with benefits that continue indefinitely. Isoniazid preventive therapy as an adjunct to ART prevents tuberculosis in high-exposure settings, with long-term treatment likely to be needed to sustain this benefit. Unfortunately, both preventive therapies are underused in low-income and high-burden settings. ART development has benefited from patient-centred simplification with several effective regimens now available as a one per day pill. We argue that co-trimoxazole and isoniazid should also be combined into a single fixed-dose pill, along with pyridoxine (vitamin B6), that would be taken once per day to help with individual uptake and national scale-up of therapies. PMID:26515525

  11. High Incidence of Tuberculosis in the Absence of Isoniazid and Cotrimoxazole Preventive Therapy in Children Living with HIV in Northern Ethiopia: A Retrospective Follow-Up Study

    PubMed Central

    Alemu, Yihun Mulugeta; Andargie, Gashaw; Gebeye, Ejigu

    2016-01-01

    Objective To identify the incidence of and predictors for tuberculosis in children living with HIV in Northern Ethiopia. Design Observational, retrospective follow-up study. Methods A total of 645 HIV-infected children were observed between September 2009 and September 2014. Cox regression analysis was used to identify predictors for developing TB. Results The incidence rate of tuberculosis was 4.2 per 100 child-years. Incidence of tuberculosis was higher for subjects who were not on cotrimoxazole preventive therapy, were not on isoniazid preventive therapy, had delayed motor development, had a CD4 cell count below the threshold, had hemoglobin level less than 10 mg/dl and were assessed as World Health Organization (WHO) clinical stage III or IV. Conclusion Incidence of TB in children living with HIV was high. This study reaffirmed that isoniazid preventive therapy is one of the best strategy to reduce incidence of TB in children living with HIV. All children living with HIV should be screened for TB but for children with delayed motor development, advanced WHO clinical stage, anemia or immune suppression, intensified screening is highly recommended. PMID:27070435

  12. Tuberculin Skin Test Reversion following Isoniazid Preventive Therapy Reflects Diversity of Immune Response to Primary Mycobacterium tuberculosis Infection

    PubMed Central

    Johnson, Denise F.; Malone, LaShaunda L.; Zalwango, Sarah; Mukisa Oketcho, Joy; Chervenak, Keith A.; Thiel, Bonnie; Mayanja-Kizza, Harriet; Stein, Catherine M.; Boom, W. Henry; Lancioni, Christina L.

    2014-01-01

    Rationale Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial. Objectives To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion. Methods Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT. Results Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters. Conclusions TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies

  13. Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis

    PubMed Central

    Verma, Ajeet Kumar; Yadav, Arti; Dewangan, Jayant; Singh, Sarvendra Vikram; Mishra, Manisha; Singh, Pradhyumna Kumar; Rath, Srikanta Kumar

    2015-01-01

    Isoniazid is used either alone or in combination with other drugs for the treatment of tuberculosis. It is also used for the prevention of tuberculosis. Chronic treatment of Isoniazid may cause severe liver damage leading to acute liver failure. The mechanism through which Isoniazid causes liver damage is investigated. Isoniazid treatment generates reactive oxygen species and induces apoptosis in Hep3B cells. It induces antioxidative and apoptotic genes leading to increase in mRNA expression and protein levels in Hep3B cells. Whole genome expression analysis of Hep3B cells treated with Isoniazid has resulted in differential expression of various genes playing prime role in regulation of apoptotic, antioxidative, DNA damage, cell signaling, cell proliferation and differentiation pathways. Isoniazid increased cytosolic Nrf2 protein level while decreased nuclear Nrf2 protein level. It also decreased ERK1 phosphorylation and treatment of Hep3B cells with ERK inhibitor followed by Isoniazid resulting in increased apoptosis in these cells. Two dimensional gel electrophoresis results have also shown differential expression of various protein species including heat shock proteins, proteins playing important role in oxidative stress, DNA damage, apoptosis, cell proliferation and differentiation. Results suggest that Isoniazid induces apoptosis through oxidative stress and also prevents Nrf2 translocation into the nucleus by reducing ERK1 phosphorylation thus preventing cytoprotective effect. PMID:26202867

  14. Preventive therapy for tuberculosis in Maryland.

    PubMed

    Rabindran, E; Matuszak, D L; Israel, E; Woodall, H; Highsmith, H; Flynn, J

    1991-09-01

    Maryland data substantiate the safety of isoniazid therapy in preventing tuberculosis. To eradicate tuberculosis in the U.S., private physicians must play an active role by offering preventive therapy to patients at high risk of developing the disease. PMID:1921656

  15. [Fe(CN)5(isoniazid)](3-): an iron isoniazid complex with redox behavior implicated in tuberculosis therapy.

    PubMed

    Sousa, Eduardo Henrique Silva; de Mesquita Vieira, Francisca Gilmara; Butler, Jennifer S; Basso, Luiz Augusto; Santiago, Diógenes S; Diógenes, Izaura C N; Lopes, Luiz Gonzaga de França; Sadler, Peter J

    2014-11-01

    Tuberculosis has re-emerged as a worldwide threat, which has motivated the development of new drugs. The antituberculosis complex Na3[Fe(CN)5(isoniazid)] (IQG607) in particular is of interest on account of its ability to overcome resistance. IQG607 has the potential for redox-mediated-activation, in which an acylpyridine (isonicotinoyl) radical could be generated without assistance from the mycobacterial KatG enzyme. Here, we have investigated the reactivity of IQG607 toward hydrogen peroxide and superoxide, well-known intracellular oxidizing agents that could play a key role in the redox-mediated-activation of this compound. HPLC, NMR and electronic spectroscopy studies showed a very fast oxidation rate for bound isoniazid, over 460-fold faster than free isoniazid oxidation. A series of EPR spin traps were used for detection of isonicotinoyl and derived radicals bound to iron. This is the first report for an isonicotinoyl radical bound to a metal complex, supported by (14)N and (1)H hyperfine splittings for the POBN and PBN trapped radicals. POBN and PBN exhibited average hyperfine coupling constants of aN=15.6, aH=2.8 and aN=15.4, aH=4.7, respectively, which are in close agreement to the isonicotinoyl radical. Radical generation is thought to play a major role in the mechanism of action of isoniazid and this work provides strong evidence for its production within IQG607, which, along with biological and chemical oxidation data, support a redox-mediated activation mechanism. More generally the concept of redox activation of metallo prodrugs could be applied more widely for the design of therapeutic agents with novel mechanisms of action. PMID:25189361

  16. Successful desensitization therapy for a patient with isoniazid-induced hypersensitivity pneumonia.

    PubMed

    Chihara, Yuichi; Takahashi, Ken-Ichi; Sakai, Naoki; Sato, Atsuo; Tsuboi, Tomomasa

    2016-01-01

    A 57-year-old male was diagnosed with mycobacterium tuberculoma and was treated with isoniazid, rifampicin, ethambutol, and pyrazinamide. Three weeks after initiation of treatment, he presented with fever and appetite loss. Chest radiograph showed diffuse micronodular shadows on both lung fields. High-resolution chest computed tomography findings were diffuse parenchymal micronodules in both lungs, which was consistent with hypersensitivity pneumonia. Because drug-induced pneumonia was suspected, the antituberculous regimen was discontinued. The symptoms and diffuse micronodular shadows improved. A drug lymphocyte stimulation test was only positive for isoniazid, so we suspected that the pneumonia was induced by isoniazid. Rifampicin and ethambutol were reintroduced without any recurrence of the abnormal shadows. Next, we tried desensitization to isoniazid over a period of two weeks, which was successful without any adverse events. Although isoniazid-induced pneumonia is extremely rare, it is important to recognize that isoniazid can cause such an adverse reaction. In addition, drug desensitization may be useful in drug-induced pneumonia. PMID:27330958

  17. Different Risk of Tuberculosis and Efficacy of Isoniazid Prophylaxis in Rheumatoid Arthritis Patients with Biologic Therapy: A Nationwide Retrospective Cohort Study in Taiwan

    PubMed Central

    Chen, Yi-Ming; Chang, Chia-Li; Chen, Hsin-Hua; Chen, Der-Yuan

    2016-01-01

    Increasing evidence indicates an increased risk of tuberculosis (TB) for rheumatoid arthritis (RA) patients receiving biologic therapy, and the effectiveness of isoniazid prophylaxis (INHP) in TB prevention. We aimed to examine 1) the incidence rate (IR) and risk factors for TB among RA patients receiving different therapies; 2) INHP effectiveness for TB prevention; 3) mortality rates after TB diagnosis in patients receiving different therapies. This retrospective study was conducted using a nationwide database: 168,720 non-RA subjects and a total of 42,180 RA patients including 36,162 csDMARDs-exposed, 3,577 etanercept-exposed, 1,678 adalimumab-exposed and 763 rituximab-exposed patients. TB risk was 2.7-fold higher in RA cohort compared with non-RA group, with an adjusted hazard ratio (aHR) of 2.58. Advanced age, male, the use of corticosteroids≧5mg/day, and the presence of diabetes mellitus (DM), chronic obstructive pulmonary disease and chronic kidney disease were risk factors for developing TB. Using csDMARDs-exposed group as reference, aHR of TB was the highest with adalimumab treatment (1.52), followed by etanercept (1.16), and the lowest with rituximab (0.08). INHP could effectively reduce TB risk in biologics-exposed patients. Mortality rates after TB diagnosis were higher in RA patients, particularly the elderly and those with DM, with lower rates in adalimumab-exposed patients compared with csDMARDs-exposed patients. In conclusion, TB risk was increased in patients receiving TNF-α inhibitors, but the risk associated with rituximab therapy was relatively low. With the effectiveness of INHP shown in the prevention of biologics-associated TB, stricter implementation of INHP should be beneficial. The mortality from biologics–associated TB may be efficiently reduced through increased awareness. PMID:27064275

  18. Different Risk of Tuberculosis and Efficacy of Isoniazid Prophylaxis in Rheumatoid Arthritis Patients with Biologic Therapy: A Nationwide Retrospective Cohort Study in Taiwan.

    PubMed

    Liao, Tsai-Ling; Lin, Ching-Heng; Chen, Yi-Ming; Chang, Chia-Li; Chen, Hsin-Hua; Chen, Der-Yuan

    2016-01-01

    Increasing evidence indicates an increased risk of tuberculosis (TB) for rheumatoid arthritis (RA) patients receiving biologic therapy, and the effectiveness of isoniazid prophylaxis (INHP) in TB prevention. We aimed to examine 1) the incidence rate (IR) and risk factors for TB among RA patients receiving different therapies; 2) INHP effectiveness for TB prevention; 3) mortality rates after TB diagnosis in patients receiving different therapies. This retrospective study was conducted using a nationwide database: 168,720 non-RA subjects and a total of 42,180 RA patients including 36,162 csDMARDs-exposed, 3,577 etanercept-exposed, 1,678 adalimumab-exposed and 763 rituximab-exposed patients. TB risk was 2.7-fold higher in RA cohort compared with non-RA group, with an adjusted hazard ratio (aHR) of 2.58. Advanced age, male, the use of corticosteroids ≧ 5 mg/day, and the presence of diabetes mellitus (DM), chronic obstructive pulmonary disease and chronic kidney disease were risk factors for developing TB. Using csDMARDs-exposed group as reference, aHR of TB was the highest with adalimumab treatment (1.52), followed by etanercept (1.16), and the lowest with rituximab (0.08). INHP could effectively reduce TB risk in biologics-exposed patients. Mortality rates after TB diagnosis were higher in RA patients, particularly the elderly and those with DM, with lower rates in adalimumab-exposed patients compared with csDMARDs-exposed patients. In conclusion, TB risk was increased in patients receiving TNF-α inhibitors, but the risk associated with rituximab therapy was relatively low. With the effectiveness of INHP shown in the prevention of biologics-associated TB, stricter implementation of INHP should be beneficial. The mortality from biologics-associated TB may be efficiently reduced through increased awareness. PMID:27064275

  19. Different Risk of Tuberculosis and Efficacy of Isoniazid Prophylaxis in Rheumatoid Arthritis Patients with Biologic Therapy: A Nationwide Retrospective Cohort Study in Taiwan.

    PubMed

    Liao, Tsai-Ling; Lin, Ching-Heng; Chen, Yi-Ming; Chang, Chia-Li; Chen, Hsin-Hua; Chen, Der-Yuan

    2016-01-01

    Increasing evidence indicates an increased risk of tuberculosis (TB) for rheumatoid arthritis (RA) patients receiving biologic therapy, and the effectiveness of isoniazid prophylaxis (INHP) in TB prevention. We aimed to examine 1) the incidence rate (IR) and risk factors for TB among RA patients receiving different therapies; 2) INHP effectiveness for TB prevention; 3) mortality rates after TB diagnosis in patients receiving different therapies. This retrospective study was conducted using a nationwide database: 168,720 non-RA subjects and a total of 42,180 RA patients including 36,162 csDMARDs-exposed, 3,577 etanercept-exposed, 1,678 adalimumab-exposed and 763 rituximab-exposed patients. TB risk was 2.7-fold higher in RA cohort compared with non-RA group, with an adjusted hazard ratio (aHR) of 2.58. Advanced age, male, the use of corticosteroids ≧ 5 mg/day, and the presence of diabetes mellitus (DM), chronic obstructive pulmonary disease and chronic kidney disease were risk factors for developing TB. Using csDMARDs-exposed group as reference, aHR of TB was the highest with adalimumab treatment (1.52), followed by etanercept (1.16), and the lowest with rituximab (0.08). INHP could effectively reduce TB risk in biologics-exposed patients. Mortality rates after TB diagnosis were higher in RA patients, particularly the elderly and those with DM, with lower rates in adalimumab-exposed patients compared with csDMARDs-exposed patients. In conclusion, TB risk was increased in patients receiving TNF-α inhibitors, but the risk associated with rituximab therapy was relatively low. With the effectiveness of INHP shown in the prevention of biologics-associated TB, stricter implementation of INHP should be beneficial. The mortality from biologics-associated TB may be efficiently reduced through increased awareness.

  20. Reparation of Isoniazid and Rifampicin Combinatorial Therapy-Induced Hepatotoxic Effects by Bacopa monnieri.

    PubMed

    Evan Prince, Sabina; Udhaya, Lavinya B; Sunitha, Priyadharshini S; Arumugam, Geetha

    2016-01-01

    Drug-induced liver injury is a major challenge in treating tuberculosis with isoniazid (INH) and rifampicin (RIF). This study was aimed at evaluating the protective effects of Bacopamonnieri (Brahmi) against INH and RIF-induced hepatotoxicity in a rat model and also to study the patterns of interaction between pregnane X receptor (PXR) and chosen active compounds of B. monnieri. Hepatotoxicity was induced in the experimental animals by the oral administration of INH and RIF (50 mg/kg b.w. each/day) for 28 days. The effects of co-administration of B. monnieri (500 mg/kg b.w./day) in INH- and RIF-induced rats were studied by the estimation of biochemical analyses. The standard hepatoprotective drug silymarin (25 mg/kg b.w./day) was used for the purpose of comparison. In silico docking experiments were carried out using the PatchDock server and the results were analysed on the PyMol molecular viewer. There was significant reduction in the antioxidant status of INH and RIF-induced rats. Also, there was significant elevation in the levels of serum liver function markers in the INH- and RIF-induced rats. B. monnieri was able to normalise the tested parameters. In silico studies reveal significant interaction between PXR and bacopaside I. B. monnieri exerts significant protective effects against INH and RIF-induced hepatotoxicity in rats.

  1. Monitoring preventive therapy patients for liver disease as well as compliance.

    PubMed

    Reichman, L B

    1975-08-01

    An apparently increasing incidence of isoniazid-associated hepatitis concurrent with interest in the problem has led to the universal teaching that patients on isoniazid preventive therapy must be carefully monitored for liver disease. This teaching has been reinforced and endorsed in a recent report of the tuberculosis advisory committee and special consultants to the director of the Center for Disease Control; this report, in turn, led to an American Thoracic Society statement concluding that the use of isoniazid with appropriate safeguards must be based on a comparison of the benefit of preventive therapy with the risk of hepatic injury and, therefore, should be used when necessary, under careful control and follow-up. In New York City, with increasing use of the tuberculin skin test leading to increased numbers of patients receiving this treatment in nurse-operated clinics, a new control form and protocol were designed. These insure that all individuals on preventive therapy are carefully monitored for liver disease as well as compliance in taking the drug. This system also insures the safeguards alluded to, as well as increasing concern and awareness among the health professionals in prescribing the treatment.

  2. Modelling the economic benefits of tuberculosis preventive therapy for people with HIV: the example of Zambia.

    PubMed

    Foster, S; Godfrey-Faussett, P; Porter, J

    1997-06-01

    The authors used available data from selected published literature to assess the economic costs and benefits of providing daily isoniazid preventive therapy for tuberculosis (TB) for 6 months in HIV-infected persons in Zambia. The base case scenario assumes recruitment at a voluntary testing and counseling site where HIV seroprevalence is 30%, HIV-infected individuals have a 25% probability of developing active TB during their lifetime, two additional cases of TB would be prevented per person completing a course of preventive therapy, compliance would be 63%, and an efficacy of isoniazid in preventing active TB of 60%. The costs under that scenario would exceed benefits by a factor of 1.16, or a benefit/cost ratio (BCR) of 0.86. However, if preventing one case of TB prevented an additional five cases, the benefits would exceed the costs by a BCR of 1.71. Other scenarios indicate likely significant net benefits from the targeted preventive therapy of HIV-infected persons whose occupation or living situation brings them into contact with a large number of other people.

  3. The Cost-Effectiveness of Tuberculosis Preventive Therapy for HIV-Infected Individuals in Southern India: A Trial-Based Analysis

    PubMed Central

    Pho, Mai T.; Swaminathan, Soumya; Kumarasamy, Nagalingeswaran; Losina, Elena; Ponnuraja, C.; Uhler, Lauren M.; Scott, Callie A.; Mayer, Kenneth H.; Freedberg, Kenneth A.; Walensky, Rochelle P.

    2012-01-01

    Background Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India. Methods We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm3, and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH). Results Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of $5,630. 6EH increased life expectancy by 0.8 months at an additional per person cost of $100 (incremental cost-effectiveness ratio (ICER) of $1,490/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of $55 (ICER of $3,120/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence. Conclusions Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care. PMID:22558301

  4. [Isoniazid-induced myopathy].

    PubMed

    Chaouch, N; Mejid, M; Zarrouk, M; Racil, H; Rouhou, S Cheikh; El Euch, G; Chabbou, A

    2011-12-01

    Drug-induced muscle disorders are now well known and vary from a simple isolated increase in muscle enzymes to severe drug-induced myopathy. The list of drugs inducing myopathy is very long and continues to grow. The onset of muscle disorders under isoniazid often falls within a drug-induced neuropathy or a drug-induced lupus. However, the occurrence of isolated isoniazid-induced drug myopathy without neuropathy is an extremely rare condition especially with non-toxic doses. The authors report the case of a 28-year-old man, without a previous medical history, hospitalized for pulmonary tuberculosis. After initiating tuberculosis treatment for five days, he presented muscle pain, fasciculation and weakness initially involving the lower left limb that quickly propagated to all four limbs. The physical examination noted a left ankle flush, a swollen left calf and fasciculation of both calves while the neurological examination was normal. The CPK was normal. Electromyography confirmed the myopathy without neuropathic findings. Isoniazid withdrawal was marked by the rapid disappearance of the symptoms. The reintroduction of a half-dose of isoniazid only induced a few transitional muscular fasciculations. The onset of the symptoms under tuberculosis treatment, the absence of later muscle disorders, the absence of any other cause of myopathy and the total disappearance of the symptoms after isoniazid withdrawal confirmed the diagnosis of isoniazid-induced myopathy.

  5. Transmission of Mycobacterium tuberculosis in a High School and School-Based Supervision of an Isoniazid-Rifapentine Regimen for Preventing Tuberculosis - Colorado, 2011-2012.

    PubMed

    2013-10-01

    Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is spread from person to person by the airborne route. It can be transmitted extensively in congregate settings, making investigating exposures and treating infected contacts challenging. In December 2011, a student at a Colorado high school with 1,381 students and school personnel received a diagnosis of pulmonary TB disease. One of five household contacts had TB disease, and the other four had latent M. tuberculosis infection (LTBI). Screening of 1,249 school contacts (90%) found one person with pulmonary TB disease, who was fully treated, and 162 with LTBI, of whom 159 started an LTBI treatment regimen for preventing progression to TB disease and 153 completed a regimen. Only the index patient required inpatient care for TB, and TB caused no deaths. Use of short-course treatment regimens, either 12-dose weekly isoniazid and rifapentine directly observed at school or 4 months of self-supervised rifampin daily, facilitated treatment completion. State and county incident command structures led by county TB control authorities guided a response team from multiple jurisdictions. News media reports brought public scrutiny, but meetings with the community addressed the concerns and enhanced public participation. Two contacts of the index patient outside of the school had TB disease diagnosed after the school investigation. As of July 2013, no additional TB disease associated with in-school exposure had been found. An emergency plan for focusing widespread resources, an integral public communications strategy, and new, efficient interventions should be considered in other large TB contact investigations.

  6. How could preventive therapy affect the prevalence of drug resistance? Causes and consequences

    PubMed Central

    Kunkel, Amber; Colijn, Caroline; Lipsitch, Marc; Cohen, Ted

    2015-01-01

    Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects. PMID:25918446

  7. How could preventive therapy affect the prevalence of drug resistance? Causes and consequences.

    PubMed

    Kunkel, Amber; Colijn, Caroline; Lipsitch, Marc; Cohen, Ted

    2015-06-01

    Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects.

  8. Preventive therapy in children exposed to Mycobacterium tuberculosis: problems and solutions.

    PubMed

    Rutherford, Merrin E; Hill, Philip C; Triasih, Rina; Sinfield, Rebecca; van Crevel, Reinout; Graham, Stephen M

    2012-10-01

    Young children living with a tuberculosis patient are at high risk of Mycobacterium tuberculosis infection and disease. WHO guidelines promote active screening and isoniazid (INH) preventive therapy (PT) for such children under 5 years, yet this well-established intervention is seldom used in endemic countries. We review the literature regarding barriers to implementation of PT and find that they are multifactorial, including difficulties in screening, poor adherence, fear of increasing INH resistance and poor acceptability among primary caregivers and healthcare workers. These barriers are largely resolvable, and proposed solutions such as the adoption of symptom-based screening and shorter drug regimens are discussed. Integrated multicomponent and site-specific solutions need to be developed and evaluated within a public health framework to overcome the policy-practice gap and provide functional PT programmes for children in endemic settings.

  9. The pharmacokinetics of lopinavir/ritonavir when given with isoniazid in South African HIV-infected individuals.

    PubMed

    Decloedt, E H; van der Walt, J S; McIlleron, H; Wiesner, L; Maartens, G

    2015-10-01

    Isoniazid preventive therapy is recommended in patients on antiretroviral treatment (ART) with latent tuberculous infection to prevent progression to active tuberculosis disease. Isoniazid (INH) inhibits cytochrome (CY) P3A4, which metabolises lopinavir (LPV). The administration of INH may cause higher LPV concentrations, which may increase LPV toxicity. LPV bioavailability is increased by co-formulated ritonavir (r), which may enhance the interaction of INH on LPV. We studied the effect of INH on LPV concentrations by administering INH for 7 days and performing intensive pharmacokinetic sampling in 16 human immunodeficiency virus infected patients established on LPV/r-based ART. INH did not significantly increase steady-state LPV area under the plasma concentration-time curve calculated for the 12 h-dosing interval.

  10. Emerging Therapies for Scar Prevention

    PubMed Central

    Block, Lisa; Gosain, Ankush; King, Timothy W.

    2015-01-01

    Significance: There are ∼12 million traumatic lacerations treated in the United States emergency rooms each year, 250 million surgical incisions created worldwide every year, and 11 million burns severe enough to warrant medical treatment worldwide. In the United States, over $20 billion dollars per year are spent on the treatment and management of scars. Recent Advances: Investigations into the management of scar therapies over the last decade have advanced our understanding related to the care of cutaneous scars. Scar treatment methods are presented including topical, intralesional, and mechanical therapies in addition to cryotherapy, radiotherapy, and laser therapy. Critical Issues: Current treatment options for scars have significant limitations. This review presents the current and emerging therapies available for scar management and the scientific evidence for scar management is discussed. Future Directions: Based upon our new understanding of scar formation, innovative scar therapies are being developed. Additional research on the basic science of scar formation will lead to additional advances and novel therapies for the treatment of cutaneous scars. PMID:26487979

  11. Sustained release isoniazid tablets. I--Formulation and in vitro evaluation.

    PubMed

    Bulut-Oner, F; Capan, Y; Kas, S; Oner, L; Hincal, A A

    1989-01-01

    Isoniazid (INH) has been widely used in the preventive therapy of tuberculosis since the early 1950's. The aim in designing a sustained release tablet form was to attain in fast inactivators sustained blood concentrations similar to those produced by ordinary INH tablets in slow acetylators during chemotherapy. In the present paper, the release of INH incorporated into three different matrix materials, polymethylmethacrylates, polyvinyl chloride and carbomer were studied. The release rate of a unit dose of conventionally formulated INH tablets was used as a basis of comparison. The best sustained effect on the release rate of INH was obtained with 30% carbomer matrix tablets.

  12. Interactions of isoniazid with foods.

    PubMed

    Hauser, M J; Baier, H

    1982-01-01

    We reviewed reactions previously reported in patients treated with isoniazid, who ate certain fish and cheeses. We observed similar reactions in two patients after they ingested cheese and wine. Isoniazid is an inhibitor of both monoamine and diamine oxidases, which contribute to the metabolism of histamine that may be present in some fish and cheeses. Monoamine oxidase also acts in the metabolism of tyramine, present in some cheeses and wines. Reactions reported after eating fish or cheese, in patients treated with isoniazid, are similar in that both are characterized by headache, palpitations, skin flushing, nausea, vomiting, and pruritus. Reactions after fish have not been associated with increased blood pressure, whereas those following cheese ingestion frequently result in modest increases in blood pressure. Patients treated with isoniazid should be alerted to the possibility of reactions after eating certain foods.

  13. Magnesium in Prevention and Therapy.

    PubMed

    Gröber, Uwe; Schmidt, Joachim; Kisters, Klaus

    2015-09-23

    Magnesium is the fourth most abundant mineral in the body. It has been recognized as a cofactor for more than 300 enzymatic reactions, where it is crucial for adenosine triphosphate (ATP) metabolism. Magnesium is required for DNA and RNA synthesis, reproduction, and protein synthesis. Moreover, magnesium is essential for the regulation of muscular contraction, blood pressure, insulin metabolism, cardiac excitability, vasomotor tone, nerve transmission and neuromuscular conduction. Imbalances in magnesium status-primarily hypomagnesemia as it is seen more common than hypermagnesemia-might result in unwanted neuromuscular, cardiac or nervous disorders. Based on magnesium's many functions within the human body, it plays an important role in prevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic diseases, such as Alzheimer's disease, insulin resistance and type-2 diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and attention deficit hyperactivity disorder (ADHD).

  14. Magnesium in Prevention and Therapy

    PubMed Central

    Gröber, Uwe; Schmidt, Joachim; Kisters, Klaus

    2015-01-01

    Magnesium is the fourth most abundant mineral in the body. It has been recognized as a cofactor for more than 300 enzymatic reactions, where it is crucial for adenosine triphosphate (ATP) metabolism. Magnesium is required for DNA and RNA synthesis, reproduction, and protein synthesis. Moreover, magnesium is essential for the regulation of muscular contraction, blood pressure, insulin metabolism, cardiac excitability, vasomotor tone, nerve transmission and neuromuscular conduction. Imbalances in magnesium status—primarily hypomagnesemia as it is seen more common than hypermagnesemia—might result in unwanted neuromuscular, cardiac or nervous disorders. Based on magnesium’s many functions within the human body, it plays an important role in prevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic diseases, such as Alzheimer’s disease, insulin resistance and type-2 diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and attention deficit hyperactivity disorder (ADHD). PMID:26404370

  15. CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

    SciTech Connect

    Cheng, Jie; Krausz, Kristopher W.; Li, Feng; Ma, Xiaochao; Gonzalez, Frank J.

    2013-01-15

    Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation. -- Highlights: ► Isoniazid metabolites were elevated only in wild-type mice. ► Isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice. ► Isoniazid elevated serum cholesterol and triglycerides, and hepatic bile acids. ► Bile acid transporters were significantly decreased in isoniazid-treated mice.

  16. Dance as a therapy for cancer prevention.

    PubMed

    Aktas, Gurbuz; Ogce, Filiz

    2005-01-01

    Even though the field of medicine has developed tremendously, the wide variety of cancer is still among chronic and life threatening disease today. Therefore, the specialists constantly research and try every possible way to find cure or preventive ways to stop its further development. For this reason, studies concerning the chronic disease such as cancer have been spread to many different fields. In this regard, many other alternative ways besides medicine, are used in prevention of cancer. Nutritional therapy, herbal therapy, sportive activities, art therapy, music therapy, dance therapy, imagery, yoga and acupuncture can be given as examples. Among these, dance/movement therapy which deals with individuals physical, emotional, cognitive as well as social integration is widely used as a popular form of physical activity. The physical benefits of dance therapy as exercise are well documented. Studies have shown that physical activity is known to increase special neurotransmitter substances in the brain (endorphins), which create a state of well-being. And total body movement such as dance enhances the functions of other body systems, such as circulatory, respiratory, skeletal, and muscular systems. Regarding its unique connection to the field of medicine, many researches have been undertaken on the effects of dance/movement therapy in special settings with physical problems such as amputations, traumatic brain injury, and stroke, chronic illnesses such as anorexia, bulimia, cancer, Alzheimer's disease, cystic fibrosis, heart disease, diabetes, asthma, AIDS, and arthritis. Today dance/movement therapy is a well recognized form of complementary therapy used in hospitals as well as at the comprehensive clinical cancer centres. PMID:16236009

  17. Isoniazid induced acute pancreatitis in a young girl.

    PubMed

    Saleem, Ali Faisal; Arbab, Saba; Naz, Farah Qamar

    2015-04-01

    Isoniazid (INH) is the mainstay of management against Mycobacterium tuberculosis. INH-induced acute pancreatitis is an uncommon association and with dearth of literature on it. We are reporting a case of an 11 years old girl who developed acute pancreatitis after 2 weeks of antituberculous therapy. An INH free regimen was started. She was discharged and followed without complications.

  18. [Usefulness of probiotics in prevention and therapy].

    PubMed

    Deibert, P; König, D; Becker, G; Berg, A

    2010-02-01

    Probiotics exert distinct effects on the intestinal mucosa and the immune system that can be used in preventive and therapeutic settings. There is evidence to support the use of probiotics in necrotizing enterocolitis in preterm infants and pouchitis. Furthermore, the immunomodulatory effects of probiotics seem to ameliorate atopic diseases, in particular atopic dermatitis. The efficacy of probiotics has been shown comparable to Mesalazine regarding the maintenance of remission in ulcerative colitis. In addition there is evidence that probiotics are useful in the prevention of pouchitis or in therapy of irritable bowel syndrome. Recent data indicate that commensals and probiotics could play a role in nutrient fermentation and energy metabolism and may be helpful in the prevention and therapy of obesity.

  19. Tuberculosis preventive therapy: an underutilised strategy to reduce individual risk of TB and contribute to TB control.

    PubMed

    Churchyard, Gavin J; Chaisson, Richard E; Maartens, Gary; Getahun, Haileyesus

    2014-05-01

    Tuberculosis (TB) remains a global health problem, and South Africa (SA) has one of the world's worst TB epidemics. The World Health Organization (WHO) estimated in 1999 that one-third of the world's population was latently infected with TB. In SA up to 88% of HIV-uninfected young adults (31 - 35 years) are latently infected with TB. In the most recent meta-analysis, 6 - 12 months of isoniazid preventive therapy (IPT) was associated with a lower incidence of active TB than placebo (relative risk (RR) 0.68; 95% confidence interval (CI) 0.54 - 0.85), with the greatest benefit among individuals with a positive tuberculin skin test (TST) (RR 0.38; 95% CI 0.25 - 0.57). A clinical trial of IPT given with antiretroviral therapy (ART) for 12 months reduced TB incidence by 37% compared with ART alone (hazard ratio (HR) 0.63; 95% CI 0.41 - 0.94). The effect of IPT is limited in high-burden countries. IPT for 36 months v. 6 months reduced TB incidence among HIV-positive, TST-positive participants by 74% (HR 0.26; 95% CI 0.09 - 0.80). A study of more than 24 000 goldminers confirmed that IPT is safe, with only 0.5% experiencing adverse events. A meta-analysis of studies of IPT since 1951 did not show an increased risk of developing resistance. Alternative TB preventive therapy regimens, including high-dose isoniazid and rifapentine given weekly for 3 months, have been shown to have similar efficacy to IPT. Mathematical modelling suggests that scaling up continuous IPT targeted to HIV-positive persons, when used in combination with other treatment and prevention strategies, may substantially improve TB control. PMID:25212199

  20. Anergy skin testing and tuberculosis [corrected] preventive therapy for HIV-infected persons: revised recommendations. Centers for Disease Control and Prevention.

    PubMed

    1997-09-01

    This report updates and supersedes previous recommendations (MMWR 1991;40[No. RR-5]:27-33) for the use of anergy skin testing in conjunction with purified protein derivative (PPD)-tuberculin skin testing of persons infected with human immunodeficiency virus (HIV). In February 1997, CDC convened a meeting of consultants to discuss current information regarding anergy skin testing, PPD skin testing, and tuberculosis (TB) preventive therapy for HIV-infected persons. In formulating these recommendations, CDC considered the results of this meeting, as well as a review of published studies pertaining to PPD and anergy skin testing of persons who are infected with HIV. Isoniazid preventive therapy is effective in reducing the incidence of active TB among persons who have HIV infection and latent TB. Because of the complications associated with TB disease in HIV-infected persons, these persons must be screened for tuberculin infection. HIV-infected persons who have positive reactions to skin testing with PPD tuberculin should be evaluated to exclude active TB and offered preventive therapy with isoniazid if indicated. However, HIV-infected persons may have compromised ability to react to PPD-tuberculin skin testing, because HIV infection is associated with an elevated risk for cutaneous anergy. Anergy testing is a diagnostic procedure used to obtain information regarding the competence of the cellular immune system. When a clinician elects to use anergy testing as part of a multifactorial assessment of a person's risk for TB, the two Food and Drug Administration-approved Mantoux-method tests (mumps and Candida), used together, with cut-off diameters of 5 mm of induration, are recommended. Efforts to apply the results of anergy testing to preventive therapy decisions must be supplemented with information concerning the person's risk for infection with Mycobacterium tuberculosis. Factors limiting the usefulness of anergy skin testing include problems with standardization and

  1. Sensitive indirect spectrophotometric determination of isoniazid

    NASA Astrophysics Data System (ADS)

    Safavi, A.; Karimi, M. A.; Hormozi Nezhad, M. R.; Kamali, R.; Saghir, N.

    2004-03-01

    A simple, rapid, sensitive and accurate indirect spectrophotometric method for the microdetermination of isoniazid (INH) in pure form and pharmaceutical formulations is developed. The procedure is based on the reaction of copper(II) with isoniazid in the presence of neocuproine (NC). In the presence of neocuproine, copper(II) is reduced easily by isoniazid to a Cu(I)-neocuproine complex, which shows an absorption maximum at 454 nm. By measuring the absorbance of the complex at this wavelength, isoniazid can be determined in the range 0.3-3.5 μg ml -1. This method was applied to the determination of isoniazid in pharmaceutical formulation and enabled the determination of the isoniazid in microgram quantities (0.3-3.5 μg ml -1). The results obtained for the assay of pharmaceutical preparations compared well with those obtained by the official method and demonstrated good accuracy and precision.

  2. Sensitive indirect spectrophotometric determination of isoniazid.

    PubMed

    Safavi, A; Karimi, M A; Hormozi Nezhad, M R; Kamali, R; Saghir, N

    2004-03-01

    A simple, rapid, sensitive and accurate indirect spectrophotometric method for the microdetermination of isoniazid (INH) in pure form and pharmaceutical formulations is developed. The procedure is based on the reaction of copper(II) with isoniazid in the presence of neocuproine (NC). In the presence of neocuproine, copper(II) is reduced easily by isoniazid to a Cu(I)-neocuproine complex, which shows an absorption maximum at 454 nm. By measuring the absorbance of the complex at this wavelength, isoniazid can be determined in the range 0.3-3.5 microgml-1. This method was applied to the determination of isoniazid in pharmaceutical formulation and enabled the determination of the isoniazid in microgram quantities (0.3-3.5 microgml-1). The results obtained for the assay of pharmaceutical preparations compared well with those obtained by the official method and demonstrated good accuracy and precision.

  3. Nanotechnology in dentistry: prevention, diagnosis, and therapy

    PubMed Central

    Abou Neel, Ensanya Ali; Bozec, Laurent; Perez, Roman A; Kim, Hae-Won; Knowles, Jonathan C

    2015-01-01

    Nanotechnology has rapidly expanded into all areas of science; it offers significant alternative ways to solve scientific and medical questions and problems. In dentistry, nanotechnology has been exploited in the development of restorative materials with some significant success. This review discusses nanointerfaces that could compromise the longevity of dental restorations, and how nanotechnolgy has been employed to modify them for providing long-term successful restorations. It also focuses on some challenging areas in dentistry, eg, oral biofilm and cancers, and how nanotechnology overcomes these challenges. The recent advances in nanodentistry and innovations in oral health-related diagnostic, preventive, and therapeutic methods required to maintain and obtain perfect oral health, have been discussed. The recent advances in nanotechnology could hold promise in bringing a paradigm shift in dental field. Although there are numerous complex therapies being developed to treat many diseases, their clinical use requires careful consideration of the expense of synthesis and implementation. PMID:26504385

  4. Nanotechnology in dentistry: prevention, diagnosis, and therapy.

    PubMed

    Abou Neel, Ensanya Ali; Bozec, Laurent; Perez, Roman A; Kim, Hae-Won; Knowles, Jonathan C

    2015-01-01

    Nanotechnology has rapidly expanded into all areas of science; it offers significant alternative ways to solve scientific and medical questions and problems. In dentistry, nanotechnology has been exploited in the development of restorative materials with some significant success. This review discusses nanointerfaces that could compromise the longevity of dental restorations, and how nanotechnolgy has been employed to modify them for providing long-term successful restorations. It also focuses on some challenging areas in dentistry, eg, oral biofilm and cancers, and how nanotechnology overcomes these challenges. The recent advances in nanodentistry and innovations in oral health-related diagnostic, preventive, and therapeutic methods required to maintain and obtain perfect oral health, have been discussed. The recent advances in nanotechnology could hold promise in bringing a paradigm shift in dental field. Although there are numerous complex therapies being developed to treat many diseases, their clinical use requires careful consideration of the expense of synthesis and implementation.

  5. Therapy and prevention of cryptosporidiosis in animals.

    PubMed

    Shahiduzzaman, Md; Daugschies, Arwid

    2012-09-10

    Cryptosporidiosis is a common gastro-intestinal illness in animals and man worldwide. The disease is devastating in immune-suppressed individuals but self-limiting in competent hosts. The infectious stages of the organism (oocysts) are shed in the faeces of affected individuals, survive in adverse environmental conditions and spread by direct contact or through contaminants (food, water). Due to the robustness of the oocysts, their tenacity, tiny size, and resistance to common disinfectants, the parasite is difficult to eradicate from contaminated environments. To obtain sufficient control both treatment of infected hosts and inactivation of oocysts are necessary. Several drugs are commonly used to treat cryptosporidiosis in man and very few in animals but none of them are completely effective in terms of both clinical and parasitological response. Only a few chemical agents are able to inactivate oocysts in the environment including water treatment plants but their application has certain limitations. Therefore, control of cryptosporidiosis remains a global challenge in both veterinary and human medicine. Extensive research has been performed on suitable drugs and disinfectants. Thousands of agents have been tested both in vivo and in vitro. Some are excitingly active in vitro but exhibit poor or no response in clinical trials. Currently, no single or combined drug therapy has proven to be completely effective against this disease. This article will focus on therapy and prevention of cryptosporidiosis in animals including perspectives for new drugs.

  6. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions

    MedlinePlus

    ... recommendations summarize what the Task Force learned: The harms of hormone therapy, when used to prevent chronic ... Primary Prevention of Chronic Conditions Potential Benefits and Harms The Task Force found that taking both estrogen ...

  7. Acute and Fatal Isoniazid-Induced Hepatotoxicity: A Case Report and Review of the Literature

    PubMed Central

    Sarkis, Aline T.; Saroufim, Paola G.

    2016-01-01

    This paper describes a case of an acute and fatal isoniazid-induced hepatotoxicity and provides a review of the literature. A 65-year-old female diagnosed with latent Mycobacterium tuberculosis infection was receiving oral isoniazid 300 mg daily. She was admitted to the hospital for epigastric and right sided flank pain of one-week duration. Laboratory results and imaging confirmed hepatitis. After ruling out all other possible causes, she was diagnosed with isoniazid-induced acute hepatitis (probable association by the Naranjo scale). After discharge, the patient was readmitted and suffered from severe coagulopathy, metabolic acidosis, acute kidney injury, hepatic encephalopathy, and cardiorespiratory arrest necessitating two rounds of cardiopulmonary resuscitation. Despite maximal hemodynamic support, the patient did not survive. A review of the literature, from several European countries and the United States of America, revealed a low incidence of mortality due to isoniazid-induced hepatotoxicity when used as a single agent for latent Mycobacterium tuberculosis infection. As for the management, the first step consists of withdrawing isoniazid and rechallenge is usually discouraged. Few treatment modalities have been proposed; however there is no robust evidence to support any of them. Routine monitoring for hepatotoxicity in patients receiving isoniazid is warranted to prevent morbidity and mortality.

  8. Acute and Fatal Isoniazid-Induced Hepatotoxicity: A Case Report and Review of the Literature

    PubMed Central

    Sarkis, Aline T.; Saroufim, Paola G.

    2016-01-01

    This paper describes a case of an acute and fatal isoniazid-induced hepatotoxicity and provides a review of the literature. A 65-year-old female diagnosed with latent Mycobacterium tuberculosis infection was receiving oral isoniazid 300 mg daily. She was admitted to the hospital for epigastric and right sided flank pain of one-week duration. Laboratory results and imaging confirmed hepatitis. After ruling out all other possible causes, she was diagnosed with isoniazid-induced acute hepatitis (probable association by the Naranjo scale). After discharge, the patient was readmitted and suffered from severe coagulopathy, metabolic acidosis, acute kidney injury, hepatic encephalopathy, and cardiorespiratory arrest necessitating two rounds of cardiopulmonary resuscitation. Despite maximal hemodynamic support, the patient did not survive. A review of the literature, from several European countries and the United States of America, revealed a low incidence of mortality due to isoniazid-induced hepatotoxicity when used as a single agent for latent Mycobacterium tuberculosis infection. As for the management, the first step consists of withdrawing isoniazid and rechallenge is usually discouraged. Few treatment modalities have been proposed; however there is no robust evidence to support any of them. Routine monitoring for hepatotoxicity in patients receiving isoniazid is warranted to prevent morbidity and mortality. PMID:27648319

  9. Acute and Fatal Isoniazid-Induced Hepatotoxicity: A Case Report and Review of the Literature.

    PubMed

    Kabbara, Wissam K; Sarkis, Aline T; Saroufim, Paola G

    2016-01-01

    This paper describes a case of an acute and fatal isoniazid-induced hepatotoxicity and provides a review of the literature. A 65-year-old female diagnosed with latent Mycobacterium tuberculosis infection was receiving oral isoniazid 300 mg daily. She was admitted to the hospital for epigastric and right sided flank pain of one-week duration. Laboratory results and imaging confirmed hepatitis. After ruling out all other possible causes, she was diagnosed with isoniazid-induced acute hepatitis (probable association by the Naranjo scale). After discharge, the patient was readmitted and suffered from severe coagulopathy, metabolic acidosis, acute kidney injury, hepatic encephalopathy, and cardiorespiratory arrest necessitating two rounds of cardiopulmonary resuscitation. Despite maximal hemodynamic support, the patient did not survive. A review of the literature, from several European countries and the United States of America, revealed a low incidence of mortality due to isoniazid-induced hepatotoxicity when used as a single agent for latent Mycobacterium tuberculosis infection. As for the management, the first step consists of withdrawing isoniazid and rechallenge is usually discouraged. Few treatment modalities have been proposed; however there is no robust evidence to support any of them. Routine monitoring for hepatotoxicity in patients receiving isoniazid is warranted to prevent morbidity and mortality. PMID:27648319

  10. [EBOLA HEMORRHAGIC FEVER: DIAGNOSTICS, ETIOTROPIC AND PATHOGENETIC THERAPY, PREVENTION].

    PubMed

    Zhdanov, K V; Zakharenko, S M; Kovalenko, A N; Semenov, A V; Fisun, A Ya

    2015-01-01

    The data on diagnostics, etiotropic and pathogenetic therapy, prevention of Ebola hemorrhagic fever are presented including diagnostic algorithms for different clinical situations. Fundamentals of pathogenetic therapy are described. Various groups of medications used for antiviral therapy of conditions caused by Ebola virus are characterized. Experimental drugs at different stages of clinical studies are considered along with candidate vaccines being developed for the prevention of the disease.

  11. Pharmacokinetics of isoniazid: influence of age.

    PubMed

    Kergueris, M F; Bourin, M; Larousse, C

    1986-01-01

    The distribution of the acetylator phenotype of isoniazid was studied in 458 patients of different ages, and the influence of age on its apparent distribution volume, clearance and half-life was investigated in slow and rapid acetylators. The doses of isoniazid for the patients were determined according to the inactivation index method, as described by Vivien. Apparent distribution volume showed no difference between slow and rapid acetylators but it did decrease significantly with age. Clearance and half-life varied significantly in slow acetylators, and these variations led to a decrease in the necessary dose of isoniazid.

  12. Isoniazid induced motor-dominant neuropathy.

    PubMed

    Arsalan, Rabeeya; Sabzwari, Saniya

    2015-10-01

    Isoniazid though a very effective treatment for tuberculosis can cause severe motor-dominant neuropathy which can be reversible with pyridoxine supplementation. A 45-year-old female diagnosed with psoas abscess, culture positive for mycobacterium tuberculosis, was started on anti- tuberculous treatment with four drugs, including isoniazid at a dose of 5 mg/kg/day. Three months later she developed severe motor weakness of lower limbs with loss of ankle and knee reflexes. She was treated with vitamin B6 injections and isoniazid treatment was continued. Her motor weakness gradually improved in a few months, but mild sensory impairment persisted even after two years. There is need for vigilance regarding neurological effects of isoniazid in seemingly low-risk individuals in whom development of symptoms should raise the suspicion about slow acetylator status. Timely therapeutic intervention with high-dose vitamin B6 can reduce the long-term morbidity associated with this easily reversible condition. PMID:26440850

  13. Gene-therapy for malaria prevention.

    PubMed

    Rodrigues, Mauricio M; Soares, Irene S

    2014-11-01

    The limited number of tools for malaria prevention and the inability to eradicate the disease have required large investments in vaccine development, as vaccines have been the only foreseeable type of immunoprophylaxis against malaria. An alternative strategy named vectored immunoprophylaxis (VIP) now would allow genetically transduced host cells to assemble and secrete antibodies that neutralize the infectivity of the malaria parasite and prevent disease.

  14. Antiplatelet therapy to prevent recurrent stroke: Three good options.

    PubMed

    Mansoor, Atizazul H; Mujtaba, Mohammad T; Silver, Brian

    2013-12-01

    Drugs that prevent platelets from sticking together-ie, aspirin, dipyridamole, and clopidogrel-are an important part of therapy to prevent recurrence of ischemic stroke of atherosclerotic origin. We discuss current indications for these drugs and review the evidence behind our current use of aspirin, dipyridamole, and clopidogrel. PMID:24307163

  15. Three cases of intentional isoniazid overdose - a life-threatening condition.

    PubMed

    Stead, David Francis; Mason, Carolyn Ruth

    2016-09-01

    Currently, isoniazid (INH) overdose seems to be a growing and life-threatening problem, partly due to the recent national roll-out of INHpreventive therapy (IPT) for HIV-positive adults. We present three cases, two of which were fatal, seen at Frere and Cecilia Makiwanehospitals, East London, South Africa over the past 16 months. PMID:27601114

  16. Cardiotoxicity in anthracycline therapy: Prevention strategies.

    PubMed

    Cruz, Margarida; Duarte-Rodrigues, Joana; Campelo, Manuel

    2016-06-01

    The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to detect, prevent or mitigate anthracycline-induced cardiomyopathy, it is essential that all patients undergo a rigorous initial cardiovascular assessment, followed by close monitoring. Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise, healthy lifestyles, control of risk factors and treatment of comorbidities; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, statins, dexrazoxane and liposomal formulations. However, there are currently no guidelines for managing prevention in these patients. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline-induced cardiotoxicity. PMID:27255173

  17. Cardiotoxicity in anthracycline therapy: Prevention strategies.

    PubMed

    Cruz, Margarida; Duarte-Rodrigues, Joana; Campelo, Manuel

    2016-06-01

    The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to detect, prevent or mitigate anthracycline-induced cardiomyopathy, it is essential that all patients undergo a rigorous initial cardiovascular assessment, followed by close monitoring. Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise, healthy lifestyles, control of risk factors and treatment of comorbidities; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, statins, dexrazoxane and liposomal formulations. However, there are currently no guidelines for managing prevention in these patients. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline-induced cardiotoxicity.

  18. Hepatoprotective Activity of Heptoplus on Isoniazid and Rifampicin Induced Liver Damage in Rats

    PubMed Central

    Sankar, M.; Rajkumar, Johanna; Sridhar, Dorai

    2015-01-01

    The present study is designed to evaluate the efficacy of heptoplus a polyherbal formulation as an oral supplementary agent for isoniazid and rifampicin induced hepatotoxicity in rats. 50 and 100 mg/kg of heptoplus supplement were fed orally to the rats along with isoniazid and rifampicin and compared to rats treated with 100 mg/kg Liv 52 standard drug. Rats treated with isoniazid and rifampicin suffered from severe oxidative stress by the virtue of free radicals induced lipid per oxidation. As a result abnormal index of serum biochemical markers for liver function and increased liver lysosomal enzymes activity was observed. However rats nourished with 100 mg/kg of heptoplus and Liv 52 protected the liver from oxidative damage by maintaining normal antioxidant profile status and restored normal serum liver biochemical markers. Increased liver lysosomal enzymes activity is prevented in the rats supplemented with heptoplus and Liv 52. Histopathological analysis also revealed severe vascular changes and lobular necrosis in the treatment of isoniazid and rifampicin. Heptoplus (100 mg/kg) and Liv 52 supplemented rats liver apparently revealed normal architecture of liver. This study confirms that heptoplus has liver protective activity against Isoniazid and Rifampicin induced liver injury in rats, in par with Liv 52. PMID:26798170

  19. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Centers for Disease Control and Prevention.

    PubMed

    1998-10-30

    instead of rifampin. Because alternatives to the use of rifampin for antituberculosis treatment are now available, the previously recommended practice of stopping protease inhibitor therapy to allow the use of rifampin for TB treatment is no longer recommended for patients with HIV-related TB. The use of rifabutin-containing antituberculosis regimens should always include an assessment of the patient's response to treatment to decide the appropriate duration of therapy (i.e., 6 months or 9 months). Physicians and patients also should be aware that paradoxical reactions might occur during the course of TB treatment when antiretroviral therapy restores immune function. Adding to CDC's current recommendations for administering isoniazid preventive therapy to HIV-infected persons with positive tuberculin skin tests and to HIV-infected persons who were exposed to patients with infectious TB, this report also describes in detail the use of new shortcourse (i.e., 2 months) multidrug regimens (e.g., a rifamycin, such as rifampin or rifabutin, combined with pyrazinamide) to prevent TB in persons with HIV infection. A continuing education component for U.S. physicians and nurses is included.

  20. Isoniazid Inhibits the Heme-Based Reactivity of Mycobacterium tuberculosis Truncated Hemoglobin N

    PubMed Central

    Ascenzi, Paolo; Coletta, Andrea; Cao, Yu; Trezza, Viviana; Leboffe, Loris; Fanali, Gabriella; Fasano, Mauro; Pesce, Alessandra; Ciaccio, Chiara; Marini, Stefano; Coletta, Massimo

    2013-01-01

    Isoniazid represents a first-line anti-tuberculosis medication in prevention and treatment. This prodrug is activated by a mycobacterial catalase-peroxidase enzyme called KatG in Mycobacterium tuberculosis), thereby inhibiting the synthesis of mycolic acid, required for the mycobacterial cell wall. Moreover, isoniazid activation by KatG produces some radical species (e.g., nitrogen monoxide), that display anti-mycobacterial activity. Remarkably, the ability of mycobacteria to persist in vivo in the presence of reactive nitrogen and oxygen species implies the presence in these bacteria of (pseudo-)enzymatic detoxification systems, including truncated hemoglobins (trHbs). Here, we report that isoniazid binds reversibly to ferric and ferrous M. tuberculosis trHb type N (or group I; Mt-trHbN(III) and Mt-trHbN(II), respectively) with a simple bimolecular process, which perturbs the heme-based spectroscopic properties. Values of thermodynamic and kinetic parameters for isoniazid binding to Mt-trHbN(III) and Mt-trHbN(II) are K = (1.1±0.1)×10−4 M, kon = (5.3±0.6)×103 M−1 s−1 and koff = (4.6±0.5)×10−1 s−1; and D = (1.2±0.2)×10−3 M, don = (1.3±0.4)×103 M−1 s−1, and doff = 1.5±0.4 s−1, respectively, at pH 7.0 and 20.0°C. Accordingly, isoniazid inhibits competitively azide binding to Mt-trHbN(III) and Mt-trHbN(III)-catalyzed peroxynitrite isomerization. Moreover, isoniazid inhibits Mt-trHbN(II) oxygenation and carbonylation. Although the structure of the Mt-trHbN-isoniazid complex is not available, here we show by docking simulation that isoniazid binding to the heme-Fe atom indeed may take place. These data suggest a direct role of isoniazid to impair fundamental functions of mycobacteria, e.g. scavenging of reactive nitrogen and oxygen species, and metabolism. PMID:23936350

  1. Non-drug therapy in prevention and control of hypertension.

    PubMed

    Sainani, G S

    2003-10-01

    Non-drug therapy is a very vital aspect in prevention and treatment of hypertension. The successive reports of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension, WHO scientific report on primary prevention of essential hypertension and national High Blood Pressure Education Program's working groups report on primary prevention of hypertension have stressed on the non-drug therapy. Today a busy family physician does not spend enough time to explain to the patient various dietary and lifestyle modifications but straightaway prescribes the drugs. Every patient of hypertension from the stage of pre-hypertension to grade 2 hypertension should follow non-drug therapy. If non-drug therapy is strictly adhered, one can prevent cases of pre-hypertension from progressing to hypertension stage and one can reduce or stop the medications in Grade I (mild) hypertension. We have discussed the role of low salt, high potassium diet, role of caffeine intake, calcium and magnesium supplements, fish oil intake, cigarette smoking, alcohol consumption, role of physical exercise, stress reduction and bio-feedback, yoga, meditation and acupuncture. These recommendations regarding diet and lifestyle modifications should be targeted to population at large through public health authorities, non-government organisations and news media.

  2. Aging intervention, prevention, and therapy through hormesis.

    PubMed

    Rattan, Suresh I S

    2004-07-01

    The phenomenon of hormesis is represented by mild stress-induced stimulation of maintenance and repair pathways resulting in beneficial effects for the cells and organisms. Anti-aging and life-prolonging effects of a wide variety of the so-called stressors, such as pro-oxidants, aldehydes, calorie restriction, irradiation, heat shock, and hypergravity, have been reported. Molecular mechanisms of hormesis due to different stresses are yet to be elucidated, but there are indications that relatively small individual hormetic effects become biologically amplified resulting in the collective significant improvement of cellular and organismic functions and survival. Accepting that some important issues with respect to establishing the optimal hormetic conditions still need to be resolved by future research, hormesis appears to be a promising and effective approach for modulating aging, for preventing or delaying the onset of age-related diseases, and for improving quality of life in old age.

  3. Novel approaches in melanoma prevention and therapy.

    PubMed

    Grimaldi, Antonio M; Cassidy, Pamela B; Leachmann, Sancy; Ascierto, Paolo A

    2014-01-01

    The incidence of cutaneous melanoma has risen at a rate significantly higher than that for other malignancies. This increase persists despite efforts to educate the public about the dangers of excess exposure to UV radiation from both the sun and tanning beds. Melanoma affects a relatively younger population and is notorious for its propensity to metastasize and for its poor response to current therapeutic regimens. These factors make prevention an integral component to the goal of decreasing melanoma-related mortality. Transformation of melanocytes into malignant melanoma involves the interplay between genetic factors, UV exposure, and the tumor microenvironment. The roles of UV radiation in the etiology of melanoma are mediated by both direct damage of DNA through formation of photoproducts and production of reactive oxygen species (ROS). Many of the promising antioxidant agents under development for the prevention of melanoma are derived from foodstuffs. B-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases that plays a role in regulating the MAP kinase/ERKs signaling pathway. About 50 % of melanomas harbor activating BRAF mutations. BRAF mutations are found in 59 % of the melanomas arising in skin with intermittent sun exposure, such as trunk and arms, as compared with only 23 % of the acral melanomas, 11 % of mucosal melanomas, and 0 % of uveal melanomas. Two new agents, ipilimumab and vemurafenib, have been shown to improve outcome of advanced melanoma as presented at the plenary session of the 2011 annual meeting of the American Society of Clinical Oncology. Vemurafenib is the first personalized compound which demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in metastatic melanoma harboring the BRAFV600 mutation and represents the first drug of a class that exerts its anti-proliferative activity through inhibition of a highly specific molecular target. GSK2118436 (dabrafenib), the

  4. [Toxoplasmosis in pregnancy. Prevention, diagnosis, and therapy].

    PubMed

    Russo, M

    1994-01-01

    Toxoplasmosis is a worldwide health problem. Infection of a pregnant woman can result in severe fetal morbidity or in subclinical neonatal infection; most subclinical cases will develop ocular and neurological sequelae. Fetal infection and clinical outcome is related to when in pregnancy toxoplasmosis was acquired. The risk of transmission increases from 14% in the first trimester to 29% in the second and 59% in the third. Conversely, clinical damage decreases from about 80% in the first to 10% in the third trimester, but up to 50% of patients with subclinical congenital toxoplasmosis will develop neurologic and ocular sequelae. Congenital toxoplasmosis can be prevented by identification of non immune women at the beginning of pregnancy, by giving information on how to avoid the infection and by a serological follow-up until the delivery. Serological follow-up is based on repeated testing for specific IgG and IgM, but other serologic methods are necessary to differentiate between acute and chronic infections and possibly on a single serum sample. Procedures to detect fetal infection are ultrasound examination, cordocentesis and amniocentesis; prenatal diagnosis relies on demonstration of toxoplasma in fetal blood or amniotic fluid by mouse inoculation. Very promising results have recently obtained by the PCR-method applied to amniotic fluid samples. All strongly suspected cases of acquired toxoplasmosis in pregnancy have to be treated.

  5. Global and Regional Burden of Isoniazid-Resistant Tuberculosis

    PubMed Central

    Yuen, Courtney M.; Jenkins, Helen E.; Rodriguez, Carly A.; Keshavjee, Salmaan

    2015-01-01

    BACKGROUND: Isoniazid has been the backbone of tuberculosis chemotherapy for 6 decades. Resistance to isoniazid threatens the efficacy of treatment of tuberculosis disease and infection. To inform policies around treatment of tuberculosis disease and infection in children, we sought to estimate both the proportion of child tuberculosis cases with isoniazid resistance and the number of incident isoniazid-resistant tuberculosis cases in children, by region. METHODS: We determined the relationship between rates of isoniazid resistance among child cases and among treatment-naive adult cases through a systematic literature review. We applied this relationship to regional isoniazid resistance estimates to estimate proportions of childhood tuberculosis cases with isoniazid resistance. We applied these proportions to childhood tuberculosis incidence estimates to estimate numbers of children with isoniazid-resistant tuberculosis. RESULTS: We estimated 12.1% (95% confidence interval [CI] 9.8% to 14.8%) of all children with tuberculosis had isoniazid-resistant disease, representing 120 872 (95% CI 96 628 to 149 059) incident cases of isoniazid-resistant tuberculosis in children in 2010. The majority of these occurred in the Western Pacific and Southeast Asia regions; the European region had the highest proportion of child tuberculosis cases with isoniazid resistance, 26.1% (95% CI: 20.0% to 33.6%). CONCLUSIONS: The burden of isoniazid-resistant tuberculosis in children is substantial, and risk varies considerably by setting. The large number of child cases signals extensive ongoing transmission from adults with isoniazid-resistant tuberculosis. The risk of isoniazid resistance must be considered when evaluating treatment options for children with disease or latent infection to avoid inadequate treatment and consequent poor outcomes. PMID:26034243

  6. Pharmacogenetics of isoniazid-induced hepatotoxicity.

    PubMed

    Perwitasari, Dyah Aryani; Atthobari, Jarir; Wilffert, Bob

    2015-05-01

    Tuberculosis is still a major problem in some developed and developing countries. The poor compliance to the treatment of tuberculosis patients due to the adverse events was supposed to be an important factor contributing to the high prevalence. This review aims to clarify the role and the pharmacological mechanism of the genes involved in the isoniazid-induced hepatotoxicity. We selected English articles of studies in human from PubMed up to May 2014 with the keywords pharmacogenetic, isoniazid and hepatotoxicity, N-acetyl transferase 2 (NAT2), CYP2E1 and glutathione S transferase (GST). Polymorphisms of NAT2, CYP2E1 and GST1 could increase patients' susceptibility to isoniazid-induced hepatotoxicity. The rapid acetylators of NAT2 and rapid metabolizers of CYP2E1 showed increased concentrations of hepatotoxic metabolites. However, the rapid metabolizers of GST1 could decrease the concentration of hepatotoxic metabolites. Some studies of human leukocyte antigen (HLA), Uridine 5'-dipphospho (UDP) glucuronosyltransferase (UGT), nitric oxide synthase (NOS), Broad complex, Tramtrack, Bric-a-brac (BTB) and cap'n'collar type of basic region leucine zipper factor family (CNC) homolog (BACH) and Maf basic leucine zipper protein (MAFK) polymorphisms showed their roles in isoniazid-induced hepatotoxicity by modifying the expression of antioxidant enzymes. A better insight into the role of polymorphisms of HLA, UGT, NOS, BACH and MAFK in addition to NAT2, CYP2E1 and GST1 in the hepatotoxicity of isoniazid may support physicians in monitoring patients hepatotoxicity symptoms and laboratory data and optimizing pharmacotherapy. Future studies about the role of such polymorphisms in different ethnicities are suggested. PMID:26095714

  7. Antiplatelet therapy in prevention of cardio- and venous thromboembolic events.

    PubMed

    Steinhubl, Steven R; Eikelboom, John W; Hylek, Elaine M; Dauerman, Harold L; Smyth, Susan S; Becker, Richard C

    2014-04-01

    The contribution of platelets in the pathophysiology of low-shear thrombosis-specifically, in atrial fibrillation (AF) and venous thromboembolic events (VTE)-remains less clear than for arterial thrombosis. AF itself appears to lead to platelet activation, offering a potential target for aspirin and other antiplatelet agents. Randomized trial results suggest a small benefit of aspirin over placebo, and of dual antiplatelet therapy (aspirin plus clopidogrel) over aspirin alone, for prevention of cardioembolic events in AF. Antiplatelet therapy thus can represent an option for patients with AF who are unsuitable for therapy with warfarin or novel oral anticoagulant agents. For VTE, the rationale for antiplatelet therapy reflects the venous response to disrupted blood flow-interactions among monocytes, neutrophil extracellular traps, and platelets. Early randomized trials generally showed poorer performance of aspirin relative to heparins and danaparoid sodium in prevention of VTE. However, results from large placebo- and dalteparin-controlled randomized trials have spurred changes in the most recent practice guidelines-aspirin is now recommended after major orthopedic surgery for patients who cannot receive other antithrombotic therapies. PMID:24221804

  8. Therapy of Chagas Disease: Implications for Levels of Prevention

    PubMed Central

    Sosa-Estani, Sergio; Colantonio, Lisandro; Segura, Elsa Leonor

    2012-01-01

    This paper reviews the evidence supporting the use of etiological treatment for Chagas disease that has changed the standard of care for patients with Trypanosoma cruzi infection in the last decades. Implications of this evidence on different levels of prevention as well as gaps in current knowledge are also discussed. In this regard, etiological treatment has shown to be beneficial as an intervention for secondary prevention to successfully cure the infection or to delay, reduce, or prevent the progression to disease, and as primary disease prevention by breaking the chain of transmission. Timely diagnosis during initial stages would allow for the prescription of appropriate therapies mainly in the primary health care system thus improving chances for a better quality of life. Based on current evidence, etiological treatment has to be considered as an essential public health strategy useful to reduce disease burden and to eliminate Chagas disease altogether. PMID:22523499

  9. Antiretroviral Therapy for Prevention of Human Immunodeficiency Virus Infection.

    PubMed

    Kalapila, Aley G; Marrazzo, Jeanne

    2016-07-01

    Human immunodeficiency virus (HIV) infection is considered a chronic medical condition. Several new drugs are available, including fixed-dose combination tablets, that have greatly simplified combination antiretroviral therapy (ART) regimens to treat HIV, while increasing the life-expectancy of infected individuals. In the last decade, multiple well-regarded studies have established the benefits of using ART in high-risk, HIV-negative persons to prevent HIV acquisition. The primary care provider must not only understand commonly encountered issues pertaining to ART, such as toxicities and drug interactions, but also needs to be aware of using ART for HIV prevention. PMID:27235622

  10. Prevention of peritoneal adhesions: A promising role for gene therapy

    PubMed Central

    Atta, Hussein M

    2011-01-01

    Adhesions are the most frequent complication of abdominopelvic surgery, yet the extent of the problem, and its serious consequences, has not been adequately recognized. Adhesions evolved as a life-saving mechanism to limit the spread of intraperitoneal inflammatory conditions. Three different pathophysiological mechanisms can independently trigger adhesion formation. Mesothelial cell injury and loss during operations, tissue hypoxia and inflammation each promotes adhesion formation separately, and potentiate the effect of each other. Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation. This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions. It explores the promising role of combinatorial gene therapy and vector modifications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field. PMID:22171139

  11. Effect of Rifampicin and Isoniazid on Liver Function

    PubMed Central

    Lal, Satinder; Singhal, S. N.; Burley, D. M.; Crossley, G.

    1972-01-01

    The effects of rifampicin and isoniazid on liver function have been studied in 63 patients with pulmonary tuberculosis; 29% showed abnormalities of serum aspartate aminotransferase (SGOT) and a similar percentage abnormalities of serum bilirubin. These usually occurred during the first 12 weeks of therapy. The average duration of the abnormalities was 14½ days, irrespective of whether treatment was interrupted or not. The relationship between raised SGOT and acetylator phenotype in a small number of patients suggests that those with raised SGOT are usually slow acetylator phenotypes. It seems that hepatic reactions in patients with previously normal liver function are usually mild and non-specific. However, patients who continue with rifampicin should be kept under close biochemical observation. PMID:5007842

  12. Synthesis, characterization, solubility and stability studies of hydrate cocrystal of antitubercular Isoniazid with antioxidant and anti-bacterial Protocatechuic acid

    NASA Astrophysics Data System (ADS)

    Mashhadi, Syed Muddassir Ali; Yunus, Uzma; Bhatti, Moazzam Hussain; Ahmed, Imtiaz; Tahir, Muhammad Nawaz

    2016-08-01

    Isoniazid is an important component used in "triple therapy" to combat tuberculosis. It has reduced Tabletting formulations stability. Anti-oxidants are obligatory to counter oxidative stress, pulmonary inflammation, and free radical burst from macrophages caused in tuberculosis and other diseases. In the present study a hydrate cocrystal of Isoniazid with anti-oxidant and anti-inflammatory and anti-bacterial Protocatechuic acid (3,4-dihydroxybenzoic acid) in 1:1 is reported. This Cocrystal may have improved tabletting stability and anti-oxidant properties. Cocrystal structure analysis confirmed the existence of pyridine-carboxylic acid synthon in the Cocrystal. Other synthons of different graph sets involving Nsbnd H···O and Osbnd H···N bonds are formed between hydrazide group of isoniazid and coformer. Solubility studies revealed that cocrystal is less soluble as compared to isoniazid in buffer at pH 7.4 at 22 °C while stability studies at 80 °C for 24 h period disclosed the fact that cocrystal has higher stability than that of isoniazid.

  13. Antibiotic therapy of aortic graft infection: treatment and prevention recommendations.

    PubMed

    Hodgkiss-Harlow, Kelley D; Bandyk, Dennis F

    2011-12-01

    Surgical site infection (SSI) after aortic intervention, an uncommon but serious vascular condition, requires patient-specific antibiotic therapy. Effective treatment and prevention requires the vascular surgeon to be cognizant of changing SSI microbiology, advances in antibiotic delivery, and patient characteristics. The majority of aortic graft infections are caused by Gram-positive bacteria, with methicillin-resistant Staphylococcus aureus now the prevalent pathogen. Nasal carriage of methicillin-sensitive or methicillin-resistant S aureus strains, diabetes mellitus, recent hospitalization, a failed arterial reconstruction, and the presence of a groin incision are important SSI risk factors. Overall, the aortic SSI rate is higher than predicted by the Centers for Disease Control and Prevention's National Nosocomial Infections Surveillance risk category system; ranging from 5% after open or endovascular aortic interventions to as high as 10% to 15% after aortofemoral bypass or uni-aortoiliac grafting with femorofemoral bypass. Perioperative measures to reduce S aureus nares and skin colonization, administration of antibiotic prophylaxis, meticulous wound closure/care, and therapy directed to optimize patient host defense regulation mechanisms (eg, temperature, oxygenation, blood sugar) can minimize SSI occurrence. Antibiotic therapy for aortic graft infection should utilize bactericidal drugs that penetrate bacteria biofilms and can be delivered to the surgical site both parenterally and locally in the form of antibiotic-impregnated beads or prosthetic grafts.

  14. Hormone replacement therapy and the prevention of postmenopausal osteoporosis.

    PubMed

    Gambacciani, Marco; Levancini, Marco

    2014-09-01

    Fracture prevention is one of the public health priorities worldwide. Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis, the most common metabolic bone disease. Different effective treatments for osteoporosis are available. Hormone replacement therapy (HRT) at different doses rapidly normalizes turnover, preserves bone mineral density (BMD) at all skeletal sites, leading to a significant, reduction in vertebral and non-vertebral fractures. Tibolone, a selective tissue estrogenic activity regulator (STEAR), is effective in the treatment of vasomotor symptoms, vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT. Selective estrogen receptor modulators (SERMs) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures. The combination of bazedoxifene and conjugated estrogens, defined as tissue selective estrogen complex (TSEC), is able to reduce climacteric symptoms, reduce bone turnover and preserve BMD. In conclusion, osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms. The use of a standard dose of HRT for osteoporosis prevention is based on biology, epidemiology, animal and preclinical data, observational studies and randomized, clinical trials. The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover, with compelling scientific evidence.

  15. Hormone replacement therapy and the prevention of postmenopausal osteoporosis

    PubMed Central

    Levancini, Marco

    2014-01-01

    Fracture prevention is one of the public health priorities worldwide. Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis, the most common metabolic bone disease. Different effective treatments for osteoporosis are available. Hormone replacement therapy (HRT) at different doses rapidly normalizes turnover, preserves bone mineral density (BMD) at all skeletal sites, leading to a significant, reduction in vertebral and non-vertebral fractures. Tibolone, a selective tissue estrogenic activity regulator (STEAR), is effective in the treatment of vasomotor symptoms, vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT. Selective estrogen receptor modulators (SERMs) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures. The combination of bazedoxifene and conjugated estrogens, defined as tissue selective estrogen complex (TSEC), is able to reduce climacteric symptoms, reduce bone turnover and preserve BMD. In conclusion, osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms. The use of a standard dose of HRT for osteoporosis prevention is based on biology, epidemiology, animal and preclinical data, observational studies and randomized, clinical trials. The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover, with compelling scientific evidence. PMID:26327857

  16. Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

    PubMed Central

    Jandial, Danielle D.; Blair, Christopher A.; Zhang, Saiyang; Krill, Lauren S.; Zhang, Yan-Bing; Zi, Xiaolin

    2014-01-01

    There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy. PMID:24467530

  17. Antiretroviral Therapy for the Prevention of HIV-1 Transmission.

    PubMed

    Cohen, Myron S; Chen, Ying Q; McCauley, Marybeth; Gamble, Theresa; Hosseinipour, Mina C; Kumarasamy, Nagalingeswaran; Hakim, James G; Kumwenda, Johnstone; Grinsztejn, Beatriz; Pilotto, Jose H S; Godbole, Sheela V; Chariyalertsak, Suwat; Santos, Breno R; Mayer, Kenneth H; Hoffman, Irving F; Eshleman, Susan H; Piwowar-Manning, Estelle; Cottle, Leslie; Zhang, Xinyi C; Makhema, Joseph; Mills, Lisa A; Panchia, Ravindre; Faesen, Sharlaa; Eron, Joseph; Gallant, Joel; Havlir, Diane; Swindells, Susan; Elharrar, Vanessa; Burns, David; Taha, Taha E; Nielsen-Saines, Karin; Celentano, David D; Essex, Max; Hudelson, Sarah E; Redd, Andrew D; Fleming, Thomas R

    2016-09-01

    Background An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission. Methods We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis. Results Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant. Conclusions The early initiation of ART led to a sustained

  18. [Anticoagulant therapy in secondary prevention of coronary events].

    PubMed

    Bultas, Jan

    2014-12-01

    Secondary prevention of atherothrombotic events is the domain of antiplatelet therapy and according to present risk is used one drug strategy or combination of acetylsalicylic acid with ADP receptor blockers. The importance of the combination of dual antiplatelet therapy together with xabans or dabigatran was investigated in 6 clinical trials. Only one of them (ATLAS ACS 2-TIMI 51) indicated that treatment with small dose of rivaroxaban (2 × 2.5 mg) may be added to dual strategy of acetylsalicylic acid and clopidogrel. The risk of major bleeding event is increased and net clinical benefit is only about 0.5 % per year. Dual therapy with aspirin and prasugrel or tikagrelor is beneficial. In the second part of the review is discussed higher incidence of myocardial infarction in controlled group in the trial comparing treatment of dabigatran with warfarin. This relationship has not been resolved, however, in patients with higher risk of coronary events and indication of anticoagulant treatment with direct oral anticoagulants it is recommended to choose from xabans (apixaban and rivaroxaban). PMID:25692828

  19. Food allergy prevalence: new possibilities for therapy and prevention.

    PubMed

    Ma, Yan

    2012-12-01

    Food allergy is an important clinical problem of increasing prevalence worldwide. Immunoglobulin E (IgE)-mediated allergic responses are the most widely recognized form of food allergy. The prevalence of food allergy is influenced by country, age, culture, and dietary habits. Strategies for the prevention of food allergy have been extensively studied. There is currently no standard treatment for food allergy and allergen-specific immunotherapy has been hindered by severe side effects in the past. A mutated recombinant major apple allergen is clinically hypoallergenic, which paves the way toward safer immunotherapy for the treatment of food-allergic patients.Traditional Chinese medicine (TCM) is one of the oldest medical practices in the world. A Chinese Food Allergy Herbal Formula-2 (FAHF-2) has been used as a therapy for food allergy patients. FAHF-2 was shown to be remarkably effective against food anaphylaxis in an animal model and in human clinical trial with the potential to be a long-lasting therapy.

  20. Therapies for Prevention and Treatment of Alzheimer's Disease

    PubMed Central

    2016-01-01

    Alzheimer's disease (AD) is the most common cause of dementia associated with a progressive neurodegenerative disorder, with a prevalence of 44 million people throughout the world in 2015, and this figure is estimated to double by 2050. This disease is characterized by blood-brain barrier disruption, oxidative stress, mitochondrial impairment, neuroinflammation, and hypometabolism; it is related to amyloid-β peptide accumulation and tau hyperphosphorylation as well as a decrease in acetylcholine levels and a reduction of cerebral blood flow. Obesity is a major risk factor for AD, because it induces adipokine dysregulation, which consists of the release of the proinflammatory adipokines and decreased anti-inflammatory adipokines, among other processes. The pharmacological treatments for AD can be divided into two categories: symptomatic treatments such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists and etiology-based treatments such as secretase inhibitors, amyloid binders, and tau therapies. Strategies for prevention of AD through nonpharmacological treatments are associated with lifestyle interventions such as exercise, mental challenges, and socialization as well as caloric restriction and a healthy diet. AD is an important health issue on which all people should be informed so that prevention strategies that minimize the risk of its development may be implemented. PMID:27547756

  1. Dexamethasone therapy for preventing delayed encephalopathy after carbon monoxide poisoning.

    PubMed

    Li, Q; Song, J J; Zhang, H Y; Fu, K; Lan, H B; Deng, Y

    2015-01-01

    We investigated dexamethasone therapy for preventing delayed encephalopathy after carbon monoxide (CO) poisoning. Eighty healthy male rats were exposed to CO and randomly divided into four groups: hyperbaric oxygen treatment (H), treatment (D), combined hyperbaric and dexamethasone treatment (C), and a control (M) group in which the rats inhaled CO to coma in the hyperbaric oxygen chamber, then were removed without further treatment. Twelve rats were put into the hyperbaric oxygen chamber and treated with air for 60 min (N) group. An eight arm maze was used to evaluate cognitive and memory abilities of these mice. Serum myelin basic protein (MBP) levels were evaluated using ELISA, and magnetic resonance imaging was used to observe brain demyelination and morbidity associated with delayed encephalopathy. A sample of the hippocampus from each group was examined by light microscopy. Cognitive and memory functions decreased in the control group M. Three days after CO poisoning, the serum MBP level of each group increased significantly. On Day 10 after CO poisoning, the MBP levels in groups C and D decreased significantly, but returned to normal on Day 18. MBP levels in the M and H groups were elevated at all time points. Brain MRIs showed significant differences among C, D, H and control M groups. Hematoxylin & eosin staining of the hippocampus showed greater damage in the control M and H groups. Early dexamethasone treatment may be useful for preventing delayed encephalopathy after CO poisoning and may reduce serum MBP levels.

  2. Therapies for Prevention and Treatment of Alzheimer's Disease.

    PubMed

    Mendiola-Precoma, J; Berumen, L C; Padilla, K; Garcia-Alcocer, G

    2016-01-01

    Alzheimer's disease (AD) is the most common cause of dementia associated with a progressive neurodegenerative disorder, with a prevalence of 44 million people throughout the world in 2015, and this figure is estimated to double by 2050. This disease is characterized by blood-brain barrier disruption, oxidative stress, mitochondrial impairment, neuroinflammation, and hypometabolism; it is related to amyloid-β peptide accumulation and tau hyperphosphorylation as well as a decrease in acetylcholine levels and a reduction of cerebral blood flow. Obesity is a major risk factor for AD, because it induces adipokine dysregulation, which consists of the release of the proinflammatory adipokines and decreased anti-inflammatory adipokines, among other processes. The pharmacological treatments for AD can be divided into two categories: symptomatic treatments such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists and etiology-based treatments such as secretase inhibitors, amyloid binders, and tau therapies. Strategies for prevention of AD through nonpharmacological treatments are associated with lifestyle interventions such as exercise, mental challenges, and socialization as well as caloric restriction and a healthy diet. AD is an important health issue on which all people should be informed so that prevention strategies that minimize the risk of its development may be implemented. PMID:27547756

  3. Hepatoprotective activity of Ficus religiosa leaves against isoniazid+rifampicin and paracetamol induced hepatotoxicity

    PubMed Central

    Parameswari, Sundaramoorthi Angala; Chetty, Challa Madhusudhana; Chandrasekhar, Kothapalli Bannoth

    2013-01-01

    Background: The present study was designed to investigate the hepato protective effect of methanolic extract of Ficus religisoa L., Moraceae, on isoniazid-rifampicin and paracetamol induced hepatotoxicity in rats. Materials and Methods: Male Wistar albino rats were divided into six groups; group 1 served as a control received vehicle (Distilled water), group 2 served as a toxic control, received isoniazid-rifampicin (100 mg/ kg, i.p.) or paracetamol 200mg/kg, p.o in sterile water, groups 3, 4 and 5 received 100, 200 and 300mg/kg bw, p.o. methanolic extract of F. religisoa along with INH+RIF or paracetamol and group 6 received Liv 52 as reference standard. All the treatment protocols followed 21 days for INH+RIF model and seven days for paracetamol model, after treatment rats were sacrificed and blood was used for biochemical and liver was used for histological studies. Results: Administration of INH+RIF and paracetamol caused a significant elevation in the levels of liver marker enzymes (P < 0.05 and P < 0.01) and thiobarbituric acid reactive substances (P < 0.001) in experimental rats. Administration of methanolic extracts of F. religisoa significantly prevented isoniazid-rifampicin and paracetamol induced elevation in the levels of serum diagnostic liver marker enzymes and TBARS level in experimental groups of rats. Moreover, total protein and reduced glutathione levels were significantly (P < 0.001) increased in treatment group. The effect of extract was compared with a standard drug, Liv 52. The changes in biochemical parameters were supported by histological profile. Conclusion: The methanolic extract of F. religisoa protects against isoniazid- rifampicin and paracetamol induced oxidative liver injury in rats. PMID:24174821

  4. [Relapse prevention group therapy for paedophiles: French adaptation].

    PubMed

    Smith, J; Petibon, C

    2005-01-01

    Psychotherapy for sex offenders has only very recently started to develop in France. The French law on compulsory treatment for sex offenders was voted in 1998, and many mental health practitioners are not trained to treat such patients yet. In our ambulatory forensic consultation, sex offenders have been treated since 1992 and group psychotherapy has been offered to them since 1994. Our first therapeutic models were the North-American behavioural-cognitive therapy and Pithers' relapse prevention model. Behavioural-cognitive theory describes paedophilia as an acquired sexual preference maintained by positive reinforcement. Pithers (1990) considered that relapse only occurs in high-risk situations, and that high-risk situations always come after offence precursors. In North America, relapse prevention consists in helping paedophiles spot their high-risk situations and offence precursors, and enhance their skills to cope with such situations or to prevent them. Therapy programs were developed according to these models, aiming to help offenders develop such skills, ie empathy, social skills, cognitive restructuring, self-esteem, etc. Trying to apply these therapy programs in France, our team quickly realised that we would have to adapt them to French culture. On the one hand, behavioural-cognitive theory did not seem satisfactory enough in explaining paedophilic behaviour and paedophilic preference. On the other hand, behavioural-cognitive therapy made patients into children too much and increased resistance. Therapy based on programs seemed too rigid for French patients and therapists, and we often felt we were working on an issue that would have been much more accurate to work on a few sessions earlier, when this issue was spontaneously brought up by a patient. We believe change occurs all the more as issues are worked on at the right moment for the patient. Moreover, on a cultural point of view, we also realised the use of programs in psychotherapy was difficult to

  5. [Repetitive strain injury (RSI): occurrence, etiology, therapy and prevention].

    PubMed

    Bongers, P M; de Vet, H C W; Blatter, B M

    2002-10-19

    In the Netherlands, work related upper-limb disorders are called Repetitive Strain Injuries (RSI). RSI is not a diagnosis but a catch-all term for symptoms and signs located in the neck, upper back, shoulder, arm, elbow, hand, wrist and fingers. These symptoms may include pain, stiffness, tingling, clumsiness, loss of co-ordination, loss of strength, skin discoloration and temperature differences. Each year, 8% of working Dutch citizens take time off work due to RSI symptoms. Although the number of people claiming disability benefit due to RSI is limited, this figure has risen consecutively over the last three years. There is consensus that repetitive work at a high frequency and possibly accompanied by exertion of force is accompanied by RSI symptoms. There are indications of a relation between visual display unit use and these symptoms. However, these relations have not been established in a longitudinal study of adequate quality. High perceived job stress and a high workload are thought to be related to RSI, and women report more symptoms than men. There is insufficient information available on the role of different coping styles, perfectionism and dealing with symptoms. There is little information on the underlying mechanisms in the development of RSI, the diagnostics, therapy and prevention. In view of the lack of clear diagnostic criteria, suggestions have been made for a standardised description of the symptoms involved in the syndrome. A multidisciplinary treatment is likely to have the most effect. In terms of prevention, an integrated approach aimed at improving the working posture, reduction of static load and job stress and at individual factors is assumed to be the most effective.

  6. Role of medication therapy management in preexposure prophylaxis therapy for HIV prevention.

    PubMed

    Ferrell, Kelli W; Woodard, Laresa M; Woodard, Todd J

    2015-02-01

    Patient medication adherence is a long-standing problem and is one that raises serious issues for patient health, public health, and health care quality. Medication nonadherence costs the US economy an estimated US$290 billion in avoidable medical spending every year. One of the most costly health conditions is HIV disease, which continues to be a serious health issue for parts of the world. About 34 million people are living with HIV around the world. With the emerging preventative treatment against HIV, known as preexposure prophylaxis (PrEP), come concerns surrounding the potential impact of nonadherence to this newly approved medication therapy. Nonadherence to antiretroviral treatments are commonly the root cause for patients not reaching their treatment goals, putting them at risk of progression and worsening of their disease and complications, such as increased risk of opportunistic infections. Therefore, it is essential to improve antiretroviral medication adherence. By identifying members who are nonadherent to their prescribed antiretroviral medications and working collaboratively with patients, physicians, and pharmacists, Medication Therapy Management (MTM) can potentially increase medication adherence by helping patients identify, resolve, and prevent issues that may affect their decision not to take a medication as intended.

  7. The Immune System in Cancer Prevention, Development and Therapy.

    PubMed

    Candeias, Serge M; Gaipl, Udo S

    2016-01-01

    The immune system plays a pivotal role in the maintenance of the integrity of an organism. Besides the protection against pathogens, it is strongly involved in cancer prevention, development and defense. This review focuses on how the immune system protects against infections and trauma and on its role in cancer development and disease. Focus is set on the interactions of the innate and adaptive immune system and tumors. The role of IFN-γ as a pleiotropic cytokine that plays a very important role at the interface of innate and adaptive immune systems in tumor development and induction of anti-tumor immune responses is outlined. Further, immune cells as prognostic and predictive markers of cancer will be discussed. Data are provided that even the brain as immune privileged organ is subjected to immune surveillance and consequently also brain tumors. Immune therapeutic approaches for glioblastoma multiforme, the most frequent and malignant brain tumor, based on vaccination with dendritic cells are outlined and application of hyperthermia in form of magnetic nanoparticles is discussed. We conclude that the immune system and developing tumors are intimately intertwined. Anti-tumor immune responses can be prominently boosted by multimodal therapies aiming on the one hand to induce immunogenic tumor cell death forms and on the other hand to actively counteract the immune suppressive microenvironment based on the tumor itself.

  8. Alternative Therapies for the Prevention of Postoperative Nausea and Vomiting.

    PubMed

    Stoicea, Nicoleta; Gan, Tong J; Joseph, Nicholas; Uribe, Alberto; Pandya, Jyoti; Dalal, Rohan; Bergese, Sergio D

    2015-01-01

    Postoperative nausea and vomiting (PONV) is a complication affecting between 20 and 40% of all surgery patients, with high-risk patients experiencing rates of up to 80%. Recent studies and publications have shed light on the uses of alternative treatment for PONV through their modulation of endogenous opioid neuropeptides and neurokinin ligands. In addition to reducing PONV, hypnosis was reported to be useful in attenuating postoperative pain and anxiety, and contributing to hemodynamic stability. Music therapy has been utilized to deepen the sedation level and decrease patient anxiety, antiemetic and analgesic requirements, hospital length of stay, and fatigue. Isopropyl alcohol and peppermint oil aromatherapy have both been used to reduce postoperative nausea. With correct training in traditional Chinese healing techniques, acupuncture (APu) at the P6 acupoint has also been shown to be useful in preventing early PONV, postdischarge nausea and vomiting, and alleviating of pain. Electro-acupuncture (EAPu), as with APu, provided analgesic and antiemetic effects through release and modulation of opioid neuropeptides. These non-pharmacological modalities of treatment contribute to an overall patient wellbeing, assisting in physical and emotional healing. PMID:26734609

  9. Nursing aspects of pressure sore prevention and therapy.

    PubMed

    Culley, F

    Pressure sores remain a significant problem in hospitals and domestic settings, affecting people of all ages, social class and race. Associated complications may be life threatening, e.g. sepsis and osteomyelitis. Other less dangerous, but nevertheless compromising outcomes such as pain, discomfort and low self-esteem and body image can cause personal suffering, and may add extra demand for limited resources. The exact state of pressure sore occurrence remains difficult to determine, particularly in the community. Recent trends in pressure area management present a multidisciplinary approach, eroding traditional perceptions of pressure sores as a solely nursing problem. Written from nursing perspective, this article summarizes principles of good practice relating to pressure sore prevention and therapy, emphasizing the importance of documenting observed events, rather than assumptions or opinions, and the need for healthcare professionals to approach problems and needs from a collaborative stance. Pressure sore risk assessment and classification are discussed, and an overview of nutrition, moving a handling, selecting support surfaces, principles of wound management, and skin care are considered.

  10. Alternative Therapies for the Prevention of Postoperative Nausea and Vomiting.

    PubMed

    Stoicea, Nicoleta; Gan, Tong J; Joseph, Nicholas; Uribe, Alberto; Pandya, Jyoti; Dalal, Rohan; Bergese, Sergio D

    2015-01-01

    Postoperative nausea and vomiting (PONV) is a complication affecting between 20 and 40% of all surgery patients, with high-risk patients experiencing rates of up to 80%. Recent studies and publications have shed light on the uses of alternative treatment for PONV through their modulation of endogenous opioid neuropeptides and neurokinin ligands. In addition to reducing PONV, hypnosis was reported to be useful in attenuating postoperative pain and anxiety, and contributing to hemodynamic stability. Music therapy has been utilized to deepen the sedation level and decrease patient anxiety, antiemetic and analgesic requirements, hospital length of stay, and fatigue. Isopropyl alcohol and peppermint oil aromatherapy have both been used to reduce postoperative nausea. With correct training in traditional Chinese healing techniques, acupuncture (APu) at the P6 acupoint has also been shown to be useful in preventing early PONV, postdischarge nausea and vomiting, and alleviating of pain. Electro-acupuncture (EAPu), as with APu, provided analgesic and antiemetic effects through release and modulation of opioid neuropeptides. These non-pharmacological modalities of treatment contribute to an overall patient wellbeing, assisting in physical and emotional healing.

  11. Alternative Therapies for the Prevention of Postoperative Nausea and Vomiting

    PubMed Central

    Stoicea, Nicoleta; Gan, Tong J.; Joseph, Nicholas; Uribe, Alberto; Pandya, Jyoti; Dalal, Rohan; Bergese, Sergio D.

    2015-01-01

    Postoperative nausea and vomiting (PONV) is a complication affecting between 20 and 40% of all surgery patients, with high-risk patients experiencing rates of up to 80%. Recent studies and publications have shed light on the uses of alternative treatment for PONV through their modulation of endogenous opioid neuropeptides and neurokinin ligands. In addition to reducing PONV, hypnosis was reported to be useful in attenuating postoperative pain and anxiety, and contributing to hemodynamic stability. Music therapy has been utilized to deepen the sedation level and decrease patient anxiety, antiemetic and analgesic requirements, hospital length of stay, and fatigue. Isopropyl alcohol and peppermint oil aromatherapy have both been used to reduce postoperative nausea. With correct training in traditional Chinese healing techniques, acupuncture (APu) at the P6 acupoint has also been shown to be useful in preventing early PONV, postdischarge nausea and vomiting, and alleviating of pain. Electro-acupuncture (EAPu), as with APu, provided analgesic and antiemetic effects through release and modulation of opioid neuropeptides. These non-pharmacological modalities of treatment contribute to an overall patient wellbeing, assisting in physical and emotional healing. PMID:26734609

  12. Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin.

    PubMed

    Raghu, Ramanathan; Karthikeyan, Sivanesan

    2016-09-01

    HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT+INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT+INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n=6 in each group) were administered AZT alone (50mg/kg b.w.), INH alone (25mg/kg, b.w.), AZT+INH (50mg/kg, b.w. and 25mg/kg, b.w.), SBN alone (100mg/kg, b.w.) and SBN+AZT+INH daily for sub-chronic period of 45days orally. The control rats received saline/propylene glycol. INH alone and AZT+INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT+INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT+INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of

  13. Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin.

    PubMed

    Raghu, Ramanathan; Karthikeyan, Sivanesan

    2016-09-01

    HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT+INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT+INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n=6 in each group) were administered AZT alone (50mg/kg b.w.), INH alone (25mg/kg, b.w.), AZT+INH (50mg/kg, b.w. and 25mg/kg, b.w.), SBN alone (100mg/kg, b.w.) and SBN+AZT+INH daily for sub-chronic period of 45days orally. The control rats received saline/propylene glycol. INH alone and AZT+INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT+INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT+INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of

  14. New Regimens to Prevent Tuberculosis in Adults with HIV Infection

    PubMed Central

    Martinson, Neil A.; Barnes, Grace L.; Moulton, Lawrence H.; Msandiwa, Reginah; Hausler, Harry; Ram, Malathi; McIntyre, James A.; Gray, Glenda E.; Chaisson, Richard E.

    2012-01-01

    BACKGROUND Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment. METHODS We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival. RESULTS The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine–isoniazid group, 2.9 per 100 person-years in the rifampin–isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance. CONCLUSIONS On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid. PMID:21732833

  15. Cognitive-Behavioral Therapy for Suicide Prevention (CBT-SP): Treatment Model, Feasibility, and Acceptability

    ERIC Educational Resources Information Center

    Stanley, Barbara; Brown, Gregory; Brent, David A.; Wells, Karen; Poling, Kim; Curry, John; Kennard, Betsy D.; Wagner, Ann; Cwik, Mary F.; Klomek, Anat Brunstein; Goldstein, Tina; Vitiello, Benedetto; Barnett, Shannon; Daniel, Stephanie; Hughes, Jennifer

    2009-01-01

    Objective: To describe the elements of a manual-based cognitive-behavioral therapy for suicide prevention (CBT-SP) and to report its feasibility in preventing the recurrence of suicidal behavior in adolescents who have recently attempted suicide. Method: The CBT-SP was developed using a risk reduction and relapse prevention approach and…

  16. Reagent Precoated Targets for Rapid In-Tissue Derivatization of the Anti-Tuberculosis Drug Isoniazid Followed by MALDI Imaging Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Manier, M. Lisa; Reyzer, Michelle L.; Goh, Anne; Dartois, Veronique; Via, Laura E.; Barry, Clifton E.; Caprioli, Richard M.

    2011-08-01

    Isoniazid (INH) is an important component of front-line anti-tuberculosis therapy with good serum pharmacokinetics but unknown ability to penetrate tuberculous lesions. However, endogenous background interferences hinder our ability to directly analyze INH in tissues. Chemical derivatization has been successfully used to measure isoniazid directly from tissue samples using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). MALDI targets were pretreated with trans-cinnamaldehyde (CA) prior to mounting tissue slices. Isoniazid present in the tissues was efficiently derivatized and the INH-CA product measured by MS/MS. Precoating of MALDI targets allows the tissues to be directly thaw-mounted and derivatized, thus simplifying the preparation. A time-course series of tissues from tuberculosis infected/INH dosed animals were assayed and the MALDI MS/MS response correlates well with the amount of INH determined to be in the tissues by high-performance liquid chromatography (HPLC)-MS/MS.

  17. DNA Methyltransferases: A Novel Target for Prevention and Therapy

    PubMed Central

    Subramaniam, Dharmalingam; Thombre, Ravi; Dhar, Animesh; Anant, Shrikant

    2013-01-01

    Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers. PMID:24822169

  18. Broad targeting of angiogenesis for cancer prevention and therapy.

    PubMed

    Wang, Zongwei; Dabrosin, Charlotta; Yin, Xin; Fuster, Mark M; Arreola, Alexandra; Rathmell, W Kimryn; Generali, Daniele; Nagaraju, Ganji P; El-Rayes, Bassel; Ribatti, Domenico; Chen, Yi Charlie; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G; Nowsheen, Somaira; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S Salman; Helferich, Bill; Yang, Xujuan; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Halicka, Dorota; Mohammed, Sulma I; Azmi, Asfar S; Bilsland, Alan; Keith, W Nicol; Jensen, Lasse D

    2015-12-01

    pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.

  19. Broad targeting of angiogenesis for cancer prevention and therapy

    PubMed Central

    Wang, Zongwei; Dabrosin, Charlotta; Yin, Xin; Fuster, Mark M.; Arreola, Alexandra; Rathmell, W. Kimryn; Generali, Daniele; Nagaraju, Ganji P.; El-Rayes, Bassel; Ribatti, Domenico; Chen, Yi Charlie; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Nowsheen, Somaira; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S. Salman; Helferich, Bill; Yang, Xujuan; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Halicka, Dorota; Mohammed, Sulma I.; Azmi, Asfar S.; Bilsland, Alan; Keith, W. Nicol; Jensen, Lasse D.

    2015-01-01

    angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies. PMID:25600295

  20. Isoniazid cocrystals with anti-oxidant hydroxy benzoic acids

    NASA Astrophysics Data System (ADS)

    Mashhadi, Syed Muddassir Ali; Yunus, Uzma; Bhatti, Moazzam Hussain; Tahir, Muhammad Nawaz

    2014-11-01

    Isoniazid is the primary constituent of “triple therapy” used to effectively treat tuberculosis. In tuberculosis and other diseases, tissue inflammation and free radical burst from macrophages results in oxidative stress. These free radicals cause pulmonary inflammation if not countered by anti-oxidants. Therefore, in the present study cocrystals of isoniazid with four anti-oxidant hydroxy benzoic acids have been reported. Gallic acid, 2,3-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, and 3-hydroxybenzoic acid resulted in the formation of cocrystals when reacted with isoniazid. Cocrystal structure analysis confirmed the existence of pyridine-carboxylic acid synthon in the cocrystals of isoniazid with Gallic acid, 2,3-dihydroxybenzoic acid and 3-hydroxybenzoic acid. While cocrystal of 3,5-dihydroxybenzoic acid formed the pyridine-hydroxy group synthon. Other synthons of different graph sets are formed between hydrazide group of isoniazid and coformers involving Nsbnd H⋯O and Osbnd H⋯N bonds. All the cocrystals were in 1:1 stoichiometric ratio.

  1. Transgenerational Solidarity: The Expanding Context of Therapy and Prevention.

    ERIC Educational Resources Information Center

    Boszormenyi-Nagy, Ivan

    1986-01-01

    Defines contextual therapy as therapeutic synthesis of family (relational), biological, and individual (psychotherapy) methodologies. Translates the ethics of "relational responsibility" into intervention methods and strategies. Explores consequences of the therapies as a common denominator for the three philosophies. (Author/ABB)

  2. Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis†

    PubMed Central

    Hazbón, Manzour Hernando; Brimacombe, Michael; Bobadilla del Valle, Miriam; Cavatore, Magali; Guerrero, Marta Inírida; Varma-Basil, Mandira; Billman-Jacobe, Helen; Lavender, Caroline; Fyfe, Janet; García-García, Lourdes; León, Clara Inés; Bose, Mridula; Chaves, Fernando; Murray, Megan; Eisenach, Kathleen D.; Sifuentes-Osornio, José; Cave, M. Donald; Ponce de León, Alfredo; Alland, David

    2006-01-01

    The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes. PMID:16870753

  3. Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis.

    PubMed

    Hazbón, Manzour Hernando; Brimacombe, Michael; Bobadilla del Valle, Miriam; Cavatore, Magali; Guerrero, Marta Inírida; Varma-Basil, Mandira; Billman-Jacobe, Helen; Lavender, Caroline; Fyfe, Janet; García-García, Lourdes; León, Clara Inés; Bose, Mridula; Chaves, Fernando; Murray, Megan; Eisenach, Kathleen D; Sifuentes-Osornio, José; Cave, M Donald; Ponce de León, Alfredo; Alland, David

    2006-08-01

    The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes. PMID:16870753

  4. Effects of Dosage, Comorbidities, and Food on Isoniazid Pharmacokinetics in Peruvian Tuberculosis Patients

    PubMed Central

    Davies, Geraint; Waterhouse, David; Ardrey, Alison; Jave, Oswaldo; López-Romero, Sonia Llanet; Ward, Stephen A.; Moore, David A. J.

    2014-01-01

    Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic (PK) parameters can be affected by several factors, such as comorbidities or the interaction of TB drugs with food. This study aimed to determine the PK of isoniazid (INH) in a Peruvian TB population under observed daily and twice-weekly (i.e., biweekly) therapy. Isoniazid levels were analyzed at 2 and 6 h after drug intake using liquid chromatography mass spectrometric methods. A total of 107 recruited patients had available PK data; of these 107 patients, 42.1% received biweekly isoniazid. The mean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day (P < 0.001), and this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 6 h (AUC0–6) were 2.77 mg/liter and 9.71 mg·h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg·h/liter, respectively, for biweekly administration. There were no differences in the Cmax with respect to gender, diabetes mellitus (DM) status, or HIV status. Food was weakly associated with lower levels of isoniazid during the continuation phase. Overall, 34% of patients during the intensive phase and 33.3% during the continuation phase did not reach the Cmax reference value. However, low levels of INH were not associated with poorer clinical outcomes. In our population, INH exposure was affected by weight-adjusted dose and by food, but comorbidities did not indicate any effect on PK. We were unable to demonstrate a clear relationship between the Cmax and treatment outcome in this data set. Twice-weekly weight-adjusted dosing of INH appears to be quite robust with respect to important potentially influential patient factors under program conditions. PMID:25224007

  5. Antiretroviral Therapy as HIV Prevention: Status and Prospects

    PubMed Central

    Venkatesh, Kartik K.

    2010-01-01

    As antiretroviral treatment of HIV infection has become increasingly accessible, attention has focused on whether these drugs can used for prevention because of increased tolerability of newer medications, decreased cost, and the limitations of other approaches. We review the status of antiretroviral HIV prevention, including chemoprophylaxis, as well as the effects of treatment of infected individuals on prevention. It is possible that the life-saving agents that have transformed the natural history of AIDS can be a critical component of HIV prevention efforts, but their ultimate role in affecting HIV transmission dynamics remains to be defined. PMID:20724682

  6. Antitubercular activity of Ru (II) isoniazid complexes.

    PubMed

    Aguiar, Inara de; Tavares, Aline; Roveda, Antonio C; da Silva, Augusto C H; Marino, Leonardo B; Lopes, Érica O; Pavan, Fernando R; Lopes, Luiz G F; Franco, Douglas W

    2015-04-01

    Despite the resistance developed by the Mycobacterium tuberculosis (MTb) strains, isoniazid (INH) has been recognized as one of the best drug for treatment of Tuberculosis (Tb). The coordination of INH to ruthenium metal centers was investigated as a strategy to enhance the activity of this drug against the sensitive and resistant strains of MTb. The complexes trans-[Ru(NH3)4(L)(INH)](2+) (L=SO2 or NH3) were isolated and their chemical and antituberculosis properties studied. The minimal inhibitory concentration (MIC) data show that [Ru(NH3)5(INH)](2+) was active in both resistant and sensitive strains, whereas free INH (non-coordinated) showed to be active only against the sensitive strain. The coordination of INH to the metal center in both [Ru(NH3)5(INH)](2+) and trans-[Ru(NH3)4(SO2)(INH)](2+) complexes led to a shift in the INH oxidation potential to less positive values compared to free INH. Despite, the ease of oxidation of INH did not lead to an increase in the in vitro INH activity against MTb, it might have provided sensitivity toward resistant strains. Furthermore, ruthenium complexes with chemical structures analogous to those described above were synthesized using the oxidation products of INH as ligands (namely, isonicotinic acid and isonicotinamide). These last compounds were not active against any strains of MTb. Moreover, according to DFT calculations the formation of the acyl radical, a proposed intermediate in the INH oxidation, is favored in the [Ru(NH3)5(INH)](2+) complex by 50.7kcalmol(-1) with respect to the free INH. This result suggests that the stabilization of the acyl radical promoted by the metal center would be a more important feature than the oxidation potential of the INH for the antituberculosis activity against resistant strains.

  7. Isoniazid interaction with phosphatidylcholine-based membranes

    NASA Astrophysics Data System (ADS)

    Marques, Amanda Vicente; Marengo Trindade, Paulo; Marques, Sheylla; Brum, Tainá; Harte, Etienne; Rodrigues, Marieli Oliveira; D'Oca, Marcelo Gonçalves Montes; da Silva, Pedro Almeida; Pohlmann, Adriana R.; Alves, Isabel Dantas; de Lima, Vânia Rodrigues

    2013-11-01

    Interaction between the anti-tuberculosis drug isoniazid (INH) and phosphatidylcholine membranes was investigated in terms of: (i) drug affinity to a lipid bilayer and (ii) drug-induced changes in the dynamic properties of liposomes, such as membrane hydration state, polar head and non-polar acyl chain order and lipid phase transition behavior. These parameters were studied by plasmon waveguide resonance spectroscopy (PWR), UV-visible, horizontal attenuated total reflectance-Fourier transform infrared (HATR-FTIR), nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC) techniques. PWR measurements showed an INH membrane dissociation constant value of 0.031 μM to phosphatidylcholine bilayers. INH induced higher membrane perturbation in the plane which is perpendicular to the membrane plane. The INH saturation concentration in phosphatidylcholine liposomes was 170 μM. At this concentration, HATR-FTIR and NMR findings showed that INH may interact with the lipid polar head, increasing the number of hydrogen bonds in the phosphate region and enhancing the choline motional freedom. DSC measurements showed that, at 115 μM, INH was responsible for a decrease in lipid phase transition temperature of approximately 2 °C and had no influence in the lipid enthalpy variation (ΔH). However, at 170 μM, INH induced the reduction of the ΔH by approximately 52%, suggesting that the drug may increase the distance among lipid molecules and enhance the freedom of the lipid acyl chains methylene groups. This paper provides information on the effects of INH on membrane dynamics which is important to understand liposome targeting of the drug and for the development of anti-TB pharmacologic systems that not only are less susceptible to resistance but also have low toxicity.

  8. Mind-body therapy in the management and prevention of coronary disease.

    PubMed

    Pandya, D P; Vyas, V H; Vyas, S H

    1999-05-01

    Conventional mind-body therapy has been proven a valuable noninvasive way to manage coronary disease. Yoga practice, especially, has been found to be valuable in preventing adverse outcomes of coronary disease by improving resistance to stress.

  9. The efficacy of sucralfate suspension in the prevention of oral mucositis due to radiation therapy

    SciTech Connect

    Epstein, J.B.; Wong, F.L.W. )

    1994-02-01

    The purpose of this study was to assess the value of sucralfate suspension in prevention of oral mucositis and for reduction of oral pain in patients who develop mucositis during radiation therapy. The study was a double-blind, placebo-controlled, randomized prospective trial of a sucralfate suspension in the prevention and management of oral mucositis during radiation therapy. Oral mucositis was assessed using a quantitative scale and symptoms were assessed using visual analogue scales. The statistical model was developed to detect a 40% reduction in mucositis. No statistically significant reduction in mucositis was seen. Early during radiation therapy less oral pain was reported in the sucralfate group, but as treatment progressed all patients experienced pain. Patients in the sucralfate group were prescribed topical and systemic analgesics later in the course of radiation therapy. Prophylactic oral rinsing with sucralfate did not prevent oral ulcerative mucositis. Sucralfate may reduce the experience of pain during radiation therapy. 32 refs., 3 tabs.

  10. Inactivation of isoniazid by Canadian Eskimos and Indians

    PubMed Central

    Jeanes, C. W. L.; Schaefer, O.; Eidus, L.

    1972-01-01

    Phenotyping for isoniazid inactivation in Canadian Eskimos and Indians showed that the former are all fast acetylators, while only 63.4% of the Indians examined belonged to the same group. Further studies are suggested to confirm this initial finding. During the investigation metabolic studies were carried out to devise a reliable urine test for phenotyping of isoniazid inactivators, to replace the fall-off technique which required venipunctures. The simplicity of the new urine test makes it suitable for mass examinations. PMID:5061127

  11. Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.

    PubMed

    Fowler, Mary G; Qin, Min; Fiscus, Susan A; Currier, Judith S; Flynn, Patricia M; Chipato, Tsungai; McIntyre, James; Gnanashanmugam, Devasena; Siberry, George K; Coletti, Anne S; Taha, Taha E; Klingman, Karin L; Martinson, Francis E; Owor, Maxensia; Violari, Avy; Moodley, Dhayendre; Theron, Gerhard B; Bhosale, Ramesh; Bobat, Raziya; Chi, Benjamin H; Strehlau, Renate; Mlay, Pendo; Loftis, Amy J; Browning, Renee; Fenton, Terence; Purdue, Lynette; Basar, Michael; Shapiro, David E; Mofenson, Lynne M

    2016-11-01

    Background Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. Methods We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. Results The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated

  12. Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights Be Translated Into Therapies?

    PubMed Central

    Kirpalani, Haresh

    2011-01-01

    Bronchopulmonary dysplasia (BPD) frequently complicates preterm birth and leads to significant long-term morbidity. Unfortunately, few therapies are known to effectively prevent or treat BPD. Ongoing research has been focusing on potential therapies to limit inflammation in the preterm lung. In this review we highlight recent bench and clinical research aimed at understanding the role of inflammation in the pathogenesis of BPD. We also critically assess currently used therapies and promising developments in the field. PMID:21646264

  13. Cognitive-Behavioral Therapy to Prevent Relapse in Pediatric Responders to Pharmacotherapy for Major Depressive Disorder

    ERIC Educational Resources Information Center

    Kennard, Betsy D.; Emslie, Graham J.; Mayes, Taryn L.; Nightingale-Teresi, Jeanne; Nakonezny, Paul A.; Hughes, Jennifer L.; Jones, Jessica M.; Tao, Rongrong; Stewart, Sunita M.; Jarrett, Robin B.

    2008-01-01

    The outcome of a sequential treatment strategy that included cognitive behavioral therapy (CBT) in the prevention of major depressive disorder relapse among 46 youths is examined. Results show that youths under the antidepressant medication management plus relapse prevention CBT treatment was at lower risk for relapse than those under the…

  14. Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin.

    PubMed

    Meng, Xiaoli; Maggs, James L; Usui, Toru; Whitaker, Paul; French, Neil S; Naisbitt, Dean J; Park, B Kevin

    2015-01-20

    Isoniazid (INH), a widely used antituberculosis drug, has been associated with serious drug-induced liver injury (DILI). INH-modified proteins have been proposed to play important roles in INH DILI; however, it remains to be determined whether INH or reactive metabolites bind irreversibly to proteins. In this study, mass spectrometry was used to define protein modifications by INH in vitro and in patients taking INH therapy. When INH was incubated with N-acetyl lysine (NAL), the same isonicotinic-NAL (IN-NAL) adducts were detected irrespective of the presence or absence of any oxidative enzymes, indicating auto-oxidation may have been involved. In addition, we found that INH could also bind to human serum albumin (HSA) via an auto-oxidation pathway, forming isonicotinic amide adducts with lysine residues in HSA. Similar adducts were detected in plasma samples isolated from patients taking INH therapy. Our results show that INH forms protein adducts in the absence of metabolism.

  15. Can antiretroviral therapy be used to prevent sexual transmission of human immunodeficiency virus type 1?

    PubMed

    Hosseinipour, Mina; Cohen, Myron S; Vernazza, Pietro L; Kashuba, Angela D M

    2002-05-15

    Approximately 5 million people annually are newly infected with human immunodeficiency virus (HIV). Although education, behavior modification, and promotion of condom use are effective transmission-prevention measures, the severity of the pandemic demands that all possible prevention strategies be explored. Antiretroviral therapy has the potential to decrease sexual transmission of HIV type 1 by reducing levels of HIV RNA and thus decreasing the risk that infected persons will transmit the disease or by its use as preexposure or postexposure prophylaxis. In this article, we explore the rationale for using antiretroviral therapy to prevent sexual transmission of HIV, as well as the limitations of this approach. PMID:11981736

  16. [The therapeutic potential of cerebrolysin in the preventive therapy of Alzheimer's disease].

    PubMed

    Gavrilova, S I; Fedorova, Ia B; Kolykhalov, I V; Odinak, M M; Emelin, A Iu; Kashin, A V; Selezneva, N D; Kalyn, Ia B; Roshchina, I F

    2008-01-01

    A potential of prolonged 2-years course of cerebrolysin therapy with courses repeated every 6 months to slow down or prevent the transition of the syndrome of mild cognitive impairment, amnestic type, to clinically relevant dementia has been studied in the open comparative study of 73 patients divided into 2 groups, one of which included patients treated with cerebrolysin and another one those who did not receive this drug. The effect of the 2-years course therapy with cerebrolysin suggested by the authors has been proven. Such therapy allows to prevent the progression of cognitive deficit and development of dementia of Alzheimer's type. The results obtained give grounds to recommend this course therapy for prevention of dementia in elderly patients with mild cognitive impairment.

  17. Comparison of isoniazid monoresistant tuberculosis with drug-susceptible tuberculosis and multidrug-resistant tuberculosis.

    PubMed

    Fox, L; Kramer, M R; Haim, I; Priess, R; Metvachuk, A; Shitrit, D

    2011-07-01

    Limited data exist about the clinical characteristics of Mycobacterium tuberculosis (TB) isolates with resistance to isoniazid (IZN). We describe the demographic and clinical characteristics and risk factor information for persons with IZN monoresistant (resistant to isoniazid) TB compared with drug-susceptible TB and multidrug-resistant (MDR) TB. From 2002 to 2009, 590 cases of TB were diagnosed. Of these, 44 (7.5%) developed MDR-TB and 38 (6.4%) had IZN monoresistant TB. Among the IZN monoresistant TB patients, more common demographic characteristics were former resident of the Soviet Union immigrant, smoker, and previous history of TB (p = 0.005, 0.025, and 0.005, respectively), while HIV, weight loss, and hemoptysis were less common (p = 0.005 for all parameters). The mean length of treatment was 24 ± 4 months for MDR-TB, 10 ± 3 months for IZN monoresistant TB cases, and 8 ± 2 months for all other TB cases. The directly observed therapy (DOT) rate was similar in all three groups. However, treatment failure, completion of TB treatment, and mortality were all similar in drug-susceptible TB and higher in MDR-TB. In multivariate analysis, only a history of previous TB (odds ratio [OR] 1.4; 95% confidence interval [CI]: 1.2-1.6) was significantly associated with IZN monoresistant TB. IZN monoresistant TB has distinct characteristics. However, the length of treatment and outcome are similar to drug-susceptible TB cases.

  18. The Wilderness Therapy Prevention Program: A Prevention Model for At-Risk Children and Adolescents

    ERIC Educational Resources Information Center

    Butler, Meghan

    2008-01-01

    Wilderness Therapy Programs have recently become a formal alternative treatment for adolescents with emotional and behavioral disorders (Hinkle, 1999; Russell & Hendee, 1999; Russell, Hendee, & Phillips-Miller, 2000; Russell, 2003a, 2003b). Adolescent populations are unique in that traditional forms of psychotherapy, including "talk-therapies,"…

  19. Sustained-release dosage forms of microencapsulated isoniazid.

    PubMed

    Jalsenjak, I; Nixon, J R; Senjkovic, R; Stivic, I

    1980-10-01

    The preparation and release characteristics of microcapsules of isoniazid have been studied. The differing techniques of microencapsulation are assessed and the dissolution of drug from suspended and tableted microcapsules prepared using the chosen technique has been monitored for in vitro release.

  20. Hepatotoxicity mechanisms of isoniazid: A mini-review.

    PubMed

    Hassan, Hozeifa M; Guo, Hong-Li; Yousef, Bashir A; Luyong, Zhang; Zhenzhou, Jiang

    2015-12-01

    Isoniazid (INH) is an antituberculosis drug associated with idiosyncratic liver injury in susceptible patients. INH-induced hepatotoxicity remains a significant clinical problem, but the underlying mechanisms are still unclear, despite the growing evidence that INH and/or its major metabolite, hydrazine, play an important role in hepatotoxicity. PMID:26095833

  1. Inhibitory activity of isoniazid and ethionamide against Cryptococcus biofilms.

    PubMed

    Cordeiro, Rossana de Aguiar; Serpa, Rosana; Marques, Francisca Jakelyne de Farias; de Melo, Charlline Vládia Silva; Evangelista, Antonio José de Jesus; Mota, Valquíria Ferreira; Brilhante, Raimunda Sâmia Nogueira; Bandeira, Tereza de Jesus Pinheiro Gomes; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa

    2015-11-01

    In recent years, the search for drugs to treat systemic and opportunistic mycoses has attracted great interest from the scientific community. This study evaluated the in vitro inhibitory effect of the antituberculosis drugs isoniazid and ethionamide alone and combined with itraconazole and fluconazole against biofilms of Cryptococcus neoformans and Cryptococcus gattii. Antimicrobials were tested at defined concentrations after susceptibility assays with Cryptococcus planktonic cells. In addition, we investigated the synergistic interaction of antituberculosis drugs and azole derivatives against Cryptococcus planktonic cells, as well as the influence of isoniazid and ethionamide on ergosterol content and cell membrane permeability. Isoniazid and ethionamide inhibited both biofilm formation and viability of mature biofilms. Combinations formed by antituberculosis drugs and azoles proved synergic against both planktonic and sessile cells, showing an ability to reduce Cryptococcus biofilms by approximately 50%. Furthermore, isoniazid and ethionamide reduced the content of ergosterol in Cryptococcus spp. planktonic cells and destabilized or permeabilized the fungal cell membrane, leading to leakage of macromolecules. Owing to the paucity of drugs able to inhibit Cryptococcus biofilms, we believe that the results presented here might be of interest in the designing of new antifungal compounds.

  2. Developing Cognitive Behavioral Therapy to Prevent Depressive Relapse in Youth

    ERIC Educational Resources Information Center

    Kennard, Betsy D.; Stewart, Sunita M.; Hughes, Jennifer L.; Jarrett, Robin B.; Emslie, Graham J.

    2008-01-01

    Relapse rates for children and adolescents with major depressive disorder (MDD) range from 30% to 40% within 1 to 2 years after acute treatment. Although relapse rates are high, there have been relatively few studies on the prevention of relapse in youth. While acute phase pharmacotherapy has been shown to reduce symptoms rapidly in depressed…

  3. Cardiovascular disease: primary prevention, disease modulation and regenerative therapy.

    PubMed

    Sultan, Sherif; Hynes, Niamh

    2012-10-01

    Cardiovascular primary prevention and regeneration programs are the contemporary frontiers in functional metabolic vascular medicine. This novel science perspective harnesses our inherent ability to modulate the interface between specialized gene receptors and bioavailable nutrients in what is labeled as the nutrient-gene interaction. By mimicking a natural process through the conveyance of highly absorbable receptor specific nutrients, it is feasible to accelerate cell repair and optimize mitochondrial function, thereby achieving cardiovascular cure. We performed a comprehensive review of PubMed, EMBASE and Cochrane Review databases for articles relating to cardiovascular regenerative medicine, nutrigenomics and primary prevention, with the aim of harmonizing their roles within contemporary clinical practice. We searched in particular for large-scale randomized controlled trials on contemporary cardiovascular pharmacotherapies and their specific adverse effects on metabolic pathways which feature prominently in cardiovascular regenerative programs, such as nitric oxide and glucose metabolism. Scientific research on 'cardiovascular-free' centenarians delineated that low sugar and low insulin are consistent findings. As we age, our insulin level increases. Those who can decelerate the rapidity of this process are prompting their cardiovascular rejuvenation. It is beginning to dawn on some clinicians that contemporary treatments are not only failing to impact on our most prevalent diseases, but they may be causing more damage than good. Primary prevention programs are crucial elements for a better outcome. Cardiovascular primary prevention and regeneration programs have enhanced clinical efficacy and quality of life and complement our conventional endovascular practice.

  4. Beta-endorphin cell therapy for cancer prevention.

    PubMed

    Zhang, Changqing; Murugan, Sengottuvelan; Boyadjieva, Nadka; Jabbar, Shaima; Shrivastava, Pallavi; Sarkar, Dipak K

    2015-01-01

    β-Endorphin (BEP)-producing neuron in the hypothalamus plays a key role in bringing the stress axis to a state of homeostasis and maintaining body immune defense system. Long-term delivery of BEP to obtain beneficial effect on chemoprevention is challenging, as the peptides rapidly develop tolerance. Using rats as animal models, we show here that transplantation of BEP neurons into the hypothalamus suppressed carcinogens- and hormone-induced cancers in various tissues and prevented growth and metastasis of established tumors via activation of innate immune functions. In addition, we show that intracerebroventricular administration of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) increased the number of BEP neurons in the hypothalamus, reduced the stress response, enhanced the innate immune function, and prevented tumor cell growth, progression, and metastasis. BEP neuronal supplementation did not produce any deleterious effects on general health but was beneficial in suppressing age-induced alterations in physical activity, metabolic, and immune functions. We conclude that the neuroimmune system has significant control over cancer growth and progression, and that activation of the neuroimmune system via BEP neuronal supplementation/induction may have therapeutic value for cancer prevention and improvement of general health. PMID:25403848

  5. Beta-endorphin Cell Therapy for Cancer Prevention

    PubMed Central

    Zhang, Changqing; Murugan, Sengottuvelan; Boyadjieva, Nadka; Jabbar, Shaima; Shrivastava, Pallavi; Sarkar, Dipak K.

    2014-01-01

    Beta-endorphin (BEP) producing neuron in the hypothalamus plays a key role in brining the stress axis to a state of homeostasis and maintaining body immune defense system. Long-term delivery of BEP to obtain beneficial effect on chemoprevention is challenging, since the peptide rapidly develop tolerance. Using rats as animal model, we show here that transplantation of beta-endorphin neurons into the hypothalamus suppressed carcinogens- and hormone-induced cancers in various tissues and prevented growth and metastasis of established tumors via activation of innate immune functions. Additionally, we show that intracerebroventricular administration of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) increased the number of BEP neurons in the hypothalamus, reduced the stress response, enhanced the innate immune function and prevented tumor cell growth, progression and metastasis. Beta-endorphin neuronal supplementation did not produce any deleterious effects on general health but was beneficial in suppressing age-induced alterations in physical activity, metabolic and immune functions. We conclude that the neuroimmune system has significant control over cancer growth and progression and that activation of the neuroimmune system via beta-endorphin neuronal supplementation/induction may have therapeutic value for cancer prevention and improvement of general health. PMID:25403848

  6. Congenital cytomegalovirus infection: new prospects for prevention and therapy.

    PubMed

    Swanson, Elizabeth C; Schleiss, Mark R

    2013-04-01

    Cytomegalovirus is the commonest congenital viral infection in the developed world, with an overall prevalence of approximately 0.6%. Approximately 10% of congenitally infected infants have signs and symptoms of disease at birth, and these symptomatic infants have a substantial risk of subsequent neurologic sequelae. These include sensorineural hearing loss, mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy. Antiviral therapy for children with symptomatic congenital cytomegalovirus infection is effective at reducing the risk of long-term disabilities and should be offered to families with affected newborns. An effective preconceptual vaccine against CMV could protect against long-term neurologic sequelae and other disabilities.

  7. Antiemetic Therapy With or Without Olanzapine in Preventing Chemotherapy-Induced Nausea and Vomiting in Patients With Cancer Receiving Highly Emetogenic Chemotherapy | Division of Cancer Prevention

    Cancer.gov

    This randomized phase III trial studies antiemetic therapy with olanzapine to see how well they work compared to antiemetic therapy alone in preventing chemotherapy-induced nausea and vomiting in patients with cancer receiving highly emetogenic (causes vomiting) chemotherapy. Antiemetic drugs, such as palonosetron hydrochloride, ondansetron, and granisetron hydrochloride, may help lessen or prevent nausea and vomiting in patients treated with chemotherapy. |

  8. Cardiotoxicity associated with cancer therapy: pathophysiology and prevention strategies.

    PubMed

    Adão, Rui; de Keulenaer, Gilles; Leite-Moreira, Adelino; Brás-Silva, Carmen

    2013-05-01

    Cardiotoxicity is one of the most significant adverse effects of cancer treatment, and is responsible for considerable morbidity and mortality. Among the effects of chemotherapeutic agents on the cardiovascular system, the most frequent and serious is heart failure with ventricular systolic dysfunction. Other toxic effects include hypertension, thromboembolic disease, pericardial disease, arrhythmias and myocardial ischemia. For several decades, cancer therapy-induced cardiomyopathy was almost exclusively associated with the use of cumulative doses of anthracyclines, which cause permanent damage at the cellular level. However, new therapeutic agents, such as the monoclonal antibody trastuzumab, induce transient reversible myocyte dysfunction which is unrelated to the dose used. Early identification of potential cardiovascular injury, accurate diagnosis of cardiotoxic events and implementation of appropriate monitoring plans are essential in patients with cancer. Close cooperation between cardiologists and oncologists is thus crucial, in order to balance the risks and benefits of cardiotoxic anticancer therapy. In this article we review the various responses to cardiotoxic cancer treatments and their relationship with the main antineoplastic drugs used in clinical practice. In addition, we discuss the main guidelines on detection and monitoring of cardiotoxicity in patients with cancer.

  9. How does cognitive therapy prevent depressive relapse and why should attentional control (mindfulness) training help?

    PubMed

    Teasdale, J D; Segal, Z; Williams, J M

    1995-01-01

    There is encouraging evidence that structured psychological treatments for depression, in particular cognitive therapy, can reduce subsequent relapse after the period of initial treatment has been completed. However, there is a continuing need for prophylactic psychological approaches that can be administered to recovered patients in euthymic mood. An information-processing analysis of depressive maintenance and relapse is used to define the requirements for effective prevention, and to propose mechanisms through which cognitive therapy achieves its prophylactic effects. This analysis suggests that similar effects can be achieved using techniques of stress-reduction based on the skills of attentional control taught in mindfulness meditation. An information-processing analysis is presented of mindfulness and mindlessness, and of their relevance to preventing depressive relapse. This analysis provides the basis for the development of Attentional Control Training, a new approach to preventing relapse that integrates features of cognitive therapy and mindfulness training and is applicable to recovered depressed patients.

  10. [Suicidality in mental illness – prevention and therapy].

    PubMed

    Röcker, Sabine; Bachmann, Silke

    2015-10-01

    The great majority of suicides and suicide attempts are related to mental illness. Special risk has been attributed to depression, psychosis, substance use, personality, and trauma-related disorders. Many affected persons seek medical attention prior to taking action. Primary care therefor plays an outstanding role in suicide prevention. Doctors should pay attention to potential risk constellations and actively address the issue. This paper presents possibly helpful models and instruments for everyday use. Most importantly, however, professionals’ empathy and time are required as well as appropriate decisions concerning a referral to a psychiatrist or psychiatric inpatient treatment.

  11. Trimetazidine therapy prevents obesity-induced cardiomyopathy in mice.

    PubMed

    Ussher, John R; Fillmore, Natasha; Keung, Wendy; Mori, Jun; Beker, Donna L; Wagg, Cory S; Jaswal, Jagdip S; Lopaschuk, Gary D

    2014-08-01

    Obesity is a significant risk factor for the development of cardiovascular disease. Inhibiting fatty acid oxidation has emerged as a novel approach for the treatment of ischemic heart disease. Our aim was to determine whether pharmacologic inhibition of 3-ketoacyl-coenzyme A thiolase (3-KAT), which catalyzes the final step of fatty acid oxidation, could improve obesity-induced cardiomyopathy. A 3-week treatment with the 3-KAT inhibitor trimetazidine prevented obesity-induced reduction in both systolic and diastolic function. Therefore, targeting cardiac fatty acid oxidation may be a novel therapeutic approach to alleviate the growing burden of obesity-related cardiomyopathy.

  12. Barriers to preventive therapy for breast and other major cancers and strategies to improve uptake.

    PubMed

    DeCensi, Andrea; Thorat, Mangesh A; Bonanni, Bernardo; Smith, Samuel G; Cuzick, Jack

    2015-01-01

    The global cancer burden continues to rise and the war on cancer can only be won if improvements in treatment go hand in hand with therapeutic cancer prevention. Despite the availability of several efficacious agents, utilisation of preventive therapy has been poor due to various barriers, such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. In this review, we discuss these barriers in detail and propose strategies to overcome them. These strategies include improving physician awareness and countering prejudices by highlighting the important differences between preventive therapy and cancer treatment. The importance of the agent-biomarker-cohort (ABC) paradigm to improve effectiveness of preventive therapy cannot be overemphasised. Future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms, and improvements in the safety profile of existing agents by experimentation with dose. We also highlight the role of drug repurposing for providing new agents as well as to address the current imbalance between therapeutic and preventive research. In order to move the field of therapeutic cancer prevention forwards, engagement with policymakers to correct research imbalance as well as to remove practical obstacles to implementation is also urgently needed. PMID:26635899

  13. Barriers to preventive therapy for breast and other major cancers and strategies to improve uptake

    PubMed Central

    DeCensi, Andrea; Thorat, Mangesh A; Bonanni, Bernardo; Smith, Samuel G; Cuzick, Jack

    2015-01-01

    The global cancer burden continues to rise and the war on cancer can only be won if improvements in treatment go hand in hand with therapeutic cancer prevention. Despite the availability of several efficacious agents, utilisation of preventive therapy has been poor due to various barriers, such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. In this review, we discuss these barriers in detail and propose strategies to overcome them. These strategies include improving physician awareness and countering prejudices by highlighting the important differences between preventive therapy and cancer treatment. The importance of the agent–biomarker–cohort (ABC) paradigm to improve effectiveness of preventive therapy cannot be overemphasised. Future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms, and improvements in the safety profile of existing agents by experimentation with dose. We also highlight the role of drug repurposing for providing new agents as well as to address the current imbalance between therapeutic and preventive research. In order to move the field of therapeutic cancer prevention forwards, engagement with policymakers to correct research imbalance as well as to remove practical obstacles to implementation is also urgently needed. PMID:26635899

  14. Antioxidants and Coronary Artery Disease: From Pathophysiology to Preventive Therapy

    PubMed Central

    Leopold, Jane A.

    2014-01-01

    Oxidant stress in the cardiovascular system may occur when antioxidant capacity is insufficient to reduce reactive oxygen species and other free radicals. Oxidant stress has been linked to the pathogenesis of atherosclerosis and incident coronary artery disease. As a result of this connection, early observational studies focused on dietary antioxidants, such as β-carotene, α-tocopherol, and ascorbic acid, and demonstrated an inverse relationship between intake of these antioxidants and major adverse cardiovascular events. These findings supported a number of randomized trials of selected antioxidants as primary and secondary prevention to decrease cardiac risk; however, many of these studies reported disappointing results with little or no observed risk reduction in antioxidant treated patients. Several plausible explanations for these findings have been suggested, including incorrect antioxidant choice or dose, synthetic versus dietary antioxidant as the intervention, and patient selection, all of which will be important to consider when designing future clinical trials. This review will focus on the contemporary evidence that is the basis for our current understanding of the role of antioxidants in cardiovascular disease prevention. PMID:25369999

  15. Antioxidants and coronary artery disease: from pathophysiology to preventive therapy.

    PubMed

    Leopold, Jane A

    2015-03-01

    Oxidant stress in the cardiovascular system may occur when antioxidant capacity is insufficient to reduce reactive oxygen species and other free radicals. Oxidant stress has been linked to the pathogenesis of atherosclerosis and incident coronary artery disease. As a result of this connection, early observational studies focused on dietary antioxidants, such as β-carotene, α-tocopherol, and ascorbic acid, and demonstrated an inverse relationship between intake of these antioxidants and major adverse cardiovascular events. These findings supported a number of randomized trials on the use of selected antioxidants as primary or secondary prevention strategies to decrease cardiac risk; however, many of these studies reported disappointing results with little or no observed risk reduction in antioxidant-treated patients. Several plausible explanations for these findings have been suggested, including incorrect antioxidant choice or dose, synthetic versus dietary antioxidants as the intervention, and patient selection, all of which will be important to consider when designing future clinical trials. This review will focus on the contemporary evidence that is the basis for our current understanding of the role of antioxidants in cardiovascular disease prevention.

  16. BRCA1 as target for breast cancer prevention and therapy.

    PubMed

    Romagnolo, Alberto P G; Romagnolo, Donato F; Selmin, Ornella I

    2015-01-01

    The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation of the BRCA1 protein, including its role associated with familial and sporadic breast cancer. The second part is an overview of the therapeutic compounds used for breast cancer treatment targeting BRCA1, and the natural food components that hold potential preventive effect against those types of breast cancer in which BRCA1 expression is either reduced or lacking. Further studies elucidating the interactions between dietary compounds and cellular pathways, involved in regulation of BRCA1expression, are necessary for the development of strategies that may successfully prevent or treat breast cancer.

  17. A virtual simulator designed for collision prevention in proton therapy

    SciTech Connect

    Jung, Hyunuk; Kum, Oyeon; Han, Youngyih Park, Hee Chul; Kim, Jin Sung; Choi, Doo Ho

    2015-10-15

    Purpose: In proton therapy, collisions between the patient and nozzle potentially occur because of the large nozzle structure and efforts to minimize the air gap. Thus, software was developed to predict such collisions between the nozzle and patient using treatment virtual simulation. Methods: Three-dimensional (3D) modeling of a gantry inner-floor, nozzle, and robotic-couch was performed using SolidWorks based on the manufacturer’s machine data. To obtain patient body information, a 3D-scanner was utilized right before CT scanning. Using the acquired images, a 3D-image of the patient’s body contour was reconstructed. The accuracy of the image was confirmed against the CT image of a humanoid phantom. The machine components and the virtual patient were combined on the treatment-room coordinate system, resulting in a virtual simulator. The simulator simulated the motion of its components such as rotation and translation of the gantry, nozzle, and couch in real scale. A collision, if any, was examined both in static and dynamic modes. The static mode assessed collisions only at fixed positions of the machine’s components, while the dynamic mode operated any time a component was in motion. A collision was identified if any voxels of two components, e.g., the nozzle and the patient or couch, overlapped when calculating volume locations. The event and collision point were visualized, and collision volumes were reported. Results: All components were successfully assembled, and the motions were accurately controlled. The 3D-shape of the phantom agreed with CT images within a deviation of 2 mm. Collision situations were simulated within minutes, and the results were displayed and reported. Conclusions: The developed software will be useful in improving patient safety and clinical efficiency of proton therapy.

  18. Human papillomavirus as a target for management, prevention and therapy.

    PubMed

    Crosbie, Emma J; Kitchener, Henry C

    2012-01-01

    The discovery that human papillomavirus (HPV) is the necessary causal factor in cervical carcinogenesis has made it a target for prophylactic and therapeutic vaccines, as well as a diagnostic tool in cervical screening. Whilst prophylactic vaccination has proven very effective in terms of preventing cervical cancer precursor lesions, therapeutic strategies have presented far greater challenges. HPV testing has shown itself to be extremely valuable in the triage of low grade cytological abnormalities, test of cure following treatment of cervical intraepithelial neoplasia (CIN), and will, over the next 10 years, gradually replace cytology as the mainstay of primary cervical screening. In this review, the latest evidence supporting HPV as both a biomarker of risk for cervical cancer and a target for prophylactic and therapeutic vaccination is presented. PMID:22690976

  19. HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients

    PubMed Central

    Meintjes, Graeme; Chirehwa, Maxwell; Wiesner, Lubbe; McIlleron, Helen; Wilkinson, Robert J.

    2016-01-01

    There are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients. We report the pharmacokinetics of rifampin, isoniazid, and pyrazinamide in a cohort of patients being treated for active tuberculosis, the majority of whom were coinfected with HIV-1 and had commenced antiretroviral therapy within 2 months of starting antituberculosis treatment. We also examined the association between antituberculosis drug concentrations and reported drug side effects at the 2-month clinical review. One hundred patients with pulmonary tuberculosis (65% coinfected with HIV-1) were intensively sampled to determine rifampin, isoniazid, and pyrazinamide plasma concentrations after 7 to 8 weeks of a daily quadruple-therapy regimen dosed according to World Health Organization (WHO) weight bands. Pharmacokinetic parameters were determined for each patient by using nonlinear mixed-effects models. HIV-1-coinfected patients had lower clearance rates for rifampin (21% decrease) and isoniazid (23% decrease) than HIV-1-uninfected patients, with resulting higher areas under the concentration-time curve from 0 to 24 h (AUC0–24) and maximum concentrations of drug in serum (Cmax). Antiretroviral therapy (ART) that included double-standard-dose lopinavir/ritonavir further lowered rifampin clearance, by 46%, and increased the AUC0–24. The current uniform dosing (per kilogram of body weight) across WHO weight bands was associated with a trend of decreased pharmacokinetic exposures for the lowest weight band. Use of fat-free mass as opposed to total body weight for allometric scaling of clearance significantly improved the model. Ambulant HIV-1-coinfected patients, the majority of whom were coprescribed ART, did not have reduced antituberculosis drug concentrations compared to HIV-1-uninfected patients. PMID:27480859

  20. Extracorporeal shock wave therapy effectively prevented diabetic neuropathy

    PubMed Central

    Chen, Yi-Ling; Chen, Kuan-Hung; Yin, Tsung-Cheng; Huang, Tien-Hung; Yuen, Chun-Man; Chung, Sheng-Ying; Sung, Pei-Hsun; Tong, Meng-Shen; Chen, Chih-Hung; Chang, Hsueh-Wen; Lin, Kun-Chen; Ko, Sheung-Fat; Yip, Hon-Kan

    2015-01-01

    Background: We tested the hypothesis that extracorporeal shock wave (ECSW) therapy can effectively protect sciatic nerve (SN) from diabetes mellitus (DM)-induced neuropathy in leptin-deficient (ob/ob) mice. Methods and results: Eighteen-week C57BL/6 mice (n=8) served as age-matched controls (group 1) and ob/ob mice (n=16) were categorized into DM (group 2) and DM + ECSW (0.12 mJ/mm2 for 4 times of 200 impulses at 3-week intervals) (group 3). The animals were sacrificed two weeks post-ECSW. In vitro results showed that the protein expressions of oxidative stress (NOX-1, NOX-2, oxidized protein), inflammation (MMP-9, TNF-α, iNOS), apoptosis (Bax, cleaved caspase-3, & PARP), and DNA-damage marker (γ-H2AX) were significantly higher in RT4-D6P2T (schwannoma cell line) treated by menadione (25 µM) compared with control group and were significantly reversed after ECSW (0.12 mJ/mm2, 200 impulses) (all p<0.001). mRNA expressions of inflammation (MMP-9, TNF-α, iNOS), oxidative stress (NOX-1, NOX-2) and apoptosis (Bax, caspase-3) in SN were significantly higher in group 2 than in group 1 and were significantly reversed in group 3, whereas the mRNA expressions of anti-oxidants (HO-1, NQO1) progressively increased from group 1 to group 3 (all p<0.001). Cellular expressions of F4/80+, CD14+, γ-H2AX+ cells, and number of vacuolar formation in SN showed a pattern identical to that of inflammation markers among all groups (all p<0.001). Microscopic findings of Schwann cells and myelin-sheath scores, and number of eNOS+ cells in SN showed a reversed pattern compared to that of inflammation among all groups (all p<0.001). Conclusions: ECSW therapy protected SN against DM-induced neuropathy. PMID:26885256

  1. Prevention is the Best Therapy: The Geneticist's Approach.

    PubMed

    Altarescu, Gheona

    2016-06-01

    Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life-altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing.

  2. Can melanoma therapy change attitudes toward prevention and tanning?

    PubMed

    Konkolova, Radmila; Provaznikova, Doc Hana; Jirakova, Anna; Hercogova, Jana

    2014-01-01

    Malignant melanoma is the most lethal skin cancer whose incidence is increasing worldwide. Important is knowledge of risk factors, early diagnosis, long-term follow-up on confirmed melanoma cases and prevention. In this study, we tested melanoma patients' attitudes toward solar radiation and perception of the value of follow-up. The present cross-sectional epidemiological study was carried out in a group of patients diagnosed with stage I and II of malignant melanoma (n = 124). They were monitored for at least 1 year. The research was carried out by anonymous questionnaire. The results revealed that the respondents welcomed the opportunity of follow-up care. Its benefits were said to outweigh the inconvenience of repeated checkups. However, the esthetic importance of a suntan was still considered quite high. Substantial reserve was found in the use of sunscreen. The need for wide public education and the protection against excessive contact with solar radiation is evident. Regular monitoring seems to be just as important.

  3. Prevention is the Best Therapy: The Geneticist's Approach.

    PubMed

    Altarescu, Gheona

    2016-06-01

    Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life-altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing. PMID:27491212

  4. Patent controversies and court cases: cancer diagnosis, therapy and prevention.

    PubMed

    Fialho, Arsenio M; Chakrabarty, Ananda M

    2012-11-01

    Patents are issued essentially by all countries on inventions that are deemed novel, non-obvious, clearly described and of significant utility or industrial application. The only exceptions to patenting an invention are abstract ideas, laws of nature and natural phenomena, although the exceptions vary depending on countries where moral, public order or human rights considerations are also taken into account. Although patent laws are updated over decades, the rapid progress of science creates situations that the patent laws on the book cannot address, leading to contentious legal issues. This is often true for life saving drugs, particularly drugs for cancers or HIV/AIDS, which are expensive and beyond the reach of poor people because of the proprietary positions of these patented drugs. Another contentious issue is the patent eligibility of human genes and mutations that are often thought of nature's contribution to human health and propagation and should be beyond the reach of patentability. In this review, we address some of these current legal issues and their implications for the development of diagnostic methods, therapeutic interventions and even prevention for cancer, a scourge of mankind.

  5. Incretin-Based Therapy for Prevention of Diabetic Vascular Complications

    PubMed Central

    Mima, Akira

    2016-01-01

    Diabetic vascular complications are the most common cause of mortality and morbidity worldwide, with numbers of affected individuals steadily increasing. Diabetic vascular complications can be divided into two categories: macrovascular andmicrovascular complications. Macrovascular complications include coronary artery diseaseand cerebrovascular disease, while microvascular complications include retinopathy and chronic kidney disease. These complications result from metabolic abnormalities, including hyperglycemia, elevated levels of free fatty acids, and insulin resistance. Multiple mechanisms have been proposed to mediate the adverse effects of these metabolic disorders on vascular tissues, including stimulation of protein kinase C signaling and activation of the polyol pathway by oxidative stress and inflammation. Additionally, the loss of tissue-specific insulin signaling induced by hyperglycemia and toxic metabolites can induce cellular dysfunction and both macro- and microvascular complications characteristic of diabetes. Despite these insights, few therapeutic methods are available for the management of diabetic complications. Recently, incretin-based therapeutic agents, such as glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, have been reported to elicit vasotropic actions, suggesting a potential for effecting an actual reduction in diabetic vascular complications. The present review will summarize the relationship between multiple adverse biological mechanisms in diabetes and putative incretin-based therapeutic interventions intended to prevent diabetic vascular complications. PMID:26881236

  6. Lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome.

    PubMed

    Thakur, B K; Verma, S; Mishra, J

    2015-06-01

    Human immunodeficiency virus-infected patients are at increased risk of drug reactions because of immune dysregulation and multiple drug intake. Lichenoid drug reactions to isoniazid have been reported previously in the literature. However, for lichenoid drug reaction to isoniazid to be so extensive to present as exfoliative dermatitis is rare. We report here a rare case of lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome.

  7. Ultrastructural characteristics of type A epithelioid cells during BCG-granulomatosis and treatment with lysosomotropic isoniazid.

    PubMed

    Shkurupii, V A; Kozyaev, M A; Nadeev, A P

    2006-04-01

    We studied BCG-granulomas, their cellular composition, and ultrastructure of type A epithelioid cells in the liver of male BALB/c mice with spontaneous granulomatous inflammation. The animals received free isoniazid or isoniazid conjugated with lysosomotropic intracellularly prolonged matrix (dialdehyde dextran, molecular weight 65-75 kDa). Lysosomotropic isoniazid was accumulated in the vacuolar apparatus of epithelioid cells and produced a stimulatory effect on plastic processes in these cells.

  8. Integrating Motivational Interviewing and Self-Determination Theory with Cognitive Behavioral Therapy to Prevent Suicide

    ERIC Educational Resources Information Center

    Britton, Peter C.; Patrick, Heather; Wenzel, Amy; Williams, Geoffrey C.

    2011-01-01

    Cognitive behavioral therapy (CBT) has been found to be effective in preventing suicide-related behavior. However, it is often difficult to engage patients who are at-risk in treatment. Motivational Interviewing (MI) has been shown to increase treatment engagement and improve treatment outcomes when it is used to complement other treatments. As a…

  9. Feasibility of a Prototype Web-Based Acceptance and Commitment Therapy Prevention Program for College Students

    ERIC Educational Resources Information Center

    Levin, Michael E.; Pistorello, Jacqueline; Seeley, John R.; Hayes, Steven C.

    2014-01-01

    Objective: This study examined the feasibility of a prototype Web-based acceptance and commitment therapy (ACT) program for preventing mental health problems among college students. Participants: Undergraduate first-year students ("N" = 76) participated between May and November 2011. Methods: Participants were randomized to ACT or a…

  10. Thyroxine administration during radiation therapy to the neck does not prevent subsequent thyroid dysfunction

    SciTech Connect

    Bantle, J.P.; Lee, C.K.; Levitt, S.H.

    1985-11-01

    In an attempt to reduce the incidence of hypothyroidism following irradiation of the neck, we administered oral L-thyroxine in doses sufficient to suppress serum TSH to 20 patients receiving radiation therapy for Hodgkin's disease or other lymphomas. L-thyroxine was discontinued when radiation therapy was completed. Twenty similar patients who did not receive L-thyroxine during radiation therapy served as a control group. After a mean follow-up period of 33 months, seven patients (35%) in the L-thyroxine group developed elevation of serum TSH and were started on chronic L-thyroxine therapy. In the control group, after mean follow-up of 19 months, five patients (25%) developed elevation of TSH and were started on chronic L-thyroxine. We conclude that suppression of serum TSH during neck irradiation does not prevent subsequent thyroid dysfunction.

  11. Review article: Medical decision models of Helicobacter pylori therapy to prevent gastric cancer.

    PubMed

    Sonnenberg, A; Inadomi, J M

    1998-02-01

    The aim of the present article is to study the utility of Helicobacter pylori eradication programmes in decreasing the incidence of gastric cancer. Three types of decision models are employed to pursue this aim, i.e. decision tree, present value, and declining exponential approximation of life expectancy (DEALE). 1) A decision tree allows one to model the interaction of multiple variables in great detail and to calculate the marginal cost, as well as the marginal cost-benefit ratio, of a preventive strategy. The cost of gastric cancer, the efficacy of H. pylori therapy in preventing cancer, and the cumulative probability of developing gastric cancer exert the largest influence on the marginal cost of cancer prevention. The high cost of future gastric cancer and a high efficacy of therapy make screening for H. pylori and its eradication the preferred strategy. 2) The present value is an economic method to adjust future costs or benefits to their current value using a discount rate and the length of time between now and a given time point in the future. It accounts for the depreciation of money and all material values over time. During childhood, the present value of future gastric cancer is very low. Vaccination of children to prevent gastric cancer would need to be very inexpensive to be practicable. Cancer prevention becomes a feasible option, only if the time period between the preventive measures and the occurrence of gastric cancer can be made relatively short. 3) The DEALE provides a means to calculate the increase in life expectancy that would occur, if death from a particular disease became preventable. Life expectancy of the general population is hardly affected by gastric cancer. For life expectancy to increase appreciably by vaccination or antibiotic therapy directed against H. pylori infection, these interventions would need to be focused towards a sub-population with an a priori high risk for gastric cancer.

  12. Barriers Prevent Patient Access to Personalized Therapies Identified by Molecular Tumor Profiling of Gynecologic Malignancies

    PubMed Central

    Hillman, R. Tyler; Ward, Kristy; Saenz, Cheryl; McHale, Michael; Plaxe, Steven

    2015-01-01

    Objective. This study was designed to evaluate the ability of commercial molecular tumor profiling to discover actionable mutations and to identify barriers that might prevent patient access to personalized therapies. Methods. We conducted an IRB-approved retrospective review of 26 patients with gynecologic malignancies who underwent commercial tumor profiling at our institution during the first 18 months of test availability. Tumor profiles reported targeted therapies and clinical trials matched to patient-specific mutations. Data analysis consisted of descriptive statistics. Results. Most patients who underwent tumor profiling had serous epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (46%). Patients underwent profiling after undergoing a median of two systemic therapies (range 0 to 13). A median of one targeted therapy was suggested per patient profile. Tumor profiling identified no clinically actionable mutations for seven patients (27%). Six patients sought insurance approval for a targeted therapy and two were declined (33%). One patient (4%) received a targeted therapy and this was discontinued due to tumor progression. Conclusions. There are formidable barriers to targeted therapy for patients with gynecologic malignancies. These barriers include a dearth of FDA-approved targeted agents for gynecologic malignancies, lack of third party insurance coverage and limited geographic availability of clinical trials. PMID:26011384

  13. The Mechanism of and Preventive Therapy for Stroke in Patients with Atrial Fibrillation

    PubMed Central

    Kim, Young-Hoon; Roh, Seung-Young

    2016-01-01

    Atrial fibrillation is a major cardiac cause of stroke, and a pathogenesis involving thrombus formation in patients with atrial fibrillation is well established. A strategy for rhythm control that involves catheter ablation and anticoagulation therapy is evolving. A strategy for rhythm control that restores and maintains sinus rhythm should reduce the risk of ischemic stroke that is associated with atrial fibrillation; however, this is yet to be proven in large-scale randomized controlled trials. This paper reviews the emerging role of rhythm control therapy for atrial fibrillation to prevent stroke. PMID:27283277

  14. FEMALE SEX AND DISCONTINUATION OF ISONIAZID DUE TO ADVERSE EFFECTS DURING THE TREATMENT OF LATENT TUBERCULOSIS

    PubMed Central

    Pettit, April C.; Bethel, James; Hirsch-Moverman, Yael; Colson, Paul W.; Sterling, Timothy R.

    2013-01-01

    SUMMARY Objectives To determine the rate of and risk factors for discontinuation of isoniazid due to adverse effects during the treatment of latent tuberculosis infection in a large, multi-site study. Methods The Tuberculosis Epidemiologic Studies Consortium (TBESC) conducted a prospective study from March 2007–September 2008 among adults initiating isoniazid for treatment of LTBI at 12 sites in the US and Canada. The relative risk for isoniazid discontinuation due to adverse effects was determined using negative binomial regression. Adjusted models were constructed using forward stepwise regression. Results Of 1,306 persons initiating isoniazid, 617 (47.2%, 95% CI 44.5–50.0%) completed treatment and 196 (15.0%, 95% CI 13.1–17.1%) discontinued due to adverse effects. In multivariable analysis, female sex (RR 1.67, 95% CI 1.32–2.10, p<0.001) and current alcohol use (RR 1.41, 95% CI 1.13–1.77, p=0.003) were independently associated with isoniazid discontinuation due to adverse effects. Conclusions The rate of discontinuation of isoniazid due to adverse effects was substantially higher than reported earlier. Women were at increased risk of discontinuing isoniazid due to adverse effects; close monitoring of women for adverse effects may be warranted. Current alcohol use was also associated with isoniazid discontinuation; counseling patients to abstain from alcohol could decrease discontinuation due to adverse effects. PMID:23845828

  15. Triple antiplatelet therapy for preventing vascular events: a systematic review and meta-analysis

    PubMed Central

    2010-01-01

    Background Dual antiplatelet therapy is usually superior to mono therapy in preventing recurrent vascular events (VEs). This systematic review assesses the safety and efficacy of triple antiplatelet therapy in comparison with dual therapy in reducing recurrent vascular events. Methods Completed randomized controlled trials investigating the effect of triple versus dual antiplatelet therapy in patients with ischaemic heart disease (IHD), cerebrovascular disease or peripheral vascular disease were identified using electronic bibliographic searches. Data were extracted on composite VEs, myocardial infarction (MI), stroke, death and bleeding and analysed with Cochrane Review Manager software. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random effects models. Results Twenty-five completed randomized trials (17,383 patients with IHD) were included which involving the use of intravenous (iv) GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban), aspirin, clopidogrel and/or cilostazol. In comparison with aspirin-based therapy, triple therapy using an intravenous GP IIb/IIIa inhibitor significantly reduced composite VEs and MI in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) (VE: OR 0.69, 95% CI 0.55-0.86; MI: OR 0.70, 95% CI 0.56-0.88) and ST elevation myocardial infarction (STEMI) (VE: OR 0.39, 95% CI 0.30-0.51; MI: OR 0.26, 95% CI 0.17-0.38). A significant reduction in death was also noted in STEMI patients treated with GP IIb/IIIa based triple therapy (OR 0.69, 95% CI 0.49-0.99). Increased minor bleeding was noted in STEMI and elective percutaneous coronary intervention (PCI) patients treated with GP IIb/IIIa based triple therapy. Stroke events were too infrequent for us to be able to identify meaningful trends and no data were available for patients recruited into trials on the basis of stroke or peripheral vascular disease. Conclusions Triple antiplatelet therapy based on iv GPIIb/IIIa inhibitors was more

  16. [Dual antiplatelet therapy for treatment and secondary prevention of coronary artery disease: indications, modalities and duration].

    PubMed

    Degrauwe, Sophie; Iglesias, Juan F

    2016-05-25

    The choice and optimal duration of dualantiplatelet therapy (DAPT) for the treatment of coronary artery disease (CAD) represent a challenging clinical dilemma. Antiplatelet treatment strategies are determined by the clinical setting, patient comorbidities and management strategy. While aspirin remains the cornerstone for secondary prevention of CAD, DAPT significantly reduces recurrent ischemic adverse events at the expense of an increased risk of major bleeding complications. A tailored approach based on individual ischemic and hemorrhagic risk assessment is currently recommended. This review aims to provide a contemporary overview on the current body of evidence concerning DAPT for treatment and secondary prevention of CAD with practical emphasis on current indications, choice, combination and optimal duration of antiplatelet therapy. PMID:27424342

  17. Prevention of Distant Lung Metastasis After Photodynamic Therapy Application in a Breast Cancer Tumor Model.

    PubMed

    Longo, João Paulo Figueiró; Muehlmann, Luis Alexandre; Miranda-Vilela, Ana Luisa; Portilho, Flávia Arruda; de Souza, Ludmilla Regina; Silva, Jaqueline Rodrigues; Lacava, Zulmira Guerrero Marques; Bocca, Anamelia Lorenzetti; Chaves, Sacha Braun; Azevedo, Ricardo Bentes

    2016-04-01

    The objective of this study was to investigate the activity of photodynamic therapy mediated by aluminum-chlorophthalocyanine contained in a polymeric nanostructured carrier composed by methyl vinyl ether-co-maleic anhydride (PVM/MA) against local subcutaneous breast cancer tumors and its effects against distant metastasis in a mouse tumor model. In our results, we observed a decrease in breast cancer tumor growth, prevention of distant lung metastases, and a significant increased survival in mice treated with photodynamic therapy. In addition to these results, we observed that tumor-bearing mice without treatment developed a significant extension of liver hematopoiesis that was significantly reduced in mice treated with photodynamic therapy. We hypothesized and showed that this reduction in (1) metastasis and (2) liver hematopoiesis may be related to the systemic activity of immature hematopoietic cells, specifically the myeloid-derived suppressor cells, which were suppressed in mice treated with photodynamic therapy. These cells produce a tolerogenic tumor environment that protects tumor tissues from immunological surveillance. Therefore, we suggest that photodynamic therapy could be employed in combination with other conventional therapies; such as surgery and radiotherapy, to improve the overall survival of patients diagnosed with breast cancer, as observed in our experimental resuIts.

  18. Prevention of Distant Lung Metastasis After Photodynamic Therapy Application in a Breast Cancer Tumor Model.

    PubMed

    Longo, João Paulo Figueiró; Muehlmann, Luis Alexandre; Miranda-Vilela, Ana Luisa; Portilho, Flávia Arruda; de Souza, Ludmilla Regina; Silva, Jaqueline Rodrigues; Lacava, Zulmira Guerrero Marques; Bocca, Anamelia Lorenzetti; Chaves, Sacha Braun; Azevedo, Ricardo Bentes

    2016-04-01

    The objective of this study was to investigate the activity of photodynamic therapy mediated by aluminum-chlorophthalocyanine contained in a polymeric nanostructured carrier composed by methyl vinyl ether-co-maleic anhydride (PVM/MA) against local subcutaneous breast cancer tumors and its effects against distant metastasis in a mouse tumor model. In our results, we observed a decrease in breast cancer tumor growth, prevention of distant lung metastases, and a significant increased survival in mice treated with photodynamic therapy. In addition to these results, we observed that tumor-bearing mice without treatment developed a significant extension of liver hematopoiesis that was significantly reduced in mice treated with photodynamic therapy. We hypothesized and showed that this reduction in (1) metastasis and (2) liver hematopoiesis may be related to the systemic activity of immature hematopoietic cells, specifically the myeloid-derived suppressor cells, which were suppressed in mice treated with photodynamic therapy. These cells produce a tolerogenic tumor environment that protects tumor tissues from immunological surveillance. Therefore, we suggest that photodynamic therapy could be employed in combination with other conventional therapies; such as surgery and radiotherapy, to improve the overall survival of patients diagnosed with breast cancer, as observed in our experimental resuIts. PMID:27301195

  19. [Isoniazid and rifampicin in the rabbit. Effect on hepatic microsomal enzyme activity].

    PubMed

    Kergueris, M F; Larousse, C; Le Normand, Y; Guillerme, G; Bourin, M

    1982-01-01

    1. Enzymatic induction or inhibition induced by isoniazid (10 mg/kg) and/or rifampicin (13 mg/kg) oral treatment of 13 days in the rabbit, is evaluated with the following parameters: --variation of antipyrine half-life measured before treatment and 24 h after the end of treatment, --cytochrome P450 content, aniline hydroxylase and aminopyrine N-demethylase activities in hepatic microsomes. Isoniazid half-life is evaluated before treatment, in order to obtain an homogeneous repartition of animals in each group: isoniazid, rifampicin, isoniazid + rifampicin and control. 2. Rifampicin treatment gives a variable enzyme induction of antipyrine metabolism, cytochrome P450 and aniline hydroxylase activity; aminopyrine N-demethylase activity is significantly inhibited. Isoniazid treatment inhibits antipyrine metabolism and increases the cytochrome P450 content.

  20. Amide derivatives of sulfonamides and isoniazid: synthesis and biological evaluation.

    PubMed

    Husain, Asif

    2009-01-01

    In the present study, various amide derivatives of sulfanilamide, sulfamethoxazole, sulfadiazine, dapsone and isoniazid have been synthesized by condensing them with appropriate 4-oxo-4-(4-substituted phenyl)butanoic acid moiety. The compounds have been evaluated for their antiinflammatory, ulcerogenic and antibacterial activities. Their structures were established on the basis of elemental analysis, 1H NMR and mass spectral data. Some of the compounds were found to have significant antiinflammatory and antibacterial activities. Additionally, these derivatives were low in their ulcerogenic action, which is the main side effect of commonly used NSAIDs. PMID:19894647

  1. Hypnotically facilitated exposure response prevention therapy for an OIF veteran with OCD.

    PubMed

    Proescher, Eric J

    2010-07-01

    The highly stressful conditions of a war zone may exacerbate or trigger a wide variety of symptoms including Obsessive Compulsive Disorder (OCD) once a service member returns home. Service members and new veterans of the Iraq and Afghanistan wars present to treatment with multiple psychosocial concerns and co-morbid psychiatric conditions. Evidence-based treatments including exposure based therapies are commonly recommended for use with returning veterans. Although studies support the efficacy of Exposure Response Prevention (ERP) therapy for treating OCD, eligibility for these studies limits participation to subjects who self-report a well-defined, circumscribed complaint. This approach is not typical of clinic clients who, more often than not, report multiple psychological issues. The following individual case study demonstrates how integrating hypnosis facilitated the cognitive-behavioral ERP therapy and treatment for a patient suffering from OCD.

  2. Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function

    PubMed Central

    Takami, Taro; Yamasaki, Takahiro; Saeki, Issei; Matsumoto, Toshihiko; Suehiro, Yutaka; Sakaida, Isao

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis.

  3. Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function.

    PubMed

    Takami, Taro; Yamasaki, Takahiro; Saeki, Issei; Matsumoto, Toshihiko; Suehiro, Yutaka; Sakaida, Isao

    2016-08-28

    Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis. PMID:27621572

  4. Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function

    PubMed Central

    Takami, Taro; Yamasaki, Takahiro; Saeki, Issei; Matsumoto, Toshihiko; Suehiro, Yutaka; Sakaida, Isao

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis. PMID:27621572

  5. Menopausal hormone therapy for the primary prevention of chronic conditions. U.S. Preventive Services Task Force recommendation statement.

    PubMed

    Kreatsoulas, Catherine; Anand, Sonia S

    2013-01-01

    Since the early 20th century, scientists have been tantalized with the hypothesis that premenopausal health benefits in women can be preserved in postmenopausal women with the supplementation of exogenous hormone replacement therapy (HRT) of estrogen (alone/with progesterone). This hypothesis was shattered when the results of 2 large randomized controlled trials (RCTs), the Heart Estrogen/Progesterone Replacement Study (HERS) and Women's Health Initiative (WHI), reported an increased risk of adverse clinical outcomes including coronary heart disease, thromboembolic events, stroke, dementia, urinary incontinence, gallbladder disease, and breast cancer. However, since the WHI was published, firestorms of critique, controversy, and multiple subgroup analyses have populated the medical literature, predominantly focused around the analysis of the age of women at entry into the trials (hypothesized as an effect modifier) and suggesting lower-dose preparations including using bioidentical hormones. Recently, the U.S. Preventive Services Task Force (USPSTF) along with other professional groups have issued recommendations against the use of HRT to prevent chronic conditions. In this review, we review the most recent evidence, including the long-term follow-up data from RCTs along a multitude of health outcomes.

  6. Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.

    PubMed

    Hartkoorn, Ruben C; Sala, Claudia; Neres, João; Pojer, Florence; Magnet, Sophie; Mukherjee, Raju; Uplekar, Swapna; Boy-Röttger, Stefanie; Altmann, Karl-Heinz; Cole, Stewart T

    2012-10-01

    Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811.

  7. Role of CYP3A in isoniazid metabolism in vivo

    PubMed Central

    Liu, Ke; Li, Feng; Lu, Jie; Gao, Zhiwei; Klaassen, Curtis D.; Ma, Xiaochao

    2014-01-01

    Summary Isoniazid (INH), a first-line drug for tuberculosis control, frequently causes liver injury. Multiple previous reports suggest that CYP3A is involved in INH metabolism, bioactivation and hepatotoxicity, although direct evidence is unavailable. In the current study, wild-type and Cyp3a-null mice were used to determine the potential role of Cyp3a in INH metabolism in vivo. Compared to wild-type mice, there were no significant differences in the pharmacokinetic profiles of INH and acetyl-isoniazid in Cyp3a-null mice after an oral administration of 50 mg/kg INH. With the same treatment, distribution of INH and its major metabolites was similar in the liver of wild-type and Cyp3a-null mice. A reactive metabolite of INH was trapped by N-α-acetyl-L-lysine in mouse liver microsomes, but Cyp3a does not contribute to this bioactivation pathway. In addition, no liver injury was observed in wild-type and Cyp3a-null mice treated with 60 or 120 mg/kg INH. In summary, Cyp3a has no effect on systemic pharmacokinetics of INH in mice. Further studies are needed to determine whether and how exactly CYP3A is involved in INH bioactivation and hepatotoxicity. PMID:24172716

  8. Towards a new tuberculosis drug: pyridomycin – nature's isoniazid

    PubMed Central

    Hartkoorn, Ruben C; Sala, Claudia; Neres, João; Pojer, Florence; Magnet, Sophie; Mukherjee, Raju; Uplekar, Swapna; Boy-Röttger, Stefanie; Altmann, Karl-Heinz; Cole, Stewart T

    2012-01-01

    Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. PMID:22987724

  9. Adjunctive Therapies to Cerclage for the Prevention of Preterm Birth: A Systematic Review

    PubMed Central

    DeFranco, Emily A.; Valent, Amy Miyoshi; Newman, Tondra; Regan, Jodi; Smith, Jessica; Muglia, Louis J.

    2013-01-01

    The aim of this paper is to provide a thorough summary of published studies that have assessed the efficacy of adjunctive therapies used in addition to cervical cerclage as a preventive measure for preterm birth. We limited our paper to patients treated with cerclage plus an additional prophylactic therapy compared to a reference group of women with cerclage alone. The specific adjunctive therapies included in this systematic review are progesterone, reinforcing or second cerclage placement, tocolytics, antibiotics, bedrest, and pessary. We searched PubMed and Cochrane databases without date criteria with restriction to English language and human studies and performed additional bibliographic review of selected articles and identified 305 total studies for review. Of those, only 12 studies compared the use of an adjunctive therapy with cerclage to a reference group of cerclage alone. None of the 12 were prospective randomized clinical trials. No comparative studies were identified addressing the issues of antibiotics, bedrest, or pessary as adjunctive treatments to cerclage. None of the 12 studies included in this paper demonstrated a clear benefit of any adjunctive therapy used in addition to cerclage over and above cerclage used alone; however, few studies with small numbers limited the strength of the conclusions. PMID:23606847

  10. Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer.

    PubMed

    Stachnik, Agnes; Yuen, Tony; Iqbal, Jameel; Sgobba, Miriam; Gupta, Yogesh; Lu, Ping; Colaianni, Graziana; Ji, Yaoting; Zhu, Ling-Ling; Kim, Se-Min; Li, Jianhua; Liu, Peng; Izadmehr, Sudeh; Sangodkar, Jaya; Scherer, Thomas; Mujtaba, Shiraz; Galsky, Matthew; Gomez, Jorge; Epstein, Solomon; Buettner, Christoph; Bian, Zhuan; Zallone, Alberta; Aggarwal, Aneel K; Haider, Shozeb; New, Maria I; Sun, Li; Narla, Goutham; Zaidi, Mone

    2014-12-16

    A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1(ΔE746-A750)-driven HCC827 NSCLCs and HER1(wt)-expressing MB231 triple negative breast cancers, but not by HER(low)-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER(low) SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-driven cancers.

  11. Pharmacologic Inhibition of Host Phosphodiesterase-4 Improves Isoniazid-Mediated Clearance of Mycobacterium tuberculosis.

    PubMed

    Subbian, Selvakumar; Koo, Mi-Sun; Tsenova, Liana; Khetani, Vikram; Zeldis, Jerome B; Fallows, Dorothy; Kaplan, Gilla

    2016-01-01

    The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment. PMID:27379099

  12. Pharmacologic Inhibition of Host Phosphodiesterase-4 Improves Isoniazid-Mediated Clearance of Mycobacterium tuberculosis

    PubMed Central

    Subbian, Selvakumar; Koo, Mi-Sun; Tsenova, Liana; Khetani, Vikram; Zeldis, Jerome B.; Fallows, Dorothy; Kaplan, Gilla

    2016-01-01

    The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment. PMID:27379099

  13. Development of a three component complex to increase isoniazid efficacy against isoniazid resistant and nonresistant Mycobacterium tuberculosis.

    PubMed

    Manning, Thomas; Plummer, Sydney; Baker, Tess; Wylie, Greg; Clingenpeel, Amy C; Phillips, Dennis

    2015-10-15

    The bacterium responsible for causing tuberculosis has evolved resistance to antibiotics used to treat the disease, resulting in new multidrug resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug resistant M. tuberculosis (XDR-TB) strains. Analytical techniques (1)H and (13)C Nuclear Magnetic Resonance (NMR), Fourier Transform-Ion Cyclotron Resonance with Electrospray Ionization (FT-ICR/ESI), and Matrix Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-TOF-MS) were used to study different aspects of the Cu(II)-polyethylene glycol (PEG-3350)-sucrose-isoniazid and Cu(II)-polyethylene glycol (PEG3350)-glucose-isoniazid complexes. The Cu(II) cation, sucrose or glucose, and the aggregate formed by PEG primarily serve as a composite drug delivery agent for the frontline antibiotic, however the improvement in MIC values produced with the CU-PEG-SUC-INH complex suggest an additional effect. Several Cu-PEG-SUC-INH complex variations were tested against INH resistant and nonresistant strains of M. tuberculosis. PMID:26341133

  14. Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI

    PubMed Central

    Bliven-Sizemore, E. E.; Sterling, T. R.; Shang, N.; Benator, D.; Schwartzman, K.; Reves, R.; Drobeniuc, J.; Bock, N.; Villarino, M. E.

    2016-01-01

    SUMMARY SETTING Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear. OBJECTIVES To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity DESIGN Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 × ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV. RESULTS Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors. CONCLUSION The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred. PMID:26260821

  15. Antithrombotic therapy for secondary prevention of atherothrombotic events in cerebrovascular disease.

    PubMed

    Capodanno, Davide; Alberts, Mark; Angiolillo, Dominick J

    2016-10-01

    Atherothrombosis is the common underlying process for numerous progressive manifestations of cardiovascular disease, including coronary artery disease (CAD) and cerebrovascular disease (CVD). Antiplatelet therapy is the cornerstone of pharmacological management in patients with atherothrombosis. Over the past 20 years, major advances in antiplatelet pharmacotherapy have been made, particularly for the treatment of patients with CAD. The treatment of patients with concomitant CAD and CVD is complex, owing to their increased risk of both ischaemia and bleeding. When CVD arises from large artery atherosclerosis, antithrombotic therapies are essential to prevent stroke or transient ischaemic attack (TIA). However, the use of antithrombotic medications in patients with CVD can put them at high risk of intracranial haemorrhage. As such, the risk-benefit profile of various combinations of antiplatelet agents in patients with both CAD and CVD is uncertain. This Review provides a state-of-the-art account of the available evidence on antithrombotic therapies for the secondary prevention of atherothrombotic events in patients with concomitant CAD and CVD, particularly those with a history of noncardioembolic stroke or TIA.

  16. Reagent Precoated Targets for Rapid In-Tissue Derivatization of the Anti-Tuberculosis Drug Isoniazid Followed by MALDI Imaging Mass Spectrometry

    PubMed Central

    Manier, M. Lisa; Reyzer, Michelle L.; Goh, Anne; Dartois, Veronique; Via, Laura E.; Barry, Clifton E.; Caprioli, Richard M.

    2012-01-01

    Isoniazid (INH) is an important component of front-line anti-tuberculosis therapy with good serum pharmacokinetics but unknown ability to penetrate tuberculous lesions. However, endogenous background interferences hinder our ability to directly analyze INH in tissues. Chemical derivatization has been successfully used to measure isoniazid directly from tissue samples using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). MALDI targets were pretreated with trans-cinnamaldehyde (CA) prior to mounting tissue slices. Isoniazid present in the tissues was efficiently derivatized and the INH-CA product measured by MS/MS. Precoating of MALDI targets allows the tissues to be directly thaw-mounted and derivatized, thus simplifying the preparation. A time-course series of tissues from tuberculosis infected/INH dosed animals were assayed and the MALDI MS/MS response correlates well with the amount of INH determined to be in the tissues by high-performance liquid chromatography (HPLC)-MS/MS. PMID:21953196

  17. Effects of glucocorticoids on mood, memory, and the hippocampus. Treatment and preventive therapy.

    PubMed

    Brown, E Sherwood

    2009-10-01

    Corticosteroids, such as prednisone and dexamethasone, are commonly prescribed medications that suppress the immune system and decrease inflammation. Common side effects of long-term treatment with corticosteroids include weight gain, osteoporosis, and diabetes mellitus. This paper reviews the literature on psychiatric and cognitive changes during corticosteroid therapy and potential treatment options. Hypomania and mania are the most common mood changes during acute corticosteroid therapy, although depression has also been reported. However, depression is reported to be more common than mania during long-term treatment with corticosteroids. A decline in declarative and working memory is also reported during corticosteroid therapy. Corticosteroids are associated with changes in the temporal lobe, detected by structural, functional, and spectroscopic imaging. The mood and cognitive symptoms are dose dependent and frequently occur during the first few weeks of therapy. Other risk factors are not well characterized. Controlled trials suggest that lithium and phenytoin can prevent mood symptoms associated with corticosteroids. Lamotrigine and memantine also have been shown to reverse, at least partially, the declarative memory effects of corticosteroids. Uncontrolled trials suggest that antipsychotics, anti-seizure medications, and perhaps some antidepressants can also be useful for normalizing mood changes associated with corticosteroids. Thus, both the symptoms and treatment response are similar to those of bipolar disorder. Moreover, corticosteroid-induced mood and cognitive alterations have been shown to be reversible with dose reduction or discontinuation of treatment.

  18. Mindfulness-based cognitive therapy for prevention of recurrence of suicidal behavior.

    PubMed

    Williams, J Mark G; Duggan, Danielle S; Crane, Catherine; Fennell, Melanie J V

    2006-02-01

    Once suicidal thoughts have emerged as a feature of depression they are likely to be reactivated as part of a suicidal mode of mind whenever sad mood reappears. This article reviews the methods and the usefulness of mindfulness-based cognitive therapy (MBCT) as a treatment for the prevention of the reactivation of the suicidal mode. MBCT integrates mindfulness meditation practices and cognitive therapy techniques. It teaches participants to develop moment-by-moment awareness, approaching ongoing experience with an attitude of nonjudgment and acceptance. Participants are increasingly able to see their thoughts as mental events rather than facts (metacognitive awareness). A case example illustrates how mindfulness skills develop with MBCT and how they relate to the cognitive processes that fuel suicidal crises. An ongoing controlled trial will provide further evidence, but pilot work suggests that MBCT is a promising intervention for those who have experienced suicidal ideation in the past.

  19. Preventing stem cell transplantation-associated viral infections using T-cell therapy

    PubMed Central

    Tzannou, Ifigeneia; Leen, Ann M

    2015-01-01

    Hematopoietic stem cell transplantation is the treatment of choice for many hematologic malignancies and genetic diseases. However, viral infections continue to account for substantial post-transplant morbidity and mortality. While antiviral drugs are available against some viruses, they are associated with significant side effects and are frequently ineffective. This review focuses on the immunotherapeutic strategies that have been used to prevent and treat infections over the past 20 years and outlines different refinements that have been introduced with the goal of moving this therapy beyond specialized academic centers. PMID:26250410

  20. How nanotechnology-enabled concepts could contribute to the prevention, diagnosis and therapy of bacterial infections.

    PubMed

    Herrmann, Inge K

    2015-05-29

    This viewpoint summarizes a selection of nanotechnology-based key concepts relevant to critical care medicine. It focuses on novel approaches for a trigger-dependent release of antimicrobial substances from degradable nano-sized carriers, the ultra-sensitive detection of analytes in body fluid samples by plasmonic and fluorescent nanoparticles, and the rapid removal of pathogens from whole blood using magnetic nanoparticles. The concepts presented here could significantly contribute to the prevention, diagnosis and therapy of bacterial infections in future and it is now our turn to bring them from the bench to the bedside.

  1. Role of emerging antithrombotic therapy in the prevention of cardioembolic complications in patients with atrial fibrillation.

    PubMed

    Deedwania, Prakash C; Huang, Grace W

    2011-08-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is an independent risk factor of potentially catastrophic cardioembolic strokes. AF patients are categorized into high-, intermediate-, and low-risk for thromboembolic complications using the CHADS(2) or CHA(2)DS(2)-VASc scoring system. Oral anticoagulation using warfarin has been the standard therapy for stroke prevention in intermediate- to high-risk AF patients. However, warfarin use has been limited by several factors such as narrow therapeutic windows, drug-drug and drug-food interactions, and hemorrhagic complications. Rigorous research evaluated dual antiplatelet therapy of clopidogrel and aspirin (acetylsalicylic acid) as a potential alternative to warfarin in the ACTIVE W trial. Dual antiplatelet therapy of clopidogrel and aspirin was found to be inferior to warfarin in preventing stroke and systemic embolism with increased bleeding risk. Other extensive research has led to the development of new antithrombotic agents. Recently, dabigatran etexilate 150 mg twice daily, a direct thrombin inhibitor, was approved by the US FDA for stroke prevention in patients with non-valvular AF after it was found to be superior to warfarin in preventing thromboembolic events and associated with less bleeding in the RE-LY trial. It was also cost effective when compared with warfarin. Dabigatran can be considered in high-risk AF patients who are unable or unwilling to comply with the frequent laboratory and clinic visits that are required when receiving treatment with warfarin. Factor Xa inhibitors are another class of new anticoagulants that have been developed. Oral rivaroxaban was non-inferior to warfarin in thromboprophylaxis and with similar bleeding in the ROCKET-AF trial (HR 0.88; p = 0.117). Apixaban, another factor Xa inhibitor, was superior to aspirin in reducing stroke and systemic embolism in patients with AF in the AVERROES trial (HR 0.45; p < 0.001). The results of the

  2. Feasibility of a Prototype Web-Based Acceptance and Commitment Therapy Prevention Program for College Students

    PubMed Central

    Levin, Michael E.; Pistorello, Jacqueline; Seeley, John R.; Hayes, Steven C.

    2013-01-01

    Objective This study examined the feasibility of a prototype web-based Acceptance and Commitment Therapy (ACT) program for preventing mental health problems among college students. Participants Undergraduate first-year students (n = 76) participated between May and November 2011. Methods Participants were randomized to ACT or a waitlist with assessments conducted at baseline, post and 3-week follow-up. Waitlist participants accessed the program after the second assessment. Results Program usability/usage data indicated high program acceptability. Significant improvements were found for ACT knowledge, education values and depression with ACT relative to waitlist. Subgroup analyses indicated ACT decreased depression and anxiety relative to waitlist among students with at least minimal distress. Within the ACT condition, significant improvements were observed from baseline to 3-week follow-up on all outcome and process measures. Conclusions Results provide preliminary support for the feasibility of a web-based ACT prevention program. PMID:24313693

  3. Prevention of post-stroke generalized anxiety disorder, using escitalopram or problem-solving therapy.

    PubMed

    Mikami, Katsunaka; Jorge, Ricardo E; Moser, David J; Arndt, Stephan; Jang, Mijin; Solodkin, Ana; Small, Steven L; Fonzetti, Pasquale; Hegel, Mark T; Robinson, Robert G

    2014-01-01

    This study examined the efficacy of antidepressant treatment for preventing the onset of generalized anxiety disorder (GAD) among patients with recent stroke. Of 799 patients assessed, 176 were randomized, and 149 patients without evidence of GAD at the initial visit were included in this double-blind treatment with escitalopram (N=47) or placebo (N=49) or non-blinded problem-solving therapy (PST; 12 total sessions; N=53). Participants given placebo over 12 months were 4.95 times more likely to develop GAD than patients given escitalopram and 4.00 times more likely to develop GAD than patients given PST. Although these results should be considered preliminary, the authors found that both escitalopram and PST were effective in preventing new onset of post-stroke GAD.

  4. Oral silicon supplementation: an effective therapy for preventing oral aluminum absorption and retention in mammals.

    PubMed

    Domingo, José L; Gómez, Mercedes; Colomina, M Teresa

    2011-01-01

    Silicon is an essential element for some lower forms of life. However, it is not generally considered an essential nutrient for mammals and the mechanisms underlying its potential essentiality remain partially unknown. In recent years, a possible association between the aluminum and silicon levels in drinking water and Alzheimer's disease (AD) has been suggested. It has been reported that silicon might have a protective effect for limiting oral aluminum absorption. This review is focused primarily on the potential role of silicon in preventing oral aluminum absorption and retention in mammals. The results of a number of studies suggest that dietary silicon supplementation could be of therapeutic value for preventing chronic aluminum accumulation in the brain, and hence, be a potential therapy for AD. However, it must be noted that controversy remains about whether aluminum accumulation in the brain is a cause or a consequence of AD. It is suggested that further investigation of this issue is warranted.

  5. Laser-triggered intraocular implant to induce photodynamic therapy for posterior capsule opacification prevention.

    PubMed

    Zhang, Zhaoguo; Huang, Wenyong; Lei, Ming; He, Yuanfeng; Yan, Mina; Zhang, Xuefei; Zhao, Chunshun

    2016-02-10

    Posterior capsule opacification (PCO) is one of the main reasons for loss of vision again after cataract surgery. In this study, intraocular lenses were modified with indocyanine green (ICG) and sealed up with PLGA to form long-term intraocular implants (ICG-IOL). When triggered by laser, ICG-IOL would induce photodynamic therapy (PDT). In-vitro cell viability assay and scratch wound healing assay demonstrated that ICG-IOL could effectively inhibit HLEpiC proliferation and migration without causing damage to the cells far away from it. Laser attenuation test indicated that ICG-IOL could be applied in vivo. In-vivo pharmacodynamics and safety study showed that ICG-IOL could significantly prevent the occurrence of PCO and was safe for intraocular normal tissue. All these results suggested that ICG-IOL would be a very promising candidate for PCO prevention.

  6. Preventive Antibacterial Therapy in Acute Ischemic Stroke: A Randomized Controlled Trial

    PubMed Central

    Klehmet, Juliane; Rogge, Witold; Drenckhahn, Christoph; Göhler, Jos; Bereswill, Stefan; Göbel, Ulf; Wernecke, Klaus Dieter; Wolf, Tilo; Arnold, Guy; Halle, Elke; Volk, Hans-Dieter; Dirnagl, Ulrich; Meisel, Andreas

    2008-01-01

    Background Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients. Methods Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance. Findings On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections. Interpretation PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the

  7. Physical Therapy for Metabolic Syndrome Prevention in Workers: Novel Role of Physical Therapist.

    PubMed

    Satoh, Tomonori; Nemoto, Yuki; Utumi, Takako; Munakata, Masanori

    2016-01-01

    In Japan, physical therapists have usually been involved in physical therapy for patients with functional disorders associated with cerebrovascular or orthopedic diseases in hospitals. With the aging of Japanese society, the number of diseased people will progressively increase; thus, it is important to pay much more attention to disease prevention. In this regard, physical therapists are expected to play a new role in the field of preventive medicine. Metabolic syndrome or central obesity with multiple cardiometabolic risks is associated with a high risk of type 2 diabetes or cardiovascular diseases and is now a central target for early detection and intervention for disease prevention. The incidence of metabolic syndrome increases with age, and men showed a higher incidence of metabolic syndrome than women in all generations. We have been involved in the guidance of workers with metabolic syndrome for a long time, and we conducted a multicenter study to establish effective guidance for these worker. In this paper, we will use our evidence to discuss the role of physical therapists in providing guidance for preventing metabolic syndrome. We are now conducting worksite supporting exercise intervention for workers who were resistant to conventional lifestyle guidance. In addition, the unique role of physical therapists in this new trial will be introduced. PMID:27246150

  8. Antiretroviral Therapy in Prevention of HIV and TB: Update on Current Research Efforts

    PubMed Central

    Granich, Reuben; Gupta, Somya; Sutha, Amitabh B; Smyth, Caoimhe; Hoos, David; Vitoria, Marco; Simao, Mariangela; Hankins, Catherine; Schwartlander, Bernard; Ridzon, Renee; Bazin, Brigitte; Williams, Brian; Lo, Ying-Ru; McClure, Craig; Montaner, Julio; Hirnschall, Gottfried

    2011-01-01

    There is considerable scientific evidence supporting the use of antiretroviral therapy (ART) in prevention of human immunodeficiency virus (HIV) and tuberculosis (TB) infections. The complex nature of the HIV and TB prevention responses, resource constraints, remaining questions about cost and feasibility, and the need to use a solid evidence base to make policy decisions, and the implementation challenges to translating trial data to operational settings require a well-organised and coordinated response to research in this area. To this end, we aimed to catalogue the ongoing and planned research activities that evaluate the impact of ART plus other interventions on HIV- and/or TB-related morbidity, mortality, risk behaviour, HIV incidence and transmission. Using a limited search methodology, 50 projects were identified examining ART as prevention, representing 5 regions and 52 countries with a global distribution. There are 24 randomised controlled clinical trials with at least 12 large randomised individual or community cluster trials in resource-constrained settings that are in the planning or early implementation stages. There is considerable heterogeneity between studies in terms of methodology, interventions and geographical location. While the identified studies will undoubtedly advance our understanding of the efficacy and effectiveness of ART for prevention, some key questions may remain unanswered or only partially answered. The large number and wide variety of research projects emphasise the importance of this research issue and clearly demonstrate the potential for synergies, partnerships and coordination across funding agencies. PMID:21999779

  9. A Pilot Study of Emollient Therapy for the Primary Prevention of Atopic Dermatitis

    PubMed Central

    Simpson, Eric L.; Berry, Trista M.; Brown, Peter A.; Hanifin, Jon M.

    2011-01-01

    Background Prevention strategies in atopic dermatitis (AD) using allergen avoidance have not been consistently effective. New research reveals the importance of the skin barrier in the development of AD and possibly food allergy and asthma. Correcting skin barrier defects from birth may prevent AD onset or moderate disease severity. Objective We sought to determine the feasibility of skin barrier protection as a novel AD prevention strategy. Methods We enrolled 22 neonates at high risk for developing AD in a feasibility pilot study using emollient therapy from birth. Results No intervention-related adverse events occurred in our cohort followed up for a mean time of 547 days. Of the 20 subjects who remained in the study, 3 (15.0%) developed AD, suggesting a protective effect when compared with historical controls. Skin barrier measurements remained within ranges seen in normal-appearing skin. Limitations No conclusions regarding efficacy can be made without a control group. Conclusions Skin barrier repair from birth represents a novel and feasible approach to AD prevention. Further studies are warranted to determine the efficacy of this approach. PMID:20692725

  10. Bone targeted therapies for the prevention of skeletal morbidity in men with prostate cancer

    PubMed Central

    Saylor, Philip J

    2014-01-01

    Men with prostate cancer suffer substantially from bone-related complications. Androgen deprivation therapy itself is a cause of loss of bone mineral density and is associated with an increased incidence of osteoporotic fractures. In advanced disease, bone is by far the most common site of metastasis. Complications of bone metastases prominently include pain and the potential for skeletal events such as spinal cord compression and pathologic fractures. Elevated osteoclast activity is an important aspect of the pathophysiology of both treatment-related osteoporosis and skeletal complications due to metastases. The osteoclast is therefore a therapeutic target. Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor-κ-B ligand that was designed to potently inhibit osteoclast activity and is the central focus of this review. Bisphosphonates, radiopharmaceuticals and systemically-active hormonal agents such as abiraterone acetate and enzalutamide have each been shown to improve skeletal morbidity in specific clinical situations. Denosumab is the only agent that has been shown to prevent osteoporotic fractures in men receiving androgen deprivation therapy and at elevated risk for fracture. It has also demonstrated superiority to the potent bisphosphonate zoledronic acid for the prevention of skeletal-related events in men with castration-resistant prostate cancer metastatic to bone. Efficacy and toxicity data will be discussed. PMID:24435057

  11. Secondary prevention after PCI: the cost-effectiveness of statin therapy in the Netherlands

    PubMed Central

    Chaplin, S.; Scuffham, P.A.; Alon, M.; van den Boom, G.

    2004-01-01

    Background Little is known about the cost-effectiveness of secondary prevention after percutaneous coronary intervention (PCI). The aim of this study was to estimate the cost-effectiveness of statin therapy. Methods A cost-effectiveness analysis was performed using data from the Lescol Intervention Prevention Study (LIPS). In the LIPS trial, patients with normal-to-moderate hypercholesterolaemia who had undergone a first PCI were randomised to receive either fluvastatin 40 mg twice-daily plus dietary counselling or dietary counselling alone. A Markov model was used to estimate the incremental costs per quality-adjusted life year (QALY) and life year gained (LYG). Costs were based on prices and reimbursed charges, utility data were drawn from literature. Monte Carlo simulations and multivariate analysis were used to assess uncertainty. Results Routine statin treatment costs an additional €734 (SD €686) per patient over ten years compared with controls. It resulted in an additional 0.078 (0.047) QALYs or 0.082 (0.041) LYG. The incremental costs per QALY and LYG were €9312 (€14,648) and €8954 (€16,617) respectively. Anticipating a willingness to pay of €20,000 per QALY, there is a 75.1% chance that fluvastatin treatment is cost-effective. Conclusion Statin therapy with fluvastatin is economically efficient with regard to reducing heart disease in the Netherlands when given routinely to all patients following PCI. PMID:25696357

  12. Primary prevention of skin dysplasia in renal transplant recipients with photodynamic therapy: a randomized controlled trial.

    PubMed

    Togsverd-Bo, K; Omland, S H; Wulf, H C; Sørensen, S S; Haedersdal, M

    2015-11-01

    Organ transplant recipients (OTRs) are at high risk of developing cutaneous squamous cell carcinoma (SCC); prevention includes early treatment of premalignant actinic keratosis (AK). Photodynamic therapy (PDT) is a noninvasive field therapy that reduces new AKs in patients with existing AK and delays SCC development in mice. We investigated the effect of repeated PDT over 5 years for primary prophylaxis of skin dysplasia. These data represent an interim analysis of an on-going randomized controlled trial. During 2008-2011, 25 renal transplant recipients with clinically normal skin were randomized to split-side PDT of the face, forearm and hand, the contralateral side serving as untreated control. Patients received PDT on inclusion and at 6-monthly intervals for 5 years. Blinded evaluation was performed at each visit. We found that prophylactic PDT significantly delayed onset of AK compared with untreated skin, p = 0.020. At 3-year follow-up, we observed AK in 63% of patients in untreated skin areas compared with 28% of patients in PDT-treated skin, with a total number of cumulated AKs in untreated skin (n = 43) compared with PDT-treated skin (n = 8), p = 0.005. These preliminary data indicate a novel approach to early prevention of skin dysplasia that may reduce morbidity from multiple AKs and SCCs in OTR. PMID:26018207

  13. Preventing cerebral oedema in acute liver failure: the case for quadruple-H therapy.

    PubMed

    Warrillow, S J; Bellomo, R

    2014-01-01

    Severe cerebral oedema is a life-threatening complication of acute liver failure. Hyperammonaemia and cerebral hyperaemia are major contributing factors. A multimodal approach, which incorporates hyperventilation, haemodiafiltration, hypernatraemia and hypothermia (quadruple-H therapy), may prevent or attenuate severe cerebral oedema. This approach is readily administered by critical care clinicians and is likely to be more effective than the use of single therapies. Targeting of PaCO2 in the mild hyperventilation range, as seen in acute liver failure patients before intubation, aims to minimise hyperaemic cerebral oedema. Haemodiafiltration aims to achieve the rapid control of elevated blood ammonia concentrations by its removal and to reduce production via the lowering of core temperature. The administration of concentrated saline increases serum tonicity and further reduces cerebral swelling. In addition, the pathologically increased cerebral blood-flow is further attenuated by therapeutic hypothermia. The combination of all four treatments in a multimodal approach may be a safe and effective means of attenuating or treating the cerebral oedema of acute liver failure and preventing death from neurological complications. PMID:24471667

  14. DNA damage response--a double-edged sword in cancer prevention and cancer therapy.

    PubMed

    Tian, Hui; Gao, Zhen; Li, HuiZhong; Zhang, BaoFu; Wang, Gang; Zhang, Qing; Pei, DongSheng; Zheng, JunNian

    2015-03-01

    Genomic stability depends on an efficient DNA damage repair system to keep the chromosomes intact. Unrepaired DNA damage not only causes cell cycle arrest, apoptosis, but also accumulates genome mutations. DNA damage response (DDR) exhibits a critical function on the protection against human cancer, as indicated by the high predisposition to cancer of individuals with germ-line mutations in DDR genes. However, a defective DNA repair is liked intimately with the unchecked proliferation and the intrinsic resistance to clinical DNA-damaging agents. Therefore, abrogation of specific proteins in DNA damage repair pathways is a promising strategy for developing targeted cancer treatments. It may sound paradoxical to inhibit DDR pathway for sensitization of clinical therapy because cancer promotion and malignant transformation are aided by deficient DNA repair pathways. Actually, DDR acts as a positive guardian of genomic stability to prevent from tumorigenesis. On the other hand, DDR also performs as a negative saboteur to resist chemo- and radiotherapy. In this regard, DDR functions as "a double-edged sword" in cancer prevention and cancer therapy. The defective DDR that makes cancer cells of high mutability should alternatively provide therapeutic opportunities that confer the lethality to cancer cells without harming normal cells. PMID:25528631

  15. [Progress of researches on prevention and treatment of sports fatigue with moxibustion therapy].

    PubMed

    Xu, Hui-Qian; Zhang, Hong-Ru; Gu, Yi-Huang

    2014-04-01

    Sports fatigue belongs to the category of functional deficiency-syndrome according to the theory of traditional Chinese medicine. The moxibustion therapy has a long history and possesses a definite therapeutic effect in the prevention and treatment of sports fatigue. In the present paper, the authors reviewed development of researches on the effects of moxibustion intervention in the prevention and treatment of sports fatigue in recent 5 years. Results of researches showed that moxibustion intervention can 1) eliminate free radicals and reduce oxidative damage; 2) increase energy (glycogen) supply to delay the production of fatigue; 3) raise serum testosterone level (relieve exercise-induced neuroendocrine disorder) and reduce post-sports fatigue; 4) raise the anaerobic exercise ability, reduce the accumulation of metabolic products in the body and strengthen the endurance capacity of the skeletal muscle; and 5) improve ischemic cardiac function, and suppress cardiomyocyte apopotosis, etc. However, we should further strengthen our investigations on the moxibustion therapy in the ancient classical literature and sum up academic thoughts of different academic schools in the successive dynasties, put emphasis on the large sample randomized controlled clinical trails, establish united treatment standards, etc., and provide much evidence for effectively treating sports fatigue in the future.

  16. Impact of nanotechnology on the delivery of natural products for cancer prevention and therapy.

    PubMed

    Siddiqui, Imtiaz A; Sanna, Vanna

    2016-06-01

    Chemoprevention of human cancer by dietary products is a practical approach of cancer control, especially when chemoprevention is involved during the early stages of the carcinogenesis process. Research over the last few decades has clearly demonstrated the efficacy of dietary products for chemoprevention in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated to bedside for clinical use. Among many reasons, inefficient systemic delivery and bioavailability of promising chemopreventive agents are considered to significantly contribute to such a disconnection. Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and therapy of the disease. In a similar trait, we introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention (Cancer Res. 2009; 69:1712-1716). This idea, which we termed as 'nanochemoprevention', was exploited by several laboratories and has now become an advancing field in chemoprevention research. This review summarizes some of these applications of nanotechnology in medicine, particularly focused on controlled and sustained release of bioactive compounds with emphasis on current and future utilization of nanochemoprevention for prevention and therapy of cancer. PMID:26935239

  17. Cinnamic acid hydrogen bonds to isoniazid and N'-(propan-2-ylidene)isonicotinohydrazide, an in situ reaction product of isoniazid and acetone.

    PubMed

    Sarcevica, Inese; Orola, Liana; Veidis, Mikelis V; Belyakov, Sergey

    2014-04-01

    A new polymorph of the cinnamic acid-isoniazid cocrystal has been prepared by slow evaporation, namely cinnamic acid-pyridine-4-carbohydrazide (1/1), C9H8O2·C6H7N3O. The crystal structure is characterized by a hydrogen-bonded tetrameric arrangement of two molecules of isoniazid and two of cinnamic acid. Possible modification of the hydrogen bonding was investigated by changing the hydrazide group of isoniazid via an in situ reaction with acetone and cocrystallization with cinnamic acid. In the structure of cinnamic acid-N'-(propan-2-ylidene)isonicotinohydrazide (1/1), C9H8O2·C9H11N3O, carboxylic acid-pyridine O-H···N and hydrazide-hydrazide N-H···O hydrogen bonds are formed.

  18. Is it possible to prevent morbidity on post cardiovascular surgery applying low level laser therapy?

    NASA Astrophysics Data System (ADS)

    Pinto, Nathali C.; Baptista, Ivany Machado d. C.; Pereira, Mara Helena C.; Serrão, Nelson F.; Pomerantzeff, Pablo M. A.; Chavantes, Maria Cristina

    2014-03-01

    Background and Objective: Complications following cardiovascular surgery incision are common in mediastinitis and wound dehiscence form, a 47% mortality rate remaining. Low Level Laser Therapy (LLLT) has been employed mainly to its effectiveness analgesic and anti-inflammatory actions, aiding the tissue repair process. The aim of this study was to evaluate infrared LLLT onto surgical incision in patients submitted to cardiovascular surgery. Materials and Methods: 40 patients were divided in two groups: Placebo Group (G1) - conventional therapy + "Laser pointer" and Laser Group (G2) - conventional therapy + Infrared Laser irradiation on surgical incision. Diode Laser was employed, C.W. mode, around the surgical wound bed, on immediate Post Operative (PO), 1st PO and 3rd PO with the following parameters: wavelength (λ): 830nm, P=35mW, E=0,75J. Results: G2 didn't present any complication and 5% of patients in G1 developed incision dehiscence and infection. On 7thPO, still a large amount of G1 patients showed pain and unquestionable inflammatory signs surrounding the surgical wound, when compared to G2. Besides, hospital stay in Laser Group was 2 times shorter than in Placebo Group (p-value=0.001). Conclusion: Infrared Laser denoted to be safe and exceptionally valuable tools in preventing morbidities on post cardiovascular surgeries.

  19. Mathematical modeling and systems pharmacology of tuberculosis: Isoniazid as a case study.

    PubMed

    Lalande, Laure; Bourguignon, Laurent; Maire, Pascal; Goutelle, Sylvain

    2016-06-21

    Tuberculosis (TB) treatment needs to be optimized as it is currently long and associated with increasing drug resistance. The antimycobacterial effect of isoniazid (INH) is characterized by a biphasic kill curve, whose causes are still debated. In this work, we developed a complete mathematical model describing the time-course of TB infection and its treatment by INH in human lung. This model was based on a pharmacokinetic model, a pharmacodynamic model and a pathophysiological model. It was used to simulate the antibacterial effect of INH during the first days of therapy. This full model adequately reproduced some qualitative and quantitative properties of the early bactericidal activity of INH observed in TB patients. The kill curves simulated with the model reproduced the biphasic killing effect of INH and the predicted declines in extracellular bacteria were comparable to clinical data. A sensitivity analysis provided interesting insights regarding the biphasic kill curve. The first phase appeared to be essentially driven by the drug effect. In the second phase, while drug pharmacology was the major determinant of the antibacterial effect, a slight influence of the dynamics of infected macrophages was also observed. This work permits to formulate hypotheses for optimizing the efficacy of TB drug candidates and confirms the utility of mathematical modeling to generate new assumptions for TB research.

  20. Novel perspectives in the tuberculosis treatment: Administration of isoniazid through the skin.

    PubMed

    Caon, Thiago; Campos, Carlos Eduardo Maduro; Simões, Cláudia Maria Oliveira; Silva, Marcos Antônio Segatto

    2015-10-15

    Despite its high efficacy in anti-tuberculosis therapy, the oral administration of isoniazid (INH) may lead to poor patient compliance due to hepatotoxicity events. In this context, the transdermal administration of INH was evaluated, for the first time, since this route avoids hepatic first pass effect. INH was applied to porcine skin in Franz diffusion chambers alone and with 5% menthol, limonene or Transcutol(®). Infrared and DSC analyses were selected for mechanistic studies. The transdermal absorption of INH was sufficient to ensure a systemic therapeutic effect. Menthol was not able to improve the absorption of INH, but it increased the drug accumulation in skin compared to the control (1.4-fold). Transcutol(®) reduced permeation flux of INH (2.2-fold) and also increased the amount of drug retained in skin (1.7-fold). Limonene was the most effective excipient since it increased permeation flux of INH (1.5-fold) and lag time was greatly shortened (2.8-fold). DSC and FTIR analyses of limonene-treated skin suggest higher degree of disorder in lipid bilayers. Transdermal delivery of INH was positively correlated with logP of chemical enhancers. INH can be efficiently delivered by skin route and specific excipients may be selected depending on intended use.

  1. Mutations in the catalase-peroxidase gene from isoniazid-resistant Mycobacterium tuberculosis isolates.

    PubMed

    Altamirano, M; Marostenmaki, J; Wong, A; FitzGerald, M; Black, W A; Smith, J A

    1994-05-01

    Isoniazid resistance in Mycobacterium tuberculosis has been associated with total deletion of the katG gene, which codes for catalase-peroxidase production. To determine whether this is a common mechanism of drug resistance, 9 isolates of isoniazid-resistant and 1 of isoniazid-sensitive M. tuberculosis were analyzed by polymerase chain reaction amplification of a 237-bp sequence of the katG gene. Amplification was observed in the isoniazid-sensitive isolate and in 8 resistant isolates; in only 1 isoniazid-resistant isolate was there no amplification of the expected band, suggesting gene deletion. DNA sequencing showed that 8 of the 9 isolates had point mutations, deletions, or insertions of 1-3 bases. Evidence corroborating the presence of mutations in the katG gene was obtained by single-strand conformation polymorphism analysis in these 8 isolates. Thus, mutations as well as insertions and deletions in the katG gene can account for inactive catalase peroxidase, leading to isoniazid resistance; gene deletion occurs only infrequently, in approximately 11% of cases.

  2. Systems Pharmacology Approach Toward the Design of Inhaled Formulations of Rifampicin and Isoniazid for Treatment of Tuberculosis.

    PubMed

    Cilfone, N A; Pienaar, E; Thurber, G M; Kirschner, D E; Linderman, J J

    2015-03-01

    Conventional oral therapies for the treatment of tuberculosis are limited by poor antibiotic distribution in granulomas, which contributes to lengthy treatment regimens and inadequate bacterial sterilization. Inhaled formulations are a promising strategy to increase antibiotic efficacy and reduce dose frequency. We develop a multiscale computational approach that accounts for simultaneous dynamics of a lung granuloma, carrier release kinetics, pharmacokinetics, and pharmacodynamics. Using this computational platform, we predict that a rationally designed inhaled formulation of isoniazid given at a significantly reduced dose frequency has better sterilizing capabilities and reduced toxicity than the current oral regimen. Furthermore, we predict that inhaled formulations of rifampicin require unrealistic carrier antibiotic loadings that lead to early toxicity concerns. Lastly, we predict that targeting carriers to macrophages has limited effects on treatment efficacy. Our platform can be extended to account for additional antibiotics and provides a new tool for rapidly prototyping the efficacy of inhaled formulations. PMID:26225241

  3. Systems Pharmacology Approach Toward the Design of Inhaled Formulations of Rifampicin and Isoniazid for Treatment of Tuberculosis

    PubMed Central

    Cilfone, NA; Pienaar, E; Thurber, GM; Kirschner, DE; Linderman, JJ

    2015-01-01

    Conventional oral therapies for the treatment of tuberculosis are limited by poor antibiotic distribution in granulomas, which contributes to lengthy treatment regimens and inadequate bacterial sterilization. Inhaled formulations are a promising strategy to increase antibiotic efficacy and reduce dose frequency. We develop a multiscale computational approach that accounts for simultaneous dynamics of a lung granuloma, carrier release kinetics, pharmacokinetics, and pharmacodynamics. Using this computational platform, we predict that a rationally designed inhaled formulation of isoniazid given at a significantly reduced dose frequency has better sterilizing capabilities and reduced toxicity than the current oral regimen. Furthermore, we predict that inhaled formulations of rifampicin require unrealistic carrier antibiotic loadings that lead to early toxicity concerns. Lastly, we predict that targeting carriers to macrophages has limited effects on treatment efficacy. Our platform can be extended to account for additional antibiotics and provides a new tool for rapidly prototyping the efficacy of inhaled formulations. PMID:26225241

  4. Single-dose radiation therapy for prevention of heterotopic ossification after total hip arthroplasty

    SciTech Connect

    Healy, W.L.; Lo, T.C.; Covall, D.J.; Pfeifer, B.A.; Wasilewski, S.A. )

    1990-12-01

    Single-dose radiation therapy was prospectively evaluated for its efficacy in prevention of heterotopic ossification in patients at high risk after total hip arthroplasty. Thirty-one patients (34 hips) were treated between 1981 and 1988. Risk factors for inclusion in the protocol included prior evidence of heterotopic ossification, ankylosing spondylitis, and diffuse idiopathic skeletal hyperostosis. Patients with hypertrophic osteoarthritis or traumatic arthritis with osteophytes were not included. Operations on 34 hips included 19 primary total and 11 revision total hip arthroplasties and 4 excisions of heterotopic ossification. All patients received radiotherapy to the hip after operation with a single dose of 700 centigray. Radiotherapy is recommended on the first postoperative day. After this single-dose radiation treatment, no patient had clinically significant heterotopic ossification. Recurrent disease developed in two hips (6%), as seen on radiography (grades 2 and 3). This series documents a 100% clinical success rate and a 94% radiographic success rate in preventing heterotopic ossification in patients at high risk after total hip arthroplasty. Single-dose radiotherapy is as effective as other radiation protocols in preventing heterotopic ossification after total hip arthroplasty. It is less expensive and easier to administer than multidose radiotherapy.

  5. Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia.

    PubMed

    McKee, M D; Nakano, Y; Masica, D L; Gray, J J; Lemire, I; Heft, R; Whyte, M P; Crine, P; Millán, J L

    2011-04-01

    Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2(-/-)) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B(6)-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2(-/-) mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD(10)). sALP-FcD(10) prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin--a marker of acellular cementum--was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2(-/-) mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life--where the majority of tooth root development occurs, including acellular cementum formation--could prevent the accelerated tooth loss seen in individuals with HPP. PMID:21212313

  6. Chemoprevention gene therapy (CGT): novel combinatorial approach for preventing and treating pancreatic cancer.

    PubMed

    Sarkar, S; Azab, B M; Das, S K; Quinn, B A; Shen, X; Dash, R; Emdad, L; Thomas, S; Dasgupta, S; Su, Z-Z; Wang, X-Y; Sarkar, D; Fisher, P B

    2013-08-01

    Pancreatic cancer remains one of the deadliest of all cancers despite aggressive surgical treatment combined with adjuvant radiotherapy and chemotherapy. Chemoresistance and radioresistance are the principal causes of failure of pancreatic cancer patients to respond to therapy. Conditionally replication competent adenovirus (CRCA)-based cancer gene therapy is an innovative strategy for treating cancers displaying inherent resistance to treatment. Limitations of current adenovirus (Ad)-based gene therapies for malignant tumors include lack of cancer-specificity, and effective and targeted delivery. To remedy this situation, CRCAs have been designed that express E1A, necessary for Ad replication, under the control of a cancer-specific progression elevated gene-3 promoter (PEG-Prom) with concomitant expression of an immunomodulatory cytokine, such as mda-7/IL-24 or interferon-γ (IFN-γ), under the control of a ubiquitous and strong cytomegalovirus promoter (CMV-Prom) from the E3 region. These bipartite CRCAs, when armed with a transgene, are called cancer terminator viruses (CTVs), i.e., Ad.PEG-E1A-CMV-mda-7 (CTV-M7) and Ad.PEG-E1A-CMV-IFN-γ (CTV-γ), because of their universal effectiveness in cancer treatment irrespective of p53/pRb/p16 or other genetic alterations in tumor cells. In addition to their selective oncolytic effects in tumor cells, the potent 'bystander antitumor' properties of MDA-7/IL-24 and IFN-γ embody the CTVs with expanded treatment properties for both primary and distant cancers. Pancreatic cancer cells display a "translational block" of mda-7/IL-24 mRNA, limiting production of MDA-7/IL-24 protein and cancer-specific apoptosis. Specific chemopreventive agents abrogate this "translational block" resulting in pancreatic cancer-specific killing. This novel chemoprevention gene therapy (CGT) strategy holds promise for both prevention and treatment of pancreatic cancers where all other strategies have proven ineffective.

  7. An update on short-course episodic and prevention therapies for herpes genitalis.

    PubMed

    Corey, Lawrence; Bodsworth, Neil; Mindel, Adrian; Patel, Raj; Schacker, Timothy; Stanberry, Lawrence

    2007-06-01

    The prevalence of herpes genitalis (genital herpes) has increased markedly over the past three decades. The most common cause is infection with the herpes simplex virus type 2 (HSV-2), but it can also occur as a result of HSV-1 infection. Herpes genitalis can cause substantial psychosexual as well as physical morbidity and, in immunocompromised individuals, such as those who are HIV-positive, HSV infection can result in severe disease with progressive and extensive lesions. The natural history of herpes genitalis and the pathways of infection are now well known; however, the factors associated with reactivation have yet to be fully defined. A number of management approaches with antiviral medications are commonly used, including episodic and suppressive treatments. For episodic therapy, the duration of both lesions and symptoms, as well as the proportion of aborted episodes, are the most important measures of efficacy. For suppressive therapy, the time to first recurrence and frequency of recurrences over time are the most important clinical measures of antiviral benefit. Regarding the duration of episodic regimens, comparisons of 1-, 2- and 3-day antiviral courses with standard 5-day regimens show similar benefits on healing and relief of symptoms, with the obvious improvement in convenience, economy and compliance. In HIV-positive patients, antiherpes therapy has proved effective in speeding healing of lesions and reducing subclinical shedding, and can be used to treat genital HSV-2 infections in this group. Suppressive antiviral therapy has been shown to decrease the risk of HSV transmission in heterosexual couples. New approaches to the prevention of HSV infection, including vaccines and topical microbicides, are under investigation.

  8. Metabolism of isoniazid by neutrophil myeloperoxidase leads to isoniazid-NAD(+) adduct formation: A comparison of the reactivity of isoniazid with its known human metabolites.

    PubMed

    Khan, Saifur R; Morgan, Andrew G M; Michail, Karim; Srivastava, Nutan; Whittal, Randy M; Aljuhani, Naif; Siraki, Arno G

    2016-04-15

    The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD(+)) via the mycobacterial catalase-peroxidase enzyme, KatG, has been described as the major component of the mode of action of isoniazid (INH). However, there are numerous human peroxidases that may catalyze this reaction. The role of neutrophil myeloperoxidase (MPO) in INH-NAD(+) adduct formation has never been explored; this is important, as neutrophils are recruited at the site of tuberculosis infection (granuloma) through infected macrophages' cell death signals. In our studies, we showed that neutrophil MPO is capable of INH metabolism using electron paramagnetic resonance (EPR) spin-trapping and UV-Vis spectroscopy. MPO or activated human neutrophils (by phorbol myristate acetate) catalyzed the oxidation of INH and formed several free radical intermediates; the inclusion of superoxide dismutase revealed a carbon-centered radical which is considered to be the reactive metabolite that binds with NAD(+). Other human metabolites, including N-acetyl-INH, N-acetylhydrazine, and hydrazine did not show formation of carbon-centered radicals, and either produced no detectable free radicals, N-centered free radicals, or superoxide, respectively. A comparison of these free radical products indicated that only the carbon-centered radical from INH is reducing in nature, based on UV-Vis measurement of nitroblue tetrazolium reduction. Furthermore, only INH oxidation by MPO led to a new product (λmax=326nm) in the presence of NAD(+). This adduct was confirmed to be isonicotinyl-NAD(+) using LC-MS analysis where the intact adduct was detected (m/z=769). The findings of this study suggest that neutrophil MPO may also play a role in INH pharmacological activity.

  9. Metabolism of isoniazid by neutrophil myeloperoxidase leads to isoniazid-NAD(+) adduct formation: A comparison of the reactivity of isoniazid with its known human metabolites.

    PubMed

    Khan, Saifur R; Morgan, Andrew G M; Michail, Karim; Srivastava, Nutan; Whittal, Randy M; Aljuhani, Naif; Siraki, Arno G

    2016-04-15

    The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD(+)) via the mycobacterial catalase-peroxidase enzyme, KatG, has been described as the major component of the mode of action of isoniazid (INH). However, there are numerous human peroxidases that may catalyze this reaction. The role of neutrophil myeloperoxidase (MPO) in INH-NAD(+) adduct formation has never been explored; this is important, as neutrophils are recruited at the site of tuberculosis infection (granuloma) through infected macrophages' cell death signals. In our studies, we showed that neutrophil MPO is capable of INH metabolism using electron paramagnetic resonance (EPR) spin-trapping and UV-Vis spectroscopy. MPO or activated human neutrophils (by phorbol myristate acetate) catalyzed the oxidation of INH and formed several free radical intermediates; the inclusion of superoxide dismutase revealed a carbon-centered radical which is considered to be the reactive metabolite that binds with NAD(+). Other human metabolites, including N-acetyl-INH, N-acetylhydrazine, and hydrazine did not show formation of carbon-centered radicals, and either produced no detectable free radicals, N-centered free radicals, or superoxide, respectively. A comparison of these free radical products indicated that only the carbon-centered radical from INH is reducing in nature, based on UV-Vis measurement of nitroblue tetrazolium reduction. Furthermore, only INH oxidation by MPO led to a new product (λmax=326nm) in the presence of NAD(+). This adduct was confirmed to be isonicotinyl-NAD(+) using LC-MS analysis where the intact adduct was detected (m/z=769). The findings of this study suggest that neutrophil MPO may also play a role in INH pharmacological activity. PMID:26867495

  10. Harnessing the Prevention Benefits of Antiretroviral Therapy to Address HIV and Tuberculosis

    PubMed Central

    Granich, Reuben; Lo, Ying-Ru; Suthar, Amitabh B; Vitoria, Marco; Baggaley, Rachel; Obermeyer, Carla Makhlouf; McClure, Craig; Souteyrand, Yves; Perriens, Jos; Kahn, James G; Bennett, Rod; Smyth, Caoimhe; Williams, Brian; Montaner, Julio; Hirnschall, Gottfried

    2011-01-01

    After 30 years we are still struggling to address a devastating HIV pandemic in which over 25 million people have died. In 2010, an estimated 34 million people were living with HIV, around 70% of whom live in sub-Saharan Africa. Furthermore, in 2009 there were an estimated 1.2 million new HIV-associated TB cases, and tuberculosis (TB) accounted for 24% of HIV-related deaths. By the end of 2010, 6.6 million people were taking antiretroviral therapy (ART), around 42% of those in need as defined by the 2010 World Health Organization (WHO) guidelines. Despite this achievement, around 9 million people were eligible and still in need of treatment, and new infections (approximately 2.6 million in 2010 alone) continue to add to the future caseload. This combined with the international fiscal crisis has led to a growing concern regarding weakening of the international commitment to universal access and delivery of the Millennium Development Goals by 2015. The recently launched UNAIDS/WHO Treatment 2.0 platform calls for accelerated simplification of ART, in line with a public health approach, to achieve and sustain universal access to ART, including maximizing the HIV and TB preventive benefit of ART by treating people earlier, in line with WHO 2010 normative guidance. The potential individual and public health prevention benefits of using treatment in the prevention of HIV and TB enhance the value of the universal access pledge from a life-saving initiative, to a strategic investment aimed at ending the HIV epidemic. This review analyzes the gaps and summarizes the evidence regarding ART in the prevention of HIV and TB. PMID:21999771

  11. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

    PubMed Central

    Law, Man Fai; Ho, Rita; Cheung, Carmen K M; Tam, Lydia H P; Ma, Karen; So, Kent C Y; Ip, Bonaventure; So, Jacqueline; Lai, Jennifer; Ng, Joyce; Tam, Tommy H C

    2016-01-01

    Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although

  12. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy.

    PubMed

    Law, Man Fai; Ho, Rita; Cheung, Carmen K M; Tam, Lydia H P; Ma, Karen; So, Kent C Y; Ip, Bonaventure; So, Jacqueline; Lai, Jennifer; Ng, Joyce; Tam, Tommy H C

    2016-07-28

    Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although

  13. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy.

    PubMed

    Law, Man Fai; Ho, Rita; Cheung, Carmen K M; Tam, Lydia H P; Ma, Karen; So, Kent C Y; Ip, Bonaventure; So, Jacqueline; Lai, Jennifer; Ng, Joyce; Tam, Tommy H C

    2016-07-28

    Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although

  14. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

    PubMed Central

    Law, Man Fai; Ho, Rita; Cheung, Carmen K M; Tam, Lydia H P; Ma, Karen; So, Kent C Y; Ip, Bonaventure; So, Jacqueline; Lai, Jennifer; Ng, Joyce; Tam, Tommy H C

    2016-01-01

    Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although

  15. Functionalized single-walled carbon nanotube (5, 0) as a carrier for isoniazid — A tuberculosis drug

    NASA Astrophysics Data System (ADS)

    Rajarajeswari, M.; Iyakutti, K.; Lakshmi, I.; Rajeswarapalanichamy, R.; Kawazoe, Y.

    2015-06-01

    Nanostructures functionalized with amino acid are able to penetrate the cell wall. In this first principle study, we have demonstrated that the amino acid alanine functionalized carbon nanotubes (CNTs) (5, 0) can be a drug carrier for the tuberculosis drug isoniazid. Isoniazid is binding with both the non-covalently and covalently functionalized CNTs through the π-π stacking and NH⋯π interactions. The planar structure of isoniazid and hydrophobic nature of CNT promote the π-π stacking interactions. The amine group present in the isoniazid enables the NH⋯π interaction with the delocalized π electron cloud of CNT.

  16. Integrating Motivational Interviewing and Self Determination Theory with Cognitive Behavioral Therapy to Prevent Suicide

    PubMed Central

    Britton, Peter C.; Patrick, Heather; Wenzel, Amy; Williams, Geoffrey C.

    2016-01-01

    Cognitive Behavioral Therapy (CBT) has been found to be effective in preventing suicide-related behavior. However, it is often difficult to engage patients who are at-risk in treatment. Motivational Interviewing (MI) has been shown to increase treatment engagement and improve treatment outcomes when it is used to complement other treatments. As a general theory of human motivation that is consistent with MI, Self-Determination Theory (SDT) provides a framework for understanding how MI may be added to CBT to increase treatment engagement and effectiveness. In this paper, we use SDT to explain how MI may complement CBT to reduce suicide-related behavior, provide a case example of using MI with a suicidal patient before CBT-based treatment, and explore future directions for research.

  17. The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease.

    PubMed

    Scheinberg, I H; Jaffe, M E; Sternlieb, I

    1987-07-23

    Penicillamine is known to be effective therapy for Wilson's disease. However, the clinical consequences of the abrupt and permanent withdrawal of penicillamine have not been investigated. We studied 11 patients who stopped their own treatment after having been treated successfully with penicillamine (1 to 2 g per day) for periods of 3 to 19 years. Eight died of hepatic decompensation or fulminant hepatitis after an average survival of only 2.6 years. In another 13 patients, penicillamine was discontinued by the physician because of serious adverse reactions. In these patients, penicillamine was replaced with trientine (1 to 1.5 g per day), a newer chelating agent. All but one of these patients (who was killed accidentally) are alive at this writing, from 2 to 15 years later. Our observations suggest that discontinuation of penicillamine in patients with Wilson's disease results in rapid clinical deterioration, which is often fatal. The replacement of penicillamine with trientine appears to prevent this adverse clinical course.

  18. Fixed-dose combination therapy for the prevention of cardiovascular disease

    PubMed Central

    de Cates, Angharad N; Farr, Matthew RB; Wright, Nicola; Jarvis, Morag C; Rees, Karen; Ebrahim, Shah; Huffman, Mark D

    2014-01-01

    Background Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, yet CVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure and cholesterol lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of CVD by up to 80% given its potential for better adherence and lower costs. Objectives To determine the effectiveness of fixed-dose combination therapy on reducing fatal and non-fatal CVD events and on improving blood pressure and lipid CVD risk factors for both primary and secondary prevention of CVD. We also aimed to determine discontinuation rates, adverse events, health-related quality of life, and costs of fixed-dose combination therapy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library(2013, Issue 6), MEDLINE Ovid (1946 to week 2 July 2013), EMBASE Ovid (1980 to Week 28 2013), ISI Web of Science (1970 to 19 July 2013), and the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), and Health Economics Evaluations Database (HEED) (2011, Issue 4) in The Cochrane Library. We used no language restrictions. Selection criteria We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure lowering and one lipid lowering component versus usual care, placebo, or a single drug active component for any treatment duration in adults ≥ 18 years old with no restrictions on presence or absence of pre-existing cardiovascular disease. Data collection and analysis Three review authors independently selected studies for inclusion and extracted the data. We evaluated risk of bias using the Cochrane risk of bias assessment tool. We sought to include outcome data on all-cause mortality, fatal and non-fatal CVD events, adverse events, changes in systolic and diastolic blood

  19. Quantifying and Qualifying the Preventive Effects of Acute-Phase Cognitive Therapy: Pathways to Personalizing Care

    PubMed Central

    Jarrett, Robin B.; Minhajuddin, Abu; Vittengl, Jeffrey R.; Clark, Lee Anna; Thase, Michael E.

    2016-01-01

    Objective To determine the extent to which prospectively identified responders to cognitive therapy (CT) for recurrent major depressive disorder (MDD) hypothesized to be lower risk show significantly less relapse/recurrence than treated higher risk counterparts across 32 months. Method Outpatients (N = 523), aged 18–70, with recurrent MDD received 12–14 weeks of CT. The last seven consecutive scores from the Hamilton Rating Scale for Depression (HRSD-17), were used to stratify/define responders (n = 290) into lower (seven HRSD-17 scores of ≤ 6; n = 49; 17%) and higher risk (n = 241; 83%). The lower risk entered the 32-month follow-up. Higher risk patients were randomized to 8 months of continuation-phase CT or clinical management plus double-blind fluoxetine or pill placebo, with a 24-month follow-up. Results Lower risk patients were significantly less likely to relapse over the first 8 months compared to higher risk (Kaplan-Meier [KM] estimates (i.e., 4.9%=lower risk; 22.1%= higher risk; log-rank χ2 = 6.83, p = .009). This increased risk was attenuated, but not completely neutralized, by active continuation-phase therapy. Over the subsequent 24 months, the lower and higher risk groups did not differ in relapse/recurrence risk. Conclusions Rapid and sustained acute-phase CT remission identifies responders who do not require continuation-phase treatment to prevent relapse (i.e., return of an index episode). To prevent recurrence (i.e., new episodes), however, strategic allocation and more frequent “dosing” of CT and/or targeted maintenance-phase treatments may be required. Longitudinal follow-up is recommended. PMID:26654211

  20. mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation?

    PubMed

    Duvoux, Christophe; Toso, Christian

    2015-07-01

    Prevention of hepatocellular carcinoma (HCC) recurrence after liver transplantation is a clinical priority. The importance of the mammalian target of rapamycin (mTOR) pathway in cell growth and survival makes it a logical target for antitumor strategies, as borne out by clinical data in various types of malignancy. A number of studies have indicated that the mTOR inhibitors everolimus and sirolimus suppress cell proliferation and tumor growth in animal models of HCC. Coadministration of an mTOR inhibitor could permit lower dosing of chemotherapeutic agents in HCC management, and trials in non-transplant HCC population are exploring combined used with various agents including sorafenib, the vascular endothelial growth factor inhibitor bevacizumab and conventional agents. In terms of a preventive effect after liver transplantation for HCC, data from retrospective studies and non-randomized prospective analyses in which patients received an mTOR inhibitor with concomitant calcineurin inhibitor therapy have indicated that HCC recurrence rates and overall survival may be improved compared to a standard calcineurin inhibitor regimen. Meta-analyses have supported these findings, but controlled trials are required before any firm conclusions can be drawn. In two of the three randomized trials which have assessed de novo mTOR inhibitor therapy after liver transplantation, there was a numerically lower rate of HCC recurrence by one year post-transplant in patients given an mTOR inhibitor versus the control arm, but absolute numbers were low. Overall, based on the available data from retrospective studies, meta-analyses, and post-hoc assessments of randomized trials, it appears advisable to consider mTOR inhibition-based immunosuppression after transplantation for HCC, particularly in patients who exceed the Milan criteria. Prospective data are awaited. PMID:26071984

  1. Escitalopram and Problem-Solving Therapy for Prevention of Poststroke Depression: A Randomized Controlled Trial

    PubMed Central

    Robinson, Robert G.; Jorge, Ricardo E.; Moser, David J.; Acion, Laura; Solodkin, Ana; Small, Steven L.; Fonzetti, Pasquale; Hegel, Mark; Arndt, Stephan

    2009-01-01

    Context Depression occurs in more than half of patients who have experienced a stroke. Poststroke depression has been shown in numerous studies to be associated with both impaired recovery in activities of daily living and increased mortality. Prevention of depression thus represents a potentially important goal. Objective To determine whether treatment with escitalopram or problem-solving therapy over the first year following acute stroke will decrease the number of depression cases that develop compared with placebo medication. Design, Setting, and Participants A multisite randomized controlled trial for prevention of depression among 176 nondepressed patients was conducted within 3 months following acute stroke from July 9, 2003, to October 1, 2007. The 12-month trial included 3 groups: a double-blind placebo-controlled comparison of escitalopram (n=59) with placebo (n=58), and a nonblinded problem-solving therapy group (n=59). Main Outcome Measures The main outcome measure was the development of major or minor poststroke depression based on symptoms elicited by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) and the diagnostic criteria from DSM-IV for depression due to stroke with major depressivelike episode or minor depression (ie, research criteria). Results Patients who received placebo were significantly more likely to develop depression than individuals who received escitalopram (11 major and 2 minor cases of depression [22.4%] vs 3 major and 2 min or cases of depression [8.5%], adjusted hazard ratio [HR], 4.5; 95% confidence interval [CI], 2.4–8.2; P<.001) and also more likely than individuals who received problem-solving therapy (5 major and 2 minor cases of depression [11.9%], adjusted HR, 2.2; 95% CI, 1.4–3.5; P<.001). These results were adjusted for history of mood disorders and remained significant after considering possible confounders such as age, sex, treatment site

  2. Role of the pharmacist in pre-exposure chemoprophylaxis (PrEP) therapy for HIV prevention.

    PubMed

    Clauson, Kevin A; Polen, Hyla H; Joseph, Shine A; Zapantis, Antonia

    2009-01-01

    With a global estimate of 2.5 million new infections of HIV occurring yearly, discovering novel methods to help stem the spread of the virus is critical. The use of antiretroviral chemoprophylaxis for preventing HIV after accidental or occupational exposure and in maternal to fetal transmission has become a widely accepted method to combat HIV. Based on this success, pre-exposure chemoprophylaxis (PrEP) is being explored in at-risk patient populations such as injecting drug users, female sex workers and men who have sex with men. This off-label and unmonitored use has created a need for education and intervention by pharmacists and other healthcare professionals. Pharmacists should educate themselves on PrEP and be prepared to counsel patients about their means of obtaining it (e.g. borrowing or sharing medications and ordering from disreputable Internet pharmacies). They should also be proactive about medication therapy management in these patients due to clinically important drug interactions with PrEP medications. Only one trial exploring the safety and efficacy of tenofovir as PrEP has been completed thus far. However, five ongoing trials are in various stages and two additional studies are scheduled for the near future. Unfortunately, studies in this arena have met with many challenges that have threatened to derail progress. Ethical controversy surrounding post-trial care of participants who seroconvert during studies, as well as concerns over emerging viral resistance and logistical site problems, have already halted several PrEP trials. Information about these early trials has already filtered down to affected individuals who are experimenting with this unproven therapy as an "evening before pill". The potential for PrEP is promising; however, more extensive trials are necessary to establish its safety and efficacy. Pharmacists are well-positioned to play a key role in helping patients make choices about PrEP, managing their therapy, and developing policy

  3. Use of corticosteroids to prevent progression of Graves' ophthalmopathy after radioiodine therapy for hyperthyroidism

    SciTech Connect

    Bartalena, L.; Marcocci, C.; Bogazzi, F.; Panicucci, M.; Lepri, A.; Pinchera, A. )

    1989-11-16

    We studied the effects of radioiodine treatment of hyperthyroidism due to Graves' disease on Graves' ophthalmopathy and the possible protective role of corticosteroids. Between June 1985 and June 1988, 26 patients were randomly assigned to treatment with radioiodine alone (group 1) and 26 to treatment with this agent and concomitant administration of systemic prednisone for four months (group 2). The initial dose of prednisone was 0.4 to 0.5 mg per kilogram of body weight for one month; the drug was gradually withdrawn over the next three months. All patients were evaluated at 3-month intervals for 18 months after they underwent radioiodine therapy. Ocular changes were assessed with the ophthalmopathy index; patients with moderate-to-severe changes (scores greater than or equal to 4) were excluded from the study. Before treatment, 10 patients in group 1 and 5 in group 2 had no evidence of ophthalmopathy: in none of them did ocular symptoms appear after radioiodine therapy. Among the patients in group 1 with an initial ophthalmopathy index greater than or equal to 1, ocular disease worsened in 56 percent (mostly involving soft-tissue changes and extraocular-muscle function) and did not change in 44 percent. In contrast, ophthalmopathy improved in 52 percent and did not change in 48 percent of group 2. The mean ophthalmopathy index increased from 1.5 to 3.0 in group 1 (P less than 0.005) and decreased from 2.2 to 1.3 in group 2 (P less than 0.05). We conclude that systemic corticosteroid treatment prevents the exacerbations of Graves' ophthalmopathy that occur after radioiodine therapy in a substantial proportion of patients with hyperthyroidism who have some degree of ocular involvement before treatment.

  4. Cancer prevention and therapy through the modulation of the tumor microenvironment.

    PubMed

    Casey, Stephanie C; Amedei, Amedeo; Aquilano, Katia; Azmi, Asfar S; Benencia, Fabian; Bhakta, Dipita; Bilsland, Alan E; Boosani, Chandra S; Chen, Sophie; Ciriolo, Maria Rosa; Crawford, Sarah; Fujii, Hiromasa; Georgakilas, Alexandros G; Guha, Gunjan; Halicka, Dorota; Helferich, William G; Heneberg, Petr; Honoki, Kanya; Keith, W Nicol; Kerkar, Sid P; Mohammed, Sulma I; Niccolai, Elena; Nowsheen, Somaira; Vasantha Rupasinghe, H P; Samadi, Abbas; Singh, Neetu; Talib, Wamidh H; Venkateswaran, Vasundara; Whelan, Richard L; Yang, Xujuan; Felsher, Dean W

    2015-12-01

    Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

  5. Antenatal Cognitive-behavioral Therapy for Prevention of Postpartum Depression: A Pilot Study

    PubMed Central

    Kwon, Jung Hye; Lee, Jeong Jae

    2008-01-01

    Purpose To examine the efficacy of cognitive-behavioral therapy (CBT) for the prevention of postpartum depression (PPD) in "at risk" women. Materials and Methods We recruited 927 pregnant women in 6 obstetric and gynecology clinics and screened them using Beck Depression Inventory (BDI). Ninety-nine of the screened women who had significantly high scores in BDI (a score above 16) were selected for the study. They were contacted through by telephone, and 27 who had consented to participate in the study were interviewed via SCID-IV-I. Twenty-seven eligible women were randomly assigned to the CBT intervention (n = 15) and control condition (n = 12). All participants were required to complete written questionnaires, assessing demographic characteristics, depressive symptoms, negative thoughts, dyadic communication satisfaction, and global marital satisfaction prior to treatment and approximately 1 month postpartum. The 15 women in the CBT condition received 9 bi-weekly 1-hour individual CBT sessions, targeting and modifying negative patterns of thinking and behaviors occurring in the context of the dyadic relationship. Results The analysis of covariance (ANCOVA) showed that there were significant differences in all postpartum measures between the 2 groups, indicating that our antenatal intervention with CBT was effective in reducing depressive symptoms and improving marital satisfaction, which lasted until the postpartum period. Conclusion Our pilot study has provided preliminary empirical evidence that antenatal CBT intervention can be an effective preventive treatment for PPD. Further study in this direction was suggested. PMID:18729297

  6. Probiotics to prevent gastrointestinal toxicity from cancer therapy: An interpretive review and call to action

    PubMed Central

    Ciorba, Matthew A; Hallemeier, Christopher L; Stenson, William F; Parikh, Parag J

    2016-01-01

    Purpose of Review There is currently an unmet need for agents that can prevent the gastrointestinal toxicity (mucositis, enteritis) associated with chemotherapy and radiation therapy of abdominal and pelvic cancers. Herein we provide an overview of how manipulation of the gut microbiota by probiotic administration affects these gastrointestinal symptoms. We focus this review on published human trials and also provide suggestions on how the field can move forward. Recent Findings Several clinical trials of varying design, patient populations and probiotic product have been reported. Lactobacillus probiotics of adequate dosage demonstrate a potential to reduce gastrointestinal toxicity when administered prophylactically. Common study limitations prevent the widespread adoption of this practice at this point, but are informative for rational design of future trials. Summary No single probiotic strain or product has emerged from human clinical trials for this indication. Further human studies are required to address limitations in the current literature. Preclinical model data should be used to inform the rational design of these new clinical trials to adequately address this important question. PMID:25872116

  7. Preventing Maltreatment with a Community-Based Implementation of Parent-Child Interaction Therapy

    PubMed Central

    Kohl, Patricia L.; Benz, Joan; Swinger, Dawn; Drake, Brett

    2013-01-01

    The purpose of this study was to examine rates of child abuse and neglect reports following a community implementation of Parent-Child Interaction Therapy (PCIT), an evidence-supported intervention for the prevention of maltreatment. Among a group of families receiving PCIT, predictors of reports were examined including family demographics, course of treatment, changes in clinical measures, and caregiver report for prior maltreatment victimization and perpetration. Participants (n=120) included families at-risk for future maltreatment with and without prior maltreatment history. Agency case records were linked with state administrative records of child welfare reports. Time to follow-up ranged from 13–40 months. Bivariate and multivariate survival analyses are used to model risk for a later report. During the follow-up period, 12.5% of families had a report for physical abuse or neglect. Reports of prior victimization as a child and prior perpetration as an adult were strong predictors of a report of perpetration after PCIT. Dosage of PCIT and change in clinical measures did not increase risk for a later report. PCIT can be an effective intervention for preventing maltreatment. Family history of child welfare involvement is a prominent factor in assessing risk for future involvement. PMID:24443637

  8. Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors

    PubMed Central

    Costa, Ana Lúcia; Abreu, Catarina; Pacheco, Teresa Raquel; Macedo, Daniela; Sousa, Ana Rita; Pulido, Catarina; Quintela, António; Costa, Luís

    2015-01-01

    Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity. PMID:26421283

  9. Fasting therapy for treating and preventing disease - current state of evidence.

    PubMed

    Michalsen, Andreas; Li, Chenying

    2013-01-01

    Periods of deliberate fasting with restriction of solid food intake are practiced worldwide, mostly based on traditional, cultural or religious reasons. There is large empirical and observational evidence that medically supervised modified fasting (fasting cure, 200-500 kcal nutritional intake per day) with periods of 7-21 days is efficacious in the treatment of rheumatic diseases, chronic pain syndromes, hypertension, and metabolic syndrome. The beneficial effects of fasting followed by vegetarian diet in rheumatoid arthritis are confirmed by randomized controlled trials. Further beneficial effects of fasting are supported by observational data and abundant evidence from experimental research which found caloric restriction and intermittent fasting being associated with deceleration or prevention of most chronic degenerative and chronic inflammatory diseases. Intermittent fasting may also be useful as an accompanying treatment during chemotherapy of cancer. A further beneficial effect of fasting relates to improvements in sustainable lifestyle modification and adoption of a healthy diet, possibly mediated by fasting-induced mood enhancement. Various identified mechanisms of fasting point to its potential health-promoting effects, e.g., fasting-induced neuroendocrine activation and hormetic stress response, increased production of neurotrophic factors, reduced mitochondrial oxidative stress, general decrease of signals associated with aging, and promotion of autophagy. Fasting therapy might contribute to the prevention and treatment of chronic diseases and should be further evaluated in controlled clinical trials and observational studies. PMID:24434759

  10. Selective determination of isoniazid using bentonite clay modified electrodes.

    PubMed

    Azad, Uday Pratap; Prajapati, Nandlal; Ganesan, Vellaichamy

    2015-02-01

    Fe(dmbpy)3(2+) (where dmbpy is 4,4'-dimethyl-2,2'-bipyridine) was immobilized by ion-exchange in a bentonite clay film coating on a glassy carbon electrode. Cyclic voltammetry characteristics of the immobilized Fe(dmbpy)3(2+) were stable and reproducible corresponding to the Fe(dmbpy)3(2+/3+) redox process. In the presence of isoniazid (IZ), the electrogenerated in film Fe(dmbpy)3(3+) oxidized IZ efficiently producing large anodic current. This current was linearly proportional to the IZ concentration in the solution. The process was described by an EC' electrocatalysis mechanism allowing for sensitive determination of IZ with a wide linear dynamic concentration range of 10.0μM to 10.0mM. The electrode was tested for its analytical suitability and possible discrimination of interferences by determining IZ in a commercially available pharmaceutical product. The paper reports on a simple, cheap, and easy to fabricate chronoamperometric chemical sensor for determination of IZ. Kinetic parameters, such as the catalytic rate constant (2.3×10(3)M(-1)s(-1)) and diffusion coefficient of IZ (5.42×10(-5)cm(2)s(-1)), were determined using CV, chronoamperometry, and chronocoulometry. PMID:25260015

  11. Prevention

    MedlinePlus

    ... our e-newsletter! Aging & Health A to Z Prevention Basic Facts & Information Some factors that affect your ... control of the things that you can change. Preventive Recommendations for Adults Aged 65 and Older The ...

  12. Oleanane triterpenoids in the prevention and therapy of breast cancer: current evidence and future perspectives

    PubMed Central

    Parikh, Nisha R.; Mandal, Animesh; Bhatia, Deepak; Siveen, Kodappully Sivaraman; Sethi, Gautam

    2014-01-01

    Breast cancer is one of the most frequently diagnosed cancers and major cause of death in women in the world. Emerging evidence underscores the value of dietary and non-dietary phytochemicals, including triterpenoids, in the prevention and treatment of breast cancer. Oleanolic acid, an oleanane-type pentacyclic triterpenoid, is present in a large number of dietary and medicinal plants. Oleanolic acid and its derivatives exhibit several promising pharmacological activities, including antioxidant, anti-inflammatory, hepatoprotective, cardioprotective, antipruritic, spasmolytic, antiallergic, antimicrobial and antiviral effects. Numerous studies indicate that oleanolic acid and other oleanane triterpenoids modulate multiple intracellular signaling pathways and exert chemopreventive and antitumor activities in various in vitro and in vivo model systems. A series of novel synthetic oleanane triterpenoids have been prepared by chemical modifications of oleanolic acid and some of these compounds are considered to be the most potent anti-inflammatory and anticarcinogenic triterpenoids. Accumulating studies provide extensive evidence that synthetic oleanane derivatives inhibit proliferation and induce apoptosis of various cancer cells in vitro and demonstrate cancer preventive or antitumor efficacy in animal models of blood, breast, colon, connective tissue, liver, lung, pancreas, prostate and skin cancer. This review critically examines the potential role of oleanolic acid, oleanane triterpenoids and related synthetic compounds in the chemoprevention and treatment of mammary neoplasia. Both in vitro and in vivo studies on these agents and related molecular mechanisms are presented. Several challenges and future directions of research to translate already available impressive preclinical knowledge to clinical practice of breast cancer prevention and therapy are also presented. PMID:25395898

  13. Adenosine Deaminase Enzyme Therapy Prevents and Reverses the Heightened Cavernosal Relaxation in Priapism

    PubMed Central

    Wen, Jiaming; Jiang, Xianzhen; Dai, Yingbo; Zhang, Yujin; Tang, Yuxin; Sun, Hong; Mi, Tiejuan; Kellems, Rodney E.; Blackburn, Michael R.; Xia, Yang

    2010-01-01

    Introduction Priapism featured with painful prolonged penile erection is dangerous and commonly seen in sickle cell disease (SCD). The preventive approaches or effective treatment options for the disorder are limited because of poor understanding of its pathogenesis. Recent studies have revealed a novel role of excess adenosine in priapism caused by heightened cavernosal relaxation, and therefore present an intriguing mechanism-based therapeutic possibility. Aim The aim of this study was to determine the therapeutic effects of adenosine deaminase (ADA) enzyme therapy to lower adenosine in priapism. Methods Both ADA-deficient mice and SCD transgenic (Tg) mice display priapism caused by excessive adenosine. Thus, we used these two distinct lines of mouse models of priapism as our investigative tools. Specifically, we treated both of these mice with different dosages of polyethylene glycol–modified ADA (PEG–ADA) to reduce adenosine levels in vivo. At the end points of the experiments, we evaluated the therapeutic effects of PEG–ADA treatment by measuring adenosine levels and monitoring the cavernosal relaxation. Main Outcome Measures Adenosine levels in penile tissues were measured by high-performance liquid chromatography, and cavernosal relaxation was quantified by electrical field stimulation (EFS)-induced corporal cavernosal strip (CCS) assays. Results We found that lowering adenosine levels in penile tissues by PEG–ADA treatment from birth in ADA-deficient mice prevented the increased EFS-induced CCS relaxation associated with priapism. Intriguingly, in both ADA-deficient mice and SCD Tg mice with established priapism, we found that normalization of adenosine levels in penile tissues by PEG–ADA treatment relieved the heightened EFS-induced cavernosal relaxation in priapism. Conclusions Our studies have identified that PEG–ADA is a novel, safe, and mechanism-based drug to prevent and correct excess adenosine-mediated increased cavernosal relaxation

  14. What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis? A systematic review and network meta-analysis

    PubMed Central

    Stagg, H R; Harris, R J; Hatherell, H-A; Obach, D; Tsuchiya, N; Kranzer, K; Nikolayevskyy, V; Kim, J; Lipman, M C; Abubakar, I

    2016-01-01

    Introduction Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy. Methods Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained. Results 12 604 records were retrieved and 118 remained postextraction, representing 59 studies—27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12–0.81)). In a random-effects model all estimates crossed the null. Conclusions Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse. Systematic review registration number PROSPERO CRD42014015025. PMID:27298314

  15. The role of oxygen free radicals in isoniazid-induced hepatotoxicity.

    PubMed

    Walubo, A; Smith, P; Folb, P I

    1998-10-01

    Isoniazid and its metabolites acetylisoniazid, hydrazine and monoacetylhydrazine were investigated for generation of oxygen free radicals during incubation with rat liver slices. Lipid peroxidation was assessed by the thiobarbituric acid reactive substances test using malonaldehyde as the external standard, while hepatotoxicity was assessed by histopathology studies. Malonaldehyde formed in liver slices after 10 hours of incubation with the drugs was 1.28 +/- 0.24 nmol/mg for isoniazid (control 1.12 +/- 0.17 nmol/mg); 0.88 +/- 0.45 nmol/mg for acetylisoniazid (control 0.84 +/- 0.42 nmol/mg); 1.43 +/- 0.14 nmol/mg for monoacetylhydrazine (control 1.10 +/- 0.12 nmol/mg) and 1.36 +/- 0.02 nmol/mg for hydrazine (control 1.13 +/- 0.04 nmol/mg). Histologically, all slices exhibited hepatic necrosis by 4 hours. However, hydrazine-induced hepatotoxicity was characterized by nuclear hyperchromatsia, karyolysis and karyohexis while monoacetylhydrazine exhibited hydropic karyomegaly only. Isoniazid and acetylisoniazid cytotoxicity exhibited a mixture of the above features such that it could be attributed to the two metabolites, hydrazine and monoacetylhydrazine. In conclusion, there was no evidence implicating oxygen free radicals in isoniazid-induced hepatotoxicity; however, the histopathology findings indicate a need for a review of our knowledge on pathognomonic features of isoniazid hepatotoxicity.

  16. Flow-injection determination of isoniazid using sodium dichloroisocyanurate- and trichloroisocyanuric acid-luminol chemiluminescence systems.

    PubMed

    Safavi, A; Karimi, M A; Hormozi Nezhad, M R

    2004-06-01

    A chemiluminescent (CL) method for the determination of isoniazid is described. The method is based on the CL generated during the oxidation of luminol by sodium dichloroisocyanurate (SDCC) and trichloroisocyanuric acid (TCCA) in alkaline medium. It was found that isoniazid greatly enhances this CL intensity when present in the luminol solution. Based on this observation, a new flow-injection CL method for the determination of isoniazid has been proposed in this paper. The detection limits were 2 and 3 ng ml(-1) isoniazid for the SDCC-luminol and TCCA-luminol CL systems, respectively. The relative CL intensity was linear with the isoniazid concentration in the range of 4-100 and 100-200 ng ml(-1) for the SDCC-luminol CL system, and 6-200 and 200-1000 ng ml(-1) for the TCCA-luminol CL system. The results obtained for the assay of pharmaceutical preparations compared well with those obtained by the official methods and demonstrated good accuracy and precision. PMID:15178311

  17. Antibodies to nucleoprotein and to hydrazide-altered soluble nucleoprotein in tuberculous patients receiving isoniazid

    PubMed Central

    Alarcón-Segovia, D.; Fishbein, Eugenia; Betancourt, V. M.

    1969-01-01

    Antibodies to calf thymus nuclei, nucleoprotein, DNA, soluble nucleoprotein and hydrazide (hydrallazine and isoniazid)-altered nucleoprotein were investigated by a standard complement-fixation method in 214 tuberculous patients receiving isoniazid. Findings were compared to those on thirty-seven sera from lupus patients receiving neither steroids nor immunosuppressants and on sixty-six sera from normal controls. The incidence of antibodies to all antigens studied except DNA was significantly higher in isoniazid-treated tuberculous patients than in the normal controls, but lower than in the lupus patients. Unlike lupus there were no detectable DNA antibodies in the tuberculous or in the control sera. Antibodies to nucleoprotein (soluble and insoluble) and particularly to hydrazide-altered nucleoprotein were the most frequently found in the isoniazid-treated tuberculous patients. In general, antinuclear antibodies were more frequent in the isoniazid-treated tuberculous female than in the male; in the adult than in the child. It is suggested that hydrazides may cause in vivo similar alteration of nucleoprotein to that which they cause in vitro. Hydrazide-altered nucleoprotein probably elicits the production of antinuclear antibodies which in turn may activate systemic lupus erythematosus in otherwise predisposed individuals. PMID:5359961

  18. Computerised Cognitive Behavioural Therapy for the Prevention and Treatment of Depression and Anxiety in Children and Adolescents: A Systematic Review

    ERIC Educational Resources Information Center

    Richardson, Thomas; Stallard, Paul; Velleman, Sophie

    2010-01-01

    Research has shown that computerised cognitive behaviour therapy (cCBT) can be effective in the treatment of depression and anxiety in adults, although the outcomes with children and adolescents are unclear. The aim of the study is to systematically review the literature on the effectiveness of cCBT for the prevention and treatment of depression…

  19. Does hormone therapy affect blood pressure changes in the Diabetes Prevention Program?

    PubMed Central

    Kim, Catherine; Golden, Sherita H.; Kong, Shengchun; Nan, Bin; Mather, Kieren J.; Barrett-Connor, Elizabeth

    2013-01-01

    Objectives To examine whether blood pressure reductions differ by estrogen use among overweight glucose-intolerant women. Methods We conducted a secondary analysis of postmenopausal Diabetes Prevention Program participants who used oral estrogen with or without progestogen at baseline and at 1-year follow-up (n=324) vs. those who did not use at either time point (n=382). Systolic (SBP) and diastolic blood pressure (DBP) changes were examined by randomization arm (intensive lifestyle change (ILS), metformin 850 mg twice daily, or placebo). Associations between changes in blood pressure with changes in sex hormone binding globulin, estradiol, testosterone, and dehydroepiandrosterone were also examined. Results Estrogen users and non-users had similar prevalences of baseline hypertension (33% vs. 34%, p=0.82) and use of blood pressure medications at baseline (p=0.25) and follow-up (p=0.10). Estrogen users and non-users randomized to ILS had similar decreases in SBP (-3.3 vs. -4.7 mmHg, p=0.45) and DBP (-3.1 vs. -4.7 mmHg, p=0.16). Among estrogen users, women randomized to ILS had significant declines in SBP (p=0.016) and DBP (p=0.009) vs. placebo. Among non-users, women randomized to ILS had significant declines in DBP (p=0.001) vs. placebo, but declines in SBP were not significant (p=0.11). Metformin was not associated with blood pressure reductions vs. placebo regardless of estrogen therapy. Blood pressure changes were not associated with changes in sex hormones regardless of estrogen therapy. Conclusions Among overweight women with dysglycemia, the magnitude of blood pressure reductions after ILS was unrelated to postmenopausal estrogen use. PMID:23942251

  20. Advances in prevention and therapy of neonatal dairy calf diarrhoea: a systematical review with emphasis on colostrum management and fluid therapy.

    PubMed

    Meganck, Vanessa; Hoflack, Geert; Opsomer, Geert

    2014-01-01

    Neonatal calf diarrhoea remains the most common cause of morbidity and mortality in preweaned dairy calves worldwide. This complex disease can be triggered by both infectious and non-infectious causes. The four most important enteropathogens leading to neonatal dairy calf diarrhoea are Escherichia coli, rota- and coronavirus, and Cryptosporidium parvum. Besides treating diarrhoeic neonatal dairy calves, the veterinarian is the most obvious person to advise the dairy farmer on prevention and treatment of this disease. This review deals with prevention and treatment of neonatal dairy calf diarrhoea focusing on the importance of a good colostrum management and a correct fluid therapy. PMID:25431305

  1. Topical management of striae distensae (stretch marks): prevention and therapy of striae rubrae and albae.

    PubMed

    Ud-Din, S; McGeorge, D; Bayat, A

    2016-02-01

    Striae distensae (SD) are common dermal lesions, with significant physical and psychological impact. Many therapeutic modalities are available but none can completely eradicate SD. The most common therapy is the application of topicals used both therapeutically and prophylactically. Even though there are many commercially available topical products, not all have sufficient level of evidence to support their continued use in SD. The aim here was to assess the evidence for the use of topicals in SD and to propose a structured approach in managing SD. A systematic search of published literature and manufacturer website information for topicals in SD was carried out. The results showed that there are few studies (n = 11) which investigate the efficacy of topicals in management of SD. Trofolastin and Alphastria creams demonstrated level-2 evidence of positive results for their prophylactic use in SD. Additionally, tretinoin used therapeutically showed varying results whilst cocoa butter and olive oil did not demonstrate any effect. Overall, there is a distinct lack of evidence for each topical formulation. The majority of topicals failed to mention their effect on early vs. later stages of SD (striae rubrae compared to striae albae) and their role in both prevention and treatment. In conclusion, there is no topical formulation, which is shown to be most effective in eradicating or improving SD. A structured approach in identification and targeted management of symptoms and signs with the appropriate topical is required. Randomized controlled trials are necessary to assess the efficacy of topical products for treatment and prevention of different stages of SD. PMID:26486318

  2. Relapse Prevention in Major Depressive Disorder: Mindfulness-Based Cognitive Therapy Versus an Active Control Condition

    PubMed Central

    Shallcross, Amanda J.; Gross, James J.; Visvanathan, Pallavi D.; Kumar, Niketa; Palfrey, Amy; Ford, Brett Q.; Dimidjian, Sona; Shirk, Stephen; Holm-Denoma, Jill; Goode, Kari M.; Cox, Erica; Chaplin, William; Mauss, Iris B.

    2015-01-01

    Objective We evaluated the comparative effectiveness of Mindfulness-based cognitive therapy (MBCT) versus an active control condition (ACC) for depression relapse prevention, depressive symptom reduction, and improvement in life satisfaction. Method Ninety-two participants in remission from Major Depressive Disorder with residual depressive symptoms were randomized to either an 8-week MBCT or a validated ACC that is structurally equivalent to MBCT and controls for non-specific effects (e.g., interaction with a facilitator, perceived social support, treatment outcome expectations). Both interventions were delivered according to their published manuals. Results Intention-to-treat analyses indicated no differences between MBCT and ACC in depression relapse rates or time to relapse over a 60-week follow-up. Both groups experienced significant and equal reductions in depressive symptoms and improvements in life satisfaction. A significant quadratic interaction (group x time) indicated that the pattern of depressive symptom reduction differed between groups. The ACC experienced immediate symptom reduction post-intervention and then a gradual increase over the 60-week follow-up. The MBCT group experienced a gradual linear symptom reduction. The pattern for life satisfaction was identical but only marginally significant. Conclusions MBCT did not differ from an ACC on rates of depression relapse, symptom reduction, or life satisfaction, suggesting that MBCT is no more effective for preventing depression relapse and reducing depressive symptoms than the active components of the ACC. Differences in trajectory of depressive symptom improvement suggest that the intervention-specific skills acquired may be associated with differential rates of therapeutic benefit. This study demonstrates the importance of comparing psychotherapeutic interventions to active control conditions. PMID:26371618

  3. Nitrite impacts the survival of Mycobacterium tuberculosis in response to isoniazid and hydrogen peroxide

    PubMed Central

    Cunningham-Bussel, Amy; Bange, Franz C; Nathan, Carl F

    2013-01-01

    When access to molecular oxygen is restricted, Mycobacterium tuberculosis (Mtb) can respire an alternative electron acceptor, nitrate. We found that Mtb within infected primary human macrophages in vitro at physiologic tissue oxygen tensions respired nitrate, generating copious nitrite. A strain of Mtb lacking a functioning nitrate reductase was more susceptible than wild-type Mtb to treatment with isoniazid during infection of macrophages. Likewise, nitrate reductase-deficient Mtb was more susceptible to isoniazid than wild-type Mtb in axenic culture, and more resistant to hydrogen peroxide. These phenotypes were reversed by the addition of exogenous nitrite. Further investigation suggested that nitrite might inhibit the bacterial catalase. To the extent that Mtb itself is the most relevant source of nitrite acting within Mtb, these findings suggest that inhibitors of Mtb's nitrate transporter or nitrate reductase could enhance the efficacy of isoniazid. PMID:24019302

  4. Rifampicin/Cotrimoxazole/Isoniazid Versus Mefloquine or Quinine + Sulfadoxine- Pyrimethamine for Malaria: A Randomized Trial

    PubMed Central

    Genton, Blaise; Mueller, Ivo; Betuela, Inoni; Casey, Gerard; Ginny, Meza; Alpers, Michael P; Reeder, John C

    2006-01-01

    Objectives: Previous studies of a fixed combination including cotrimoxazole, rifampicin, and isoniazid (Cotrifazid) showed efficacy against resistant strains of Plasmodium falciparum in animal models and in small-scale human studies. We conducted a multicentric noninferiority trial to assess the safety and efficacy of Cotrifazid against drug-resistant malaria in Papua New Guinea. Design: The trial design was open-label, block-randomised, comparative, and multicentric. Setting: The trial was conducted in four primary care health facilities, two in urban and two in rural areas of Madang and East Sepik Province, Papua New Guinea. Participants: Patients of all ages with recurrent uncomplicated malaria were included. Interventions: Patients were randomly assigned to receive Cotrifazid, mefloquine, or the standard treatment of quinine with sulfadoxine–pyrimethamine (SP). Outcome Measures: Incidence of clinical and laboratory adverse events and rate of clinical and/or parasitological failure at day 14 were recorded. Results: The safety analysis population included 123 patients assigned to Cotrifazid, 123 to mefloquine, and 123 to quinine + SP. The Cotrifazid group experienced lower overall incidence of adverse events than the other groups. Among the efficacy analysis population (72 Cotrifazid, 71 mefloquine, and 75 quinine + SP), clinical failure rate (symptoms and parasite load) on day 14 was equivalent for the three groups (0% for Cotrifazid and mefloquine; 1% for quinine + SP), but parasitological failure rate (P. falciparum asexual blood-stage) was higher for Cotrifazid than for mefloquine or quinine + SP (9% [PCR corrected 8%] versus 0% and 3%, respectively [p = 0.02]). Conclusion: Despite what appears to be short-term clinical equivalence, the notable parasitological failure at day 14 in both P. falciparum and P. vivax makes Cotrifazid in its current formulation and regimen a poor alternative combination therapy for malaria. PMID:17192794

  5. Determination of the acute toxicity of isoniazid to three invasive carp species and rainbow trout in static exposures

    USGS Publications Warehouse

    Schreier, Theresa M.; Hubert, Terrance D.

    2015-01-01

    Three invasive fishes of considerable concern to aquatic resource managers are the Hypophthalmichthys nobilis (bighead carp),Hypophthalmichthys molitrix (silver carp), and Ctenopharyngodon idella (grass carp), collectively known as Asian carps. There is a need for an effective chemical control agent for Asian carps. Isoniazid was identified as a potential toxicant for grass carp. The selective toxicity of isoniazid to grass carp was verified as a response to an anecdotal report received in 2013. In addition, the toxicity of isoniazid to bighead carp, silver carp, and Oncorhynchus mykiss (rainbow trout) was evaluated. Isoniazid was not toxic to grass carp at the reported anecdotal concentration, which was 13 milligrams per liter. Isoniazid (130 milligrams per liter) was not selectively toxic to bighead carp, silver carp, or grass carp when compared to rainbow trout.

  6. Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315

    PubMed Central

    Pullan, Steven T.; Allnutt, Jon C.; Freire-Martin, Irene; Hendon-Dunn, Charlotte L.; Watson, Robert; Witney, Adam A.; Tyler, Richard H.; Arnold, Catherine; Marsh, Philip D.; McHugh, Timothy D.; Bacon, Joanna

    2015-01-01

    An important aim for improving TB treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. In any M. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be because of pre-existing populations of slow growing/non replicating bacteria that are protected from antibiotic action due to the expression of a phenotype that limits drug activity. We addressed this question by observing populations of either slow growing (constant 69.3h mean generation time) or fast growing bacilli (constant 23.1h mean generation time) in their response to the effects of isoniazid exposure, using controlled and defined growth in chemostats. Phenotypic differences were detected between the populations at the two growth rates including expression of efflux mechanisms and the involvement of antisense RNA/small RNA in the regulation of a drug-tolerant phenotype, which has not been explored previously for M. tuberculosis. Genotypic analyses showed that slow growing bacilli develop resistance to isoniazid through mutations specifically in katG codon Ser315 which are present in approximately 50–90% of all isoniazid-resistant clinical isolates. The fast growing bacilli persisted as a mixed population with katG mutations distributed throughout the gene. Mutations in katG codon Ser315 appear to have a fitness cost in vitro and particularly in fast growing cultures. Our results suggest a requirement for functional katG-encoded catalase-peroxide in the slow growers but not the fast-growing bacteria, which may explain why katG codon Ser315 mutations are favoured in the slow growing cultures. PMID:26382066

  7. Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315.

    PubMed

    Jeeves, Rose E; Marriott, Alice A N; Pullan, Steven T; Hatch, Kim A; Allnutt, Jon C; Freire-Martin, Irene; Hendon-Dunn, Charlotte L; Watson, Robert; Witney, Adam A; Tyler, Richard H; Arnold, Catherine; Marsh, Philip D; McHugh, Timothy D; Bacon, Joanna

    2015-01-01

    An important aim for improving TB treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. In any M. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be because of pre-existing populations of slow growing/non replicating bacteria that are protected from antibiotic action due to the expression of a phenotype that limits drug activity. We addressed this question by observing populations of either slow growing (constant 69.3h mean generation time) or fast growing bacilli (constant 23.1h mean generation time) in their response to the effects of isoniazid exposure, using controlled and defined growth in chemostats. Phenotypic differences were detected between the populations at the two growth rates including expression of efflux mechanisms and the involvement of antisense RNA/small RNA in the regulation of a drug-tolerant phenotype, which has not been explored previously for M. tuberculosis. Genotypic analyses showed that slow growing bacilli develop resistance to isoniazid through mutations specifically in katG codon Ser315 which are present in approximately 50-90% of all isoniazid-resistant clinical isolates. The fast growing bacilli persisted as a mixed population with katG mutations distributed throughout the gene. Mutations in katG codon Ser315 appear to have a fitness cost in vitro and particularly in fast growing cultures. Our results suggest a requirement for functional katG-encoded catalase-peroxide in the slow growers but not the fast-growing bacteria, which may explain why katG codon Ser315 mutations are favoured in the slow growing cultures.

  8. Continuation Electroconvulsive Therapy vs Pharmacotherapy for Relapse Prevention in Major Depression

    PubMed Central

    Kellner, Charles H.; Knapp, Rebecca G.; Petrides, Georgios; Rummans, Teresa A.; Husain, Mustafa M.; Rasmussen, Keith; Mueller, Martina; Bernstein, Hilary J.; O’Connor, Kevin; Smith, Glenn; Biggs, Melanie; Bailine, Samuel H.; Malur, Chitra; Yim, Eunsil; McClintock, Shawn; Sampson, Shirlene; Fink, Max

    2013-01-01

    Background Although electroconvulsive therapy (ECT) has been shown to be extremely effective for the acute treatment of major depression, it has never been systematically assessed as a strategy for relapse prevention. Objective To evaluate the comparative efficacy of continuation ECT (C-ECT) and the combination of lithium carbonate plus nortriptyline hydrochloride (C-Pharm) in the prevention of depressive relapse. Design Multisite, randomized, parallel design, 6-month trial performed from 1997 to 2004. Setting Five academic medical centers and their outpatient psychiatry clinics. Patients Two hundred one patients with Structured Clinical Interview for DSM-IV–diagnosed unipolar depression who had remitted with a course of bilateral ECT. Interventions Random assignment to 2 treatment groups receiving either C-ECT (10 treatments) or C-Pharm for 6 months. Main Outcome Measure Relapse of depression, compared between the C-ECT and C-Pharm groups. Results In the C-ECT group, 37.1% experienced disease relapse, 46.1% continued to have disease remission at the study end, and 16.8% dropped out of the study. In the C-Pharm group, 31.6% experienced disease relapse, 46.3% continued to have disease remission, and 22.1% dropped out of the study. Both Kaplan-Meier and Cox proportional hazards regression analyses indicated no statistically significant differences in overall survival curves and time to relapse for the groups. Mean±SD time to relapse for the C-ECT group was 9.1±7.0 weeks compared with 6.7±4.6 weeks for the C-Pharm group (P=.13). Both groups had relapse proportions significantly lower than a historical placebo control from a similarly designed study. Conclusions Both C-ECT and C-Pharm were shown to be superior to a historical placebo control, but both had limited efficacy, with more than half of patients either experiencing disease relapse or dropping out of the study. Even more effective strategies for relapse prevention in mood disorders are urgently needed

  9. The Potential of Plant Phenolics in Prevention and Therapy of Skin Disorders

    PubMed Central

    Działo, Magdalena; Mierziak, Justyna; Korzun, Urszula; Preisner, Marta; Szopa, Jan; Kulma, Anna

    2016-01-01

    Phenolic compounds constitute a group of secondary metabolites which have important functions in plants. Besides the beneficial effects on the plant host, phenolic metabolites (polyphenols) exhibit a series of biological properties that influence the human in a health-promoting manner. Evidence suggests that people can benefit from plant phenolics obtained either by the diet or through skin application, because they can alleviate symptoms and inhibit the development of various skin disorders. Due to their natural origin and low toxicity, phenolic compounds are a promising tool in eliminating the causes and effects of skin aging, skin diseases, and skin damage, including wounds and burns. Polyphenols also act protectively and help prevent or attenuate the progression of certain skin disorders, both embarrassing minor problems (e.g., wrinkles, acne) or serious, potentially life-threatening diseases such as cancer. This paper reviews the latest reports on the potential therapy of skin disorders through treatment with phenolic compounds, considering mostly a single specific compound or a combination of compounds in a plant extract. PMID:26901191

  10. Phage Therapy as an Approach to Prevent Vibrio anguillarum Infections in Fish Larvae Production

    PubMed Central

    Silva, Yolanda J.; Costa, Liliana; Pereira, Carla; Mateus, Cristiana; Cunha, Ângela; Calado, Ricardo; Gomes, Newton C. M.; Pardo, Miguel A.; Hernandez, Igor; Almeida, Adelaide

    2014-01-01

    Fish larvae in aquaculture have high mortality rates due to pathogenic bacteria, especially the Vibrio species, and ineffective prophylactic strategies. Vaccination is not feasible in larvae and antibiotics have reduced efficacy against multidrug resistant bacteria. A novel approach to controlling Vibrio infections in aquaculture is needed. The potential of phage therapy to combat vibriosis in fish larvae production has not yet been examined. We describe the isolation and characterization of two bacteriophages capable of infecting pathogenic Vibrio and their application to prevent bacterial infection in fish larvae. Two groups of zebrafish larvae were infected with V. anguillarum (∼106 CFU mL−1) and one was later treated with a phage lysate (∼108 PFU mL−1). A third group was only added with phages. A fourth group received neither bacteria nor phages (fish control). Larvae mortality, after 72 h, in the infected and treated group was similar to normal levels and significantly lower than that of the infected but not treated group, indicating that phage treatment was effective. Thus, directly supplying phages to the culture water could be an effective and inexpensive approach toward reducing the negative impact of vibriosis in larviculture. PMID:25464504

  11. Therapy for triggered acute risk prevention in subjects at increased cardiovascular risk.

    PubMed

    Tofler, Geoffrey H; Spinaze, Monica; Shaw, Elizabeth; Buckley, Thomas

    2013-06-15

    Heavy physical exertion, emotional stress, heavy meals, and respiratory infection transiently increase the risk of myocardial infarction, sudden cardiac death, and stroke; however, it remains uncertain how to use this information for disease prevention. We determined whether it was feasible for those with either risk factors for cardiovascular disease (CVD) or known CVD to take targeted medication for the hazard duration of the triggering activity to reduce their risk. After a run-in of 1 month, 20 subjects (12 women and 8 men) aged 68.6 years (range 58 to 83) recorded for 2 months all episodes of physical and emotional stress, heavy meal consumption, and respiratory infection. For each episode, the subjects were instructed to take either aspirin 100 mg and propranolol 10 mg (for physical exertion and emotional stress) or aspirin 100 mg alone (for respiratory infection and heavy meal consumption) and to record their adherence. Adherence with taking the appropriate medication was 86% according to the diary entries, with 15 of 20 subjects (75%) achieving ≥80% adherence. Propranolol taken before exertion reduced the peak heart rate compared with similar exercise during the run-in period (118 ± 21 vs 132 ± 16 beats/min, p = 0.016). Most subjects (85%) reported that it was feasible to continue taking the medication in this manner. In conclusion, it is feasible for those with increased CVD risk to identify potential triggers of acute CVD and to take targeted therapy at the time of these triggers.

  12. Advances in the development of novel antioxidant therapies as an approach for fetal alcohol syndrome prevention.

    PubMed

    Joya, Xavier; Garcia-Algar, Oscar; Salat-Batlle, Judith; Pujades, Cristina; Vall, Oriol

    2015-03-01

    Ethanol is the most common human teratogen, and its consumption during pregnancy can produce a wide range of abnormalities in infants known as fetal alcohol spectrum disorder (FASD). The major characteristics of FASD can be divided into: (i) growth retardation, (ii) craniofacial abnormalities, and (iii) central nervous system (CNS) dysfunction. FASD is the most common cause of nongenetic mental retardation in Western countries. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, the induction of oxidative stress is believed to be one central process linked to the development of the disease. Currently, there is no known effective strategy for prevention (other than alcohol avoidance) or treatment. In the present review we will provide the state of art in the evidence for the use of antioxidants as a potential therapeutic strategy for the treatment using whole-embryo and culture cells models of FASD. We conclude that the imbalance of the intracellular redox state contributes to the pathogenesis observed in FASD models, and we suggest that antioxidant therapy can be considered a new efficient strategy to mitigate the effects of prenatal ethanol exposure.

  13. The Potential of Plant Phenolics in Prevention and Therapy of Skin Disorders.

    PubMed

    Działo, Magdalena; Mierziak, Justyna; Korzun, Urszula; Preisner, Marta; Szopa, Jan; Kulma, Anna

    2016-02-18

    Phenolic compounds constitute a group of secondary metabolites which have important functions in plants. Besides the beneficial effects on the plant host, phenolic metabolites (polyphenols) exhibit a series of biological properties that influence the human in a health-promoting manner. Evidence suggests that people can benefit from plant phenolics obtained either by the diet or through skin application, because they can alleviate symptoms and inhibit the development of various skin disorders. Due to their natural origin and low toxicity, phenolic compounds are a promising tool in eliminating the causes and effects of skin aging, skin diseases, and skin damage, including wounds and burns. Polyphenols also act protectively and help prevent or attenuate the progression of certain skin disorders, both embarrassing minor problems (e.g., wrinkles, acne) or serious, potentially life-threatening diseases such as cancer. This paper reviews the latest reports on the potential therapy of skin disorders through treatment with phenolic compounds, considering mostly a single specific compound or a combination of compounds in a plant extract.

  14. Moxibustion Therapy at CV4 Prevents Postoperative Dysuria after Procedure for Prolapse and Hemorrhoids

    PubMed Central

    Bian, Xue-Mei; Lv, Ling; Lin, Wan-Bing; Liang, Hai-Hong; Zhang, Ying

    2013-01-01

    Objective. To explore the intervention methods of the patients with dysuria after performing the procedure for prolapse and hemorrhoids (PPH). Methods. 100 cases with hemorrhoids were randomly divided into experimental and control groups. The control group received routine nursing care. As comparison, the experimental group, on the basis of conventional care, was treated with moxa roll moxibustion 1 hour after the operation for 30 minutes. The autonomous urination within 1 h, 2 h, 4 h, 6 h, and 8 h after operation and the catheterization rate 8 h after operation of two groups of patients were observed. Results. The median time of autonomous urination of control group (8 h) was significantly greater than that of the experimental group (6 h) (P < 0.001). Cox regression analysis showed that the moxibustion therapy was positively correlated with automatic micturition in the patients after PPH. The probability of automatic micturition in the experimental group was 2.032 times that in the control group (RR = 2.032, 95% CI: 1.278~3.230). The catheterization rate of control group (38%) was significantly higher than that of the experimental group (10%) (P < 0.001). Conclusion. The Guanyuan acupoint moxibustion can prevent dysuria after PPH and reduce the urethral catheterization. PMID:24386005

  15. Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome.

    PubMed Central

    Ballard, P L; Granberg, P; Ballard, R A

    1975-01-01

    Serum glucocorticoid levels were determined in 20 mothers and 43 premature infants who received prenatal betamethasone therapy for prevention of respiratory distress syndrome (RDS). Maternal betamethasone peaked at 75 microg cortisol equivalents per 100 ml 1 h after injection of 12 mg steroid and declined to half by 6 h. Betamethasone in cord blood was 14.3 microg cortisol equivalents per 100 ml at 1 h, decreased to a level of 4.7 at 20 h, and was not detected 2 days after a second dose at 24 h. After the second dose, the mean level of cortisol in cord blood was 5.9 microg per 100 ml compared with 13.05 microg per 100 ml (p less than 0.001) in untreated premature infants. The unbound glucocorticoid activity in treated infants delivered 1-10 h after the second dose (mean, 8.4 microg per 100 ml) is similar to the unbound cortisol level after birth in untreated premature infants who develop RDS. These findings indicate that (a) serum glucocorticoid levels in the physiologic stress range can induce lung maturation in the human and (b) antenatal treatment with this dose of betamethasone does not expose the human fetus to potentially harmful pharmacologic levels of steroid. PMID:1202085

  16. Advances in the development of novel antioxidant therapies as an approach for fetal alcohol syndrome prevention.

    PubMed

    Joya, Xavier; Garcia-Algar, Oscar; Salat-Batlle, Judith; Pujades, Cristina; Vall, Oriol

    2015-03-01

    Ethanol is the most common human teratogen, and its consumption during pregnancy can produce a wide range of abnormalities in infants known as fetal alcohol spectrum disorder (FASD). The major characteristics of FASD can be divided into: (i) growth retardation, (ii) craniofacial abnormalities, and (iii) central nervous system (CNS) dysfunction. FASD is the most common cause of nongenetic mental retardation in Western countries. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, the induction of oxidative stress is believed to be one central process linked to the development of the disease. Currently, there is no known effective strategy for prevention (other than alcohol avoidance) or treatment. In the present review we will provide the state of art in the evidence for the use of antioxidants as a potential therapeutic strategy for the treatment using whole-embryo and culture cells models of FASD. We conclude that the imbalance of the intracellular redox state contributes to the pathogenesis observed in FASD models, and we suggest that antioxidant therapy can be considered a new efficient strategy to mitigate the effects of prenatal ethanol exposure. PMID:25131946

  17. Partial molar volumes of isoniazid solutions in aqueous-ethanol mixtures at 298.15 K

    NASA Astrophysics Data System (ADS)

    Deosarkar, S. D.; Sawale, R. T.; Tawde, P. D.; Kalyankar, T. M.

    2015-02-01

    Densities (ρ) of antitubercular drug isoniazid solutions in water, aqueous-ethanol (20-80 vol % EtOH) and in pure ethanol at 298.15 K with different molar concentrations (0.01-0.16 mol dm-3) were measured. Experimental density data were used to calculate apparent molar volumes (φ v ) of isoniazid in different media. The φ v data were fitted to Massons relation and partial molar volumes (φ{/v 0}) of drug for infinitely dilute solution were determined for each solution. Experimental and derived properties were interpreted in terms of drug-solvent molecular interactions and structural fittings in studied systems.

  18. Novel mutations in ndh in isoniazid-resistant Mycobacterium tuberculosis isolates.

    PubMed

    Lee, A S; Teo, A S; Wong, S Y

    2001-07-01

    Novel mutations in NADH dehydrogenase (ndh) were detected in 8 of 84 (9.5%) isoniazid (INH)-resistant isolates (T110A [n = 1], R268H [n = 7]), but not in 22 INH-susceptible isolates of Mycobacterium tuberculosis. Significantly, all eight isolates with mutations at ndh did not have mutations at katG, kasA, or the promoter regions of inhA or ahpC, except for one isolate. Mutations in ndh appear to be an additional molecular mechanism for isoniazid resistance in M. tuberculosis. PMID:11408244

  19. Prevention

    MedlinePlus

    ... Prevention Treatment 2003 U.S. Outbreak African Rodent Importation Ban For Clinicians Clinical Recognition Specimen Collection Treatment Smallpox ... Examining Animals with Suspected Monkeypox African Rodent Importation Ban Resources Related Links Poxvirus Molluscum Contagiosum Orf Virus ( ...

  20. Mode of binding of the tuberculosis prodrug isoniazid to heme peroxidases: binding studies and crystal structure of bovine lactoperoxidase with isoniazid at 2.7 A resolution.

    PubMed

    Singh, Amit K; Kumar, Ramasamy P; Pandey, Nisha; Singh, Nagendra; Sinha, Mau; Bhushan, Asha; Kaur, Punit; Sharma, Sujata; Singh, Tej P

    2010-01-01

    Isoniazid (INH) is an anti-tuberculosis prodrug that is activated by mammalian lactoperoxidase and Mycobacterium tuberculosis catalase peroxidase (MtCP). We report here binding studies, an enzyme assay involving INH, and the crystal structure of the complex of bovine lactoperoxidase (LPO) with INH to illuminate binding properties and INH activation as well as the mode of diffusion and interactions together with a detailed structural and functional comparison with MtCP. The structure determination shows that isoniazid binds to LPO at the substrate binding site on the distal heme side. The substrate binding site is connected to the protein surface through a long hydrophobic channel. The acyl hydrazide moiety of isoniazid interacts with Phe(422) O, Gln(423) O(epsilon1), and Phe(254) O. In this arrangement, pyridinyl nitrogen forms a hydrogen bond with a water molecule, W-1, which in turn forms three hydrogen bonds with Fe(3+), His(109) N(epsilon2), and Gln(105) N(epsilon2). The remaining two sides of isoniazid form hydrophobic interactions with the atoms of heme pyrrole ring A, C(beta) and C(gamma) atoms of Glu(258), and C(gamma) and C(delta) atoms of Arg(255). The binding studies indicate that INH binds to LPO with a value of 0.9 x 10(-6) m for the dissociation constant. The nitro blue tetrazolium reduction assay shows that INH is activated by the reaction of LPO-H(2)O(2) with INH. This suggests that LPO can be used for INH activation. It also indicates that the conversion of INH into isonicotinoyl radical by LPO may be the cause of INH toxicity.

  1. The ability of low level laser therapy to prevent muscle tissue damage induced by snake venom.

    PubMed

    Doin-Silva, Rosany; Baranauskas, Vitor; Rodrigues-Simioni, Lea; da Cruz-Höfling, Maria Alice

    2009-01-01

    Antivenom therapy has been ineffective in neutralizing the severe local fast developing tissue damage following snakebite envenoming. Herein, some effects of in situ helium neon (HeNe) laser irradiation on rat nerve-muscle preparation injected with Bothrops jararacussu venom are described. The tibialis anterior muscle was injected with venom diluted in 0.9% saline solution (60 microg/0.02 mL) or saline solution alone. Sixty minutes after venom injection, laser (HeNe) treatment was administered at three incident energy densities: dose 1, a single exposure of 3.5 J cm(-2); dose 2, three exposures of 3.5 J cm(-2); dose 3, a single exposure of 10.5 J cm(-2). Muscle function was assessed through twitch tension recordings whereas muscle damage was evaluated through histopathologic analysis, morphometry of area of tissue affected and creatine kinase (CK) serum levels, and compared to unirradiated muscles. Laser application at the dose of 3.5 J cm(-2) reduced the area of injury by 64% (15.9 +/- 1.5%vs 44.2 +/- 5.7%), decreased the neuromuscular blockade (NMB) by 62% (11.5 +/- 2.5%vs 30.4 +/- 5.2%) and reduced CK levels by 58% (from 455 +/- 4.5% to 190.3 +/- 23.4%) when compared with unirradiated controls. Dose 2 showed a poorer benefit than dose 1, and dose 3 was ineffective in preventing the venom effects. Measurements of the absorbance of unirradiated and irradiated venom solution showed no difference in absorption spectra. In addition, no difference in the intensity of partial NMB in nerve-muscle preparation was shown by unirradiated and irradiated venom. The results indicate that the laser light did not alter venom toxicity. We conclude that HeNe laser irradiation at a dosage of 3.5 J cm(-2) effectively reduces myonecrosis and the neuromuscular transmission blocking effect caused by B. jararacussu snake venom. Thus, low level laser therapy may be a promising tool to minimize the severity of some of the local effects of snake envenoming. PMID:18643907

  2. [Progress of Clinical Trials on Bone Marrow Mesenchymal Stem Cells for Prevention and Therapy of Graft-Versus-Host Disease].

    PubMed

    Zhong, Dan-Li; Tu, San-Fang; Li, Yu-Hua

    2015-12-01

    Graft-versus-host disease (GVHD) is a major complication following allogenetic hematopoietic stem cell transplantation, which shows a great threat to patients' survival and life quality. Along with multiple differentiation potential to various types of progenitor cells, bone marrow mesenchymal stem cells (BMMSC) have been confirmed to possess low immunogenicity and exert favorable immunomodulation. The recent studies show that the safety and high efficiency of BMMSC to prevent and cure GVHD greatly improved survival rate of the hosts. The most recent progress on prevention and therapy of GVHD is summarized in this review based on biology of BMMSC and pathogenesis of GVHD, so as to provide the effective evidence for further research.

  3. Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples

    PubMed Central

    Anglemyer, Andrew; Rutherford, George W; Horvath, Tara; Baggaley, Rachel C; Egger, Matthias; Siegfried, Nandi

    2014-01-01

    subgroup analyses among the observational studies to see if the effect of ART on prevention of HIV differed by the index partner’s CD4 cell count. Among couples in which the infected partner had ≥350 CD4 cells/µL, we estimated a rate ratio of 0.12 [95% CI 0.01, 1.99]. In this subgroup, there were 247 transmissions in untreated couples and 30 in treated couples. Authors’ conclusions ART is a potent intervention for prevention of HIV in discordant couples in which the index partner has ≤550 CD4 cells/µL. A recent multicentre RCT confirms the suspected benefit seen in earlier observational studies and reported in more recent ones. Questions remain about durability of protection, the balance of benefits and adverse events associated with earlier therapy, long-term adherence and transmission of ART-resistant strains to partners. Resource limitations and implementation challenges must also be addressed. Counselling, support, and follow up, as well as mutual disclosure, may have a role in supporting adherence, so programmes should be designed with these components. In addition to ART provision, the operational aspects of delivering such programmes must be considered. PMID:23633367

  4. Adherence to Antiretroviral Therapy for the Success of Emerging Interventions to Prevent HIV Transmission: A Wake up Call

    PubMed Central

    Nachega, Jean B; Uthman, Olalekan A; Mills, Edward J; Quinn, Thomas C

    2012-01-01

    Despite recent successes in several HIV prevention trials, the epidemic continues to increase in many countries. The most successful biomedical interventions to prevent HIV have been the use of Antiretroviral Therapy (ART) to Prevent Mother-To-Child Transmission (PMTCT), and sexual transmission via microbicides, PreExposure Prophylaxis (PrEP), and treatment of the infected person within discordant couples. In addition medical male circumcision has also been shown to be highly effective in prevention of HIV acquisition. However, emerging data demonstrate that adherence to several of these prevention interventions is critical. ART adherence during and after pregnancy has been shown to be significantly below that recommended for adequate virologic suppression, particularly during the postpartum period. Five recent PrEP trials also demonstrate that the success of PrEP as a public health intervention will necessitate monitoring ART adherence and will include additional interventions to improve or maintain adherence to optimal levels. New successes in HIV prevention research have been tempered by suboptimal adherence. There is a critical need to define practical and effective adherence monitoring strategies as well as controlled trials of adherence interventions in the era of PrEP, Treatment as Prevention (TasP), and PMTCT to maximize their benefit. PMID:24032088

  5. Isoniazid Induced Cutaneous Leukocytoclastic Vasculitis in Extra Pulmonary Tuberculosis (Pott’s Spine): A Case Report

    PubMed Central

    V, Dharma Rao; Rampure, Dilip; S, Rama Rao

    2014-01-01

    Anti-tuberculosis drugs frequently result in cutaneous adverse reactions but Isoniazid is known to have least toxic potential for cutaneous reactions. We report a rare case of Isoniazid induced cutaneous leucocytoclastic vasculitis. A 64-year-old male was diagnosed to have Pott’s spine with multiple vertebral body involvement (D8-12 vertebrae). Subsequently, he was treated with first line anti-TB drugs i.e., Isoniazid, Rifampicin, Pyrazinamide and Ethambutol. On the fourth day of treatment with Anti Tuberculosis Treatment (ATT), the patient developed an erythematosus rash over right upper limb not associated with itching or pain, non-blanchable macules and papules over bilateral shins on lower limbs, petechiae on both forearms and hyper pigmented, scaly rash over right axilla and buttocks. The skin biopsy report was consistent with cutaneous leukocytoclastic vasculitis. Although rare, Isoniazid among anti-tuberculosis drugs should be considered as potential cause of drug-induced cutaneous leukocytoclastic vasculitis in the differential diagnosis of erythematosus rash with petechiae. PMID:25302231

  6. The safety and tolerability profile of therapies for the prevention and treatment of osteoporosis in postmenopausal women.

    PubMed

    Komm, Barry S; Morgenstern, Diana; A Yamamoto, Luis; Jenkins, Simon N

    2015-01-01

    At a time when the prevalence of osteoporosis and related fractures is increasing, initiation and continuation of pharmacologic therapies for prevention and treatment of postmenopausal osteoporosis have declined. This decline has been at least in part attributable to concerns about safety of these agents, such as atypical fractures with bisphosphonates and breast cancer with estrogen/progestin therapy, particularly when they are used long term by older women. However, in many cases, absolute risk of serious adverse effects is small and should be balanced against the larger potential for fracture reduction. Here, we review the safety and tolerability of available therapies for postmenopausal osteoporosis. Taking into consideration their relative efficacy, we also provide strategies for optimization of the risk:benefit ratio. PMID:26482902

  7. The safety and tolerability profile of therapies for the prevention and treatment of osteoporosis in postmenopausal women.

    PubMed

    Komm, Barry S; Morgenstern, Diana; A Yamamoto, Luis; Jenkins, Simon N

    2015-01-01

    At a time when the prevalence of osteoporosis and related fractures is increasing, initiation and continuation of pharmacologic therapies for prevention and treatment of postmenopausal osteoporosis have declined. This decline has been at least in part attributable to concerns about safety of these agents, such as atypical fractures with bisphosphonates and breast cancer with estrogen/progestin therapy, particularly when they are used long term by older women. However, in many cases, absolute risk of serious adverse effects is small and should be balanced against the larger potential for fracture reduction. Here, we review the safety and tolerability of available therapies for postmenopausal osteoporosis. Taking into consideration their relative efficacy, we also provide strategies for optimization of the risk:benefit ratio.

  8. A survey on hematology-oncology pediatric AIEOP centers: prophylaxis, empirical therapy and nursing prevention procedures of infectious complications.

    PubMed

    Livadiotti, Susanna; Milano, Giuseppe Maria; Serra, Annalisa; Folgori, Laura; Jenkner, Alessandro; Castagnola, Elio; Cesaro, Simone; Rossi, Mario R; Barone, Angelica; Zanazzo, Giulio; Nesi, Francesca; Licciardello, Maria; De Santis, Raffaella; Ziino, Ottavio; Cellini, Monica; Porta, Fulvio; Caselli, Desiree; Pontrelli, Giuseppe

    2012-01-01

    A nationwide questionnaire-based survey was designed to evaluate the management and prophylaxis of febrile neutropenia in pediatric patients admitted to hematology-oncology and hematopoietic stem cell transplant units. Of the 34 participating centers, 40 and 63%, respectively, continue to prescribe antibacterial and antimycotic prophylaxis in low-risk subjects and 78 and 94% in transplant patients. Approximately half of the centers prescribe a combination antibiotic regimen as first-line therapy in low-risk patients and up to 81% in high-risk patients. When initial empirical therapy fails after seven days, 63% of the centers add empirical antimycotic therapy in low-and 81% in high-risk patients. Overall management varies significantly across centers. Preventive nursing procedures are in accordance with international guidelines. This survey is the first to focus on prescribing practices in children with cancer and could help to implement practice guidelines.

  9. Hybrid therapy with locoregional steroid injection and polyglycolic acid sheets to prevent stricture after esophageal endoscopic submucosal dissection

    PubMed Central

    Nagami, Yasuaki; Shiba, Masatsugu; Tominaga, Kazunari; Ominami, Masaki; Fukunaga, Shusei; Sugimori, Satoshi; Tanaka, Fumio; Kamata, Noriko; Tanigawa, Tetsuya; Yamagami, Hirokazu; Watanabe, Toshio; Fujiwara, Yasuhiro; Arakawa, Tetsuo

    2016-01-01

    Background and study aim: The incidence of stricture formation caused by endoscopic submucosal dissection (ESD) for widespread lesions is high, and stricture formation can reduce quality of life. We evaluated the prophylactic efficacy of hybrid therapy using a locoregional steroid injection and polyglycolic acid (PGA) sheets with fibrin glue to prevent stricture formation after esophageal ESD in high risk patients in whom we predicted stricture formation would be difficult to prevent with a single prophylactic steroid injection. Methods: Ten patients who underwent esophageal ESD were enrolled (entire-circumference: n = 6; sub-circumference, more than 5/6 of the circumference: n = 4). A single locoregional steroid injection and PGA sheets with fibrin glue were used after ESD. We evaluated the incidence of stricture formation, the number of endoscopic balloon dilation (EBD) procedures needed to treat the stricture formation, and adverse events of the therapy. Results: Esophageal stricture formation occurred in 50.0 % of patients (5/10) (median EBD sessions 0.5, range 0 – 16). Subanalysis showed that stricture formation occurred in 37.5 % of patients (3/8) excluded the lesions located near a previous scar from ESD or surgical anastomosis site (median EBD sessions 0, range 0 – 4). Conclusion: Hybrid therapy using a locoregional steroid injection and PGA sheets with fibrin glue may have the potential to prevent esophageal stricture formation after esophageal ESD in high risk patients.

  10. Hybrid therapy with locoregional steroid injection and polyglycolic acid sheets to prevent stricture after esophageal endoscopic submucosal dissection

    PubMed Central

    Nagami, Yasuaki; Shiba, Masatsugu; Tominaga, Kazunari; Ominami, Masaki; Fukunaga, Shusei; Sugimori, Satoshi; Tanaka, Fumio; Kamata, Noriko; Tanigawa, Tetsuya; Yamagami, Hirokazu; Watanabe, Toshio; Fujiwara, Yasuhiro; Arakawa, Tetsuo

    2016-01-01

    Background and study aim: The incidence of stricture formation caused by endoscopic submucosal dissection (ESD) for widespread lesions is high, and stricture formation can reduce quality of life. We evaluated the prophylactic efficacy of hybrid therapy using a locoregional steroid injection and polyglycolic acid (PGA) sheets with fibrin glue to prevent stricture formation after esophageal ESD in high risk patients in whom we predicted stricture formation would be difficult to prevent with a single prophylactic steroid injection. Methods: Ten patients who underwent esophageal ESD were enrolled (entire-circumference: n = 6; sub-circumference, more than 5/6 of the circumference: n = 4). A single locoregional steroid injection and PGA sheets with fibrin glue were used after ESD. We evaluated the incidence of stricture formation, the number of endoscopic balloon dilation (EBD) procedures needed to treat the stricture formation, and adverse events of the therapy. Results: Esophageal stricture formation occurred in 50.0 % of patients (5/10) (median EBD sessions 0.5, range 0 – 16). Subanalysis showed that stricture formation occurred in 37.5 % of patients (3/8) excluded the lesions located near a previous scar from ESD or surgical anastomosis site (median EBD sessions 0, range 0 – 4). Conclusion: Hybrid therapy using a locoregional steroid injection and PGA sheets with fibrin glue may have the potential to prevent esophageal stricture formation after esophageal ESD in high risk patients. PMID:27652294

  11. A descriptive study of a manual therapy intervention within a randomised controlled trial for hamstring and lower limb injury prevention

    PubMed Central

    2010-01-01

    Background There is little literature describing the use of manual therapy performed on athletes. It was our purpose to document the usage of a sports chiropractic manual therapy intervention within a RCT by identifying the type, amount, frequency, location and reason for treatment provided. This information is useful for the uptake of the intervention into clinical settings and to allow clinicians to better understand a role that sports chiropractors offer. Methods All treatment rendered to 29 semi-elite Australian Rules footballers in the sports chiropractic intervention group of an 8 month RCT investigating hamstring and lower-limb injury prevention was recorded. Treatment was pragmatically and individually determined and could consist of high-velocity, low-amplitude (HVLA) manipulation, mobilization and/or supporting soft tissue therapies. Descriptive statistics recorded the treatment rendered for symptomatic or asymptomatic benefit, delivered to joint or soft tissue structures and categorized into body regions. For the joint therapy, it was recorded whether treatment consisted of HVLA manipulation, HVLA manipulation and mobilization, or mobilization only. Breakdown of the HVLA technique was performed. Results A total of 487 treatments were provided (mean 16.8 consultations/player) with 64% of treatment for asymptomatic benefit (73% joint therapies, 57% soft tissue therapies). Treatment was delivered to approximately 4 soft tissue and 4 joint regions each consultation. The most common asymptomatic regions treated with joint therapies were thoracic (22%), knee (20%), hip (19%), sacroiliac joint (13%) and lumbar (11%). For soft tissue therapies it was gluteal (22%), hip flexor (14%), knee (12%) and lumbar (11%). The most common symptomatic regions treated with joint therapies were lumbar (25%), thoracic (15%) and hip (14%). For soft tissue therapies it was gluteal (22%), lumbar (15%) and posterior thigh (8%). Of the joint therapy, 56% was HVLA manipulation only

  12. Transjugular intrahepatic portosystemic shunt vs endoscopic therapy in preventing variceal rebleeding

    PubMed Central

    Xue, Hui; Zhang, Meng; Pang, Jack XQ; Yan, Fei; Li, Ying-Chao; Lv, Liang-Shan; Yuan, Jia; Palikhe, Muna; Li, Wei-Zhi; Wang, Zhi-Lun

    2012-01-01

    AIM: To compare early use of transjugular intrahepatic portosystemic shunt (TIPS) with endoscopic treatment (ET) for the prophylaxis of recurrent variceal bleeding. METHODS: In-patient data were collected from 190 patients between January 2007 and June 2010 who suffured from variceal bleeding. Patients who were older than 75 years; previously received surgical treatment or endoscopic therapy for variceal bleeding; and complicated with hepatic encephalopathy or hepatic cancer, were excluded from this research. Thirty-five cases lost to follow-up were also excluded. Retrospective analysis was done in 126 eligible cases. Among them, 64 patients received TIPS (TIPS group) while 62 patients received endoscopic therapy (ET group). The relevant data were collected by patient review or telephone calls. The occurrence of rebleeding, hepatic encephalopathy or other complications, survival rate and cost of treatment were compared between the two groups. RESULTS: During the follow-up period (median, 20.7 and 18.7 mo in TIPS and ET groups, respectively), rebleeding from any source occurred in 11 patients in the TIPS group as compared with 31 patients in the ET group (Kaplan-Meier analysis and log-rank test, P = 0.000). Rebleeding rates at any time point (6 wk, 1 year and 2 year) in the TIPS group were lower than in the ET group (Bonferroni correction α’ = α/3). Eight patients in the TIPS group and 16 in the ET group died with the cumulative survival rates of 80.6% and 64.9% (Kaplan-Meier analysis and log-rank test χ2 = 4.864, P = 0.02), respectively. There was no significant difference between the two groups with respect to 6-wk survival rates (Bonferroni correction α’ = α/3). However, significant differences were observed between the two groups in the 1-year survival rates (92% and 79%) and the 2-year survival rates (89% and 64.9%) (Bonferroni correction α’ = α/3). No significant differences were observed between the two treatment groups in the occurrence of

  13. Intestinal permeability--a new target for disease prevention and therapy.

    PubMed

    Bischoff, Stephan C; Barbara, Giovanni; Buurman, Wim; Ockhuizen, Theo; Schulzke, Jörg-Dieter; Serino, Matteo; Tilg, Herbert; Watson, Alastair; Wells, Jerry M

    2014-11-18

    Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms 'intestinal barrier' and 'intestinal permeability' are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by 'intestinal permeability'. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and--more recently recognized

  14. Postoperative hormonal therapy prevents recovery of neurological damage after surgery in patients with breast cancer

    PubMed Central

    Sekiguchi, Atsushi; Sato, Chiho; Matsudaira, Izumi; Kotozaki, Yuka; Nouchi, Rui; Takeuchi, Hikaru; Kawai, Masaaki; Tada, Hiroshi; Ishida, Takanori; Taki, Yasuyuki; Ohuchi, Noriaki; Kawashima, Ryuta

    2016-01-01

    Cancer survivors are exposed to several risk factors for cognitive dysfunction, such as general anesthesia, surgical trauma, and adjuvant therapies. In our recent study we showed that thalamic volume reduction and attentional dysfunction occurred shortly after surgery. Here, we examined the 6-month prognosis of the 20 patients with breast cancer who underwent surgery. Seven patients did not receive any adjuvant therapy after the surgery and 13 patients received a hormonal therapy after the surgery. We assessed their attentional functions, and thalamic volumes shortly after and 6 months after surgery. We found a significant group x time interaction in the attentional functions (p = 0.033) and the right thalamus (p <  0.05, small volume correction), suggesting the thalamic volume reduction and attentional dysfunction recovered in patients without adjuvant therapy. Our findings provide a better understanding of the potential role of hormonal therapy in relation to the cognitive dysfunction of cancer survivors. PMID:27708377

  15. Computer-aided study of the relationship between structure and antituberculosis activity of a series of isoniazid derivatives

    NASA Astrophysics Data System (ADS)

    Klopman, Gilles; Fercu, Dan; Jacob, Jason

    1996-04-01

    The Multiple Computer Automated Structure Evaluation (MultiCASE) program was used to analyze the relationship between the structure and antituberculous activity of a series of 136 hydrazides, most of them isoniazid related. The structural features revealed by this analysis are discussed. The most significant one seemed to be the distance between the pyridinic nitrogen and the terminal nitrogen of the hydrazido group. Given the affiliation of these two heteroatoms with a planar conjugated system, we suggest that Schiff base chemistry similar to that of vitamin B 6 may be involved in the mode of action of isoniazid and its related compounds. A mechanism of action of isoniazid is proposed and suggestions for the design of new isoniazid-type drugs are made.

  16. Risk Factors for Acquired Rifamycin and Isoniazid Resistance: A Systematic Review and Meta-Analysis

    PubMed Central

    Rockwood, Neesha; Abdullahi, Leila H.; Wilkinson, Robert J.; Meintjes, Graeme

    2015-01-01

    Background Studies looking at acquired drug resistance (ADR) are diverse with respect to geographical distribution, HIV co-infection rates, retreatment status and programmatic factors such as regimens administered and directly observed therapy. Our objective was to examine and consolidate evidence from clinical studies of the multifactorial aetiology of acquired rifamycin and/or isoniazid resistance within the scope of a single systematic review. This is important to inform policy and identify key areas for further studies. Methods Case-control and cohort studies and randomised controlled trials that reported ADR as an outcome during antitubercular treatment regimens including a rifamycin and examined the association of at least 1 risk factor were included. Post hoc, we carried out random effects Mantel-Haenszel weighted meta-analyses of the impact of 2 key risk factors 1) HIV and 2) baseline drug resistance on the binary outcome of ADR. Heterogeneity was assessed used I2 statistic. As a secondary outcome, we calculated median cumulative incidence of ADR, weighted by the sample size of the studies. Results Meta-analysis of 15 studies showed increased risk of ADR with baseline mono- or polyresistance (RR 4.85 95% CI 3.26 to 7.23, heterogeneity I2 58%, 95% CI 26 to 76%). Meta-analysis of 8 studies showed that HIV co-infection was associated with increased risk of ADR (RR 3.02, 95% CI 1.28 to 7.11); there was considerable heterogeneity amongst these studies (I2 81%, 95% CI 64 to 90%). Non-adherence, extrapulmonary/disseminated disease and advanced immunosuppression in HIV co-infection were other risk factors noted. The weighted median cumulative incidence of acquired multi drug resistance calculated in 24 studies (assuming whole cohort as denominator, regardless of follow up DST) was 0.1% (5th to 95th percentile 0.07 to 3.2%). Conclusion Baseline drug resistance and HIV co-infection were significant risk factors for ADR. There was a trend of positive association with

  17. Preemptive therapy in the prevention of cytomegalovirus disease in high- and low-risk heart transplant recipients.

    PubMed

    Casquero, S; Rangel, D; Lage, E; Sobrino, M; Cristobo, P; Cordero, E; Cisneros, J M

    2012-09-01

    Cytomegalovirus (CMV) infection remains a major complication in recipients of solid organ transplantation. Based on available evidence, most centers are committed to an aggressive strategy, especially in high-risk patients, consisting of the use of universal prophylaxis in the posttransplantation period of maximum risk (3 months). In seropositive recipients there is no ideal model for prevention, although there is more acceptance in the international community for preemptive therapy. This paper shows the results obtained after analysis of a cohort of 86 patients undergoing heart transplantation in 2005-2011 at the Virgen del Rocío University Hospital, Seville. The 86 patients followed a strategy of preemptive therapy for both high- and low-risk recipients based on the use of antivirals for a variable period of ∼3 weeks when rising antigenemia was detected, determined by polymerase chain reaction above a set threshold. The incidence of CMV disease in our cohort was 4.6%. There are no data available from randomized clinical trials to establish which of the 2 strategies is more effective and safer in these patients, although there is a little experience with preemptive therapy in high-risk patients. Given our positive results and considering the adverse effects of antiviral prophylaxis derivatives, together with the development of resistance and the economic cost, we suggest an individualized prevention strategy at each center.

  18. Hepatitis C virus in the new era: Perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy

    PubMed Central

    Ansaldi, Filippo; Orsi, Andrea; Sticchi, Laura; Bruzzone, Bianca; Icardi, Giancarlo

    2014-01-01

    Despite the great successes achieved in the fields of virology and diagnostics, several difficulties affect improvements in hepatitis C virus (HCV) infection control and eradication in the new era. New HCV infections still occur, especially in some of the poorest regions of the world, where HCV is endemic and long-term sequelae have a growing economic and health burden. An HCV vaccine is still no available, despite years of researches and discoveries about the natural history of infection and host-virus interactions: several HCV vaccine candidates have been developed in the last years, targeting different HCV antigens or using alternative delivery systems, but viral variability and adaption ability constitute major challenges for vaccine development. Many new antiviral drugs for HCV therapy are in preclinical or early clinical development, but different limitations affect treatment validity. Treatment predictors are important tools, as they provide some guidance for the management of therapy in patients with chronic HCV infection: in particular, the role of host genomics in HCV infection outcomes in the new era of direct-acting antivirals may evolve for new therapeutic targets, representing a chance for modulated and personalized treatment management, when also very potent therapies will be available. In the present review we discuss the most recent data about HCV epidemiology, the new perspectives for the prevention of HCV infection and the most recent evidence regarding HCV diagnosis, therapy and predictors of response to it. PMID:25110404

  19. The Effect of Cognitive Behavioral Therapy and Cognitive Behavioral Therapy Plus Media on the Reduction of Bullying and Victimization and the Increase of Empathy and Bystander Response in a Bully Prevention Program for Urban Sixth-Grade Students

    ERIC Educational Resources Information Center

    McLaughlin, Laura Pierce

    2009-01-01

    The purpose of this study was to investigate the effect of cognitive behavioral therapy and cognitive behavioral therapy plus media on the reduction of bullying and victimization and the increase in empathy and bystander response in a bully prevention program for urban sixth-graders. Sixty-eight students participated. Because one of the…

  20. Development and Validation of an HPLC Method for Simultaneous Determination of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochloride in Pharmaceutical Formulations.

    PubMed

    Chellini, Paula R; Lages, Eduardo B; Franco, Pedro H C; Nogueira, Fernando H A; César, Isabela C; Pianetti, Gerson A

    2015-01-01

    Tuberculosis treatment consists of a fixed dose combination of rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ), and ethambutol hydrochloride (EMB). The combined treatment using various drugs is necessary for patient curing, without recrudescence, and for prevention of drug-resistant mutants, which may occur during treatment. An HPLC-diode array detector (DAD) method for the simultaneous determination of RIF, INH, PYZ, and EMB in fixed dose combination tablets was developed and validated. Chromatographic experiments were performed on an Agilent 1200 HPLC system, and the separation was carried out on a Purospher STAR RP18e (250×4.6 mm id, 5 μm, Merck) analytical column. Gradient elution was carried out with a mobile phase of 20 mM monobasic sodium phosphate buffer with 0.2% triethylamine (pH 7.0) and acetonitrile at a flow rate of 1.5 mL/min. The total run time was 12 min, and the re-equilibration time was 5 min. EMB detection was performed at 210 nm, and RIF, INH, and PYZ were detected at 238 nm, using a DAD. The method proved to be specific, linear (r2>0.99), precise (RSD<2%), accurate, and robust and may be applied to the QC analysis of pharmaceutical formulations. PMID:26525241

  1. Spectroscopic and theoretical study of the o-vanillin hydrazone of the mycobactericidal drug isoniazid

    NASA Astrophysics Data System (ADS)

    González-Baró, Ana C.; Pis-Diez, Reinaldo; Parajón-Costa, Beatriz S.; Rey, Nicolás A.

    2012-01-01

    A complete and detailed study of the hydrazone obtained from condensation of antituberculous isoniazid (hydrazide of the isonicotinic acid, INH) and o-vanillin (2-hydroxy-3-methoxybenzaldehyde, o-HVa) is performed. It includes structural and spectroscopic analyses, comparing experimental and theoretical results. The compound was obtained as a chloride of the pyridinic salt (INHOVA +Cl -) but it will be referred as INHOVA for the sake of simplicity. The conformational space was searched and optimized geometries were determined both in gas phase and including solvent effects. Vibrational (IR and Raman), electronic and NMR spectra were registered and assigned with the help of computational methods based on the Density Functional Theory. Isoniazid hydrazones are good candidates for therapeutic agents against tuberculosis with conserved efficiency and lower toxicity and resistance than parent INH.

  2. Analysis of the role of Mycobacterium tuberculosis kasA gene mutations in isoniazid resistance.

    PubMed

    Sun, Y-J; Lee, A S G; Wong, S-Y; Paton, N I

    2007-08-01

    Previous studies have suggested that Mycobacterium tuberculosis kasA G312S and G269S gene mutations may represent sequence polymorphisms of the M. tuberculosis East-African-Indian (EAI) and T families, respectively, rather than relating to isoniazid resistance. The present study examined polymorphisms of these two codons in 98 drug-susceptible M. tuberculosis isolates (68 EAI and 30 T isolates). Twenty-eight isolates belonging to a sub-lineage of the EAI family had the kasA G312S mutation, but none of the 30 T isolates had the G269S mutation. The data suggest that the kasA G312S mutation is not related to isoniazid resistance, but represents a sequence polymorphism in a sub-lineage of the EAI family. PMID:17501974

  3. RELATIONSHIP OF COGNITIVE BEHAVIORAL THERAPY EFFECTS AND HOMEWORK IN AN INDICATED PREVENTION OF DEPRESSION INTERVENTION FOR NON-PROFESSIONAL CAREGIVERS (.).

    PubMed

    Otero, Patricia; Vázquez, Fernando L; Hermida, Elisabet; Díaz, Olga; Torres, Ángela

    2015-06-01

    Activities designed to be performed outside of the intervention are considered an essential aspect of the effectiveness of cognitive-behavioral therapy. However, these have received little attention in interventions aimed at individuals with subclinical depressive symptoms who do not yet meet diagnostic criteria for depression (indicated prevention). In this study, the completion of tasks given as homework and their relationship with post-treatment depressive symptoms was with relation to an indicated prevention of depression intervention. Eighty-nine female non-professional caregivers recruited from an official registry completed an intervention involving 11 homework tasks. Tasks performed were recorded and depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D). Among caregivers, 80.9% completed 9-11 tasks. The number of tasks performed was associated with post-treatment depressive symptoms, with 9 being optimal for clinically significant improvement. These findings highlight the relationship between homework and post-treatment depressive symptoms. PMID:25799123

  4. RELATIONSHIP OF COGNITIVE BEHAVIORAL THERAPY EFFECTS AND HOMEWORK IN AN INDICATED PREVENTION OF DEPRESSION INTERVENTION FOR NON-PROFESSIONAL CAREGIVERS (.).

    PubMed

    Otero, Patricia; Vázquez, Fernando L; Hermida, Elisabet; Díaz, Olga; Torres, Ángela

    2015-06-01

    Activities designed to be performed outside of the intervention are considered an essential aspect of the effectiveness of cognitive-behavioral therapy. However, these have received little attention in interventions aimed at individuals with subclinical depressive symptoms who do not yet meet diagnostic criteria for depression (indicated prevention). In this study, the completion of tasks given as homework and their relationship with post-treatment depressive symptoms was with relation to an indicated prevention of depression intervention. Eighty-nine female non-professional caregivers recruited from an official registry completed an intervention involving 11 homework tasks. Tasks performed were recorded and depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D). Among caregivers, 80.9% completed 9-11 tasks. The number of tasks performed was associated with post-treatment depressive symptoms, with 9 being optimal for clinically significant improvement. These findings highlight the relationship between homework and post-treatment depressive symptoms.

  5. Induction of protective effector immunity to prevent pathogenesis caused by the respiratory syncytial virus. Implications on therapy and vaccine design

    PubMed Central

    Espinoza, Janyra A; Bueno, Susan M; Riedel, Claudia A; Kalergis, Alexis M

    2014-01-01

    Human respiratory syncytial virus (hRSV) is the leading cause of respiratory illness in infants and young children around the globe. This pathogen, which was discovered in 1956, continues to cause a huge number of hospitalizations due to respiratory disease and it is considered a health and economic burden worldwide, especially in developing countries. The immune response elicited by hRSV infection leads to lung and systemic inflammation, which results in lung damage but is not efficient at preventing viral replication. Indeed, natural hRSV infection induces a poor immune memory that allows recurrent infections. Here, we review the most recent knowledge about the lifecycle of hRSV, the immune response elicited by this virus and the subsequent pathology induced in response to infection in the airways. Novel findings about the alterations that this virus causes in the central nervous system and potential therapies and vaccines designed to treat or prevent hRSV infection are discussed. PMID:24801878

  6. Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes

    SciTech Connect

    Chen, Yanyan; Xue, Peng; Hou, Yongyong; Zhang, Hao; Zheng, Hongzhi; Zhou, Tong; Qu, Weidong; Teng, Weiping; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

    2013-12-15

    Transcriptional signaling through the antioxidant response element (ARE), orchestrated by the Nuclear factor E2-related factor 2 (Nrf2), is a major cellular defense mechanism against oxidative or electrophilic stress. Here, we reported that isoniazid (INH), a widely used antitubercular drug, displays a substantial inhibitory property against ARE activities in diverse mouse and human cells. In 3T3-L1 preadipocytes, INH concentration-dependently suppressed the ARE-luciferase reporter activity and mRNA expression of various ARE-dependent antioxidant genes under basal and oxidative stressed conditions. In keeping with our previous findings that Nrf2-ARE plays a critical role in adipogenesis by regulating expression of CCAAT/enhancer-binding protein β (C/EBPβ) and peroxisome proliferator-activated receptor γ (PPARγ), suppression of ARE signaling by INH hampered adipogenic differentiation of 3T3-L1 cells and human adipose-derived stem cells (ADSCs). Following adipogenesis induced by hormonal cocktails, INH-treated 3T3-L1 cells and ADSCs displayed significantly reduced levels of lipid accumulation and attenuated expression of C/EBPα and PPARγ. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by INH occurred in the early stage of terminal adipogenic differentiation, where reduced expression of C/EBPβ and C/EBPδ was observed. To our knowledge, the present study is the first to demonstrate that INH suppresses ARE signaling and interrupts with the transcriptional network of adipogenesis, leading to impaired adipogenic differentiation. The inhibition of ARE signaling may be a potential underlying mechanism by which INH attenuates cellular antioxidant response contributing to various complications. - Highlights: • Isoniazid suppresses ARE-mediated transcriptional activity. • Isoniazid inhibits adipogenesis in preadipocytes. • Isoniazid suppresses adipogenic gene expression during adipogenesis.

  7. Characterization of mutations causing rifampicin and isoniazid resistance of Mycobacterium tuberculosis in Syria.

    PubMed

    Madania, Ammar; Habous, Maya; Zarzour, Hana; Ghoury, Ifad; Hebbo, Barea

    2012-01-01

    In order to characterize mutations causing rifampicin and isoniazid resistance of M. tuberculosis in Syria, 69 rifampicin resistant (Rif(r)) and 72 isoniazid resistant (Inh(r)) isolates were screened for point mutations in hot spots of the rpoB, katG and inhA genes by DNA sequencing and real time PCR. Of 69 Rif(r) isolates, 62 (90%) had mutations in the rifampin resistance determining region (RRDR) of the rpoB gene, with codons 531 (61%), 526 (13%), and 516 (8.7%) being the most commonly mutated. We found two new mutations (Asp516Thr and Ser531Gly) described for the first time in the rpoB-RRDR in association with rifampicin resistance. Only one mutation (Ile572Phe) was found outside the rpoB-RRDR. Of 72 Inh(r) strains, 30 (41.6%) had a mutation in katGcodon315 (with Ser315Thr being the predominant alteration), and 23 (32%) harbored the inhA(-15C-->T) mutation. While the general pattern of rpoB-RRDR and katG mutations reflected those found worldwide, the prevalence of the inhA(-15C-->T mutation was above the value found in most other countries, emphasizing the great importance of testing the inhA(-15C-->T) mutation for prediction of isoniazid resistance in Syria. Sensitivity of a rapid test using real time PCR and 3'-Minor groove binder (MGB) probes in detecting Rif(r) and Inh(r) isolates was 90% and 69.4%, respectively. This demonstrates that a small set of MGB-probes can be used in real time PCR in order to detect most mutations causing resistance to rifampicin and isoniazid.

  8. Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania

    PubMed Central

    Chigutsa, Emmanuel; Faurholt-Jepsen, Daniel; PrayGod, George; Range, Nyagosya; Castel, Sandra; Wiesner, Lubbe; Hagen, Christian Munch; Christiansen, Michael; Changalucha, John; McIlleron, Helen; Friis, Henrik; Andersen, Aase Bengaard

    2015-01-01

    Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients. PMID:26501782

  9. Signature gene expression profiles discriminate between isoniazid-, thiolactomycin-, and triclosan-treated Mycobacterium tuberculosis.

    PubMed

    Betts, Joanna C; McLaren, Alistair; Lennon, Mark G; Kelly, Fiona M; Lukey, Pauline T; Blakemore, Steve J; Duncan, Ken

    2003-09-01

    Genomic technologies have the potential to greatly increase the efficiency of the drug development process. As part of our tuberculosis drug discovery program, we used DNA microarray technology to profile drug-induced effects in Mycobacterium tuberculosis. Expression profiles of M. tuberculosis treated with compounds that inhibit key metabolic pathways are required as references for the assessment of novel antimycobacterial agents. We have studied the response of M. tuberculosis to treatment with the mycolic acid biosynthesis inhibitors isoniazid, thiolactomycin, and triclosan. Thiolactomycin targets the beta-ketoacyl-acyl carrier protein (ACP) synthases KasA and KasB, while triclosan inhibits the enoyl-ACP reductase InhA. However, controversy surrounds the precise mode of action of isoniazid, with both InhA and KasA having been proposed as the primary target. We have shown that although the global response profiles of isoniazid and thiolactomycin are more closely related to each other than to that of triclosan, there are differences that distinguish the mode of action of these two drugs. In addition, we have identified two groups of genes, possibly forming efflux and detoxification systems, through which M. tuberculosis may limit the effects of triclosan. We have developed a mathematical model, based on the expression of 21 genes, which is able to perfectly discriminate between isoniazid-, thiolactomycin-, or triclosan-treated M. tuberculosis. This model is likely to prove invaluable as a tool to improve the efficiency of our drug development programs by providing a means to rapidly confirm the mode of action of thiolactomycin analogues or novel InhA inhibitors as well as helping to translate enzyme activity into whole-cell activity. PMID:12936993

  10. New concepts and challenges in the clinical translation of cancer preventive therapies: the role of pharmacodynamic biomarkers.

    PubMed

    Brown, Karen; Rufini, Alessandro

    2015-01-01

    Implementation of therapeutic cancer prevention strategies has enormous potential for reducing cancer incidence and related mortality. Trials of drugs including tamoxifen and aspirin have led the way in demonstrating proof-of-principle that prevention of breast and colorectal cancer is feasible. Many other compounds ranging from drugs in widespread use for various indications, including metformin, bisphosphonates, and vitamin D, to dietary agents such as the phytochemicals resveratrol and curcumin, show preventive activity against several cancers in preclinical models. Notwithstanding the wealth of opportunities, major challenges have hindered the development process and only a handful of therapies are currently approved for cancer risk reduction. One of the major obstacles to successful clinical translation of promising preventive agents is a lack of pharmacodynamic biomarkers to provide an early read out of biological activity in humans and for optimising doses to take into large scale randomised clinical trials. A further confounding factor is a lack of consideration of clinical pharmacokinetics in the design of preclinical experiments, meaning results are frequently reported from studies that use irrelevant or unachievable concentrations. This article focuses on recent findings from investigations with dietary-derived agents to illustrate how a thorough understanding of the mechanisms of action, using models that mimic the clinical scenario, together with the development of compound-specific accompanying pharmacodynamic biomarkers could accelerate the developmental pipeline for preventive agents and maximise the chances of success in future clinical trials. Moreover, the concept of a bell-shaped dose-response curve for therapeutic cancer prevention is discussed, along with the need to rethink the traditional 'more is better' approach for dose selection. PMID:26635905

  11. An open trial of mindfulness-based cognitive therapy for the prevention of perinatal depressive relapse/recurrence.

    PubMed

    Dimidjian, Sona; Goodman, Sherryl H; Felder, Jennifer N; Gallop, Robert; Brown, Amanda P; Beck, Arne

    2015-02-01

    Pregnant women with histories of depression are at high risk of depressive relapse/recurrence during the perinatal period, and options for relapse/recurrence prevention are limited. Mindfulness-based cognitive therapy (MBCT) has strong evidence among general populations but has not been studied among at-risk pregnant women to prevent depression. We examined the feasibility, acceptability, and clinical outcomes of depression symptom severity and relapse/recurrence associated with MBCT adapted for perinatal women (MBCT-PD). Pregnant women with depression histories were recruited from obstetrics clinics in a large health maintenance organization at two sites and enrolled in MBCT-PD (N = 49). Self-reported depressive symptoms and interview-based assessments of depression relapse/recurrence status were measured at baseline, during MBCT-PD, and through 6-months postpartum. Pregnant women reported interest, engagement, and satisfaction with the program. Retention rates were high, as were rates of completion of daily homework practices. Intent to treat analyses indicated a significant improvement in depression symptom levels and an 18 % rate of relapse/recurrence through 6 months postpartum. MBCT-PD shows promise as an acceptable, feasible, and clinically beneficial brief psychosocial prevention option for pregnant women with histories of depression. Randomized controlled trials are needed to examine the efficacy of MBCT-PD for the prevention of depressive relapse/recurrence during pregnancy and postpartum. PMID:25298253

  12. Early, But Not Late Onset Estrogen Replacement Therapy Prevents Oxidative Stress and Metabolic Alterations Caused by Ovariectomy

    PubMed Central

    López-Grueso, Raúl; Gambini, Juan; Abdelaziz, Kheira M.; Monleón, Daniel; Díaz, Ana; El Alami, Marya; Bonet-Costa, Vicent; Borrás, Consuelo

    2014-01-01

    Abstract Aims: The usefulness of estrogen replacement therapy (ERT) in preventing oxidative stress associated with menopause is controversial. We aimed to study if there is a critical time window for effective treatment of the effects of ovariectomy with estrogens at the molecular, metabolic, and cellular level. Results: Our main finding is that early, but not late onset of ERT prevents an ovariectomy-associated increase in mitochondrial hydrogen peroxide levels, oxidative damage to lipids and proteins, and a decrease in glutathione peroxidase and catalase activity in rats. This may be due to a change in the estrogen receptor (ER) expression profile: ovariectomy increases the ER α/β ratio and immediate estrogen replacement prevents it. Positron emission tomography analysis shows that ovariectomy decreases the brain glucose uptake in vivo and that estrogen administration is beneficial, but only if administered immediately after deprivation. Ovariectomy decreases GLUT-1 and 3 glucose transporters in the brain, and only early onset estrogen administration prevents it. Plasma from rats treated with estrogens immediately after ovariectomy show similar metabolomics profiles as controls. Innovation: We provide molecular basis for the recommendation of early onset ERT and explain its lack of effectiveness if a significant time period elapses after ovariectomy and probably after the onset of menopause. Conclusion: Only early, but not late onset administration of estrogens after ovariectomy has beneficial effects at molecular levels on oxidative stress, brain glucose uptake, and metabolomic profiles. Antioxid. Redox Signal. 20, 236–246. PMID:23725100

  13. Preventive measures to prevent loss to follow-up in highly active antiretroviral therapy (HAART): implementing a strategy in Ziguinchor (Casamance, Senegal) in 2014.

    PubMed

    Randé, H; Rouffy, D

    2016-05-01

    Since 2010, the Pharmacie et Aide Humanitaire (PAH) in Casamance (Senegal) has been maintaining a software package (Tacojo) that allows monthly monitoring of the distribution of treatment to every patient with HIV infection receiving highly active antiretroviral therapy (HAART). We used this program to set up measures to prevent the loss to follow-up of patients receiving HAART. Our involvement focused on two main areas. First, each patient is routinely contacted after inclusion, to help us to understand the patient's experience of the disease and the treatment. This process aims to improve adherence to the treatment. Then, all patients who miss an appointment are routinely contacted by telephone within seven days of that appointment. The goal is to understand the reasons for the absence and to encourage patients to continue their treatment. Despite the lack of distance due to the relative newness of this program, these preventive measures have shown hopeful results (80% of the patients came back after a call). It would be interesting to apply it in a sustainable manner and in more medical facilities. PMID:27412981

  14. Expert position paper on prolonged dual antiplatelet therapy in secondary prevention following myocardial infarction.

    PubMed

    Weiss, Thomas W; Aichinger, Josef; Huber, Kurt; Speidl, Walter S; Watzinger, Norbert; Zweiker, Robert; Alber, Hannes F

    2016-06-01

    The protective effect of dual antiplatelet therapy (DAPT) following acute coronary syndrome is undisputed, but its duration is subject of debate. Several studies show that prolonged therapy provides a clinical benefit in patients following acute coronary syndrome. The aim of this position paper authored by Austrian experts is to outline the current evidence and provide an overview of recent studies. It is also intended to serve as a practical guide to identify those patients who may benefit from prolonged DAPT. PMID:27278134

  15. Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples.

    PubMed

    Anglemyer, Andrew; Horvath, Tara; Rutherford, George

    2013-10-16

    CLINICAL QUESTION Does treating the HIV-infected partner in a serodiscordant couple reduce the risk of HIV transmission to the uninfected partner? BOTTOM LINE Compared with serodiscordant couples without treatment, couples in which the infected partner is treated with antiretroviral therapy have a lower risk of HIV transmission.

  16. Mindfulness-Based Cognitive Therapy to Prevent Relapse in Recurrent Depression

    ERIC Educational Resources Information Center

    Kuyken, Willem; Byford, Sarah; Taylor, Rod S.; Watkins, Ed; Holden, Emily; White, Kat; Barrett, Barbara; Byng, Richard; Evans, Alison; Mullan, Eugene; Teasdale, John D.

    2008-01-01

    For people at risk of depressive relapse, mindfulness-based cognitive therapy (MBCT) has an additive benefit to usual care (H. F. Coelho, P. H. Canter, & E. Ernst, 2007). This study asked if, among patients with recurrent depression who are treated with antidepressant medication (ADM), MBCT is comparable to treatment with maintenance ADM (m-ADM)…

  17. Accumulating Evidence for Parent-Child Interaction Therapy in the Prevention of Child Maltreatment

    ERIC Educational Resources Information Center

    Thomas, Rae; Zimmer-Gembeck, Melanie J.

    2011-01-01

    In a randomized controlled trial, the effectiveness of Parent-Child Interaction Therapy (PCIT) and correlates of maltreatment outcomes were examined. Mothers (N = 150) had a history or were at high risk of maltreating their children. After 12 weeks and compared to waitlist, PCIT mothers were observed to have improved parent-child interactions and…

  18. Vibration Therapy to Prevent Bone Loss and Falls: Mechanisms and Efficacy.

    PubMed

    Beck, Belinda R

    2015-12-01

    A considerable volume of evidence has accumulated to suggest that whole-body vibration (WBV) may have a therapeutic role to play in the prevention of osteoporotic fracture, particularly for individuals who are unable to tolerate vigorous exercise interventions. There is moderate to strong evidence that WBV will prevent falls (likely due to enhanced neuromuscular function), but also some indication that the effects of WBV do not outstrip those of targeted exercise. Animal data indicates that WBV will also improve bone mass, including preventing loss due to hormone withdrawal, disuse and glucocorticoid exposure. Human trials, however, have produced equivocal outcomes for bone. Positive trends are apparent at the hip and spine, but shortcomings in study designs have limited statistical power. The mechanism of the vibration effect on bone tissue is likely to be mechanical coupling between an oscillating cell nucleus and the cytoskeleton. More robust dose-response human data are required before therapeutic guidelines can be developed.

  19. Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.

    PubMed

    Koo, Mi-Sun; Manca, Claudia; Yang, Guibin; O'Brien, Paul; Sung, Nackmoon; Tsenova, Liana; Subbian, Selvakumar; Fallows, Dorothy; Muller, George; Ehrt, Sabine; Kaplan, Gilla

    2011-02-25

    Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

  20. Maji: A New Tool to Prevent Overhydration of Children Receiving Intravenous Fluid Therapy in Low-Resource Settings

    PubMed Central

    Shah, Kamal; Skerrett, Erica; Nojoomi, Matthew; Walker, Thor; Maynard, Kelley; Pan, Michael; Flynn, Bailey; Yuan, Melissa; Horton, Paige; Vaughn, Taylor; Miros, Robert; Molyneux, Elizabeth; Saterbak, Ann; Oden, Z Maria; Richards-Kortum, Rebecca

    2015-01-01

    We designed and evaluated the accuracy and usability of a device to regulate the volume of fluid dispensed during intravenous drip therapy. The mechanical system was developed in response to a pressing need articulated by clinicians in pediatric wards throughout sub-Saharan Africa, who require a tool to prevent overhydration in children receiving intravenous fluid in settings that lack burettes or electronic infusion pumps. The device is compatible with most intravenous bags and limits the volume dispensed to a preset amount that can be adjusted in 50 mL increments. Laboratory accuracy over a range of clinically-relevant flow rates, initial bag volumes, and target volumes was within 12.0 mL of the target volume. The ease of use is “excellent,” with a mean system usability score of 84.4 out of 100. Use of the device limits the volume of fluid dispensed during intravenous therapy and could potentially reduce the morbidity and mortality associated with overhydration in children receiving intravenous therapy. PMID:25732685

  1. The impact of the 2013 WHO antiretroviral therapy guidelines on the feasibility of HIV population prevention trials

    PubMed Central

    Ross, Eric L.; Tanser, Frank; Pei, Pamela P.; Newell, Marie-Louise; Losina, Elena; Thiebaut, Rodolphe; Weinstein, Milton C.; Freedberg, Kenneth A.; Anglaret, Xavier; Scott, Callie A.; Dabis, Francois; Walensky, Rochelle P.

    2014-01-01

    Introduction Several cluster-randomized HIV prevention trials aim to demonstrate the population-level preventive impact of antiretroviral therapy (ART). 2013 World Health Organization guidelines raising the ART initiation threshold to CD4<500/µL could attenuate these trials’ effect size by increasing ART usage in control clusters. Methods We used a computational model to simulate strategies from a hypothetical cluster-randomized HIV prevention trial. The primary model outcome was the relative reduction in 24-month HIV incidence between control (ART offered with CD4 below threshold) and intervention (ART offered to all) strategies. We assessed this incidence reduction using the revised (CD4<500/µL) and prior (CD4<350/µL) control ART initiation thresholds. Additionally, we evaluated changes to trial characteristics that could bolster the incidence reduction. Results With a control ART initiation threshold of CD4<350/µL, 24-month HIV incidence under control and intervention strategies was 2.46/100PY and 1.96/100PY, a 21% reduction. Raising the threshold to CD4<500/µL decreased the incidence reduction by more than one-third, to 12%. Using this higher threshold, moving to a 36-month horizon (vs. 24-month), yearly control-strategy HIV screening (vs. biannual), and 2-monthly intervention-strategy screening (vs. biannual), resulted in a 31% incidence reduction, similar to effect size projections for ongoing trials. Alternate assumptions regarding cross-cluster contamination had the greatest influence on the incidence reduction. Conclusions Implementing the 2013 WHO HIV treatment threshold could substantially diminish the incidence reduction in HIV population prevention trials. Alternative HIV testing frequencies and trial horizons can bolster this incidence reduction, but could be logistically and ethically challenging. The feasibility of HIV population prevention trials should be reassessed as implementation of treatment guidelines evolves. PMID:25350957

  2. Impact of preventive therapy on the risk of breast cancer among women with benign breast disease.

    PubMed

    Cuzick, Jack; Sestak, Ivana; Thorat, Mangesh A

    2015-11-01

    There are three main ways in which women can be identified as being at high risk of breast cancer i) family history of breast and/or ovarian cancer, which includes genetic factors ii) mammographically identified high breast density, and iii) certain types of benign breast disease. The last category is the least common, but in some ways the easiest one for which treatment can be offered, because these women have already entered into the treatment system. The highest risk is seen in women with lobular carcinoma in situ (LCIS), but this is very rare. More common is atypical hyperplasia (AH), which carries a 4-5-fold risk of breast cancer as compared to general population. Even more common is hyperplasia of the usual type and carries a roughly two-fold increased risk. Women with aspirated cysts are also at increased risk of subsequent breast cancer. Tamoxifen has been shown to be particularly effective in preventing subsequent breast cancer in women with AH, with a more than 70% reduction in the P1 trial and a 60% reduction in IBIS-I. The aromatase inhibitors (AIs) also are highly effective for AH and LCIS. There are no published data on the effectiveness of tamoxifen or the AIs for breast cancer prevention in women with hyperplasia of the usual type, or for women with aspirated cysts. Improving diagnostic consistency, breast cancer risk prediction and education of physicians and patients regarding therapeutic prevention in women with benign breast disease may strengthen breast cancer prevention efforts.

  3. Menopausal Estrogen Therapy Benefits and Risks Vary by Age, WHI Analysis Suggests | Division of Cancer Prevention

    Cancer.gov

    Long-term follow-up data from the Women’s Health Initiative (WHI) provide important new information about the potential risks and benefits of hormone therapy to treat symptoms or conditions related to menopause, including its effect on breast cancer risk. The results were published April 5 in the Journal of the American Medical Association. |

  4. N-feruloylserotonin in preventive combination therapy with methotrexate reduced inflammation in adjuvant arthritis.

    PubMed

    Kuncirova, Viera; Ponist, Silvester; Mihalova, Danica; Drafi, Frantisek; Nosal, Radomir; Acquaviva, Alessandra; Gardi, Concetta; Harmatha, Juraj; Hradkova, Iveta; Bauerova, Katarina

    2014-12-01

    Many of disease-modifying anti-rheumatic drugs often have side effects at high doses and/or during long-term administration. Increased efficacy without increased toxicity is expected for combination therapy of rheumatoid arthritis (RA). The aim of the study was to examine the effect of N-feruloylserotonin (N-f-5HT) and methotrexate (MTX) in monotherapy and in combination therapy on disease progression and inflammation in arthritic rats. Adjuvant arthritis was induced by intradermal injection of Mycobacterium butyricum in incomplete Freund's adjuvant in Lewis rats. The experiment included healthy animals, arthritic animals without any drug administration, arthritic animals with administration of N-f-5HT in the oral daily dose of 15 mg/kg b.w., arthritic animals with administration of MTX in the oral dose of 0.3 mg/kg b.w. twice a week and arthritic animals treated with the combination of N-f-5HT and MTX. N-f-5HT in monotherapy reduced only activation of NF-κB and did not have any significant effect on other parameters monitored. Low-dose treatment of MTX decreased the level of IL-1β and MCP-1 on day 14 and activation of NF-κB in liver without significant effect on other parameters. N-f-5HT and MTX combination showed both the anti-arthritic (hind paw volume and arthritic score) and anti-inflammatory effect (plasmatic levels of IL-1β, IL-17, MCP-1, CRP, and activation of NF-κB in liver). In combination with MTX, N-f-5HT markedly potentiated the therapeutic effect of MTX low dose, which resulted in significant improvement of all parameters measured. The findings showed that the combination therapy simultaneously decreased multiple markers of inflammation, a result crucial for future therapy of RA.

  5. Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD.

    PubMed

    Jacob, Noam; Targan, Stephan R; Shih, David Q

    2016-08-01

    The frequency of fibrosing Crohn's disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis. PMID:27536363

  6. Early cystic fibrosis lung disease: Role of airway surface dehydration and lessons from preventive rehydration therapies in mice.

    PubMed

    Mall, Marcus A; Graeber, Simon Y; Stahl, Mirjam; Zhou-Suckow, Zhe

    2014-07-01

    Cystic fibrosis (CF) lung disease starts in the first months of life and remains one of the most common fatal hereditary diseases. Early therapeutic interventions may provide an opportunity to prevent irreversible lung damage and improve outcome. Airway surface dehydration is a key disease mechanism in CF, however, its role in the in vivo pathogenesis and as therapeutic target in early lung disease remains poorly understood. Mice with airway-specific overexpression of the epithelial Na(+) channel (βENaC-Tg) recapitulate airway surface dehydration and phenocopy CF lung disease. Recent studies in neonatal βENaC-Tg mice demonstrated that airway surface dehydration produces early mucus plugging in the absence of mucus hypersecretion, which triggers airway inflammation, promotes bacterial infection and causes early mortality. Preventive rehydration therapy with hypertonic saline or amiloride effectively reduced mucus plugging and mortality in neonatal βENaC-Tg mice. These results support clinical testing of preventive/early rehydration strategies in infants and young children with CF. PMID:24561284

  7. Treatment with lithium prevents serum thyroid hormone increase after thionamide withdrawal and radioiodine therapy in patients with Graves' disease.

    PubMed

    Bogazzi, Fausto; Bartalena, Luigi; Campomori, Alberto; Brogioni, Sandra; Traino, Claudio; De Martino, Fabio; Rossi, Giuseppe; Lippi, Francesco; Pinchera, Aldo; Martino, Enio

    2002-10-01

    concentrations are prevented by lithium; and 4) the increased effectiveness of RAI therapy in lithium-treated patients is related to the increased RAI retention in the thyroid gland. Accordingly, a short course of lithium therapy can be considered a useful adjunct to RAI therapy to obtain a prompter control of thyrotoxicosis and avoid its transient exacerbation because of MMI withdrawal and RAI administration.

  8. Post reperfusion syndrome during liver transplantation: From pathophysiology to therapy and preventive strategies

    PubMed Central

    Siniscalchi, Antonio; Gamberini, Lorenzo; Laici, Cristiana; Bardi, Tommaso; Ercolani, Giorgio; Lorenzini, Laura; Faenza, Stefano

    2016-01-01

    This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A PubMed search was conducted using the MeSH database, “Reperfusion” AND “liver transplantation” were the combined MeSH headings; EMBASE and the Cochrane library were also searched using the same terms. 52 relevant studies and one ongoing trial were found. The concept of post reperfusion syndrome has evolved through years to a multisystemic disorder. The implications of the main organ, recipient and procedure related factors in the genesis of this complex syndrome are discussed in the text as the novel pharmacologic and technical approaches to reduce its incidence. However the available evidence about risk factors, physiopathology and preventive measures is still confusing, the presence of two main definitions and the numerosity of possible confounding factors greatly complicates the interpretation of the studies. PMID:26819522

  9. Prevention and treatment of nephrolithiasis: a review on the role of spa therapy.

    PubMed

    Mennuni, G; Serio, A; Fontana, M; Nocchi, S; Costantino, C; Tanzi, G; Stornelli, G; Fraioli, A

    2015-01-01

    The prevalence and incidence of nephrolithiasis is reported to be increasing across the world. It is a disease of increased urinary concentration of stone-forming salts. The physicochemical mechanism of stone formation includes precipitation, homogenous/heterogeneous nucleation, growth, aggregation and concretion of various modulators in urine. Necessary condition to develop stones is urinary supersaturation, due to reduced urinary volume or to an excesses solutes. Fluid intake is the main determinant of urine volume. Urine dilution can significantly decrease both the crystallization rate of the urinary salts and the aggregation of the crystals. A correct fluid intake can act on different effects: urinary tract washing, urinary volume increasing and dilution of solutes. In addition mineral waters have other particular features: greater diuretic effect, more important urinary dilution with solutes and microbial concentration reduction, urinary pH changes, superior washout effect due to mechanical effects and ureteral contractions. Adequate water intake is the most important conservative strategy in urolithiasis prevention; particularly hydropinotherapy with oligomineral water should be considered as an important instrument to prevent stones in subjects predisposed to the disease (family members of people suffering from kidney stones), to reduce relapses, and can help to eliminate residual fragments also after extracorporeal shock wave lithotripsy. It is recommended a management with increased mineral water intake to promote urine volume of at least 2.5L each day to prevent stone formation. Obviously water intake shall be varied in relation to the presence of contraindications or any diseases. PMID:26550821

  10. Prevention and treatment of nephrolithiasis: a review on the role of spa therapy.

    PubMed

    Mennuni, G; Serio, A; Fontana, M; Nocchi, S; Costantino, C; Tanzi, G; Stornelli, G; Fraioli, A

    2015-01-01

    The prevalence and incidence of nephrolithiasis is reported to be increasing across the world. It is a disease of increased urinary concentration of stone-forming salts. The physicochemical mechanism of stone formation includes precipitation, homogenous/heterogeneous nucleation, growth, aggregation and concretion of various modulators in urine. Necessary condition to develop stones is urinary supersaturation, due to reduced urinary volume or to an excesses solutes. Fluid intake is the main determinant of urine volume. Urine dilution can significantly decrease both the crystallization rate of the urinary salts and the aggregation of the crystals. A correct fluid intake can act on different effects: urinary tract washing, urinary volume increasing and dilution of solutes. In addition mineral waters have other particular features: greater diuretic effect, more important urinary dilution with solutes and microbial concentration reduction, urinary pH changes, superior washout effect due to mechanical effects and ureteral contractions. Adequate water intake is the most important conservative strategy in urolithiasis prevention; particularly hydropinotherapy with oligomineral water should be considered as an important instrument to prevent stones in subjects predisposed to the disease (family members of people suffering from kidney stones), to reduce relapses, and can help to eliminate residual fragments also after extracorporeal shock wave lithotripsy. It is recommended a management with increased mineral water intake to promote urine volume of at least 2.5L each day to prevent stone formation. Obviously water intake shall be varied in relation to the presence of contraindications or any diseases.

  11. [The new concept of osteoporosis. Early diagnosis, prevention and therapy are possible today].

    PubMed

    Hesch, R D; Harms, H; Rittinghaus, E F; Brabant, G

    1990-04-15

    A paradigma of osteoporosis pathology is discussed, at the center of which is the hormone-related disturbance of the osteoblast/osteoclast functional unit. A liberal replacement of estrogen-gestagen in post-menopausal women is advocated. Early diagnosis with the aid of quantitative computed tomography makes it possible to establish the indication for timely hormonal treatment in the future, which can result in a measureable increase in bone mass. Late therapy, that is, treatment initiated after the occurrence of fractures, has proven largely ineffective. PMID:2358288

  12. [The new concept of osteoporosis. Early diagnosis, prevention and therapy are possible today].

    PubMed

    Hesch, R D; Harms, H; Rittinghaus, E F; Brabant, G

    1990-04-15

    A paradigma of osteoporosis pathology is discussed, at the center of which is the hormone-related disturbance of the osteoblast/osteoclast functional unit. A liberal replacement of estrogen-gestagen in post-menopausal women is advocated. Early diagnosis with the aid of quantitative computed tomography makes it possible to establish the indication for timely hormonal treatment in the future, which can result in a measureable increase in bone mass. Late therapy, that is, treatment initiated after the occurrence of fractures, has proven largely ineffective.

  13. [Clinical efficacy instant goat milk in the complex therapy and prevention of osteoporosis in patients with rheumatoid arthritis].

    PubMed

    Shostak, N A; Muradiants, A A; Kondrashov, A A; Denisova, S N

    2014-01-01

    Osteoporosis (OP) in rheumatoid arthritis (RA) refers to a secondary immune-mediated metabolic osteopathy characterized by periarticular and systemic decreased bone mass, impaired bone strength and increased risk of fractures. According to some studies, adding milk in the diet helps to increase bone mineral density and to reduce the risk of osteoporosis and maintain normal levels of vitamin D. To study the state of mineral and bone metabolism in RA patients zeith osteopenic syndrome and to evaluate the effectiveness of treatment and prevention of OP by adding dry goat milk "Amalteya" in the diet. The study included 42 patients with a documented diagnosis of RA (ACR, 1987) - 23 men (mean age 59 years) and 19 postmenopausal women (mean age 62 years) with the presence of osteoporosis and osteopenia according to the dual-energy X-ray absorptiometry. 21 (50%) RA patients (main group) received standard antiosteoporotichesky (alendronate 70 mg/week + calcium 1000 mg/day + Vitamin D3 800 IU/day) therapy and milk powder Amalteya® (400 ml/day). The control group (21 patients with RA) received only standard antiosteoporotic therapy. Follow-up lasted for 6 months. The concentration of total calcium in the blood of RA patients was on average 2.33 mmol/l, ionized Ca - 1,18 mmol/l and inorganic P - 1,09 mmol/l, which corresponds to normal values. Vitamin D deficiency was found in 17,5% of patients, and failure - in 32,5% of patients with RA. After 6 months of the treatment it was found that b-CrossLaps levels tend to be reducing in both of the groups and with reduction of bone formation marker osteocalcin in the group not receiving goat milk. Also, due to the background of ongoing combinative therapy it was clear that concentrations of 1,25(OH)2D and 25(OH)D in the blood serum are increasing (by 18,5-28,2% at the main group and by 8,0-17,9% at the control group), however, inter-group differences was below the level of the reliable importance. It was strongly marked in the group

  14. [Clinical efficacy instant goat milk in the complex therapy and prevention of osteoporosis in patients with rheumatoid arthritis].

    PubMed

    Shostak, N A; Muradiants, A A; Kondrashov, A A; Denisova, S N

    2014-01-01

    Osteoporosis (OP) in rheumatoid arthritis (RA) refers to a secondary immune-mediated metabolic osteopathy characterized by periarticular and systemic decreased bone mass, impaired bone strength and increased risk of fractures. According to some studies, adding milk in the diet helps to increase bone mineral density and to reduce the risk of osteoporosis and maintain normal levels of vitamin D. To study the state of mineral and bone metabolism in RA patients zeith osteopenic syndrome and to evaluate the effectiveness of treatment and prevention of OP by adding dry goat milk "Amalteya" in the diet. The study included 42 patients with a documented diagnosis of RA (ACR, 1987) - 23 men (mean age 59 years) and 19 postmenopausal women (mean age 62 years) with the presence of osteoporosis and osteopenia according to the dual-energy X-ray absorptiometry. 21 (50%) RA patients (main group) received standard antiosteoporotichesky (alendronate 70 mg/week + calcium 1000 mg/day + Vitamin D3 800 IU/day) therapy and milk powder Amalteya® (400 ml/day). The control group (21 patients with RA) received only standard antiosteoporotic therapy. Follow-up lasted for 6 months. The concentration of total calcium in the blood of RA patients was on average 2.33 mmol/l, ionized Ca - 1,18 mmol/l and inorganic P - 1,09 mmol/l, which corresponds to normal values. Vitamin D deficiency was found in 17,5% of patients, and failure - in 32,5% of patients with RA. After 6 months of the treatment it was found that b-CrossLaps levels tend to be reducing in both of the groups and with reduction of bone formation marker osteocalcin in the group not receiving goat milk. Also, due to the background of ongoing combinative therapy it was clear that concentrations of 1,25(OH)2D and 25(OH)D in the blood serum are increasing (by 18,5-28,2% at the main group and by 8,0-17,9% at the control group), however, inter-group differences was below the level of the reliable importance. It was strongly marked in the group

  15. EGFR blockade prevents glioma escape from BRAFV600E targeted therapy

    PubMed Central

    Prados, Michael; Weiss, William A.; James, C. David; Nicolaides, Theodore

    2015-01-01

    Mutational activation of BRAF (BRAFV600E) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAFV600E displays efficacy in pre-clinical models of glioma, however xenograft tumors adapt rapidly and escape from the growth-inhibitory effects of BRAF-targeted therapy. Here, we show that intrinsic resistance to a BRAFV600E specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAFV600E inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity. We demonstrated that overexpression of PTPN9 reduces EGFR phosphorylation and cooperates with BRAFV600E inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAFV600E to reduce growth of glioma cell lines and orthotopic glioma xenograft by decreasing tumor cell proliferation while increasing apoptosis, with resultant significant extension of animal subject survival. Our data support clinical evaluation of BRAFV600E and EGFR targeted therapy in treating BRAFV600E glioma. PMID:26023796

  16. Recent advances in the prevention and treatment of skin cancer using photodynamic therapy

    PubMed Central

    Zhao, Baozhong; He, Yu-Ying

    2011-01-01

    Photodynamic therapy (PDT) is a noninvasive procedure that involves a photosensitizing drug and its subsequent activation by light to produce reactive oxygen species that specifically destroy target cells. Recently, PDT has been widely used in treating non-melanoma skin malignancies, the most common cancer in the USA, with superior cosmetic outcomes compared with conventional therapies. The topical ‘photosensitizers’ commonly used are 5-aminolevulinic acid (ALA) and its esterified derivative methyl 5-aminolevulinate, which are precursors of the endogenous photosensitizer protoporphyrin IX. After treatment with ALA or methyl 5-aminolevulinate, protoporphyrin IX preferentially accumulates in the lesion area of various skin diseases, which allows not only PDT treatment but also fluorescence diagnosis with ALA-induced porphyrins. Susceptible lesions include various forms of non-melanoma skin cancer such as actinic keratosis, basal cell carcinoma and squamous cell carcinoma. The most recent and promising developments in PDT include the discovery of new photosensitizers, the exploitation of new drug delivery systems and the combination of other modalities, which will all contribute to increasing PDT therapeutic efficacy and improving outcome. This article summarizes the main principles of PDT and its current clinical use in the management of non-melanoma skin cancers, as well as recent developments and possible future research directions. PMID:21080805

  17. Challenges with nitrate therapy and nitrate tolerance: prevalence, prevention, and clinical relevance.

    PubMed

    Thadani, Udho

    2014-08-01

    Nitrate therapy has been an effective treatment for ischemic heart disease for over 100 years. The anti-ischemic and exercise-promoting benefits of sublingually administered nitrates are well established. Nitroglycerin is indicated for the relief of an established attack of angina and for prophylactic use, but its effects are short lived. In an effort to increase the duration of beneficial effects, long-acting orally administered and topical applications of nitrates have been developed; however, following their continued or frequent daily use, patients soon develop tolerance to these long-acting nitrate preparations. Once tolerance develops, patients begin losing the protective effects of the long-acting nitrate therapy. By providing a nitrate-free interval, or declining nitrate levels at night, one can overcome or reduce the development of tolerance, but cannot provide 24-h anti-anginal and anti-ischemic protection. In addition, patients may be vulnerable to occurrence of rebound angina and myocardial ischemia during periods of absent nitrate levels at night and early hours of the morning, and worsening of exercise capacity prior to the morning dose of the medication. This has been a concern with nitroglycerin patches but not with oral formulations of isosorbide-5 mononitrates, and has not been adequately studied with isosorbide dinitrate. This paper describes problems associated with nitrate tolerance, reviews mechanisms by which nitrate tolerance and loss of efficacy develop, and presents strategies to avoid nitrate tolerance and maintain efficacy when using long-acting nitrate formulations.

  18. CCR5 Targeted Cell Therapy for HIV and Prevention of Viral Escape.

    PubMed

    Hütter, Gero; Bodor, Josef; Ledger, Scott; Boyd, Maureen; Millington, Michelle; Tsie, Marlene; Symonds, Geoff

    2015-07-27

    Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC) to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN), clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9), transcription activator-like effectors nuclease (TALEN), short hairpin RNA (shRNA), and a ribozyme. While there are multiple gene therapy strategies being tested, in this review we reflect on our current knowledge of inhibition of CCR5 specifically and whether this approach allows for consequent viral escape.

  19. CCR5 Targeted Cell Therapy for HIV and Prevention of Viral Escape

    PubMed Central

    Hütter, Gero; Bodor, Josef; Ledger, Scott; Boyd, Maureen; Millington, Michelle; Tsie, Marlene; Symonds, Geoff

    2015-01-01

    Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC) to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN), clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9), transcription activator-like effectors nuclease (TALEN), short hairpin RNA (shRNA), and a ribozyme. While there are multiple gene therapy strategies being tested, in this review we reflect on our current knowledge of inhibition of CCR5 specifically and whether this approach allows for consequent viral escape. PMID:26225991

  20. Does antibiotic lock therapy prevent catheter-associated bacteremia in hemodialysis?

    PubMed

    Jiménez, Macarena; Madrid, Trinidad

    2015-01-22

    Central venous catheter-related blood stream infection is a major cause of morbidity and mortality in patients with renal disease treated with hemodialysis. Antibiotic lock solutions can be effective in preventing this complication in patients with hemodialysis. Searching in Epistemonikos database, which is maintained by screening more than twenty databases, we identified eight systematic reviews including seventeen randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded that antibiotic lock solutions probably decrease catheter-related blood stream infection in hemodialysis patients.

  1. Sporadic colorectal cancer: microbial contributors to disease prevention, development and therapy

    PubMed Central

    Drewes, Julia L; Housseau, Franck; Sears, Cynthia L

    2016-01-01

    The gut microbiota has been hailed as an accessory organ, with functions critical to the host including dietary metabolic activities and assistance in the development of a proper functioning immune system. However, an aberrant microbiota (dysbiosis) may influence disease processes such as colorectal cancer. In this review, we discuss recent advances in our understanding of the contributions of the microbiota to prevention, initiation/progression, and treatment of colorectal cancer, with a major focus on biofilms and the antimicrobial and antitumoural immune response. PMID:27380134

  2. Emerging role of dual antiplatelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma.

    PubMed

    Aiolfi, Roberto; Sitia, Giovanni

    2014-01-01

    Platelets, the chief effectors of vascular homeostasis, have been identified as important players in the pathogenesis of both acute and chronic liver disease in preclinical models of hepatitis B viral infection. Platelets are thought to promote the accumulation of virus-specific T-cells into the liver parenchyma. Importantly, the inhibition of platelet activation by clinically relevant doses of aspirin and clopidogrel was able to reduce immune-mediated necroinflammatory liver disease, extracellular matrix deposition, and hepatocellular carcinoma development; the same treatment was able to improve overall survival. These results strongly support the design of clinical trials aiming to define the potential of antiplatelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma.

  3. Decreasing cariogenic bacteria with a natural, alternative prevention therapy utilizing phytochemistry (plant extracts).

    PubMed

    Ramakrishna, Y; Goda, H; Baliga, M S; Munshi, A K

    2011-01-01

    The association between the oral microbiota and oral diseases is well established. Various antimicrobial agents including antibiotics are commercially available against oral pathogenic bacteria. For the reasons of antibiotic resistance, their adverse effects and financial considerations in the developing countries, there is a need for alternate preventive and curative treatment options that are also safe, effective and economical. Traditional medicines have been used since ancient times for the treatment of oral diseases including dental caries, periodontal diseases that affect the majority of the population and can affect a person's overall health. Natural phytochemicals are certain organic components isolated from plants and some of these extracts are considered to be beneficial to health. They serve as antioxidants, enhance immune response, provide protection against oral cancer and other diseases and also repair DNA damage caused by smoking and other toxic exposure, and detoxify carcinogens. The natural products derived from medicinal plants have proven to be an abundant source of biologically active compounds, many of which have been the basis for the development of new lead chemicals for pharmaceuticals. They are considered to be good alternatives to synthetic chemicals. This article presents a review of natural alternatives derived from plants and plant products that can serve as a prevention and treatment option against cariogenic bacteria.

  4. Knowledge of the hormonal peculiarities of essential arterial hypertension may direct therapy and prevent errors.

    PubMed

    Popovici, D; Cristoveanu, A; Stefănescu, A M; Juvină, E

    1980-01-01

    The endocrine system becomes involved in the physiopathologic mechanisms of essential arterial hypertension (EAH) by the interference of hormones with the pressor and depressor substances. A "depressor" pharmacodynamic model with beta-blockers based on the variations of hormone-dependent data offers a series of characteristics for assessing the vasoconstrictive and volemic components, evolution (accelerated for instance) and treatment. Hormone data are also useful for avoiding errors and for increasing the efficiency and control of the therapy. It is not uncommon for EAH to become endocrine-dependent, for instance: increase in aldosterone secretion by activation of the renin-angiotensin (RA) system or of the hypophysis- corticoadrenal system and the adreno-sympathetic system, transforms the relatively "benign" evolution of EAH into an "accelerated" one. The incidence of hyperreactive corticoadrenal (with or without altered steroidogenesis), corticoadrenal hyperplasia or adenoma, is in reality higher than commonly diagnosed.

  5. Mechanisms of termination and prevention of atrial fibrillation by drug therapy.

    PubMed

    Workman, A J; Smith, G L; Rankin, A C

    2011-08-01

    Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na(+) channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca(2+) channel blockers; the "upstream therapies", e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as "atrial-selective" multiple ion channel blockers, gap junction-enhancers, and intracellular Ca(2+)-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms.

  6. Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis

    PubMed Central

    Yoshimatsu, Yasushi; Yamada, Akihiro; Furukawa, Ryuichi; Sono, Koji; Osamura, Aisaku; Nakamura, Kentaro; Aoki, Hiroshi; Tsuda, Yukiko; Hosoe, Nobuo; Takada, Nobuo; Suzuki, Yasuo

    2015-01-01

    AIM: To evaluate the effectiveness of probiotic therapy for suppressing relapse in patients with inactive ulcerative colitis (UC). METHODS: Bio-Three tablets, each containing 2 mg of lactomin (Streptococcus faecalis T-110), 10 mg of Clostridium butyricum TO-A, and 10 mg of Bacillus mesentericus TO-A, were used as probiotic therapy. Sixty outpatients with UC in remission were randomly assigned to receive 9 Bio-Three tablets/day (Bio-Three group) or 9 placebo tablets/day (placebo group) for 12 mo in addition to their ongoing medications. Clinical symptoms were evaluated monthly or on the exacerbation of symptoms or need for additional medication. Fecal samples were collected to analyze bacterial DNA at baseline and 3-mo intervals. Terminal restriction fragment length polymorphism and cluster analyses were done to examine bacterial components of the fecal microflora. RESULTS: Forty-six patients, 23 in each group, completed the study, and 14 were excluded. The relapse rates in the Bio-Three and placebo groups were respectively 0.0% vs 17.4% at 3 mo (P = 0.036), 8.7% vs 26.1% at 6 mo (P = 0.119), and 21.7% vs 34.8% (P = 0.326) at 9 mo. At 12 mo, the remission rate was 69.5% in the Bio-Three group and 56.6% in the placebo group (P = 0.248). On cluster analysis of fecal flora, 7 patients belonged to cluster I, 32 to cluster II, and 7 to cluster III. CONCLUSION: Probiotics may be effective for maintaining clinical remission in patients with quiescent UC, especially those who belong to cluster I on fecal bacterial analysis. PMID:26019464

  7. An update on short-course intermittent and prevention therapies for herpes labialis.

    PubMed

    Gilbert, Stanley; Corey, Lawrence; Cunningham, Anthony; Malkin, Jean-Elie; Stanberry, Lawrence; Whitley, Richard; Spruance, Spotswood

    2007-06-01

    Infection with herpes simplex virus (HSV) has increased in prevalence worldwide over the past two decades, making it a major public health concern. Approximately 90% of recurrent HSV type 1 (HSV-1) infections manifest as non-genital disease, primarily as orofacial lesions known as herpes labialis. Improvements in our understanding of the natural history of herpes labialis support the rationale for early treatment (during the prodrome or erythema stages) with high doses of antiviral agents in order to maximize drug benefit. When evaluating the efficacy of different antiviral and anti-inflammatory agents in clinical trials, episode duration, lesion healing time, reduction in maximum lesion size and the proportion of aborted lesions should be used as the most reliable measures of therapeutic efficacy. There has also been considerable research into the most beneficial treatment for recurrent episodes of herpes labialis in immunocompetent individuals. Data from clinical studies confirm that short-course, high-dose oral antiviral therapy should be offered to patients with recurrent herpes labialis to accelerate healing, reduce pain and most likely increase treatment adherence. Optimal benefits may be obtained when these oral antiviral agents are combined with topical corticosteroids, but more research is needed with this combination. Patients undergoing facial cosmetic procedures (i.e.facial resurfacing) are at risk of HSV reactivation, but further data are required on the actual risk according to the specific procedure. Aciclovir, valaciclovir and famciclovir all provide effective prophylaxis against HSV-1 reactivation following ablative facial resurfacing. However, no definitive recommendations can be made regarding prophylactic therapy for minimally invasive procedures at present.

  8. Preventing Depressive Relapse and Recurrence in Higher Risk Cognitive Therapy Responders: A Randomized Trial of Continuation Phase Cognitive Therapy, Fluoxetine, or Matched Pill Placebo

    PubMed Central

    Jarrett, Robin B.; Minhajuddin, Abu; Gershenfeld, Howard; Friedman, Edward S.; Thase, Michael E.

    2014-01-01

    Context Strategies to improve the course of recurrent major depressive disorder (MDD) have great public health relevance. To reduce the risk of relapse/recurrence after acute phase Cognitive Therapy (CT), a continuation phase model of therapy (C-CT) may improve outcomes. Objectives To test the efficacy of C-CT and fluoxetine (FLX) for relapse prevention in a placebo (PBO) controlled randomized trial and compare the durability of prophylaxis after discontinuation of treatments. Design A sequential, three stage design with: acute phase (all patients received 12 weeks of CT), 8 month experimental phase (responders at higher risk were randomized to C-CT, FLX, or PBO), and 24 months of longitudinal, post-treatment follow-up. Setting Two university-based specialty clinics. Patients 523 adults with recurrent MDD began acute phase CT, of which 241 “higher risk” responders were randomized and 181 subsequently entered the follow-up. Interventions CT responders at higher risk for relapse were randomized to receive 8 months of C-CT (n = 86), FLX (n = 86) or PBO (n = 69). Main Outcome Measures Survival analyses of relapse/recurrence rates, as determined by “blinded” evaluators using DSM-IV criteria and the LIFE interview. Results As predicted, the C-CT or FLX groups were significantly less likely to relapse than the PBO group across 8 months. Relapse/recurrence rates for C-CT and FLX were nearly identical during the 8 months of treatment, although C-CT patients were more likely to accept randomization, stayed in treatment longer, and attended more sessions than those in FLX/PBO. Contrary to prediction, relapse/recurrence rates following the discontinuation of C-CT and FLX did not differ. Conclusions Relapse risk was reduced by both C-CT and FLX in an “enriched” randomization sampling only CT responders. The preventive effects of C-CT were not significantly more ‘durable’ than those of FLX after treatment was stopped, suggesting that some higher risk patients may

  9. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia.

    PubMed

    Perdomini, Morgane; Belbellaa, Brahim; Monassier, Laurent; Reutenauer, Laurence; Messaddeq, Nadia; Cartier, Nathalie; Crystal, Ronald G; Aubourg, Patrick; Puccio, Hélène

    2014-05-01

    Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA. No treatment exists as yet for FRDA cardiomyopathy. A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cre-Fxn(L3/L-) mice) recapitulates most features of FRDA cardiomyopathy, albeit with a more rapid and severe course. Here we show that adeno-associated virus rh10 vector expressing human FXN injected intravenously in these mice fully prevented the onset of cardiac disease. Moreover, later administration of the frataxin-expressing vector, after the onset of heart failure, was able to completely reverse the cardiomyopathy of these mice at the functional, cellular and molecular levels within a few days. Our results demonstrate that cardiomyocytes with severe energy failure and ultrastructure disorganization can be rapidly rescued and remodeled by gene therapy and establish the preclinical proof of concept for the potential of gene therapy in treating FRDA cardiomyopathy.

  10. Development of a biocompatible nanodelivery system for tuberculosis drugs based on isoniazid-Mg/Al layered double hydroxide

    PubMed Central

    Saifullah, Bullo; Arulselvan, Palanisamy; El Zowalaty, Mohamed Ezzat; Fakurazi, Sharida; Webster, Thomas J; Geilich, Benjamin M; Hussein, Mohd Zobir

    2014-01-01

    The primary challenge in finding a treatment for tuberculosis (TB) is patient non-compliance to treatment due to long treatment duration, high dosing frequency, and adverse effects of anti-TB drugs. This study reports on the development of a nanodelivery system that intercalates the anti-TB drug isoniazid into Mg/Al layered double hydroxides (LDHs). Isoniazid was found to be released in a sustained manner from the novel nanodelivery system in humans in simulated phosphate buffer solutions at pH 4.8 and pH 7.4. The nanodelivery formulation was highly biocompatible compared to free isoniazid against human normal lung and 3T3 mouse fibroblast cells. The formulation was active against Mycobacterium tuberculosis and gram-positive bacteria and gram-negative bacteria. Thus results show significant promise for the further study of these nanocomposites for the treatment of TB. PMID:25336952

  11. [Epidural abscess due to a Mycobacterium tuberculosis strain with primary resistance to isoniazid and ethambutol].

    PubMed

    Sener, Alper; Akçalı, Alper; Karatağ, Ozan; Koşar, Sule; Değirmenci, Yıldız; Akman, Tarık

    2012-10-01

    Tuberculosis is primarily characterized by pulmonary involvement, however, one third of the cases exhibit extrapulmonary tuberculosis. In this report, a case of epidural abscess due to Mycobacterium tuberculosis with primary resistance to isoniazid and ethambutol was presented. A 57-year-old male patient was admitted to emergency service with ten days history of weakness in legs, disability of walking and fever. Neurological examination revealed paraplegia of lower extremities, numbness distal to T2 disc level and hyperactivity of deep tendon reflexes indicating transverse myelitis. Laboratory findings were as follows; ESR: 74 mm/hour, CRP: 22 g/L, ALT: 42 IU/L, AST: 45 IU/L and white blood cell count 23.000/mm3 (45% polymorphonuclear leukocyte, 45% lymphocyte, 10% monocyte). Spinal magnetic resonance imaging showed a fusiform abscess localized at anterior epidural space and extending along levels of C5-6 and C6-7. The longitudinal dimension of the abscess was 3 cm. The lesion was hypointense on T1 and hyperintense on T2 weighted MRI images with prominent rim shaped contrast enhancement on contrast-enhanced T1-weighted images. At fourth day of hospitalization the patient underwent neurosurgical management. M.tuberculosis was isolated from the cultures of operation material by Mycobacteria Growth Incubator Tube system (MGIT, BBL; BD, USA) on the 12th day. The isolate was found susceptible to streptomycin and rifampisin, but resistant to isoniazid and ethambutol. The treatment was initiated with rifampicin 600 mg/day, pyrazinamid 2 g/day, ethambutol 1.5 g/day and levofloxacin 500 mg/day. At the end of second month levofloxacin 500 mg/day and rifampisin 600 mg/day combination was sustained and total treatment period was planned as nine months. As far as the national literature was considered, this was the first case of extrapulmonary tuberculosis with primary resistance to isoniazid and ethambutol. PMID:23188583

  12. Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

    PubMed Central

    Subbian, Selvakumar; Tsenova, Liana; O'Brien, Paul; Yang, Guibin; Koo, Mi-Sun; Peixoto, Blas; Fallows, Dorothy; Dartois, Veronique; Muller, George; Kaplan, Gilla

    2011-01-01

    Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment. PMID:21949656

  13. Population pharmacokinetics, optimised design and sample size determination for rifampicin, isoniazid, ethambutol and pyrazinamide in the mouse.

    PubMed

    Chen, Chunli; Ortega, Fatima; Alameda, Laura; Ferrer, Santiago; Simonsson, Ulrika S H

    2016-10-10

    The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug. The RIF, INH, EMB and PZA blood concentrations after single oral and IV doses and multiple-dose oral administrations based on the original designs were used in the PopPK analysis using NONMEM software. The final PopPK models described the data well. Stochastic simulation and estimation were used to optimise the designs. The relative bias and relative imprecision of each pharmacokinetic parameter for each drug were derived and assessed to choose the final designs. The final single-dose IV and oral designs included up to eight samples per mouse with a total of 24 mice required for RIF and EMB and 33 mice for INH and PZA. In the new multiple-dose (zipper) oral designs, the mice were divided into two groups of three per dose, and four samples were taken from each mouse to cover all seven or eight sampling time points. The final number of mice required for the multiple-dose oral designs was 30 for RIF, INH and EMB, 36 for PZA. The number of mice required in the new designs for RIF, INH and EMB was decreased by up to 7-fold and the relative bias and relative imprecision in the parameter estimates were at least similar to those in the original designs. PMID:27473307

  14. Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis.

    PubMed

    Lipton, Allan; Goessl, Carsten

    2011-01-01

    The clinical sequelae from bone metastases, termed skeletal-related events, are among the most frequent and debilitating complications in patients with advanced cancer. Bone metastases are characterized by pathologically increased osteoclast activity, and accumulating evidence indicates that tumor cells interact within the bone to stimulate the RANK-RANK ligand (RANKL) pathway. RANKL is an essential mediator of osteoclast formation, function, and survival. Because of the central role of RANKL in cancer-induced bone destruction, the inhibition of RANKL has the potential to result in the reduction of pathologic bone resorption. Denosumab is a fully human monoclonal antibody specific for RANKL that inhibits the formation, activation, and survival of osteoclasts. This in turn decreases bone resorption and reduces cancer-induced bone destruction. As a result of its unique and specific mechanism of action, denosumab is being investigated for use in patients with advanced malignancies involving bone to prevent the occurrence of skeletal-related events.

  15. [Recommendations for the prevention and therapy of hypertrophic scars and keloids].

    PubMed

    Gauglitz, G G; Kunte, C

    2011-05-01

    Hypertrophic scars and keloids form due to aberrations in the physiologic wound healing cascade characterized by greater and more sustained ECM deposition. Both entities are frequently associated with pain, pruritus and contractures, and are thus significantly affecting the patient's quality of life. Genetic susceptibility, specific anatomic locations, prolonged inflammation and delayed epithelialization significantly contribute to excessive scar formation. However, despite intensive scientific work in this field the complex mechanisms underlying the processes of scarring and wound contraction remain poorly understood and most therapeutic approaches are clinically unsatisfactory. Nevertheless, based on a rising number of clinical studies next to well-known therapeutic concepts including cryotherapy and intralesional triamcinolone, recent techniques extend the spectrum for treating excessive scars. Nonetheless, prevention of pathologic scarring is undoubtedly more effective than to later attempts to treat it. PMID:21468729

  16. The role of sexual behavior in head and neck cancer: implications for prevention and therapy.

    PubMed

    Rettig, Eleni; Kiess, Ana Ponce; Fakhry, Carole

    2015-01-01

    HPV-positive oropharyngeal squamous cell carcinoma (HPV-OSCC) is associated with oral sexual behaviors. The sharp rise in incidence of HPV-OSCC in the USA has been attributed to changes in sexual norms over the past five decades, with lower age at sexual debut and higher numbers of sexual partners per individual. In addition, variations in HPV-OSCC prevalence by race, age cohort and gender may be attributable to differences in oral sexual behaviors among these groups. Oral HPV infection is the putative precursor to HPV-OSCC. Risk factors for oral HPV incidence, prevalence, clearance and persistence are crucial to understanding how, and in whom, oral HPV infection progresses to malignancy. Future investigation should focus on elucidating the natural history of oral HPV infection persistence and malignant transformation, developing effective screening tools and exploring opportunities for prevention such as vaccination and public health education.

  17. Genetic Mutations Associated with Isoniazid Resistance in Mycobacterium tuberculosis: A Systematic Review

    PubMed Central

    Seifert, Marva; Catanzaro, Donald; Catanzaro, Antonino; Rodwell, Timothy C.

    2015-01-01

    Background Tuberculosis (TB) incidence and mortality are declining worldwide; however, poor detection of drug-resistant disease threatens to reverse current progress toward global TB control. Multiple, rapid molecular diagnostic tests have recently been developed to detect genetic mutations in Mycobacterium tuberculosis (Mtb) genes known to confer first-line drug resistance. Their utility, though, depends on the frequency and distribution of the resistance associated mutations in the pathogen population. Mutations associated with rifampicin resistance, one of the two first-line drugs, are well understood and appear to occur in a single gene region in >95% of phenotypically resistant isolates. Mutations associated with isoniazid, the other first-line drug, are more complex and occur in multiple Mtb genes. Objectives/Methodology A systematic review of all published studies from January 2000 through August 2013 was conducted to quantify the frequency of the most common mutations associated with isoniazid resistance, to describe the frequency at which these mutations co-occur, and to identify the regional differences in the distribution of these mutations. Mutation data from 118 publications were extracted and analyzed for 11,411 Mtb isolates from 49 countries. Principal Findings/Conclusions Globally, 64% of all observed phenotypic isoniazid resistance was associated with the katG315 mutation. The second most frequently observed mutation, inhA-15, was reported among 19% of phenotypically resistant isolates. These two mutations, katG315 and inhA-15, combined with ten of the most commonly occurring mutations in the inhA promoter and the ahpC-oxyR intergenic region explain 84% of global phenotypic isoniazid resistance. Regional variation in the frequency of individual mutations may limit the sensitivity of molecular diagnostic tests. Well-designed systematic surveys and whole genome sequencing are needed to identify mutation frequencies in geographic regions where rapid

  18. Contribution of kasA analysis to detection of isoniazid-resistant Mycobacterium tuberculosis in Singapore.

    PubMed

    Lee, A S; Lim, I H; Tang, L L; Telenti, A; Wong, S Y

    1999-08-01

    Genotypic analysis of resistance to isoniazid (INH) in Mycobacterium tuberculosis is complex due to the various genes potentially involved. Mutations in ketoacyl acyl carrier protein synthase (encoded by kasA) were present in 16 of 160 (10%) INH-resistant isolates (R121K [n = 1], G269S [n = 3], G312S [n = 11], G387D [n = 1]). However, G312S was also present in 6 of 32 (19%) susceptible strains. kasA analysis contributed marginally to the performance of INH genotypic testing in Singapore. The significance of kasA polymorphisms in INH resistance should be carefully established. PMID:10428945

  19. The Impact of Directly Observed Therapy on Preventive Treatment for Latent Tuberculosis Infection among Students in Dalian, China.

    PubMed

    Chen, Qi; Wang, Xue Mei; Qi, Yi; Liu, Xiao Fang; Jiang, Li Ping; Hou, Wen; Zhou, Ling; Lu, Xi Wei

    2015-08-01

    Preventive treatment has an essential effect on latent tuberculosis infection (LTBI) [purified protein derivative (PPD) induration ⋝ 15 mm]. Between 2010 and 2013, there were 6 tuberculosis (TB) outbreaks in the universities in Dalian, China. So far, in Dalian, the directly observed therapy (DOT) and full course management (FCM) were widely used in the preventive treatment of LTBI. However, it is yet to be determined which one of them has better efficacy. Therefore, the purpose of our study was to explore the performance of these two strategies for LTBI preventive treatment. The chi-square test and exact test were used to perform statistical analysis. In total, 794 LTBI patients were enrolled in this study, of which 443 were included in the DOT group and 351 in the FCM group. In 287 students who said ditto to take prophylactic treatment (DOT 149 and FCM 79), the compliance rate for the DOT group was 90.3% (149/165), while that for the FCM group was 64.8% (79/122). This difference between the two groups was statistically significant (χ²=28.03, P=1.19E-07). The DOT group showed an effective intervention rate of 81.5%, while that for the FCM group was 28.5%. Again, this difference was significant (χ²=56.17, P=6.63E-14). Further, in 228 students who truly started taking treatment, 26 cases exhibited various adverse reactions (11.4%, 26/228), the most frequent one being elevated liver enzyme levels (6.6%, 15/228). In addition, the major reason for the treatment interruption was adverse reactions in the DOT group, and 6 (28.6%) LTBI patients discontinued treatment due to the adverse reactions of the anti-TB drugs. We also performed a one-year follow-up after the completion of the 3-month treatment. Out of the 794 close contacts, a total of 9 cases (1.1%) developed active TB. These results show that DOT is an effective preventive treatment for LTBI and would play an irreplaceable role in improving preventive treatment adherence and treatment outcomes.

  20. Levothyroxine replacement therapy with vitamin E supplementation prevents oxidative stress and cognitive deficit in experimental hypothyroidism.

    PubMed

    Pan, Tianrong; Zhong, Mingkui; Zhong, Xing; Zhang, Yanqing; Zhu, Defa

    2013-04-01

    Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status.

  1. Model-guided therapy for hepatocellular carcinoma: a role for information technology in predictive, preventive and personalized medicine

    PubMed Central

    2014-01-01

    Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different

  2. Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy

    PubMed Central

    Gnabre, John; Bates, Robert; Huang, Ru Chih

    2015-01-01

    The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies. PMID:26151022

  3. Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance.

    PubMed

    Nichol, Daniel; Jeavons, Peter; Fletcher, Alexander G; Bonomo, Robert A; Maini, Philip K; Paul, Jerome L; Gatenby, Robert A; Anderson, Alexander R A; Scott, Jacob G

    2015-09-01

    The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2-4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically 'steer' the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic-resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy.

  4. Low-level laser therapy for prevention of noise-induced hearing loss in rats.

    PubMed

    Tamura, Atsushi; Matsunobu, Takeshi; Mizutari, Kunio; Niwa, Katsuki; Kurioka, Takaomi; Kawauchi, Satoko; Satoh, Shunichi; Hiroi, Sadayuki; Satoh, Yasushi; Nibuya, Masashi; Tamura, Risa; Shiotani, Akihiro

    2015-05-19

    Noninvasive low-level laser therapy (LLLT) is neuroprotective, but the mechanism of this effect is not fully understood. In this study, the use of LLLT as a novel treatment for noise-induced hearing loss (NIHL) is investigated. Sprague-Dawley rats were exposed to intense noise and their right ears were irradiated with an 808nm diode laser at an output power density of 110 or 165mW/cm(2) for a 30min period for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with LLLT compared with the non-treatment group at days 2, 4, 7 and 14 after noise exposure. Morphological observations also revealed a significantly higher outer hair cell survival rate in the LLLT groups. Immunohistochemical analyses for inducible nitric oxide synthase (iNOS) and cleaved caspase-3 were used to examine oxidative stress and apoptosis. Strong immunoreactivities were observed in the inner ear tissues of the non-treatment group, whereas these signals were decreased in the LLLT group at 165mW/cm(2) power density. Our findings suggest that LLLT has cytoprotective effects against NIHL via the inhibition of iNOS expression and apoptosis.

  5. A Mechanism-Based Approach to Prevention of and Therapy for Fibromyalgia

    PubMed Central

    Vierck, Charles J.

    2012-01-01

    Fibromyalgia syndrome (FMS) is characterized by pain referred to deep tissues. Diagnosis and treatment of FMS are complicated by a variable coexistence with regional pain, fatigue, sleep disruption, difficulty with mentation, and depression. The widespread, deep pain of FMS can be a consequence of chronic psychological stress with autonomic dysregulation. Stress acts centrally to facilitate pain and acts peripherally, via sympathetic vasoconstriction, to establish painful muscular ischemia. FMS pain, with or without a coexistent regional pain condition, is stressful, setting up a vicious circle of reciprocal interaction. Also, stress interacts reciprocally with systems of control over depression, mentation, and sleep, establishing FMS as a multiple-system disorder. Thus, stress and the ischemic pain it generates are fundamental to the multiple disorders of FMS, and a therapeutic procedure that attenuates stress and peripheral vasoconstriction should be highly beneficial for FMS. Physical exercise has been shown to counteract peripheral vasoconstriction and to attenuate stress, depression, and fatigue and improve mentation and sleep quality. Thus, exercise can interrupt the reciprocal interactions between psychological stress and each of the multiple-system disorders of FMS. The large literature supporting these conclusions indicates that exercise should be considered strongly as a first-line approach to FMS therapy. PMID:22110947

  6. Creosote bush lignans for human disease treatment and prevention: Perspectives on combination therapy.

    PubMed

    Gnabre, John; Bates, Robert; Huang, Ru Chih

    2015-07-01

    The medicinal properties of the most successful plant in the deserts of the western hemisphere, the creosote bush (Larrea tridentata), are evidenced by the long traditional usage of the plants by the Native Americans Indian tribes in Southwestern North America and the Amerindians from South America. The plant is rich in simple bisphenyl lignans and tricyclic lignans known as cyclolignans. These compounds are responsible for many of the pharmacological activities of extracts of the plants. Some of these activities, namely antiherpes, antioxidant, antifungal, and anti-inflammatory, were known a century ago. Only recently have further studies revealed other crucial activities of the same plant molecules as powerful agents against human immunodeficiency virus, human papillomavirus, cancer, neurodegenerative diseases, and symptoms of aging. Molecular mechanisms underlying the antiviral and anticancer activities have been elucidated and involve the inhibition of SP1 dependent gene transcription. This review summarizes the recent findings on creosote bush lignans. We introduce the concept of a cocktail of safe well-characterized natural products from the creosote bush that would represent a bridge between oriental herbal medicines and Western drug-based therapies. PMID:26151022

  7. Photodynamic Therapy: Occupational Hazards and Preventative Recommendations for Clinical Administration by Healthcare Providers

    PubMed Central

    Lacey, Steven E.; Vesper, Benjamin J.; Paradise, William A.; Radosevich, James A.; Colvard, Michael D.

    2013-01-01

    Abstract Objective: Photodynamic therapy (PDT) as a medical treatment for cancers is an increasing practice in clinical settings, as new photosensitizing chemicals and light source technologies are developed and applied. PDT involves dosing patients with photosensitizing drugs, and then exposing them to light using a directed energy device in order to manifest a therapeutic effect. Healthcare professionals providing PDT should be aware of potential occupational health and safety hazards posed by these treatment devices and photosensitizing agents administered to patients. Materials and methods: Here we outline and identify pertinent health and safety considerations to be taken by healthcare staff during PDT procedures. Results: Physical hazards (for example, non-ionizing radiation generated by the light-emitting device, with potential for skin and eye exposure) and chemical hazards (including the photosensitizing agents administered to patients that have the potential for exposure via skin, subcutaneous, ingestion, or inhalation routes) must be considered for safe use of PDT by the healthcare professional. Conclusions: Engineering, administrative, and personal protective equipment controls are recommendations for the safe use and handling of PDT agents and light-emitting technologies. PMID:23859750

  8. Targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever

    PubMed Central

    McLay, Lisa; Ansari, Aftab; Liang, Yuying; Ly, Hinh

    2012-01-01

    A number of arenaviruses are pathogenic for humans, but they differ significantly in virulence. Lassa virus, found in West Afri ca, causes severe hemorrhagic fever (HF), while the other principal Old World arenavirus, lymphocytic choriomeningitis virus, causes mild illness in persons with normal immune function, and poses a threat only to immunocompromised individuals. The New World agents, including Junin, Machupo and Sabia virus, are highly pathogenic for humans. Arenaviral HF is characterized by high viremia and general immune suppression, the mechanism of which is unknown. Studies using viral reverse genetics, cell-based assays, animal models and human genome-wide association analysis have revealed potential mechanisms by which arenaviruses cause severe disease in humans. Each of the four viral gene products (GPC, L polymerase, NP, and Z matrix protein) and several host-cell factors (e.g., α-dystroglycan) are responsible for mediating viral entry, genome replication, and the inhibition of apoptosis, translation and interferon-beta (IFNβ) production. This review summarizes current knowledge of the role of each viral protein and host factor in the pathogenesis of arenaviral HF. Insights from recent studies are being exploited for the development of novel therapies. PMID:23261843

  9. Prevention of comorbidity and acute attack of gout by uric acid lowering therapy.

    PubMed

    Joo, Kowoon; Kwon, Seong-Ryul; Lim, Mie-Jin; Jung, Kyong-Hee; Joo, Hoyeon; Park, Won

    2014-05-01

    The object of this study was to evaluate the effect of uric acid lowering therapy in reducing the new development of comorbidities and the frequency of acute attacks in gout patients. We retrospectively reviewed patients who were diagnosed to have gout with at least 3 yr of follow up. They were divided into 2 groups; 53 patients with mean serum uric acid level (sUA)<6 mg/dL and 147 patients with mean sUA≥6 mg/dL. Comorbidities of gout such as hypertension (HTN), type II diabetes mellitus (DM), chronic kidney disease, cardiovascular disease (CVD) and urolithiasis were compared in each group at baseline and at last follow-up visit. Frequency of acute gout attacks were also compared between the groups. During the mean follow up period of 7.6 yr, the yearly rate of acute attack and the new development of HTN, DM, CVD and urolithiasis was lower in the adequately treated group compared to the inadequately treated group. Tight control of uric acid decreases the incidence of acute gout attacks and comorbidities of gout such as HTN, DM, CVD and urolithiasis.

  10. Memantine in the prevention or alleviation of electroconvulsive therapy induces cognitive disorders: A placebo controlled trial.

    PubMed

    Abbasinazari, Mohammad; Adib-Eshgh, Ladan; Rostami, Azin; Beyraghi, Narges; Dabir, Shideh; Jafari, Reyhaneh

    2015-06-01

    The purpose of this study was to evaluate the effect of memantine administration on the adverse cognitive effects of electroconvulsive therapy (ECT). Forty patients diagnosed with a major depressive disorder for which ECT was indicated as a treatment for their current episode were randomly allocated to either the memantine (5mg/day) group or the placebo group. All patients underwent the same protocol for anaesthesia and ECT procedures. The patients received memantine or the placebo for the whole period of ECT treatment, starting the day before ECT and continuing until the fourth session of ECT. The Modified Mental State Examination (MMSE) was used for the assessment of cognition before and after the trial. Regarding MMSE and item 3 MMSE (related to recent memory), the memantine group scored significantly higher at the end of ECT sessions than the control group (P=0.02, P<0.001, respectively). Our data support the hypothesis that memantine may reduce cognitive impairment following ECT. Memantine could be both a safe and well-tolerated treatment for use with ECT.

  11. Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance

    PubMed Central

    Nichol, Daniel; Jeavons, Peter; Fletcher, Alexander G.; Bonomo, Robert A.; Maini, Philip K.; Paul, Jerome L.; Gatenby, Robert A.; Anderson, Alexander R.A.; Scott, Jacob G.

    2015-01-01

    The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2–4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically ‘steer’ the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic–resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy. PMID:26360300

  12. Testosterone Replacement Therapy Prevents Alterations of Coronary Vascular Reactivity Caused by Hormone Deficiency Induced by Castration.

    PubMed

    Rouver, Wender Nascimento; Delgado, Nathalie Tristão Banhos; Menezes, Jussara Bezerra; Santos, Roger Lyrio; Moyses, Margareth Ribeiro

    2015-01-01

    The present study aimed to determine the effects of chronic treatment with different doses of testosterone on endothelium-dependent coronary vascular reactivity in male rats. Adult male rats were divided into four experimental groups: control (SHAM), castrated (CAST), castrated and immediately treated subcutaneously with a physiological dose (0.5 mg/kg/day, PHYSIO group) or supraphysiological dose (2.5 mg/kg/day, SUPRA group) of testosterone for 15 days. Systolic blood pressure (SBP) was assessed at the end of treatment through tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed using the Langendorff retrograde perfusion technique. A dose-response curve for bradykinin (BK) was constructed, followed by inhibition with 100 μM L-NAME, 2.8 μM indomethacin (INDO), L-NAME + INDO, or L-NAME + INDO + 0.75 μM clotrimazole (CLOT). We observed significant endothelium-dependent, BK-induced coronary vasodilation, which was abolished in the castrated group and restored in the PHYSIO and SUPRA groups. Furthermore, castration modulated the lipid and hormonal profiles and decreased body weight, and testosterone therapy restored all of these parameters. Our results revealed an increase in SBP in the SUPRA group. In addition, our data led us to conclude that physiological concentrations of testosterone may play a beneficial role in the cardiovascular system by maintaining an environment that is favourable for the activity of an endothelium-dependent vasodilator without increasing SBP. PMID:26322637

  13. Targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever.

    PubMed

    McLay, Lisa; Ansari, Aftab; Liang, Yuying; Ly, Hinh

    2013-02-01

    A number of arenaviruses are pathogenic for humans, but they differ significantly in virulence. Lassa virus, found in West Africa, causes severe hemorrhagic fever (HF), while the other principal Old World arenavirus, lymphocytic choriomeningitis virus, causes mild illness in persons with normal immune function, and poses a threat only to immunocompromised individuals. The New World agents, including Junin, Machupo and Sabia virus, are highly pathogenic for humans. Arenaviral HF is characterized by high viremia and general immune suppression, the mechanism of which is unknown. Studies using viral reverse genetics, cell-based assays, animal models and human genome-wide association analysis have revealed potential mechanisms by which arenaviruses cause severe disease in humans. Each of the four viral gene products (GPC, L polymerase, NP, and Z matrix protein) and several host-cell factors (e.g., α-dystroglycan) are responsible for mediating viral entry, genome replication, and the inhibition of apoptosis, translation and interferon-beta (IFNβ) production. This review summarizes current knowledge of the role of each viral protein and host factor in the pathogenesis of arenaviral HF. Insights from recent studies are being exploited for the development of novel therapies.

  14. Benefits & risks of statin therapy for primary prevention of cardiovascular disease in Asian Indians - a population with the highest risk of premature coronary artery disease & diabetes.

    PubMed

    Enas, Enas A; Kuruvila, Arun; Khanna, Pravien; Pitchumoni, C S; Mohan, Viswanathan

    2013-10-01

    Several reviews and meta-analyses have demonstrated the incontrovertible benefits of statin therapy in patients with cardiovascular disease (CVD). But the role for statins in primary prevention remained unclear. The updated 2013 Cochrane review has put to rest all lingering doubts about the overwhelming benefits of long-term statin therapy in primary prevention by conclusively demonstrating highly significant reductions in all-cause mortality, major adverse cardiovascular events (MACE) and the need for coronary artery revascularization procedures (CARPs). More importantly, these benefits of statin therapy are similar at all levels of CVD risk, including subjects at low (<1% per year) risk of a MACE. In addition to preventing myocardial infarction (MI), stroke, and death, primary prevention with statins is also highly effective in delaying and avoiding expensive CARPs such as angioplasties, stents, and bypass surgeries. There is no evidence of any serious harm or threat to life caused by statin therapy, though several adverse effects that affect the quality of life, especially diabetes mellitus (DM) have been reported. Asian Indians have the highest risk of premature coronary artery disease (CAD) and diabetes. When compared with Whites, Asian Indians have double the risk of CAD and triple the risk of DM, when adjusted for traditional risk factors for these diseases. Available evidence supports the use of statin therapy for primary prevention in Asian Indians at a younger age and with lower targets for low-density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein (non-HDL-C), than those currently recommended for Americans and Europeans. Early and aggressive statin therapy offers the greatest potential for reducing the continuing epidemic of CAD among Indians.

  15. Neuroglobin Gene Therapy Prevents Optic Atrophy and Preserves Durably Visual Function in Harlequin Mice

    PubMed Central

    Lechauve, Christophe; Augustin, Sébastien; Cwerman-Thibault, Hélène; Reboussin, Élodie; Roussel, Delphine; Lai-Kuen, René; Saubamea, Bruno; Sahel, José-Alain; Debeir, Thomas; Corral-Debrinski, Marisol

    2014-01-01

    Neuroglobin (NGB) is considered as an endogenous neuroprotective molecule against stroke, since the protein alleviates the adverse effects of hypoxic and ischemic insults. We previously demonstrated the functional link between NGB and mitochondria since it is required for respiratory chain function. Thus, here, we evaluated the relevance of this effect in the Harlequin (Hq) mouse strain, which exhibits retinal ganglion cell (RGC) loss and optic atrophy due to a respiratory chain complex I (CI) defect. A twofold decrease of NGB amounts was observed in Hq retinas. We constructed a recombinant adeno-associated virus which combines to the mouse NGB open reading frame, its 5′ and 3′UTR, for guarantying mRNA stability and translation capacity. The vector was administrated intravitreally to Hq mice and NGB expression was stable for up to 7 months without negative effect on retinal architecture or function. On the contrary, RGCs and their axons were substantially preserved from degeneration; consequently, CI activity in optic nerves was protected conferring improvements in vision. Hence, we established that NGB prevents respiratory chain impairment, therefore, protecting visual function otherwise compromised by mitochondrial energetic failure. PMID:24622090

  16. Can colorectal cancer be prevented or treated by oral hormone replacement therapy?

    PubMed Central

    Li, P.; Lin, J.E.; Schulz, S.; Pitari, G.M.; Waldman, S.A.

    2011-01-01

    Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands. PMID:20021465

  17. Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia

    PubMed Central

    Sibai, H.; Seki, J.T.; Wang, T.Q.; Sakurai, N.; Atenafu, E.G.; Yee, K.W.L.; Schuh, A.C.; Gupta, V.; Minden, M.D.; Schimmer, A.D.; Brandwein, J.M.

    2016-01-01

    Background Venous thromboembolism (vte) is a recognized complication in patients treated with asparaginase-containing chemotherapy regimens; the optimal preventive strategy is unclear. We assessed the safety and efficacy of prophylaxis using low-dose low molecular weight heparin in adult patients with acute lymphoblastic leukemia in complete remission treated with an asparaginase-based post-remission chemotherapy regimen. Methods As part of the intensification phase of the Dana-Farber Cancer Institute 91-01 regimen, asparaginase was administered weekly to 41 consecutive patients for 21–30 weeks; these patients also received prophylaxis with enoxaparin 40 mg daily (60 mg for patients ≥80 kg). Outcomes were assessed against outcomes in a comparable cohort of 99 patients who received the same chemotherapy regimen without anticoagulation prophylaxis. Results The overall rate of symptomatic venous thrombosis was not significantly different in the prophylaxis and non-prophylaxis cohorts (18.92% and 21.74% respectively). Among patients receiving prophylaxis, vte occurred in higher proportion in those who weighed at least 80 kg (42.86% vs. 4.35%, p = 0.0070). No major bleeding complications occurred in the prophylaxis group (minor bleeding: 8.1%). Conclusions Prophylaxis with low-dose enoxaparin during the intensification phase was safe, but was not associated with a lower overall proportion of vte. PMID:27536184

  18. Cancer Prevention and Therapy: Integrating Traditional Korean Medicine Into Modern Cancer Care.

    PubMed

    Yoon, Seong Woo; Jeong, Jong Soo; Kim, Ji Hye; Aggarwal, Bharat B

    2014-07-01

    In spite of billions of dollars spent on cancer research each year, overall cancer incidence and cancer survival has not changed significantly in the last half century. Instead, the recent projection from the World Health Organization suggests that global cancer incidence and death is expected to double within the next decade. This requires an "out of the box" thinking approach. While traditional medicine used for thousands of years is safe and affordable, its efficacy and mechanism of action are not fully reported. Demonstrating that traditional medicine is efficacious and how it works can provide a "bed to bench" and "bench to bed" back approach toward prevention and treatment of cancer. This current review is an attempt to describe the contributions of traditional Korean medicine (TKM) to modern medicine and, in particular, cancer treatment. TKM suggests that cancer is an outcome of an imbalance of body, mind, and spirit; thus, it requires a multimodal treatment approach that involves lifestyle modification, herbal prescription, acupuncture, moxibustion, traditional exercise, and meditation to restore the balance. Old wisdoms in combination with modern science can find a new way to deal with the "emperor of all maladies."

  19. Systematic review of occupational therapy and mental health promotion, prevention, and intervention for children and youth.

    PubMed

    Arbesman, Marian; Bazyk, Susan; Nochajski, Susan M

    2013-01-01

    We describe the results of a systematic review of the literature on children's mental health using a public health model consisting of three levels of mental health service: universal, targeted, and intensive. At the universal level, strong evidence exists for the effectiveness of occupation- and activity-based interventions in many areas, including programs that focus on social-emotional learning; schoolwide bullying prevention; and after-school, performing arts, and stress management activities. At the targeted level, strong evidence indicates that social and life skills programs are effective for children who are aggressive, have been rejected, and are teenage mothers. The evidence also is strong that children with intellectual impairments, developmental delays, and learning disabilities benefit from social skills programming and play, leisure, and recreational activities. Additionally, evidence of the effectiveness of social skills programs is strong for children requiring services at the intensive level (e.g., those with autism spectrum disorder, diagnosed mental illness, serious behavior disorders) to improve social behavior and self-management. PMID:24195907

  20. Developing preventive therapies for chronic diseases: lessons learned from Alzheimer's disease.

    PubMed

    Selkoe, Dennis J

    2007-12-01

    A remarkable rise in life expectancy during the past century has made Alzheimer's disease (AD) the most common form of progressive intellectual failure in humans. Patients with AD lose their most human qualities-reasoning, abstraction, language, and memory. The brain plaques that Alois Alzheimer first described 100 years ago have inspired the search for genetic alterations that underlie AD. Four genes have been unequivocally implicated to date in inherited forms of AD, where mutations or natural variations in these genes cause excessive accumulation of the amyloid beta-protein, the building block of amyloid plaques. This aggregation leads to subsequent neuronal degeneration in brain regions important for memory and cognition. The discovery of the genes involved in the mechanisms of amyloid beta-protein build-up in AD, coupled with cell culture and animal models of their involved pathways, has led to the development of specific pharmacological strategies to lower amyloid beta-protein levels as a way of treating or preventing all forms of the disease. While hard work lies ahead, the movement from basic research to the clinic in AD represents a triumph of reductionist biology applied to the most complex of all biological systems, the human cerebral cortex.

  1. Neuroglobin gene therapy prevents optic atrophy and preserves durably visual function in Harlequin mice.

    PubMed

    Lechauve, Christophe; Augustin, Sébastien; Cwerman-Thibault, Hélène; Reboussin, Élodie; Roussel, Delphine; Lai-Kuen, René; Saubamea, Bruno; Sahel, José-Alain; Debeir, Thomas; Corral-Debrinski, Marisol

    2014-06-01

    Neuroglobin (NGB) is considered as an endogenous neuroprotective molecule against stroke, since the protein alleviates the adverse effects of hypoxic and ischemic insults. We previously demonstrated the functional link between NGB and mitochondria since it is required for respiratory chain function. Thus, here, we evaluated the relevance of this effect in the Harlequin (Hq) mouse strain, which exhibits retinal ganglion cell (RGC) loss and optic atrophy due to a respiratory chain complex I (CI) defect. A twofold decrease of NGB amounts was observed in Hq retinas. We constructed a recombinant adeno-associated virus which combines to the mouse NGB open reading frame, its 5' and 3'UTR, for guarantying mRNA stability and translation capacity. The vector was administrated intravitreally to Hq mice and NGB expression was stable for up to 7 months without negative effect on retinal architecture or function. On the contrary, RGCs and their axons were substantially preserved from degeneration; consequently, CI activity in optic nerves was protected conferring improvements in vision. Hence, we established that NGB prevents respiratory chain impairment, therefore, protecting visual function otherwise compromised by mitochondrial energetic failure. PMID:24622090

  2. Beta-blocker therapy after myocardial infarction: secondary prevention in all patients?

    PubMed

    Griggs, T; Adams, K; Narvarte, H; Sheps, D

    1985-01-01

    The ability of beta-adrenergic blocking drugs to prevent death in patients after myocardial infarction has been demonstrated by several large trials. However, the need to treat patients at low risk has been challenged. Retrospective analysis of the data from one of these studies plus results from many additional studies have shown that electrical, mechanical and ischemic complications after myocardial infarction imply a high risk of subsequent death or recurrent infarction. On the other hand, absence of complications with a negative exercise tolerance test, good exercise tolerance, absence of arrhythmias and normal increase of ejection fraction with exercise documents a very low risk. These considerations lead to the following practical implications: The physician should watch for any evidence of left ventricular dysfunction or arrhythmia. Any such complication justifies treatment or more intensive study. Patients without complications can be further characterized with exercise testing, exercise radionuclide blood pool ventriculography, and Holter monitoring. If these tests expose risk indicators, treatment or more study should again be recommended. Because the beta-blockers are probably life-saving in a considerable portion of the patients with moderate and high risk, the decision to treat or not to treat should be made with due, affirmative consideration. In those patients with a carefully documented uncomplicated course and who have a normal exercise test and appropriate increase in ventricular ejection fraction with stress, beta-blockade is probably of no benefit. Under these conditions, a physician and patient might logically decide not to use the drug.

  3. Resistance Training for Diabetes Prevention and Therapy: Experimental Findings and Molecular Mechanisms

    PubMed Central

    2013-01-01

    Type 2 diabetes mellitus (T2D) is characterized by insulin resistance, impaired glycogen synthesis, lipid accumulation, and impaired mitochondrial function. Exercise training has received increasing recognition as a cornerstone in the prevention and treatment of T2D. Emerging research suggests that resistance training (RT) has the power to combat metabolic dysfunction in patients with T2D and seems to be an effective measure to improve overall metabolic health and reduce metabolic risk factors in diabetic patients. However, there is limited mechanistic insight into how these adaptations occur. This review provides an overview of the intervention data on the impact of RT on glucose metabolism. In addition, the molecular mechanisms that lead to adaptation in skeletal muscle in response to RT and that are associated with possible beneficial metabolic responses are discussed. Some of the beneficial adaptations exerted by RT include increased GLUT4 translocation in skeletal muscle, increased insulin sensitivity and hence restored metabolic flexibility. Increased energy expenditure and excess postexercise oxygen consumption in response to RT may be other beneficial effects. RT is increasingly establishing itself as an effective measure to improve overall metabolic health and reduce metabolic risk factors in diabetic patients. PMID:24455726

  4. Ketorolac therapy for the prevention of acute pseudophakic cystoid macular edema: a systematic review

    PubMed Central

    Yilmaz, T; Cordero-Coma, M; Gallagher, M J

    2012-01-01

    To assess the effectiveness of ketorolac vs control for prevention of acute pseudophakic cystoid macular edema (CME). The following databases were searched: Medline (1950–June 11, 2011), The Cochrane Library (Issue 2, 2011), and the TRIP Database (up to 11 June 2011), using no language or other limits. Randomized controlled clinical trials (RCTs) were included that consisted of patients with acute pseudophakic cystoid macular edema, those comparing ketorolac with control, and those having at least a minimum follow-up of 28 days. In the four RCTs evaluating ketorolac vs control, treatment with ketorolac significantly reduced the risk of CME development at the end of treatment (∼4 weeks) compared to control (P=0.008; 95% confidence interval (0.03–0.58)). When analyzed individually, each individual study was statistically nonsignificant in its findings with the exception of one study. When the pooled relative risk was calculated, the large sample size of this systematic review led to overall statistical significance, which is attributable to the review's large sample size and not to the individual studies themselves. In this systematic review of four RCTs, two of which compared ketorolac with no treatment and two of which evaluated ketorolac vs placebo drops, treatment with ketorolac significantly reduced the risk of developing CME at the end of ∼4 weeks of treatment compared with controls. These results, however, should be interpreted with caution considering the paucity of large randomized clinical trials in the literature. PMID:22094296

  5. Interferon-alpha gene therapy prevents aflatoxin and carbon tetrachloride promoted hepatic carcinogenesis in rats.

    PubMed

    Aziz, Talaat Abdel; Aziz, Mohammed Abdel; Fouad, Hanan Hassan; Rashed, Laila Ahmed; Salama, Hosny; Abd-Alla, Samira; Wehab, Mosaad Attia Abdel; Ahmed, Tauseef

    2005-01-01

    Retrovirus-mediated interferon alpha (IFN-alpha) gene transfer was evaluated with regard to its possible protective effects against aflatoxin B1 (AFB1)-initiated and carbon tetrachloride (CCl4)-promoted hepatic carcinogenesis in rats. To our knowledge, this is the first time an experimental in vivo gene therapy trial was conducted in Egypt. Two genes were examined in liver tissue by RT-PCR: the first was glutathione-S-transferase placental (GST-P) isoenzyme, as an early marker to detect hepatic malignancy; the second was IFN-alpha gene expression to detect the efficiency of gene uptake and its persistence after transduction. Forty male rats, divided equally into 4 groups, were included in the study: the first group was the control; the second group received CCl4 0.2 ml subcutaneously twice weekly for 12 weeks and AFB1 0.25 mg/kg body wt intraperitoneally twice weekly for 6 weeks; the third group received IFN-alpha (10(8) pfu) intravenously in the tail vein prior to the start of CCl4 and AFB1 injections; and the fourth group received IFN-alpha (10(8) pfu) by intrahepatic injection under ultrasonography guide after termination of the CCl4 and AFB1 injection schedule. The results showed that IFN-alpha has a marked and significant protective effect against hepatic fibrogenesis as well as hepatic carcinogenesis. Pathological examination of liver tissue proved that IFN-alpha minimized both fibrotic and cirrhotic processes. The amount of fibrosis was less in both groups receiving IFN-alpha, with more protection in the group that received IFN-alpha intravenously prior to CCl4 and AFB1. The results of RT-PCR showed that the IFN-alpha gene was significantly expressed in both groups receiving IFN-alpha, with a more intense expression in the group that received IFN-alpha by intrahepatic injection after termination of CCl4 and AFB1 injections. The IFN-alpha gene was detected after three months of gene transduction in rats receiving IFN-alpha intravenously prior to CCl4 and AFB1

  6. Mechanisms of termination and prevention of atrial fibrillation by drug therapy

    PubMed Central

    Workman, AJ; Smith, GL; Rankin, AC

    2011-01-01

    Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na+ channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca2+ channel blockers; the “upstream therapies”, e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as “atrial-selective” multiple ion channel blockers, gap junction-enhancers, and intracellular Ca2+-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms. PMID:21334377

  7. Statin Therapy for the Prevention of Atrial Fibrillation Trial (SToP AF trial)

    PubMed Central

    Negi, Smita; Shukrullah, Irfan; Veledar, Emir; Bloom, Heather L.; Jones, Dean P.; Dudley, Samuel C.

    2010-01-01

    Background Inflammation and oxidative stress are associated with atrial fibrillation (AF). Statins have antioxidant and anti-inflammatory properties. We tested if atorvastatin reduced AF recurrence after DC cardioversion (CV) by modifying systemic oxidative stress and inflammation. (NCT00252967) Methods and Results In a randomized, double-blinded, placebo-controlled trial, patients with atrial fibrillation/flutter (AF) were randomized to receive either atorvastatin 80 mg (n=33) or placebo (n=31) before CV. Treatment was continued for 12 months or until AF recurred. Serum oxidative stress markers (ratios of oxidized to reduced glutathione and cysteine, derivatives of reactive oxygen species, isoprostanes) and inflammatory markers [ high sensitivity C- reactive protein (hs-CRP), interleukin-6 (IL-6), interleukin-1β(IL-1β), tumor necrosis factor-α (TNFα)] were measured at baseline and on follow-up. AF recurred in 22 (66.7%) of atorvastatin and 26 (83.9%) of placebo group (p=0.2). The adjusted hazard ratio of having recurrence on atorvastatin versus on placebo was 0.99 (95% CI: 0.98-1.01, p=0.3). There was no significant difference in the time to recurrence using Kaplan-Meier survival estimates (median (IR): 29 (2-145) days vs. 22 (7-70) days, p=0.9). While no significant effect was seen on oxidative stress, 2 of 4 inflammatory markers, IL-6 (adjusted OR: 0.59, 95% CI: 0.35-0.97, p= 0.04) and hs-CRP (adjusted OR: 0.59, 95% CI: 0.37-0.95, p=0.03) were significantly lowered with atorvastatin. Cholesterol levels significantly decreased with atorvastatin (p=0.03). Conclusions High dose atorvastatin did not reduce the recurrence of AF after CV. It reduced selective markers of inflammation without affecting systemic oxidative stress. Failure of atorvastatin to prevent AF recurrence may be due to its failure to affect oxidative stress. PMID:20946227

  8. Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons.

    PubMed

    Rocha, Emily M; Smith, Gaynor A; Park, Eric; Cao, Hongmei; Brown, Eilish; Hayes, Melissa A; Beagan, Jonathan; McLean, Jesse R; Izen, Sarah C; Perez-Torres, Eduardo; Hallett, Penelope J; Isacson, Ole

    2015-10-01

    Diminished lysosomal function can lead to abnormal cellular accumulation of specific proteins, including α-synuclein, contributing to disease pathogenesis of vulnerable neurons in Parkinson's disease (PD) and related α-synucleinopathies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and mutations in GBA1 are a prominent genetic risk factor for PD. Previous studies showed that in sporadic PD, and in normal aging, GCase brain activity is reduced and levels of corresponding glycolipid substrates are increased. The present study tested whether increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would reduce the accumulation of α-synuclein and protect midbrain dopamine neurons from α-synuclein-mediated neuronal damage. In the first model, transgenic mice overexpressing wildtype α-synuclein throughout the brain (ASO mice) were used, and in the second model, a rat model of selective dopamine neuron degeneration was induced by AAV-A53T mutant α-synuclein. In ASO mice, intra-cerebral AAV-GBA1 injections into several brain regions increased GCase activity and reduced the accumulation of α-synuclein in the substantia nigra and striatum. In rats, co-injection of AAV-GBA1 with AAV-A53T α-synuclein into the substantia nigra prevented α-synuclein-mediated degeneration of nigrostriatal dopamine neurons by 6 months. These neuroprotective effects were associated with altered protein expression of markers of autophagy. These experiments demonstrate, for the first time, the neuroprotective effects of increasing GCase against dopaminergic neuron degeneration, and support the development of therapeutics targeting GCase or other lysosomal genes to improve neuronal handling of α-synuclein.

  9. Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA

    PubMed Central

    Kumar, Vivek; Sobhia, M. Elizabeth

    2015-01-01

    Examination of InhA mutants I16T, I21V, I47T, S94A, and I95P showed that direct and water mediated H-bond interactions between NADH and binding site residues reduced drastically. It allowed conformational flexibility to NADH, particularly at the pyrophosphate region, leading to weakening of its binding at dinucleotide binding site. The highly scattered distribution of pyrophosphate dihedral angles and chi1 side chain dihedral angles of corresponding active site residues therein confirmed weak bonding between InhA and NADH. The average direct and water mediated bridged H-bond interactions between NADH and mutants were observed weaker as compared to wild type. Further, estimated NADH binding free energy in mutants supported the observed weakening of InhA-NADH interactions. Similarly, per residue contribution to NADH binding was also found little less as compared to corresponding residues in wild type. This investigation clearly depicted and supported the effect of mutations on NADH binding and can be accounted for isoniazid resistance as suggested by previous biochemical and mutagenic studies. Further, structural analysis of InhA provided the crucial points to enhance the NADH binding affinity towards InhA mutants in the presence of direct InhA inhibitors to combat isoniazid drug resistance. This combination could be a potential alternative for treatment of drug resistant tuberculosis. PMID:26658674

  10. Preparation and characterization of magnetic Fe3O4-chitosan nanoparticles loaded with isoniazid

    NASA Astrophysics Data System (ADS)

    Qin, H.; Wang, C. M.; Dong, Q. Q.; Zhang, L.; Zhang, X.; Ma, Z. Y.; Han, Q. R.

    2015-05-01

    A novel and simple method has been proposed to prepare magnetic Fe3O4-chitosan nanoparticles loaded with isoniazid (Fe3O4/CS/INH nanocomposites). Efforts have been made to develop isoniazid (INH) loaded chitosan (CS) nanoparticles by ionic gelation of chitosan with tripolyphosphate (TPP). The factors that influence the preparation of chitosan nanoparticles, including the TPP concentration, the chitosan/TPP weight ratio and the chitosan concentration on loading capacity and encapsulation efficiency of chitosan nanoparticles were studied. The magnetic Fe3O4 nanoparticles were prepared by co-precipitation method of Fe2+ and Fe3+. Then the magnetic Fe3O4/CS/INH nanocomposites were prepared by ionic gelation method. The magnetic Fe3O4 nanoparticles and magnetic Fe3O4/CS/INH nanocomposites were characterized by XRD, TEM, FTIR and SQUID magnetometry. The in vitro release of Fe3O4/CS/INH nanocomposites showed an initial burst release in the first 10 h, followed by a more gradual and sustained release for 48 h. It is suggested that the magnetic Fe3O4/CS/INH nanocomposites may be exploited as potential drug carriers for controlled-release applications in magnetic targeted drugs delivery system.

  11. Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA.

    PubMed

    Kumar, Vivek; Sobhia, M Elizabeth

    2015-01-01

    Examination of InhA mutants I16T, I21V, I47T, S94A, and I95P showed that direct and water mediated H-bond interactions between NADH and binding site residues reduced drastically. It allowed conformational flexibility to NADH, particularly at the pyrophosphate region, leading to weakening of its binding at dinucleotide binding site. The highly scattered distribution of pyrophosphate dihedral angles and chi1 side chain dihedral angles of corresponding active site residues therein confirmed weak bonding between InhA and NADH. The average direct and water mediated bridged H-bond interactions between NADH and mutants were observed weaker as compared to wild type. Further, estimated NADH binding free energy in mutants supported the observed weakening of InhA-NADH interactions. Similarly, per residue contribution to NADH binding was also found little less as compared to corresponding residues in wild type. This investigation clearly depicted and supported the effect of mutations on NADH binding and can be accounted for isoniazid resistance as suggested by previous biochemical and mutagenic studies. Further, structural analysis of InhA provided the crucial points to enhance the NADH binding affinity towards InhA mutants in the presence of direct InhA inhibitors to combat isoniazid drug resistance. This combination could be a potential alternative for treatment of drug resistant tuberculosis. PMID:26658674

  12. pH-Responsive Isoniazid-Loaded Nanoparticles Markedly Improve Tuberculosis Treatment in Mice.

    PubMed

    Hwang, Angela A; Lee, Bai-Yu; Clemens, Daniel L; Dillon, Barbara Jane; Zink, Jeffrey I; Horwitz, Marcus A

    2015-10-01

    Tuberculosis is a major global health problem for which improved therapeutics are needed to shorten the course of treatment and combat emergence of drug resistance. Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of mononuclear phagocytes. As such, it is an ideal pathogen for nanotherapeutics because macrophages avidly ingest nanoparticles even without specific targeting molecules. Hence, a nanoparticle drug delivery system has the potential to target and deliver high concentrations of drug directly into M. tuberculosis-infected cells-greatly enhancing efficacy while avoiding off-target toxicities. Stimulus-responsive mesoporous silica nanoparticles of two different sizes, 100 and 50 nm, are developed as carriers for the major anti-tuberculosis drug isoniazid in a prodrug configuration. The drug is captured by the aldehyde-functionalized nanoparticle via hydrazone bond formation and coated with poly(ethylene imine)-poly(ethylene glycol) (PEI-PEG). The drug is released from the nanoparticles in response to acidic pH at levels that naturally occur within acidified endolysosomes. It is demonstrated that isoniazid-loaded PEI-PEG-coated nanoparticles are avidly ingested by M. tuberculosis-infected human macrophages and kill the intracellular bacteria in a dose-dependent manner. It is further demonstrated in a mouse model of pulmonary tuberculosis that the nanoparticles are well tolerated and much more efficacious than an equivalent amount of free drug.

  13. Treatment-Specific Changes in Decentering Following Mindfulness-Based Cognitive Therapy versus Antidepressant Medication or Placebo for Prevention of Depressive Relapse

    ERIC Educational Resources Information Center

    Bieling, Peter J.; Hawley, Lance L.; Bloch, Richard T.; Corcoran, Kathleen M.; Levitan, Robert D.; Young, L. Trevor; MacQueen, Glenda M.; Segal, Zindel V.

    2012-01-01

    Objective: To examine whether metacognitive psychological skills, acquired in mindfulness-based cognitive therapy (MBCT), are also present in patients receiving medication treatments for prevention of depressive relapse and whether these skills mediate MBCT's effectiveness. Method: This study, embedded within a randomized efficacy trial of MBCT,…

  14. Guidelines of Care for the Management of Atopic Dermatitis Part 4: Prevention of Disease Flares and Use of Adjunctive Therapies and Approaches

    PubMed Central

    Sidbury, Robert; Tom, Wynnis L.; Bergman, James N.; Cooper, Kevin D.; Silverman, Robert A.; Berger, Timothy G.; Chamlin, Sarah L.; Cohen, David E.; Cordoro, Kelly M.; Davis, Dawn M.; Feldman, Steven R.; Hanifin, Jon M.; Krol, Alfons; Margolis, David J.; Paller, Amy S.; Schwarzenberger, Kathryn; Simpson, Eric L.; Williams, Hywel C.; Elmets, Craig A.; Block, Julie; Harrod, Christopher G.; Begolka, Wendy Smith; Eichenfield, Lawrence F.

    2015-01-01

    Atopic dermatitis (AD) is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on utilization are given based on available evidence. PMID:25264237

  15. Unified theory of Alzheimer's disease (UTAD): implications for prevention and curative therapy.

    PubMed

    Nehls, Michael

    2016-01-01

    The aim of this review is to propose a Unified Theory of Alzheimer's disease (UTAD) that integrates all key behavioural, genetic and environmental risk factors in a causal chain of etiological and pathogenetic events. It is based on three concepts that emanate from human's evolutionary history: (1) The grandmother-hypothesis (GMH), which explains human longevity due to an evolutionary advantage in reproduction by trans-generational transfer of acquired knowledge. Consequently it is argued that mental health at old-age must be the default pathway of humans' genetic program and not development of AD. (2) Therefore, mechanism like neuronal rejuvenation (NRJ) and adult hippocampal neurogenesis (AHN) that still function efficiently even at old age provide the required lifelong ability to memorize personal experiences important for survival. Cumulative evidence from a multitude of experimental and epidemiological studies indicate that behavioural and environmental risk factors, which impair productive AHN, result in reduced episodic memory performance and in reduced psychological resilience. This leads to avoidance of novelty, dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and cortisol hypersecretion, which drives key pathogenic mechanisms of AD like the accumulation and oligomerization of synaptotoxic amyloid beta, chronic neuroinflammation and neuronal insulin resistance. (3) By applying to AHN the law of the minimum (LOM), which defines the basic requirements of biological growth processes, the UTAD explains why and how different lifestyle deficiencies initiate the AD process by impairing AHN and causing dysregulation of the HPA-axis, and how environmental and genetic risk factors such as toxins or ApoE4, respectively, turn into disease accelerators under these unnatural conditions. Consequently, the UTAD provides a rational strategy for the prevention of mental decline and a system-biological approach for the causal treatment of AD, which might even

  16. Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy.

    PubMed

    Trump, Donald L; Deeb, Kristin K; Johnson, Candace S

    2010-01-01

    Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression, and therapy for cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity, and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps, the most robust of these epidemiologic studies is that of Giovannucci et al, who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among >40,000 individuals in the Health Professionals Study, an increase in 25(OH) cholecalciferol level of 62.5 ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers, and acute leukemia by >50%. Unfortunately, very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells, as well as vascular endothelial cells derived from tumors, to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large

  17. Vitamin D: Considerations in the Continued Development as an Agent for Cancer Prevention and Therapy

    PubMed Central

    Trump, Donald L.; Deeb, Kristen; Johnson, Candace S.

    2010-01-01

    Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression and therapy of cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps the most robust of these epidemiologic studies is that of Giovannucci and colleagues who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among more than 40,000 individuals in the Health professionals Study an increase in 25(OH) cholecalciferol level of 62.5ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers and acute leukemia by >50%. Unfortunately very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells – as well as vascular endothelial cells derived from tumors - to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to

  18. Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy.

    PubMed

    Trump, Donald L; Deeb, Kristin K; Johnson, Candace S

    2010-01-01

    Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression, and therapy for cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity, and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps, the most robust of these epidemiologic studies is that of Giovannucci et al, who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among >40,000 individuals in the Health Professionals Study, an increase in 25(OH) cholecalciferol level of 62.5 ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers, and acute leukemia by >50%. Unfortunately, very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells, as well as vascular endothelial cells derived from tumors, to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large

  19. Impact of Maintenance Therapy for the Prevention of Peri-implant Diseases: A Systematic Review and Meta-analysis.

    PubMed

    Monje, A; Aranda, L; Diaz, K T; Alarcón, M A; Bagramian, R A; Wang, H L; Catena, A

    2016-04-01

    At the present time, peri-implantitis has become a global burden that occurs with a frequency from 1% to 47% at implant level. Therefore, we aimed herein at assessing the impact of peri-implant maintenance therapy (PIMT) on the prevention of peri-implant diseases. Electronic and manual literature searches were conducted by 3 independent reviewers using several databases, including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register, for articles up to June 2015 without language restriction. Articles were included if they were clinical trials aimed at demonstrating the incidence of peri-implant diseases under a strict regime or not of PIMT. Implant survival and failure rate were studied as secondary outcomes. A meta-analysis was conducted to evaluate the influence of PIMT and other reported variables upon peri-implant diseases. Thirteen and 10 clinical trials were included in the qualitative and quantitative analysis, respectively. Mucositis was affected by history of periodontitis and mean PIMT at implant and patient levels, respectively. Similarly, significant effects of history of periodontal disease were obtained for peri-implantitis for both implant and patient levels. Furthermore, mean PIMT interval was demonstrated to influence the incidence of peri-implantitis at implant but not patient level. PIMT interval showed significance at both levels. For implant survival, implants under PIMT have 0.958 the incident event than those with no PIMT. Within the limitations of the present systematic review, it can be concluded that implant therapy must not be limited to the placement and restoration of dental implants but to the implementation of PIMT to potentially prevent biologic complications and hence to heighten the long-term success rate. Although it must be tailored to a patient's risk profiling, our findings suggest reason to claim a minimum recall PIMT interval of 5 to 6 mo. Additionally, it must be

  20. Impact of Maintenance Therapy for the Prevention of Peri-implant Diseases: A Systematic Review and Meta-analysis.

    PubMed

    Monje, A; Aranda, L; Diaz, K T; Alarcón, M A; Bagramian, R A; Wang, H L; Catena, A

    2016-04-01

    At the present time, peri-implantitis has become a global burden that occurs with a frequency from 1% to 47% at implant level. Therefore, we aimed herein at assessing the impact of peri-implant maintenance therapy (PIMT) on the prevention of peri-implant diseases. Electronic and manual literature searches were conducted by 3 independent reviewers using several databases, including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register, for articles up to June 2015 without language restriction. Articles were included if they were clinical trials aimed at demonstrating the incidence of peri-implant diseases under a strict regime or not of PIMT. Implant survival and failure rate were studied as secondary outcomes. A meta-analysis was conducted to evaluate the influence of PIMT and other reported variables upon peri-implant diseases. Thirteen and 10 clinical trials were included in the qualitative and quantitative analysis, respectively. Mucositis was affected by history of periodontitis and mean PIMT at implant and patient levels, respectively. Similarly, significant effects of history of periodontal disease were obtained for peri-implantitis for both implant and patient levels. Furthermore, mean PIMT interval was demonstrated to influence the incidence of peri-implantitis at implant but not patient level. PIMT interval showed significance at both levels. For implant survival, implants under PIMT have 0.958 the incident event than those with no PIMT. Within the limitations of the present systematic review, it can be concluded that implant therapy must not be limited to the placement and restoration of dental implants but to the implementation of PIMT to potentially prevent biologic complications and hence to heighten the long-term success rate. Although it must be tailored to a patient's risk profiling, our findings suggest reason to claim a minimum recall PIMT interval of 5 to 6 mo. Additionally, it must be

  1. Mindfulness-based cognitive therapy is effective as relapse prevention for patients with recurrent depression in Scandinavian primary health care.

    PubMed

    Lilja, Josefine L; Zelleroth, Clara; Axberg, Ulf; Norlander, Torsten

    2016-10-01

    This study examined the effectiveness of mindfulness-based cognitive therapy (MBCT) in primary care for patients with recurrent depression (major depressive disorder: MDD). According to the World Health Organization (WHO), MDD is now the leading cause of disease burden in middle- and high-income countries. Patients (N = 45) with three or more previous depressive episodes were recruited to participate in MBCT as a preventative intervention. Using a benchmarking approach, outcome data was compared with data from a recent efficacy study. The methodology is a rigorous approach to assessing effectiveness when evidence-based UK protocols are transferred into the existing Scandinavian service delivery. Additionally, a person-centred methodological approach was used to assess clinical significance on the Reliable Change Index (RCI). The analysis revealed comparable or larger effects from pre-test to post-test in reduced psychiatric symptoms, increased quality of life and level of mindfulness, and the effects were maintained over 14 months. Analysis of the relapse rate in the current study (16%) compared to the TAU in the efficacy study (68%) yielded an h value of 0.78, a moderate effect size. Only 13% dropped out of the treatment. According to the RCI findings, 65% to 67% of participants in the clinical group improved, no individual worsened, and women showed a significantly greater improvement of depression and anxiety than men. Therapeutic alliance and motivation had no impact on the outcome. The overall result suggests that MBCT can be implemented successfully in Scandinavian primary health care as a preventive intervention for patients with recurrent depression. PMID:27358165

  2. Natural forms of vitamin E: metabolism, antioxidant and anti-inflammatory activities and the role in disease prevention and therapy

    PubMed Central

    Jiang, Qing

    2014-01-01

    The Vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol (αT) is the predominant form of vitamin E in tissues and its deficiency leads to ataxia in humans. However, results from many clinical studies do not support protective roles of αT in disease prevention in people with adequate nutrient status. On the other hand, recent mechanistic studies indicate that other forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT) and γ-tocotrienol (γTE) have unique antioxidant and anti-inflammatory properties that are superior to αT in prevention and therapy against chronic diseases. These vitamin E forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress pro-inflammatory signaling such as NF-κB and STAT3/6. Unlike αT, other vitamin E forms are significantly metabolized to carboxychromanols via cytochrome P-450 (CYP4F2)-initiated side-chain ω-oxidation. Long-chain carboxychromanols, esp.13’-carboxychromanols, are shown to have stronger anti-inflammatory effects than un-metabolized vitamins and may therefore contribute to beneficial effects of vitamin E forms in vivo. Consistent with mechanistic findings, animal and human studies show that γT and tocotrienols may be useful against inflammation-associated diseases. This review focuses on non-αT forms of vitamin E with respect to their metabolism, anti-inflammatory effects and mechanisms and in vivo efficacy in preclinical models as well as human clinical intervention studies. PMID:24704972

  3. MicroRNA-122 is involved in oxidative stress in isoniazid-induced liver injury in mice.

    PubMed

    Song, L; Zhang, Z R; Zhang, J L; Zhu, X B; He, L; Shi, Z; Gao, L; Li, Y; Hu, B; Feng, F M

    2015-10-27

    Many studies have shown that the pathogenesis of liver injury includes oxidative stress. MicroRNA-122 may be a marker for the early diagnosis of drug-induced liver injury. However, the relationship between microRNA-122 and oxidative stress in anti-tuberculosis drug-induced liver injury remains unknown. We measured changes in tissue microRNA-122 levels and indices of oxidative stress during liver injury in mice after administration of isoniazid, a first-line anti-tuberculosis drug. We quantified microRNA-122 expression and indices of oxidative stress at 7 time points, including 1, 3, and 5 days and 1, 2, 3, and 4 weeks. The tissue microRNA-122 levels and oxidative stress significantly changed at 3 and 5 days, suggesting that isoniazid-induced liver injury reduces oxidative stress and microRNA-122 expression compared to in the control group (P < 0.05). Notably, over the time course of isoniazid-induced liver injury, mitochondrial ribosome protein S11 gene, the target of microRNA-122, began to change at 5 days (P < 0.05). The tissue microRNA-122 profile may affect oxidative stress by regulating mitochondrial ribosome protein S11 gene during isoniazid-induced liver injury, which may contribute to the response mechanisms of microRNA-122 and oxidative stress.

  4. Lupus érythémateux systémique induit par l'isoniazide: une complication rare à craindre

    PubMed Central

    Jguirim, Mahbouba; Jbeli, Amna; Brahim, Hajer Ben; Mhenni, Amira; Youssef, Monia; Touzi, Mongi; Zrour, Sawssen; Bejia, Ismail; Bergaoui, Naceur

    2015-01-01

    Le lupus induit est défini comme un syndrome lupique généralement cutanéo-articulaire secondaire à une exposition continue à un traitement et qui disparaît après arrêt de celle-ci. Nous rapportons deux cas de lupus induit par l'isoniazide. Il s'agissait de deux femmes âgées respectivement de 30 et 35 ans. Elles présentaient un lupus induit par l'isoniazide après un et deux mois de traitement d'une tuberculose ganglionnaire. La maladie s'est manifestée par des signes articulaires, une éruption cutanée, une leucopénie et une anémie. Les anticorps antinucléaires et les anticorps antihistone étaient présents dans le sérum des deux malades. L’évolution était favorable après arrêt de l'isoniazide et une corticothérapie per os. Les médicaments antituberculeux notamment l'isoniazide sont responsables d'effets indésirables fréquents. Le lupus induit doit être évoqué lorsqu'un patient présente un tableau clinico-biologique évocateur. PMID:26430478

  5. The pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in Asian elephants (Elephas maximus).

    PubMed

    P Brock, A; Isaza, R; Egelund, E F; Hunter, R P; Peloquin, C A

    2014-10-01

    Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants.

  6. The pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in Asian elephants (Elephas maximus).

    PubMed

    P Brock, A; Isaza, R; Egelund, E F; Hunter, R P; Peloquin, C A

    2014-10-01

    Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants. PMID:24684601

  7. Prevalence, Risk Factors, and Treatment Outcomes of Isoniazid- and Rifampicin- Mono-Resistant Pulmonary Tuberculosis in Lima, Peru

    PubMed Central

    Villegas, Leonela; Huaman, Moises A.; Van der Stuyft, Patrick; Gotuzzo, Eduardo; Seas, Carlos

    2016-01-01

    Background Isoniazid and rifampicin are the two most efficacious first-line agents for tuberculosis (TB) treatment. We assessed the prevalence of isoniazid and rifampicin mono-resistance, associated risk factors, and the association of mono-resistance on treatment outcomes. Methods A prospective, observational cohort study enrolled adults with a first episode of smear-positive pulmonary TB from 34 health facilities in a northern district of Lima, Peru, from March 2010 through December 2011. Participants were interviewed and a sputum sample was cultured on Löwenstein-Jensen (LJ) media. Drug susceptibility testing was performed using the proportion method. Medication regimens were documented for each patient. Our primary outcomes were treatment outcome at the end of treatment. The secondary outcome included recurrent episodes among cured patients within two years after completion of the treatment. Results Of 1292 patients enrolled, 1039 (80%) were culture-positive. From this subpopulation, isoniazid mono-resistance was present in 85 (8%) patients and rifampicin mono-resistance was present in 24 (2%) patients. In the multivariate logistic regression model, isoniazid mono-resistance was associated with illicit drug use (adjusted odds ratio (aOR) = 2.10; 95% confidence interval (CI): 1.1–4.1), and rifampicin mono-resistance was associated with HIV infection (aOR = 9.43; 95%CI: 1.9–47.8). Isoniazid mono-resistant patients had a higher risk of poor treatment outcomes including treatment failure (2/85, 2%, p-value<0.01) and death (4/85, 5%, p<0.02). Rifampicin mono-resistant patients had a higher risk of death (2/24, 8%, p<0.01). Conclusion A high prevalence of isoniazid and rifampicin mono-resistance was found among TB patients in our low HIV burden setting which were similar to regions with high HIV burden. Patients with isoniazid and rifampicin mono-resistance had an increased risk of poor treatment outcomes. PMID:27045684

  8. Antiretroviral Therapy to Prevent HIV Acquisition in Serodiscordant Couples in a Hyperendemic Community in Rural South Africa

    PubMed Central

    Oldenburg, Catherine E.; Bärnighausen, Till; Tanser, Frank; Iwuji, Collins C.; De Gruttola, Victor; Seage, George R.; Mimiaga, Matthew J.; Mayer, Kenneth H.; Pillay, Deenan; Harling, Guy

    2016-01-01

    Background. Antiretroviral therapy (ART) was highly efficacious in preventing human immunodeficiency virus (HIV) transmission in stable serodiscordant couples in the HPTN-052 study, a resource-intensive randomized controlled trial with near-perfect ART adherence and mutual HIV status disclosure among all participating couples. However, minimal evidence exists of the effectiveness of ART in preventing HIV acquisition in stable serodiscordant couples in “real-life” population-based settings in hyperendemic communities of sub-Saharan Africa, where health systems are typically resource-poor and overburdened, adherence to ART is often low, and partners commonly do not disclose their HIV status to each other. Methods. Data arose from a population-based open cohort in KwaZulu-Natal, South Africa. A total of 17 016 HIV-uninfected individuals present between January 2005 and December 2013 were included. Interval-censored time-updated proportional hazards regression was used to assess how the ART status affected HIV transmission risk in stable serodiscordant relationships. Results. We observed 1619 HIV seroconversions in 17 016 individuals, over 60 349 person-years follow-up time. During the follow-up period, 1846 individuals had an HIV-uninfected and 196 had an HIV-infected stable partner HIV incidence was 3.8/100 person-years (PY) among individuals with an HIV-infected partner (95% confidence interval [CI], 2.3–5.6), 1.4/100 PY (.4–3.5) among those with HIV-infected partners receiving ART, and 5.6/100 PY (3.5–8.4) among those with HIV-infected partners not receiving ART. Use of ART was associated with a 77% decrease in HIV acquisition risk among serodiscordant couples (adjusted hazard ratio, 0.23; 95% CI, .07–.80). Conclusions. ART initiation was associated with a very large reduction in HIV acquisition in serodiscordant couples in rural KwaZulu-Natal. However, this “real-life” effect was substantially lower than the effect observed in the HPTN-052

  9. Web-Based Cognitive Behavioral Therapy Intervention for the Prevention of Suicidal Ideation in Medical Interns: A Randomized Controlled Trial

    PubMed Central

    Guille, Constance; Zhao, Zhuo; Krystal, John; Nichols, Breck; Brady, Kathleen; Sen, Srijan

    2016-01-01

    Importance In the United States, approximately one physician dies by suicide every day. Training physicians are at particularly high risk, with suicidal ideation increasing over four-fold during the first three months of internship year. Despite this dramatic increase, very few efforts have been made to prevent the escalation of suicidal thoughts among training physicians. Objective To assess the effectiveness of a Web-based Cognitive Behavioral Therapy (wCBT) program delivered prior to the start of internship year in the prevention of suicidal ideation in medical interns. Design, Setting and Participants A randomized controlled trial conducted at two university hospitals with 199 interns from multiple specialties during academic years 2009-10 or 2011-12. Interventions Interns were randomly assigned to study groups (wCBT, n=100; attention-control group (ACG), n=99), and completed study activities lasting 30-minutes each week for four weeks prior to starting internship year. Subjects assigned to wCBT completed online-CBT modules and subjects assigned to ACG received emails with general information about depression, suicidal thinking and local mental health providers. Main Outcome Measure The Patient Health Questionnaire (PHQ-9) was employed to assess suicidal ideation (i.e., “thoughts that you would be better off dead, or hurting yourself in some way”) prior to the start of intern year and at 3-month intervals throughout the year. Results 62.2% (199/320) of individuals agreed to take part in the study. During at least one time point over the course of internship year 12% (12/100) of interns assigned to wCBT endorsed suicidal ideation, compared to 21%(21/99) of interns assigned to ACG. After adjusting for covariates identified a priori that have previously shown to increase the risk for suicidal ideation, interns assigned to wCBT were 60% less likely to endorse suicidal ideation during internship year (RR: 0.40, 95% CI 0.17-0.91; p=0.03), compared to those

  10. Multitargeted prevention and therapy of cancer by diallyl trisulfide and related Allium vegetable-derived organosulfur compounds

    PubMed Central

    Powolny, Anna A.; Singh, Shivendra V.

    2008-01-01

    Allium vegetables, such as garlic, have been used for medicinal purposes throughout the recorded history. The known health benefits of Allium vegetables constituents include cardiovascular effects, improvement of the immune function, lowering of blood glucose level, radioprotection, protection against microbial infections, and anticancer effects. Initial evidence for the anticancer effect of Allium vegetables was provided by population-based case-control studies. Subsequent laboratory studies showed that the Allium vegetable constituents, such as diallyl disulfide, S-allylcysteine, and ajoene can not only offer protection against chemically-induced cancer in animal models by altering carcinogen metabolism, but also suppress growth of cancer cells in culture and in vivo by causing cell cycle arrest and apoptosis induction. Suppression of angiogenesis and experimental metastasis by Allium constituents has also been reported. Defining the mechanism by which sulfur compounds derived from Allium vegetables inhibit cancer cell growth has been the topic of intense research in the last two decades. Some Allium vegetable constituents have also entered clinical trials to assess their safety and anticancer efficacy. This article summarizes preclinical and limited clinical data to warrant further clinical evaluation of Allium vegetable constituents for prevention and therapy of human cancers. PMID:18579286

  11. AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse.

    PubMed

    Lee, E K; Hu, C; Bhargava, R; Ponnusamy, R; Park, H; Novicoff, S; Rozengurt, N; Marescau, B; De Deyn, P; Stout, D; Schlichting, L; Grody, W W; Cederbaum, S D; Lipshutz, G S

    2013-08-01

    Complete arginase I deficiency is the least severe urea cycle disorder, characterized by hyperargininemia and infrequent episodes of hyperammonemia. Patients suffer from neurological impairment with cortical and pyramidal tract deterioration, spasticity, loss of ambulation and seizures, and is associated with intellectual disability. In mice, onset is heralded by weight loss beginning around day 15; gait instability follows progressing to inability to stand and development of tail tremor with seizure-like activity and death. Here we report that hyperargininemic mice treated neonatally with an adeno-associated virus (AAV)-expressing arginase and followed long-term lack any presentation consistent with brain dysfunction. Behavioral and histopathological evaluation demonstrated that treated mice are indistinguishable from littermates, and that putative compounds associated with neurotoxicity are diminished. In addition, treatment results in near complete resolution of metabolic abnormalities early in life; however, there is the development of some derangement later with decline in transgene expression. Ammonium challenging revealed that treated mice are affected by exogenous loading much greater than littermates. These results demonstrate that AAV-based therapy for hyperargininemia is effective and prevents development of neurological abnormalities and cognitive dysfunction in a mouse model of hyperargininemia; however, nitrogen challenging reveals that these mice remain impaired in the handling of waste nitrogen.

  12. Factors affecting breastfeeding cessation after discontinuation of antiretroviral therapy to prevent mother-to-child transmission of HIV.

    PubMed

    Morgan, Melissa C; Masaba, Rose O; Nyikuri, Mary; Thomas, Timothy K

    2010-07-01

    In the Kisumu Breastfeeding Study (KiBS), prevention of mother-to-child HIV transmission study, highly active antiretroviral therapy (HAART) is provided from 34 weeks gestation, through delivery to six months postpartum. The study recommends that women practice exclusive breastfeeding for six months, then wean abruptly. We sought to explore factors such as, education, family support, cultural norms, and sources of information about perinatal HIV transmission, which may influence a mother's decision to comply or not comply with the study's recommendation to stop breastfeeding when HAART is discontinued. We used semi-structured interviews of a purposive sample of 18 mothers participating in the KiBS. By interviewing 10 mothers who stopped breastfeeding and eight mothers who continued, it was possible to examine how different factors may have affected the groups of participants. All participants stated that it was not traditional to stop breastfeeding at six months. Participants who stopped breastfeeding reported more family support, were more educated, and were more likely to disclose their HIV status. Participants who continued breastfeeding more often expressed concern about stigma. Participants learned about mother-to-child transmission from clinics, churches, community groups, and other HIV-positive mothers. This substudy suggests that family support, education, and cultural norms are important factors that may influence a mother's decision regarding breastfeeding cessation. Thus, counseling and family support may play integral roles in the promotion of early breastfeeding cessation.

  13. Isoniazid-resistance conferring mutations in Mycobacterium tuberculosis KatG: Catalase, peroxidase, and INH-NADH adduct formation activities

    PubMed Central

    Cade, Christine E; Dlouhy, Adrienne C; Medzihradszky, Katalin F; Salas-Castillo, Saida Patricia; Ghiladi, Reza A

    2010-01-01

    Mycobacterium tuberculosis catalase-peroxidase (KatG) is a bifunctional hemoprotein that has been shown to activate isoniazid (INH), a pro-drug that is integral to frontline antituberculosis treatments. The activated species, presumed to be an isonicotinoyl radical, couples to NAD+/NADH forming an isoniazid-NADH adduct that ultimately confers anti-tubercular activity. To better understand the mechanisms of isoniazid activation as well as the origins of KatG-derived INH-resistance, we have compared the catalytic properties (including the ability to form the INH-NADH adduct) of the wild-type enzyme to 23 KatG mutants which have been associated with isoniazid resistance in clinical M. tuberculosis isolates. Neither catalase nor peroxidase activities, the two inherent enzymatic functions of KatG, were found to correlate with isoniazid resistance. Furthermore, catalase function was lost in mutants which lacked the Met-Tyr-Trp crosslink, the biogenic cofactor in KatG which has been previously shown to be integral to this activity. The presence or absence of the crosslink itself, however, was also found to not correlate with INH resistance. The KatG resistance-conferring mutants were then assayed for their ability to generate the INH-NADH adduct in the presence of peroxide (t-BuOOH and H2O2), superoxide, and no exogenous oxidant (air-only background control). The results demonstrate that residue location plays a critical role in determining INH-resistance mechanisms associated with INH activation; however, different mutations at the same location can produce vastly different reactivities that are oxidant-specific. Furthermore, the data can be interpreted to suggest the presence of a second mechanism of INH-resistance that is not correlated with the formation of the INH-NADH adduct. PMID:20054829

  14. In Vitro Inhibition of the Mycobacterium tuberculosis β-Ketoacyl-Acyl Carrier Protein Reductase MabA by Isoniazid

    PubMed Central

    Ducasse-Cabanot, Stéphanie; Cohen-Gonsaud, Martin; Marrakchi, Hedia; Nguyen, Michel; Zerbib, Didier; Bernadou, Jean; Daffé, Mamadou; Labesse, Gilles; Quémard, Annaíik

    2004-01-01

    The first-line specific antituberculous drug isoniazid inhibits the fatty acid elongation system (FAS) FAS-II involved in the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The MabA protein that catalyzes the second step of the FAS-II elongation cycle is structurally and functionally related to the in vivo target of isoniazid, InhA, an NADH-dependent enoyl-acyl carrier protein reductase. The present work shows that the NADPH-dependent β-ketoacyl reduction activity of MabA is efficiently inhibited by isoniazid in vitro by a mechanism similar to that by which isoniazid inhibits InhA activity. It involves the formation of a covalent adduct between MnIII-activated isoniazid and the MabA cofactor. Liquid chromatography-mass spectrometry analyses revealed that the isonicotinoyl-NADP adduct has multiple chemical forms in dynamic equilibrium. Both kinetic experiments with isolated forms and purification of the enzyme-ligand complex strongly suggested that the molecules active against MabA activity are the oxidized derivative and a major cyclic form. Spectrofluorimetry showed that the adduct binds to the MabA active site. Modeling of the MabA-adduct complex predicted an interaction between the isonicotinoyl moiety of the inhibitor and Tyr185. This hypothesis was supported by the fact that a higher 50% inhibitory concentration of the adduct was measured for MabA Y185L than for the wild-type enzyme, while both proteins presented similar affinities for NADP+. The crystal structure of MabA Y185L that was solved showed that the substitution of Tyr185 induced no significant conformational change. The description of the first inhibitor of the β-ketoacyl reduction step of fatty acid biosynthesis should help in the design of new antituberculous drugs efficient against multidrug-resistant tubercle bacilli. PMID:14693546

  15. An Atypical and Resistant Case of Obsessive Compulsive Disorder Responding Satisfactorily with an Unusual way of Exposure and Response Prevention Therapy

    PubMed Central

    Nath, Kamal; Victor, Robin

    2016-01-01

    It is well established fact that a combination of pharmacological therapy plus cognitive behaviour therapy (CBT) - exposure and response prevention (ERP) is considered first line for the treatment of obsessive compulsive disorder (OCD). This case presented here supports this point in unusual way of ERP administration in an atypical and resistant case of OCD proved to be beneficial over pharmacotherapy. The case was atypical in the sense that it had many overvalued ideas, superstitions and religious beliefs playing major role in its aetiology. Also, misconstruction of chance associations, intense stimulus generalization and invivo exposure proving the best modality of treatment made it atypical. PMID:27134980

  16. Optimization of SABRE for polarization of the tuberculosis drugs pyrazinamide and isoniazid

    NASA Astrophysics Data System (ADS)

    Zeng, Haifeng; Xu, Jiadi; Gillen, Joseph; McMahon, Michael T.; Artemov, Dmitri; Tyburn, Jean-Max; Lohman, Joost A. B.; Mewis, Ryan E.; Atkinson, Kevin D.; Green, Gary G. R.; Duckett, Simon B.; van Zijl, Peter C. M.

    2013-12-01

    Hyperpolarization produces nuclear spin polarization that is several orders of magnitude larger than that achieved at thermal equilibrium thus providing extraordinary contrast and sensitivity. As a parahydrogen induced polarization (PHIP) technique that does not require chemical modification of the substrate to polarize, Signal Amplification by Reversible Exchange (SABRE) has attracted a lot of attention. Using a prototype parahydrogen polarizer, we polarize two drugs used in the treatment of tuberculosis, namely pyrazinamide and isoniazid. We examine this approach in four solvents, methanol-d4, methanol, ethanol and DMSO and optimize the polarization transfer magnetic field strength, the temperature as well as intensity and duration of hydrogen bubbling to achieve the best overall signal enhancement and hence hyperpolarization level.

  17. Impact of isoniazid resistance on virulence of global and south Indian clinical isolates of Mycobacterium tuberculosis.

    PubMed

    Ameeruddin, Nusrath Unissa; Luke Elizabeth, Hanna

    2014-12-01

    Isoniazid (INH) is the only anti-tuberculous drug for which a relationship has been noticed between acquisition of resistance and lack of virulence. Mutation in katG gene is the chief cause for INH resistance in Mycobacterium tuberculosis (MTB). Classical studies have demonstrated that INH-resistant (INH(r)) mutants with a defective katG gene were catalase deficient and markedly attenuated in guinea pigs. Also, earlier studies on south Indian INH(r) isolates were shown to have lower virulence and higher susceptibility to H2O2. However, later studies including that of our's suggest that INH resistance is not always accompanied by compromised virulence and/or survival. Therefore, this review focuses on the influence of INH resistance on virulence of MTB from global and south Indian isolates.

  18. Development of interstitial pneumonia in a patient with rheumatoid arthritis induced by isoniazid for tuberculosis chemoprophylaxis.

    PubMed

    Migita, Kiyoshi; Umeno, Tetsuya; Miyagawa, Kana; Izumi, Yasumori; Sasaki, Eisuke; Kakugawa, Tomoyuki; Ito, Masahiro; Kinoshita, Akitoshi; Miyashita, Taichiro

    2012-05-01

    Here, we report a 56-year-old patient with rheumatoid arthritis (RA) who had been treated with methotrexate and sulfuasalazine, but the disease activity remained high. Therefore, we planned TNF-blocker treatment for this patient. A tuberculin skin test was positive, we started anti-tuberculosis (TB) chemoprophylaxis with isoniazid (INH). However, liver dysfunction was appeared after 2 weeks from the start of INH. Therefore, we discontinued INH transiently and tried the desensitization of INH. However, interstitial pneumonia was developed 2 weeks after the re-start of INH, we decided to stop the INH prophylaxis. Interstitial pneumonia was improved by corticosteroid treatments. This case report shows that INH-induced IP can be occurred during the course of anti-TB chemoprophylaxis in patients with RA.

  19. Rv3080c regulates the rate of inhibition of mycobacteria by isoniazid through FabD.

    PubMed

    Kumari, Ruma; Saxena, Richa; Tiwari, Sameer; Tripathi, Dinesh K; Srivastava, Kishore K

    2013-02-01

    The mycobacterial FASII multi-enzyme complex has been identified to be a target of Ser/Thr protein kinases (STPKs) of Mycobacterium tuberculosis (MTB), with substrates, including the malonyl-CoA:ACP transacylase (FabD) and the β-ketoacyl-ACP synthases KasA and KasB. These proteins are phosphorylated by various kinases in vitro. The present study links the correlation of FASII pathway with serine threonine protein kinase of MTB. In the preliminary finding, we have shown that mycobacterial protein Rv3080c (PknK) phosphorylates FabD and the knockdown of PknK protein in mycobacteria down regulates FabD expression. This event leads to the differential inhibition of mycobacteria in the presence of isoniazid (INH), as the inhibition of growth of mycobacteria in the presence of INH is enhanced in PknK deficient mycobacteria. PMID:23180244

  20. Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid.

    PubMed

    Mdluli, K; Slayden, R A; Zhu, Y; Ramaswamy, S; Pan, X; Mead, D; Crane, D D; Musser, J M; Barry, C E

    1998-06-01

    Although isoniazid (isonicotinic acid hydrazide, INH) is widely used for the treatment of tuberculosis, its molecular target has remained elusive. In response to INH treatment, saturated hexacosanoic acid (C26:0) accumulated on a 12-kilodalton acyl carrier protein (AcpM) that normally carried mycolic acid precursors as long as C50. A protein species purified from INH-treated Mycobacterium tuberculosis was shown to consist of a covalent complex of INH, AcpM, and a beta-ketoacyl acyl carrier protein synthase, KasA. Amino acid-altering mutations in the KasA protein were identified in INH-resistant patient isolates that lacked other mutations associated with resistance to this drug. PMID:9616124

  1. Acupuncture in Treating Dry Mouth Caused By Radiation Therapy in Patients With Head and Neck Cancer | Division of Cancer Prevention

    Cancer.gov

    RATIONALE: Acupuncture may help relieve dry mouth caused by radiation therapy. PURPOSE: This randomized phase III trial is studying to see how well one set of acupuncture points work in comparison to a different set of acupuncture points or standard therapy in treating dry mouth caused by radiation therapy in patients with head and neck cancer. |

  2. Cost-effectiveness of antiviral therapy during late pregnancy to prevent perinatal transmission of hepatitis B virus.

    PubMed

    Wang, Wenjun; Wang, Jingjing; Dang, Shuangsuo; Zhuang, Guihua

    2016-01-01

    Background. Hepatitis B virus (HBV) infections are perinatally transmitted from chronically infected mothers. Supplemental antiviral therapy during late pregnancy with lamivudine (LAM), telbivudine (LdT), or tenofovir (TDF) can substantially reduce perinatal HBV transmission compared to postnatal immunoprophylaxis (IP) alone. However, the cost-effectiveness of these measures is not clear. Aim. This study evaluated the cost-effectiveness from a societal perspective of supplemental antiviral agents for preventing perinatal HBV transmission in mothers with high viral load (>6 log10 copies/mL). Methods. A systematic review and network meta-analysis were performed for the risk of perinatal HBV transmission with antiviral therapies. A decision analysis was conducted to evaluate the clinical and economic outcomes in China of four competing strategies: postnatal IP alone (strategy IP), or in combination with perinatal LAM (strategy LAM + IP), LdT (strategy LdT + IP), or TDF (strategy TDF + IP). Antiviral treatments were administered from week 28 of gestation to 4 weeks after birth. Outcomes included treatment-related costs, number of infections, and quality-adjusted life years (QALYs). One- and two-way sensitivity analyses were performed to identify influential clinical and cost-related variables. Probabilistic sensitivity analyses were used to estimate the probabilities of being cost-effective for each strategy. Results. LdT + IP and TDF + IP averted the most infections and HBV-related deaths, and gained the most QALYs. IP and TDF + IP were dominated as they resulted in less or equal QALYs with higher associated costs. LdT + IP had an incremental $2,891 per QALY gained (95% CI [$932-$20,372]) compared to LAM + IP (GDP per capita for China in 2013 was $6,800). One-way sensitivity analyses showed that the cost-effectiveness of LdT + IP was only sensitive to the relative risk of HBV transmission comparing LdT + IP with LAM + IP. Probabilistic sensitivity analyses

  3. Highly purified omega-3 polyunsaturated fatty acids are effective as adjunct therapy for secondary prevention of myocardial infarction.

    PubMed

    Verboom, Cees N

    2006-12-01

    Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione was the first large randomized trial to produce evidence that a pharmaceutical preparation of highly purified omega-3 polyunsaturated fatty acids (PUFAs), administered as an adjunct to other accepted interventions, had a favorable effect on hard clinical end-points in post-myocardial infarction patients. Much of the 20% all-cause mortality benefit recorded during the study could be attributed to a 45% reduction in sudden death--a fatal outcome that traditionally has proved resistant to medical intervention. These results were obtained with an omega-3 PUFA dose of 1 g/day, which is much lower than was routinely being used at the time the study was initiated (e.g. 4 g/day for hypertriglyceridemia). One consequence of this low-dose regimen was that the tolerability profile of omega-3 PUFAs during GISSI-Prevenzione was considered highly satisfactory, with low adverse event incidence rates and low rates of discontinuation due to adverse events. Time-course analysis established that much of the survival benefit of omega-3 PUFA treatment in GISSI-Prevenzione was realized during the early months of the trial. The beneficial effects of omega-3 PUFA treatment were observed on top of standard, secondary pharmacological prevention therapy like anti-platelet agents, statins, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. The benefits of omega-3 PUFA therapy were also apparent in patients at all standards of adherence to a healthy diet and may have been augmented in patients with the best dietary profile. Patients with diabetes mellitus (approximately 15% of the study cohort) appeared to benefit from omega-3 PUFAs to at least the same extent as the general study population; the treatment effect on sudden death was progressively more pronounced as left ejection fraction declined. Cost-effectiveness analyses undertaken from a third-party payer perspective for Italy

  4. Systematic Review and Meta-Analysis of Artemisinin Based Therapies for the Treatment and Prevention of Schistosomiasis

    PubMed Central

    Pérez del Villar, Luis; Burguillo, Francisco J.; López-Abán, Julio; Muro, Antonio

    2012-01-01

    Background Chemotherapy based on repeated doses of praziquantel is still the most effective control strategy against Schistosomiasis, however artemisinin derivatives emerged as a family of compounds with schistomicide activity. The aim of the present work is to compare the efficacy of artemisinin-based therapies in the treatment and prophylaxis of human schistosomiasis. The design of this work involved a quantitative systematic review and meta-analysis. Methodology/Principal Findings Retrieval of published studies was carried out through an electronic search of the PubMed (MEDLINE), EMBASE, Cochrane Library and CINAHL databases. This included reports comparing the therapeutic efficacy of artesunate alone, artesunate plus sulfadoxine-pyrimethamine and a combination of artemisinin derivatives plus praziquantel against praziquantel alone on different types of schistosomiasis. Moreover, studies on artesunate and artemether used as preventive drugs were also analyzed against placebo. The primary outcome measure for schistosomiasis treatment was “parasitological cure”, whereas for the prophylaxis the outcome evaluated was “infection rate”. Our results show that patients treated with artesunate alone have significantly lower cure rates than those treated with praziquantel (OR = 0.27 (95% C.I. 0.13–0.53; p<0.001)) and that the combined therapy of artesunate plus sulfadoxine-pyrimethamine is also significantly less effective than praziquantel treatment (OR = 0.14 (95% C.I. 0.02–0.92; p = 0.04)). However, the combination of an artemisinin derivatives plus praziquantel showed a higher cure rate than praziquantel monotherapy with OR = 2.07 (95% C.I. 1.27–3.36; p = 0.003). Finally, chemoprophylaxis with either artesunate (RR = 0.11 (95% C.I. 0.06–0.22; p<0.001)) or artemether (RR = 0.25 (95% C.I. 0.16–0.40; p<0.001)) was significantly better than a placebo in both cases. Conclusions/Significance This meta-analysis confirms that

  5. Chitosan-isoniazid conjugates: Synthesis, evaluation of tuberculostatic activity, biodegradability and toxicity.

    PubMed

    Berezin, Alexander S; Skorik, Yury A

    2015-08-20

    Novel water-soluble chitosan-isoniazid conjugates were synthesized by two methods: (1) the carbodiimide method using isoniazid (INH) and N-(2-carboxyethyl)chitosan (CEC), and (2) the reaction between INH and N-(3-chloro-2-hydroxypropyl)chitosan (CHPC). The solubility of the conjugates under physiological conditions was enhanced by phosphorylation. Method (1) is preferable in terms of obtaining conjugates with a high content of active substance; depending on reaction conditions, the degree of substitution in the INH-CEC conjugates varies from 0.08 to 0.39. Ultrasound treatment increased the reaction rate by a factor of 1.3-1.5, but caused partial degradation of the polymer. Consecutive modification led to a considerable decrease in polymer biodegradability in the following order: chitosan>CEC or CHPC>conjugate. In vitro screening of the antimicrobial activity against Mycobacterium tuberculosis H37Rv demonstrated a comparable or slightly higher minimum inhibitory concentration for conjugates than for INH itself (0.20, 0.25, and 1.05 μg INH/mL for INH, CEC-INH, and CHPC-INH, respectively). A slug mucosal irritation test employing Limax flavus revealed a lower toxicity for the conjugates than for INH by a factor of 3-4; the most noticeable toxicity decrease was observed for the conjugates obtained by method (1). Studies of acute toxicity in mice revealed a 3-4-fold increase in median lethal dose for the conjugates compared with INH (LD50 210, 850, and 650 mg INH/kg for INH, CEC-INH, and CHPC-INH, respectively).

  6. Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

    SciTech Connect

    Arruda Viani, Gustavo; Bernardes da Silva, Lucas Godoi; Stefano, Eduardo Jose

    2012-07-15

    Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

  7. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis

    PubMed Central

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    2016-01-01

    Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis. PMID:27729789

  8. Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial. Italian Chemoprevention Group.

    PubMed Central

    Decensi, A.; Robertson, C.; Rotmensz, N.; Severi, G.; Maisonneuve, P.; Sacchini, V.; Boyle, P.; Costa, A.; Veronesi, U.

    1998-01-01

    The combination of tamoxifen and transdermal hormone replacement therapy (HRT) may potentially reduce risks and side-effects of either agent, but an adverse interaction could attenuate their beneficial effects. We assessed the effects of their combination on cardiovascular risk factors within a prevention trial of tamoxifen. Baseline and 12-month measurements of total, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, platelets and white blood cells were obtained in the following four groups: tamoxifen (n = 1117), placebo (n = 1112), tamoxifen and HRT (n = 68), placebo and HRT (n = 87). The analysis was further extended to women who were on HRT at randomization but discontinued it during the 12-month intervention period (n = 33 on tamoxifen and n = 35 on placebo) and to women who were not on HRT but started it during intervention (n = 36 in both arms of the study). Compared with small changes in the placebo group, tamoxifen was associated with changes in total, LDL- and HDL-cholesterol of approximately -9%, -19% and +0.2% in continuous HRT users compared with -9%, -14% and -0.8% in never HRT users. Similarly, there was no interaction on platelet count. In contrast, the decrease in total and LDL-cholesterol levels induced by tamoxifen was blunted by two-thirds in women who started HRT while on tamoxifen (P = 0.051 for the interaction term). We conclude that the beneficial effects of tamoxifen on cardiovascular risk factors are unchanged in current HRT users, whereas they may be attenuated in women who start transdermal HRT while on tamoxifen. Whereas a trial of tamoxifen in women already on transdermal HRT is warranted, prescription of HRT during tamoxifen may attenuate its activity. PMID:9744493

  9. Comprehensive Suppression of All Apoptosis-Induced Proliferation Pathways as a Proposed Approach to Colorectal Cancer Prevention and Therapy

    PubMed Central

    Bordonaro, Michael; Drago, Eric; Atamna, Wafa; Lazarova, Darina L.

    2014-01-01

    Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs), and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1) the signaling heterogeneity of CRC cell populations, and (2) the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents. We explored the strategy of augmenting CRC cell death by inhibiting all survival pathways induced by the pro-apoptotic agent LBH589, a histone deacetylase inhibitor: AKT, JAK/STAT, and ERK signaling. The apoptosis-enhancing ability of a cocktail of synthetic inhibitors of proliferation was compared to the effects of the natural product propolis. We utilized colorectal adenoma, drug-sensitive and drug-resistant colorectal carcinoma cells to evaluate the apoptotic potential of the combination treatments. The results suggest that an effective approach to CRC combination therapy is to combine apoptosis-inducing drugs (e.g., histone deacetylase inhibitors, such as LBH589) with agents that suppress all compensatory survival pathways induced during apoptosis (such as the cocktail of inhibitors of apoptosis-associated proliferation). The same paradigm can be applied to a CRC prevention approach, as the apoptotic effect of butyrate, a diet-derived histone deacetylase inhibitor, is augmented by other dietary agents that modulate survival pathways (e.g., propolis and coffee extract). Thus, dietary supplements composed by fermentable fiber, propolis, and coffee extract may effectively counteract neoplastic growth in the colon. PMID:25500581

  10. The Association of Elective Hormone Therapy with Changes in Lipids Among Glucose Intolerant Postmenopausal Women in the Diabetes Prevention Program

    PubMed Central

    Golden, Sherita H.; Kim, Catherine; Barrett-Connor, Elizabeth; Nan, Bin; Kong, Shengchun; Goldberg, Ronald

    2013-01-01

    Objective It is unclear how lipids change in response to lifestyle modification or metformin among postmenopausal glucose intolerant women using and not using hormone therapy (HT). We examined the one-year changes in lipids among postmenopausal, prediabetic women in the Diabetes Prevention Program (DPP), and whether changes were mediated by sex hormones. Materials/Methods We performed a secondary analysis of a randomized controlled trial of 342 women who used HT at baseline and year 1 and 382 women who did not use HT at either time point. Interventions included intensive lifestyle (ILS) with goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, or metformin or placebo administered 850 mg up to twice a day. Women were not randomized to HT. Main outcome measures were changes between baseline and study year 1 in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Results Compared to placebo, both ILS and metformin significantly reduced LDL-C and raised HDL-C among HT users, changes partially explained by change in estradiol and testosterone but independent of changes in waist circumference and 1/fasting insulin. In contrast, DPP interventions had no effect on LDL-C and HDL-C among non-HT users. ILS significantly lowered triglycerides among non-users but did not significantly change triglycerides among HT users. Metformin did not significantly change triglycerides among non-users but increased triglycerides among HT users. Conclusions The beneficial effects of ILS and metformin on lowering LDL-C and raising HDL-C differ depending upon concurrent HT use. PMID:23660512

  11. Mycobacterium bovis spondylodiscitis after intravesical Bacillus Calmette-Guérin therapy

    PubMed Central

    Obaid, Sami; Weil, Alexander G.; Rahme, Ralph; Gendron, Cathy; Shedid, Daniel

    2011-01-01

    Background: Intravesical instillations of live-attenuated Bacillus Calmette-Guérin (BCG) are a well-known and effective method for prevention and treatment of bladder carcinoma and carcinoma in situ. Although considered a safe procedure with rare side effects, local and systemic complications may occur. While long bone ostemolyelitis has been well described, very few reports of BCG spondylodiscitis exist in the literature. Case Description: A 67-year-old man developed low back pain, anorexia, and weight loss 11 months after a 6-week course of intravesical BCG instillations for the treatment of bladder carcinoma in situ. Imaging studies revealed L1-L2 spondylodiscitis with epidural and bilateral psoas abscesses. Tissue cultures obtained by percutaneous computed tomography-guided aspiration were positive for Mycobacterium bovis. Despite triple antituberculous therapy (isoniazid, rifampin, and ethambutol), clinical and radiological progression occurred. Therefore, L1 and L2 corpectomies with extensive debridement were performed, followed by 360° anterior-posterior instrumented fusion. After 20 months of follow-up, the patient remains asymptomatic and recurrence-free. Conclusion: Mycobacterium bovis spondylodiscitis is a rare complication of intravesical BCG therapy. Although medical therapy with antituberculous agents is the first-line treatment, surgical decompression, debridement, and stabilization may be necessary in refractory cases. PMID:22140647

  12. Rapid Antiretroviral Therapy Initiation for Women in an HIV-1 Prevention Clinical Trial Experiencing Primary HIV-1 Infection during Pregnancy or Breastfeeding.

    PubMed

    Morrison, Susan; John-Stewart, Grace; Egessa, John J; Mubezi, Sezi; Kusemererwa, Sylvia; Bii, Dennis K; Bulya, Nulu; Mugume, Francis; Campbell, James D; Wangisi, Jonathan; Bukusi, Elizabeth A; Celum, Connie; Baeten, Jared M

    2015-01-01

    During an HIV-1 prevention clinical trial in East Africa, we observed 16 cases of primary HIV-1 infection in women coincident with pregnancy or breastfeeding. Nine of eleven pregnant women initiated rapid combination antiretroviral therapy (ART), despite having CD4 counts exceeding national criteria for ART initiation; breastfeeding women initiated ART or replacement feeding. Rapid ART initiation during primary HIV-1 infection during pregnancy and breastfeeding is feasible in this setting.

  13. Lymphadenitis caused by infection with an isoniazid- and rifampin-resistant strain of Mycobacterium bovis BCG in an infant with IFN-γ/IL-12 pathway defect*

    PubMed Central

    Diniz, Lilian Martins Oliveira; Guimarães, Tiago; de Oliveira, Maria das Graças Rodrigues; Pinto, Jorge Andrade; de Miranda, Silvana Spindola

    2014-01-01

    We report a rare case in a female infant (age, 3.5 months) with primary immunodeficiency (IFN-γ/IL-12 pathway defect) who presented with suppurative lymphadenitis after Mycobacterium bovis BCG vaccination. The strain of M. bovis BCG identified was found to be resistant to isoniazid and rifampin. The patient was treated with a special pharmacological regimen involving isoniazid (in a limited, strategic manner), ethambutol, streptomycin, and IFN-γ, after which there was complete resolution of the lesions. PMID:24831405

  14. Increased incidence of liver enzymes abnormalities in patients treated with isoniazid in combination with disease modifying and/or biologic agents.

    PubMed

    Bourré-Tessier, Josiane; Arino-Torregrosa, Mireia; Choquette, Denis

    2014-08-01

    Reactivation of latent tuberculosis (LTB) has been described with the use of anti-TNFs. Combined treatment of isoniazid (INH) and disease modifying antirheumatic drugs (DMARDs) can potentially increase the risk of hepatotoxicity. The goal of this study was to investigate the risk of hepatotoxicity in rheumatic patients taking INH while on DMARDs and/or biologics. We reviewed the Institut de Rhumatologie de Montréal database (Rhumadata®) for rheumatic patients with positive tuberculin skin test or quantiFERON who took INH between August 2001 and April 2011. Liver function tests (LFTs) were collected at baseline and during therapy, and LFTs up to 9 months prior to INH initiation were used as controls. Of 922 patients screened for LTB, 87 patients tested positive. During INH treatment, 75.9 % were taking DMARDs, 82.8 % were taking biologics. A total of 375 LFTs performed while on INH were compared to 211 available tests collected prior to INH therapy. Twenty-four percent of the patients had abnormal LFTs during INH compared to 12.1 % prior to INH (p = 0.0481). Most of these abnormalities were mild or transient, but 8 % (seven patients) had significant abnormalities leading to INH discontinuation. Among these patients, mean (min, max) was 241 (52, 617) for AST and 262 (92, 669) for ALT. Although the use of INH therapy in combination with DMARDs and/or biologics was generally well tolerated, the rate of LFT abnormalities was higher when patients were exposed to INH, and significant abnormalities were more frequent than reported in the INH literature. It is prudent to closely follow the LFTs of these patients.

  15. The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis.

    PubMed

    Slayden, R A; Barry, C E

    2002-01-01

    Mycobacterium tuberculosis has two discrete beta-ketoacyl synthases encoded by kasA and kasB that are located in tandem within a five-gene operon that has been implicated in isoniazid-sensitivity and mycolic acid synthesis. We have developed an in vitro meromycolic acid synthase assay to elucidate the anabolic role of these enzymes. Overproduction of KasA and KasB individually and together in M. smegmatis enabled cell-free incorporation of [(14)C]malonyl-CoA into lipids whose chain length was dependent upon the M. tuberculosis elongating enzyme used. KasA specifically elongated palmitoyl-CoA to monounsaturated fatty acids that averaged 40 carbons in length. KasB hyperproduction in the presence of KasA produced longer chain multiunsaturated hydrocarbons averaging 54 carbons in length. These products comigrated with a synthetic standard of meromycolic acid and their production was sensitive to isoniazid, thiolactomycin, and triclosan. KasA mutations associated with isoniazid resistance produced an enzyme that had a diminished overall catalytic activity but conferred enhanced resistance to isoniazid. In vivo analysis confirmed that overexpression of each of the four mutant KasAs enhanced isoniazid resistance when compared to overexpression of wild-type KasA. These results suggest discrete anabolic roles for both KasA and KasB in mycolic acid synthesis and substantiate the involvement of KasA mutations in isoniazid resistance. PMID:12464486

  16. Biomedical HIV Prevention Including Pre-exposure Prophylaxis and Opiate Agonist Therapy for Women Who Inject Drugs: State of Research and Future Directions.

    PubMed

    Page, Kimberly; Tsui, Judith; Maher, Lisa; Choopanya, Kachit; Vanichseni, Suphak; Mock, Philip A; Celum, Connie; Martin, Michael

    2015-06-01

    Women who inject drugs (WWID) are at higher risk of HIV compared with their male counterparts as a result of multiple factors, including biological, behavioral, and sociostructural factors, yet comparatively little effort has been invested in testing and delivering prevention methods that directly target this group. In this article, we discuss the need for expanded prevention interventions for WWID, focusing on 2 safe, effective, and approved, yet underutilized biomedical prevention methods: opiate agonist therapy (OAT) and oral pre-exposure prophylaxis (PrEP). Although both interventions are well researched, they have not been well examined in the context of gender. We discuss the drivers of women injectors' higher HIV risk, review the effectiveness of OAT and PrEP interventions among women, and explain why these new HIV prevention tools should be prioritized for WWID. There is substantial potential for impact of OAT and PrEP programs for WWID in the context of broader gender-responsive HIV prevention initiatives. Although awaiting efficacy data on other biomedical approaches in the HIV prevention research "pipeline," we propose that the scale-up and implementation of these proven, safe, and effective interventions are needed now.

  17. Biomedical HIV prevention including pre-exposure prophylaxis and opiate agonist therapy for women who inject drugs: State of research and future directions

    PubMed Central

    Page, Kimberly; Tsui, Judith; Maher, Lisa; Choopanya, Kachit; Vanichseni, Suphak; Mock, Philip A.; Celum, Connie; Martin, Michael

    2015-01-01

    Women who inject drugs are at higher risk of HIV compared to their male counterparts as a result of multiple factors including biological, behavioral and socio-structural, yet comparatively little effort has been invested in testing and delivering prevention methods that directly target this group. In this paper, we discuss the need for expanded prevention interventions for women who inject drugs, focusing on two safe, effective, and approved, yet underutilized biomedical prevention methods: opiate agonist therapy (OAT) and oral pre-exposure prophylaxis (PrEP). While both interventions are well researched they have not been well examined in the context of gender. We discuss the drivers of women injectors’ higher HIV risk, review the effectiveness of OAT and PrEP interventions among women, and explain why these new HIV prevention tools should be prioritized for women who inject drugs. There is substantial potential for impact of OAT and PrEP programs for women who inject drugs in the context of broader gender-responsive HIV prevention initiatives. While awaiting efficacy data on other biomedical approaches in the HIV prevention research ‘pipeline’, we propose that the scale up and implementation of these proven, safe, and effective interventions are needed now. PMID:25978484

  18. Global protein expression dataset acquired during isoniazid-induced cytoprotection against H2O2 challenge in HL-60 cells.

    PubMed

    Khan, Saifur R; Baghdasarian, Argishti; Fahlman, Richard P; Siraki, Arno G

    2016-03-01

    Isoniazid (INH) is one of the first-line anti-tuberculosis drugs. Its effect on oxidative stress, however, is unknown. Here we used a model of oxidative stress by employing glucose/glucose oxidase (GOx), which (based on the availability of glucose and oxygen) is known to produce H2O2. This reaction induces oxidative stress culminating in necrotic cell death in HL-60 cells (a human promyelocytic leukemia cell line). The changes in protein levels have been quantified using global proteome expression changes through stable isotope labeling by amino acids in cell culture (SILAC) followed by LC-MS/MS analysis. A total of 1459 and 1712 proteins were identified in forward and reverse experiments, respectively. However, only 390 proteins were reproducibly identified in both samples. These 390 proteins were taken into account for further analysis which has been described in "Cytoprotective effect of isoniazid against H2O2 derived injury in HL-60 cells" [1].

  19. Adipose tissue-derived stem cell therapy for prevention and treatment of erectile dysfunction in a rat model of Peyronie's disease.

    PubMed

    Gokce, A; Abd Elmageed, Z Y; Lasker, G F; Bouljihad, M; Kim, H; Trost, L W; Kadowitz, P J; Abdel-Mageed, A B; Sikka, S C; Hellstrom, W J

    2014-03-01

    Peyronie's disease (PD) is a localized connective tissue disorder that involves the tunica albuginea (TA) of the penis. While surgical correction remains the gold standard, the search for an effective and less invasive therapy continues. The objective of this study was to evaluate the effects of intratunical injection of adipose tissue-derived stem cells (ADSCs) for the prevention and treatment of erectile dysfunction in a rat model of PD. Twenty-four male Sprague-Dawley rats (300-350 g) were randomly divided into four groups: sham, PD, PD + ADSC (prevention) and PD + ADSC (treatment). All rats underwent penile injections into the TA with 50 μL vehicle (sham) or 0.5 μg transforming growth factor (TGF)-β1 (remaining groups). The ADSC groups received intratunical injections with 0.5 million rat-labelled ADSCs on day 0 (prevention) or day 30 (treatment). Forty-five days following TGF-β1 injection, rats underwent cavernous nerve stimulation (CNS) with total intracavernous-to-mean arterial pressure ratio (ICP/MAP) and total ICP recorded to measure response to therapy. Tissues were evaluated histologically and for mRNA expression of tissue inhibitors of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs) and zymographic activity of MMPs. Statistical analysis was performed by analysis of variance followed by the Tukey test for post hoc comparisons. In both prevention and treatment groups, intratunical injection of ADSCs resulted in significantly higher ICP/MAP and total ICP in response to CNS compared with the PD group. Local injection of ADSCs prevented and/or reduced Peyronie's-like changes by decreasing the expression of TIMPs, and stimulating expression and activity of MMPs. This study documents the preventive and therapeutic benefits of ADSC on penile fibrosis and erectile function in an animal model of PD.

  20. Evaluation of GenoFlow DR-MTB Array Test for Detection of Rifampin and Isoniazid Resistance in Mycobacterium tuberculosis

    PubMed Central

    Molina-Moya, B.; Kazdaglis, G.; Lacoma, A.; Prat, C.; Gómez, A.; Villar-Hernández, R.; García-García, E.; Haba, L.; Maldonado, J.; Samper, S.; Ruiz-Manzano, J.; Ausina, V.

    2016-01-01

    The aim of this study was to evaluate the GenoFlow DR-MTB array test (DiagCor Bioscience, Hong Kong) on 70 cultured isolates and 50 sputum specimens. The GenoFlow array test showed good sensitivity and specificity compared to the phenotypic Bactec 460TB. This array accurately detected mutations in rpoB, katG, and inhA associated with resistance to rifampin and isoniazid. PMID:26865688

  1. Evaluation of GenoFlow DR-MTB Array Test for Detection of Rifampin and Isoniazid Resistance in Mycobacterium tuberculosis.

    PubMed

    Molina-Moya, B; Kazdaglis, G; Lacoma, A; Prat, C; Gómez, A; Villar-Hernández, R; García-García, E; Haba, L; Maldonado, J; Samper, S; Ruiz-Manzano, J; Ausina, V; Domínguez, J

    2016-04-01

    The aim of this study was to evaluate the GenoFlow DR-MTB array test (DiagCor Bioscience, Hong Kong) on 70 cultured isolates and 50 sputum specimens. The GenoFlow array test showed good sensitivity and specificity compared to the phenotypic Bactec 460TB. This array accurately detected mutations inrpoB,katG, andinhAassociated with resistance to rifampin and isoniazid. PMID:26865688

  2. Improving the prevention, diagnosis and treatment of TB among people living with HIV: the role of operational research

    PubMed Central

    2011-01-01

    Operational research is necessary to improve the access to and delivery of tuberculosis prevention, diagnosis and treatment interventions for people living with HIV. We conducted an extensive review of the literature and reports from recent expert consultations and research-related meetings organized by the World Health Organization and the Stop TB Partnership to identify a TB/HIV operational research agenda. We present critical operational research questions in a series of key areas: optimizing TB prevention by enhancing the uptake of isoniazid preventive therapy and the implementation of infection control measures; assessing the effectiveness of existing diagnostic tools and scaling up new technologies; improving service delivery models; and reducing risk factors for mortality among TB patients living with HIV. We discuss the potential impact that addressing the operational research questions may have on improving programmes’ performance, assessing new strategies or interventions for TB control, or informing global or national policy formulation. Financial resources to implement these operational research questions should be mobilized from existing and new funding mechanisms. National TB and HIV/AIDS programmes should develop their operational research agendas based on these questions, and conduct the research that they consider crucial for improving TB and HIV control in their settings in collaboration with research stakeholders. PMID:21967874

  3. [Analysis on acupoint prescription for acupoint sticking therapy of treating winter diseases in summer for preventing and curing chronic cough and asthma].

    PubMed

    Wen, Bi-ling; Zhou, Hua; Liu, Bao-yan; Sun, Guo-jie; Liu, Wei-hong; Peng, Jin; Hu, Jing-qing; He, Li-yun; Fang, Yi-gong; Zi, Ming-jie

    2010-08-01

    Based on ZhangShi YiTong written by ZHANG Lu of Qing dynasty, and the record that external application of Baijiezi (seeds of Brassica Alba) for treating asthma of cold syndrome, retrospective study is conducted to modern literature of treating winter diseases in summer with acupoint sticking therapy for preventing and treating chronic cough and asthma. Learning from thoughts and methods of evidence-based medicine, and according to subject characteristics of TCM and acupuncture, acupoints and point-selecting discipline of prescription for preventing and treating chronic cough and asthma in summer with acupoint sticking are analyzed. The results show that the top ten common acupoints used for acupoint sticking therapy of treating winter diseases in summer are Feishu (BL 13), Dingchuan (EX-B 1), Xinshu (BL 15), Geshu (BL 17), Danzhong (CV 17), Shenshu (BL 23), Gaohuang (BL 43), Dazhui (GV 14), Pishu (BL 20), Tiantu (CV 22), most of which belong to the Bladder Meridian of Foot-Taiyang, Conception Vessel and Governor Vessel or extra-meridian points. It refers that the core acupoints of acupoint sticking therapy are Feishu (BL 13), Dingchuan (EX-B 1), Xinshu (BL 15), Geshu (BL 17), Danzhong (CV 17), and adjunct points can be selected by syndrome, disease different stage, disease or symptoms. PMID:20942281

  4. Effect of twelve-months therapy with oral ambroxol in preventing exacerbations in patients with COPD. Double-blind, randomized, multicenter, placebo-controlled study (the AMETHIST Trial).

    PubMed

    Malerba, Mario; Ponticiello, Antonio; Radaeli, Alessandro; Bensi, Giuliano; Grassi, Vittorio

    2004-01-01

    The objective of this prospective, randomized, double-blind, placebo-controlled, multicenter parallel-group study was to evaluate the effect of long-term ambroxol treatment in preventing exacerbations of chronic obstructive pulmonary disease (COPD). Two hundred and forty-two outpatients with COPD defined by ATS criteria with value of FEV1 between > or =60 and 80% of predicted and history of one or more exacerbations in the previous year were recruited by 26 Respiratory Medicine Centers in Italy and treated for 1 year with one ambroxol retard capsule of 75 mg twice daily or placebo. The percentage of patients free from exacerbation at 6 months was 63% with ambroxol and 60% with placebo (p=0.366) and at 12 months 56% with ambroxol and 53% with placebo (p=0.363). In a subset of 45 patients with more severe baseline symptoms, ambroxol therapy was associated with a significant higher percentage of patients free from exacerbation compared to placebo: 63 vs. 38% (p=0.038). In conclusion, we did not find a significant difference between long-term ambroxol therapy and placebo, in preventing exacerbations in patients with COPD. In patients with more severe respiratory symptoms at baseline, however, we observed a significant difference in the cumulative exacerbation-free persistence between ambroxol and placebo, suggesting that long-term muco-regulatory therapy with ambroxol could be useful in highly symptomatic patients with COPD.

  5. A proposal to incorporate trial data into a hybrid ACC/AHA algorithm for the allocation of statin therapy in primary prevention.

    PubMed

    Ridker, Paul M; Rose, Lynda; Cook, Nancy R

    2015-03-10

    Current algorithms for statin allocation in primary prevention use epidemiologic estimates of absolute risk. However, a global risk prediction score has not been used as an enrollment criterion in any randomized trial of statin therapy. Moreover, completed statin trials show greater relative risk reductions for those patients at lower levels of absolute risk. Thus, risk calculators that rely solely on epidemiologic modeling do not ensure that those who will benefit are selected for treatment. We propose a hybrid approach to statin prescription for apparently healthy men and women that strongly endorses pharmacologic treatment for those who have estimated 10-year risks ≥7.5% and for whom trial-based evidence supports statin efficacy in primary prevention. Although individuals could still be treated on the basis of absolute risk alone, the hybrid approach is evidence-based, is easily applied in clinical practice, and may increase the transparency of physician-patient interactions concerning prescription of statin therapy in primary prevention.

  6. Multidimensional infrared spectroscopy reveals the vibrational and solvation dynamics of isoniazid

    NASA Astrophysics Data System (ADS)

    Shaw, Daniel J.; Adamczyk, Katrin; Frederix, Pim W. J. M.; Simpson, Niall; Robb, Kirsty; Greetham, Gregory M.; Towrie, Michael; Parker, Anthony W.; Hoskisson, Paul A.; Hunt, Neil T.

    2015-06-01

    The results of infrared spectroscopic investigations into the band assignments, vibrational relaxation, and solvation dynamics of the common anti-tuberculosis treatment Isoniazid (INH) are reported. INH is known to inhibit InhA, a 2-trans-enoyl-acyl carrier protein reductase enzyme responsible for the maintenance of cell walls in Mycobacterium tuberculosis but as new drug-resistant strains of the bacterium appear, next-generation therapeutics will be essential to combat the rise of the disease. Small molecules such as INH offer the potential for use as a biomolecular marker through which ultrafast multidimensional spectroscopies can probe drug binding and so inform design strategies but a complete characterization of the spectroscopy and dynamics of INH in solution is required to inform such activity. Infrared absorption spectroscopy, in combination with density functional theory calculations, is used to assign the vibrational modes of INH in the 1400-1700 cm-1 region of the infrared spectrum while ultrafast multidimensional spectroscopy measurements determine the vibrational relaxation dynamics and the effects of solvation via spectral diffusion of the carbonyl stretching vibrational mode. These results are discussed in the context of previous linear spectroscopy studies on solid-phase INH and its usefulness as a biomolecular probe.

  7. Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons

    SciTech Connect

    Liu, L.; Hooker, J.; Liu, L.; Xu, Y.; Shea, C.; Fowler, J.S.; Hooker, J.M.; Tonge, P.J.

    2010-03-03

    The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [{sup 11}C]CH{sub 3}I to label RIF and [{sup 11}C]HCN to label INH and PZA. Following iv administration, INH, PZA, RIF, and/or their radiolabeled metabolites clear rapidly from many tissues; however, INH, PZA, and/or their radiolabeled metabolites accumulate in the bladder while RIF and/or its radiolabeled metabolites accumulates in the liver and gall bladder, consistent with the known routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood-brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth of Mycobacterium tuberculosis (MTB). The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain and pave the way for imaging the distribution of the pathogen in vivo.

  8. Rapid in vivo detection of isoniazid-sensitive Mycobacterium tuberculosis by breath test

    PubMed Central

    Maiga, Mariama C.; Atudorei, Viorel; Sharp, Zachary D.; Bishai, William R.; Timmins, Graham S.

    2014-01-01

    There is urgent need for rapid, point of care diagnostic tools for tuberculosis (TB) and drug sensitivity. Current methods based on in vitro growth take weeks, while DNA amplification can neither differentiate live from dead organisms nor determine phenotypic drug resistance. Here we show the development and evaluation of a rapid breath test for isoniazid (INH)-sensitive TB based on detection of labeled N2 gas formed specifically from labeled INH by mycobacterial KatG enzyme. In vitro data shows the assay is specific, dependent on mycobacterial abundance, and discriminates between INH-sensitive and resistant (S315T mutant KatG) TB. In vivo, the assay is rapid with maximal detection of 15N2 in exhaled breath of infected rabbits within five to ten minutes. No increase in 15N2 is detected in un-infected animals, and the increases in 15N2 are dependent on infection dose. This test may allow rapid detection of INH-sensitive TB. PMID:25247851

  9. Synthesis, characterization, and efficacy of antituberculosis isoniazid zinc aluminum-layered double hydroxide based nanocomposites.

    PubMed

    Saifullah, Bullo; El Zowalaty, Mohamed Ezzat; Arulselvan, Palanisamy; Fakurazi, Sharida; Webster, Thomas J; Geilich, Benjamin Mahler; Hussein, Mohd Zobir

    2016-01-01

    The chemotherapy for tuberculosis (TB) is complicated by its long-term treatment, its frequent drug dosing, and the adverse effects of anti-TB drugs. In this study, we have developed two nanocomposites (A and B) by intercalating the anti-TB drug isoniazid (INH) into Zn/Al-layered double hydroxides. The average size of the nanocomposites was found to bê164 nm. The efficacy of the Zn/Al-layered double hydroxides intercalated INH against Mycobacterium tuberculosis was increased by approximately three times more than free INH. The nanocomposites were also found to be active against Gram-positive and -negative bacteria. Compared to the free INH, the nanodelivery formulation was determined to be three times more biocompatible with human normal lung fibroblast MRC-5 cells and 3T3 fibroblast cells at a very high concentration of 50 µg/mL for up to 72 hours. The in vitro release of INH from the Zn/Al-layered double hydroxides was found to be sustained in human body-simulated buffer solutions of pH 4.8 and 7.4. This research is a step forward in making the TB chemotherapy patient friendly. PMID:27486322

  10. Effect of isoniazid on the pharmacodynamics of cefazolin-induced seizures in rats.

    PubMed

    Ishiwata, Yasuyoshi; Nagata, Masashi; Yasuhara, Masato

    2005-04-01

    Both isoniazid (INH) and cefazolin (CEZ) can have serious adverse effects on the central nervous system (CNS), causing seizures. In this study, we investigated the effect of INH on the pharmacodynamics of CEZ-induced seizures in rats. Male Wistar rats pretreated with INH (150 mg/kg i.p.) or saline received an intravenous infusion of CEZ at 3.2 g/h/rat until the onset of seizures, then samples of cerebrospinal fluid (CSF), blood (for serum), and brain were obtained immediately. The administration of INH was associated with a reduction in the total dose of CEZ required to produce seizures. The concentrations of CEZ in serum, brain, and CSF in INH-treated rats at the onset of seizures were significantly lower than those in control rats. In rats coadministered with pyridoxine (150 mg/kg s.c.), the concentration of CEZ in CSF at the onset of seizures was significantly higher than that in rats administered INH only. These results suggest that INH potentiates the sensitivity of the CNS to CEZ-induced seizures, and that the increased sensitivity is associated with the inhibition of vitamin B(6) metabolism by INH.

  11. Circadian variation in murine hepatotoxicity to the antituberculosis agent «Isoniazide».

    PubMed

    Souayed, Nouha; Chennoufi, Malek; Boughattas, Fida; Haouas, Zohra; Maaroufi, Khira; Miled, Abdelhedi; Ben-Attia, Mosaddok; Aouam, Karim; Reinberg, Alain; Boughattas, Naceur A

    2015-01-01

    The circadian time is an important process affecting both pharmacokinetics and pharmacodynamics of drugs. Consequently, the desired and/or undesired effects vary according to the time of drug administration in the 24 h scale. This study investigates whether the toxicity in liver as well as oxidative stress varies according to the circadian dosing-time of isoniazid (INH) in mice. A potentially toxic INH dose (120 mg/kg) was injected by i.p. route to different groups of animals at three different circadian times: 1, 9, and 17 Zeitgeber time (ZT). INH administration at 1 ZT resulted in a maximum hepatotoxicity assessed by the significant increase in both serum transaminase (ALAT: alanine aminotransferase) and (ASAT: aspartate aminotransferase) and antioxidant enzyme activities (catalase: CAT and superoxide dismutase: SOD). The highest malondialdehyde (MDA) level indicating an induction of lipid peroxidation resulting in oxidative damage was also observed at 1 ZT. Liver histopathology from INH groups at 9 ZT and at 1 ZT showed moderate to severe cytoplasma vacuolation, hepatocyte hypertrophy, ballooning, and necrosis. The circadian variation in INH toxicity may help realize a chronotherapy protocol in humans based on the selection of the best time associated to optimal tolerance or least side effects.

  12. Cytoprotective effect of isoniazid against H2O2 derived injury in HL-60 cells.

    PubMed

    Khan, Saifur R; Aljuhani, Naif; Morgan, Andrew G M; Baghdasarian, Argishti; Fahlman, Richard P; Siraki, Arno G

    2016-01-25

    To combat tuberculosis (TB), host phagocytic cells need to survive against self-generating oxidative stress-induced necrosis. However, the effect of isoniazid (INH) in protecting cells from oxidative stress-induced necrosis has not been previously investigated. In this in vitro study, the cytotoxic effect of H2O2 generation using glucose oxidase (a model of oxidative stress) was found to be abrogated by INH in a concentration-dependent manner in HL-60 cells (a human promyelocytic leukemia cell). In cells treated with glucose oxidase, both ATP and mitochondrial membrane potential were found to be decreased. However, treatment with INH demonstrated small but significant attenuation in decreasing ATP levels, and complete reversal for the decrease in mitochondrial membrane potential. Quantitative proteomics analysis identified up-regulation of 15 proteins and down-regulation of 14 proteins which all together suggest that these proteomic changes signal for increasing cellular replication, structural integrity, ATP synthesis, and inhibiting cell death. In addition, studies demonstrated that myeloperoxidase (MPO) was involved in catalyzing INH-protein adduct formation. Unexpectedly, these covalent protein adducts were correlated with INH-induced cytoprotection in HL-60 cells. Further studies are needed to determine whether the INH-protein adducts were causative in the mechanism of cytoprotection.

  13. Quantitative proteomics reveals novel insights into isoniazid susceptibility in mycobacteria mediated by a universal stress protein.

    PubMed

    Hu, Xinling; Li, Xiaojing; Huang, Lige; Chan, John; Chen, Yuling; Deng, Haiteng; Mi, Kaixia

    2015-03-01

    Tuberculosis (TB) is caused by the ancient pathogen, Mycobacterium tuberculosis, and is one of the most serious infectious diseases in the world. Isoniazid (INH) is an important first-line drug for the treatment of active and latent TB. INH resistance is an increasing problem in the treatment of TB. Phenotypic resistance to INH, however, is poorly understood. In this study, we constructed a strain of Mycobacterium bovis BCG that overexpresses the latency-related universal stress protein (USP), BCG_2013, and designated this strain BCG-2013. BCG_2013 overexpression increased susceptibility to INH compared with that of the wild-type strain, BCG-pMV261. Quantitative proteomic analysis revealed that BCG_2013 overexpression resulted in the upregulation of 50 proteins and the downregulation of 26 proteins among the 1500 proteins identified. Upregulation of catalase-peroxidase KatG expression in BCG-2013 was observed and confirmed by qPCR, whereas expression of other INH resistance-related proteins did not change. In addition, differential expression of the mycobacterial persistence regulator MprA and its regulatory proteins was observed. BCG_2013 and katG mRNA levels increased in a Wayne dormancy model, whereas MprA mRNA levels decreased. Taken together, our results suggest that the increase in KatG levels induced by increased BCG_2013 levels underlies the phenotypic susceptibility of mycobacteria to INH.

  14. A silent mutation in mabA confers isoniazid resistance on Mycobacterium tuberculosis.

    PubMed

    Ando, Hiroki; Miyoshi-Akiyama, Tohru; Watanabe, Shinya; Kirikae, Teruo

    2014-02-01

    Drug resistance in Mycobacterium tuberculosis (Mtb) is caused by mutations in restricted regions of the genome. Mutations in katG, the promoter region of the mabA-inhA operon, and inhA are those most frequently responsible for isoniazid (INH) resistance. Several INH-resistant (INH(r) ) Mtb clinical isolates without mutations in these regions have been described, however, indicating that there are as yet undetermined mechanisms of INH resistance. We identified the mabA(g609a) silent mutation in a significant number of INH(r)  Mtb clinical isolates without known INH resistance mutations. A laboratory strain, H37Rv, constructed with mabA(g609a) , was resistant to INH. We show here that the mabA(g609a) mutation resulted in the upregulation of inhA, a gene encoding a target for INH, converting the region adjacent to the mutation into an alternative promoter for inhA. The mabA(g609a) silent mutation results in a novel mechanism of INH resistance, filling in a missing piece of INH resistance in Mtb.

  15. [Effects of ascorbic acid on the free radical formations of isoniazid and its metabolites].

    PubMed

    Matsuki, Y; Akazawa, M; Tsuchiya, K; Sakurai, H; Kiwada, H; Goromaru, T

    1991-10-01

    By the use of electron spin resonance (ESR) spectroscopy and of spin-trapping technique, the effects of ascorbic acid on the formation of the free radical intermediates due to isoniazid (INAH) and its metabolites were investigated with a microsomal system. When alpha-(4-pyridyl 1-oxide)-N-tert butylnitrone (4-POBN) was used as a spin trapping agent, the ESR signal due to hydrazine (Hy) was formed to be most intensive among others. Therefore, it was presumed that Hy is a potent intermediate to cause an INAH-induced hepatic injury. In the presence of ascorbic acid (AA), the free radical formation of Hy, INAH and acetyl hydrazine was significantly inhibited, suggesting that AA may affect the INAH-hepatitis. By the addition of inhibitors of cytochrome P-450 like metyrapone and CO, the generation of the radical from Hy decreased, confirming that the radical is formed by the cytochrome P-450 dependent microsome systems. The 4-POBN-trapped radical species generated from Hy was presumed to be the hydrazyl radical by the results of mass spectrometry.

  16. Effects of glucose and ascorbic acid on absorption and first pass metabolism of isoniazid in rats.

    PubMed

    Matsuki, Y; Katakuse, Y; Matsuura, H; Kiwada, H; Goromaru, T

    1991-02-01

    We examined the effect of glucose (Glu) and ascorbic acid (AA) on absorption and metabolism of isoniazid (INAH). After p.o. administration of INAH with or without Glu or AA, plasma concentration and urinary excretion of INAH and its metabolites, acetyl INAH (AcINAH), acetyl hydrazine (AcHy) and hydrazine (Hy), were determined by means of gas chromatography-mass spectrometry using stable isotope labeled compounds as internal standard. The combined administration of INAH with Glu or AA led to a significant decrease in the excretion of INAH and Hy, and a significant increase in the excretion of AcINAH and AcHy. The absorption amount of INAH was reduced to about one-half by the addition of Glu and the absorption rate of INAH markedly decreased in the case of co-administration of AA. Comparing the oral case with the results of i.v. administration, Glu and AA only affect the absorption process containing the first pass metabolism of INAH.

  17. Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria.

    PubMed

    Ahadpour, Morteza; Eskandari, Mohammad Reza; Mashayekhi, Vida; Haj Mohammad Ebrahim Tehrani, Kamaleddin; Jafarian, Iman; Naserzadeh, Parvaneh; Hosseini, Mir-Jamal

    2016-01-01

    Isoniazid (INH or isonicotinic hydrazide) is used for the treatment and prophylaxis of tuberculosis. Liver and brain are two important target organs in INH toxicity. However, the exact mechanisms behind the INH hepatotoxicity or neurotoxicity have not yet been completely understood. Considering the mitochondria as one of the possible molecular targets for INH toxicity, the aim of this study was to evaluate the mechanisms of INH mitochondrial toxicity on isolated mitochondria. Mitochondria were isolated by differential ultracentrifugation from male Sprague-Dawley rats and incubated with different concentrations of INH (25-2000 μM) for the investigation of mitochondrial parameters. The results indicated that INH could interact with mitochondrial respiratory chain and inhibit its activity. Our results showed an elevation in mitochondrial reactive oxygen species (ROS) formation, lipid peroxidation and mitochondrial membrane potential collapse after exposure of isolated liver mitochondria in INH. However, different results were obtained in brain mitochondria. Noteworthy, significant glutathione oxidation, adenosine triphosphate (ATP) depletion and lipid peroxidation were observed in higher concentration of INH, as compared to liver mitochondria. In conclusion, our results suggest that INH may initiate its toxicity in liver mitochondria through interaction with electron transfer chain, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion which ultimately lead to cell death signaling.

  18. PROPOSAL OF ANTI-TUBERCULOSIS REGIMENS BASED ON SUSCEPTIBILITY TO ISONIAZID AND RIFAMPICIN

    PubMed Central

    Mendoza-Ticona, Alberto; Moore, David AJ; Alarcón, Valentina; Samalvides, Frine; Seas, Carlos

    2014-01-01

    Objective To elaborate optimal anti-tuberculosis regimens following drug susceptibility testing (DST) to isoniazid (H) and rifampicin (R). Design 12 311 M. tuberculosis strains (National Health Institute of Peru 2007-2009) were classified in four groups according H and R resistance. In each group the sensitivity to ethambutol (E), pirazinamide (Z), streptomycin (S), kanamycin (Km), capreomycin (Cm), ciprofloxacin (Cfx), ethionamide (Eto), cicloserine (Cs) and p-amino salicilic acid (PAS) was determined. Based on resistance profiles, domestic costs, and following WHO guidelines, we elaborated and selected optimal putative regimens for each group. The potential efficacy (PE) variable was defined as the proportion of strains sensitive to at least three or four drugs for each regimen evaluated. Results Selected regimes with the lowest cost, and highest PE of containing 3 and 4 effective drugs for TB sensitive to H and R were: HRZ (99,5%) and HREZ (99,1%), respectively; RZECfx (PE=98,9%) and RZECfxKm (PE=97,7%) for TB resistant to H; HZECfx (96,8%) and HZECfxKm (95,4%) for TB resistant to R; and EZCfxKmEtoCs (82.9%) for MDR-TB. Conclusion Based on resistance to H and R it was possible to select anti-tuberculosis regimens with high probability of success. This proposal is a feasible alternative to tackle tuberculosis in Peru where the access to rapid DST to H and R is improving progressively. PMID:23949502

  19. Synthesis and Antifungal Activity In Vitro of Isoniazid Derivatives against Histoplasma capsulatum var. capsulatum

    PubMed Central

    de Farias Marques, Francisca Jakelyne; de Aguiar Cordeiro, Rebecca; da Silva, Marcos Reinaldo; Donato Maia Malaquias, Angela; Silva de Melo, Charlline Vládia; Mafezoli, Jair; Ferreira de Oliveira, Maria da Conceição; Nogueira Brilhante, Raimunda Sâmia; Gadelha Rocha, Marcos Fábio; Pinheiro Gomes Bandeira, Tereza de Jesus; Costa Sidrim, José Júlio

    2014-01-01

    Histoplasmosis is a severe infection that affects millions of patients worldwide and is endemic in the Americas. Amphotericin B (AMB) and itraconazole are highly effective for the treatment of severe and milder forms of the disease, but AMB is toxic, and the bioavailability of itraconazole is erratic. Therefore, it is important to investigate new classes of drugs for histoplasmosis treatment. In this study, a series of nine isoniazid hydrazone derivatives were synthesized and evaluated for their antifungal activities in vitro against the dimorphic fungus Histoplasma capsulatum var. capsulatum. The drugs were tested by microdilution in accordance with CLSI guidelines. The compound N′-(1-phenylethylidene)isonicotinohydrazide had the lowest MIC range of all the compounds for the yeast and filamentous forms of H. capsulatum. The in vitro synergy of this compound with AMB against the planktonic and biofilm forms of H. capsulatum cells was assessed by the checkerboard method. The effects of this hydrazone on cellular ergosterol content and membrane integrity were also investigated. The study showed that the compound alone is able to reduce the ergosterol content of planktonic cells and can alter the membrane permeability of the fungus. Furthermore, the compound alone or in combination with AMB showed inhibitory effects against mature biofilms of H. capsulatum. N′-(1-Phenylethylidene)isonicotinohydrazide alone or combined with AMB might be of interest in the management of histoplasmosis. PMID:24514090

  20. Radiosynthesis and Bioimaging of the Tuberculosis Chemotherapeutics Isoniazid, Rifampicin and Pyrazinamide in Baboons

    PubMed Central

    Liu, Li; Xu, Youwen; Shea, Colleen; Fowler, Joanna S.; Hooker, Jacob M.; Tonge, Peter J.

    2010-01-01

    The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [11C]CH3I to label RIF, and [11C]HCN to label INH and PZA. Following i.v. administration, INH, PZA, RIF and/or their radiolabeled metabolites clear rapidly from many tissues, however INH, PZA and/or their metabolites accumulate in the bladder while RIF and/or its metabolites accumulates in the liver and gall bladder, consistent with the routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood-brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth. The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain, and pave the way for imaging the distribution of the pathogen in vivo. PMID:20205479

  1. Hepatoprotection by carotenoids in isoniazid-rifampicin induced hepatic injury in rats.

    PubMed

    Rana, S V; Pal, R; Vaiphei, K; Ola, R P; Singh, K

    2010-10-01

    This study evaluates the hepatoprotective effect of carotenoids against isoniazid (INH) and rifampicin (RIF). Thirty-six adult rats were divided into the following 4 groups: (1) control group treated with normal saline; (2) INH + RIF group treated with 50 mg·(kg body mass)-1·day-1 of INH and RIF each; (3) INH + RIF+ carotenoids group treated with 50 mg·(kg body mass)-1·day-1 of INH and RIF each and 10 mg·(kg body mass)-1·day-1 of carotenoids; and (4) carotenoids group treated with 10 mg·(kg body mass)-1·day-1 of carotenoids for 28 days intragastrically. Oxidative stress and antioxidant levels in liver and blood, liver histology and change in transaminases were measured in all the above-mentioned groups. There was an increase in lipid peroxidation with a reduction in thiols, catalase, and superoxide dismutase (SOD) in the liver and blood of rats accompanied by an increase in transaminases, bilirubin, and alkaline phosphatase. Treatment with carotenoids along with INH + RIF partially reversed lipid peroxidation, thiols, catalase, and SOD in the liver and blood of rats. Elevated levels of the enzymes in serum were also reversed partially by this treatment. The degree of necrosis, portal triaditis, and inflammation were also lowered in the carotenoids group. In conclusion, carotenoids supplementation in INH + RIF treated rats showed partial protection.

  2. New Multiplex PCR for Rapid Detection of Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates

    PubMed Central

    Herrera-León, Laura; Molina, Tamara; Saíz, Pilar; Sáez-Nieto, Juan Antonio; Soledad Jiménez, Maria

    2005-01-01

    In this study, we describe a multiplex PCR to detect a AGC→ACC (serine to threonine) mutation in the katG gene and a −15 C-to-T substitution (inhAC−15T) at the 5′ end of a presumed ribosome binding site in the promoter of the mabA-inhA operon. These mutations have been reported in the majority of previous studies as the most frequent mutations involved in the resistance to isoniazid (INH) of Mycobacterium tuberculosis clinical strains with high levels of resistance. The method was optimized and validated after an analysis of 30 M. tuberculosis clinical isolates with known sequences of the relevant part of the katG gene and the regulatory region of the mabA-inhA operon. We analyzed 297 INH-resistant M. tuberculosis isolates collected in Spain from 1996 to 2003 by PCR-restriction fragment length polymorphism (using the katG gene), DNA sequencing, and the newly developed multiplex PCR. The results were concordant for all 297 isolates tested. The analysis revealed that 204 (68.7%) of the isolates carried one or both of the mutations. This finding suggests that with further development this multiplex PCR will be able to detect the majority of the INH-resistant M. tuberculosis clinical isolates from Spain and other countries where a high frequency of similar mutations occur. PMID:15616288

  3. Synthesis, characterization, and efficacy of antituberculosis isoniazid zinc aluminum-layered double hydroxide based nanocomposites

    PubMed Central

    Saifullah, Bullo; El Zowalaty, Mohamed Ezzat; Arulselvan, Palanisamy; Fakurazi, Sharida; Webster, Thomas J; Geilich, Benjamin Mahler; Hussein, Mohd Zobir

    2016-01-01

    The chemotherapy for tuberculosis (TB) is complicated by its long-term treatment, its frequent drug dosing, and the adverse effects of anti-TB drugs. In this study, we have developed two nanocomposites (A and B) by intercalating the anti-TB drug isoniazid (INH) into Zn/Al-layered double hydroxides. The average size of the nanocomposites was found to bê164 nm. The efficacy of the Zn/Al-layered double hydroxides intercalated INH against Mycobacterium tuberculosis was increased by approximately three times more than free INH. The nanocomposites were also found to be active against Gram-positive and -negative bacteria. Compared to the free INH, the nanodelivery formulation was determined to be three times more biocompatible with human normal lung fibroblast MRC-5 cells and 3T3 fibroblast cells at a very high concentration of 50 µg/mL for up to 72 hours. The in vitro release of INH from the Zn/Al-layered double hydroxides was found to be sustained in human body-simulated buffer solutions of pH 4.8 and 7.4. This research is a step forward in making the TB chemotherapy patient friendly. PMID:27486322

  4. Molecular analysis of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from India.

    PubMed

    Nusrath Unissa, A; Selvakumar, N; Narayanan, Sujatha; Narayanan, P R

    2008-01-01

    The presence of mutations in specific regions of katG, inhA, oxyR-ahpC and kasA associated with isoniazid (INH)-resistant clinical isolates of Mycobacterium tuberculosis from India were analysed by DNA sequencing. Point mutations in the katG gene at codon 315 and a mutation at codon 138 were detected in 64.3% (45/70) and 4% (1/25) of isolates, respectively. Polymorphisms at codon 463 of the katG gene were found both in resistant and sensitive isolates. Mutation at the inhA and oxyR-ahpC promoter regions occurred in 11.4% (8/70) and 35.0% (14/40) of the isolates, respectively. No mutation was found to occur in kasA and inhA structural gene regions. Of the 70 resistant isolates studied, 55 (78.6%) showed mutation in the regions sequenced. This is the first comprehensive molecular analysis of INH resistance in India, which suggests that point mutation rather than deletion and insertion is the major cause of INH resistance. PMID:18006278

  5. Detection of mutations associated with isoniazid resistance in Mycobacterium tuberculosis isolates from China.

    PubMed

    Zhang, Min; Yue, Jun; Yang, Yan-Ping; Zhang, Hong-Mei; Lei, Jian-Qiang; Jin, Rui-Liang; Zhang, Xue-Lian; Wang, Hong-Hai

    2005-11-01

    Nine structural genes (furA, katG, inhA, kasA, Rv0340, iniB, iniA, iniC, and efpA) and two regulatory regions (the oxyR-ahpC intergenic region and the promoter of mabA-inhA) in 87 isoniazid (INH)-monoresistant and 50 INH-susceptible Mycobacterium tuberculosis isolates collected from five provinces of China were analyzed by sequencing. Eighty-two (94.3%) INH-resistant isolates had mutations in the katG gene, with the katG Ser315Thr mutation predominant (55.2%). No mutation at codon 463 of katG was detected among the 50 INH-susceptible isolates with different IS6110 fingerprints. In addition, there were 35 (40.2%) INH-resistant isolates that had a mutation at codon 463 of katG. Of the INH-resistant strains, 20 (23.0%) isolates harbored double mutations at two separate loci of katG. Mutations in the inhA promoter region occurred in 13 (14.9%) isolates; 4.6% of the isolates had inhA structural gene mutations, and 11.5% harbored mutations in the oxyR-ahpC intergenic region. Drug resistance-associated mutations were detected in the iniBAC region and efpA. PMID:16272473

  6. Susceptibilities of Mycobacterium tuberculosis to isoniazid and rifampin on blood agar.

    PubMed

    Coban, Ahmet Yilmaz; Bilgin, Kemal; Uzun, Meltem; Tasdelen Fisgin, Nuriye; Akgunes, Alper; Cihan, Cigdem Cekic; Birinci, Asuman; Durupinar, Belma

    2005-04-01

    In this study, blood agar was used instead of 7H10 agar for the susceptibility testing of 34 clinical isolates of Mycobacterium tuberculosis to isoniazid (INH) and rifampin (RIF) in accordance with the NCCLS. The BACTEC 460 TB system (Becton Dickinson, Sparks, Md.) was used as a "gold standard." Results for both media were in agreement for RIF and INH at 100 and 94.1%, respectively. For INH, the specificity, sensitivity, positive predictive value, and negative predictive value were found to be 71.4, 100, 93.1, and 100%, respectively, while these values were 100% for RIF. In addition, the results of the susceptibility test performed with blood agar were obtained on day 14 of incubation. In conclusion, results were obtained much earlier with blood agar (2 weeks) than with 7H10 agar (3 weeks), and the results of this study suggest that blood agar may be used as an alternative medium for the susceptibility testing of M. tuberculosis to INH and RIF.

  7. Blood agar validation for susceptibility testing of isoniazid, rifampicin, ethambutol, and streptomycin to Mycobacterium tuberculosis isolates.

    PubMed

    Coban, Ahmet Yilmaz

    2013-01-01

    In recent studies, it was shown that blood agar can be used at least as effectively as Löwenstein-Jensen medium for growing Mycobacterium tuberculosis. It was also shown that susceptibility testing can be performed on blood agar. Additional validation of blood agar was performed on regional M. tuberculosis isolates from Turkey to determine critical concentrations of isoniazid (INH), rifampicin (RIF), ethambutol (ETM), and streptomycin (STR). In the current study, 40 M. tuberculosis clinical isolates were tested. H37Rv, which is susceptible to all antituberculosis agents, ATCC 35822 (INH-resistant), ATCC 35838 (RIF-resistant), ATCC 35837 (ETM-resistant), and ATCC 35820 (STR-resistant) quality control strains were used as control strains. Proportion method on 7H11 agar was considered as gold standard in the study. MIC values of the control strains and clinical isolates were detected on blood and 7H11 agar. Categorical agreements were 100% for each antibiotic, and essential agreements were 100%, 97.5%, 82.5%, and 95% for INH, RIF, ETM, and STR, respectively. According to the data, 0.2 µg/mL for INH, 1 µg/mL for RIF, 4 µg/mL for ETM, and 2 µg/mL for STR were appropriate breakpoint values for susceptibility testing on blood agar. Blood agar may be recommended for use in both developed and developing countries for the susceptibility testing of M. tuberculosis isolates to primary antituberculosis drugs.

  8. Genotypic and phenotypic characteristics of tunisian isoniazid-resistant Mycobacterium tuberculosis strains.

    PubMed

    Soudani, Alya; Hadjfredj, Sondess; Zribi, Meriem; Messaadi, Feriel; Messaoud, Taieb; Masmoudi, Afef; Zribi, Mohamed; Fendri, Chedlia

    2011-06-01

    Forty three isoniazid (INH)-resistant Mycobacterium tuberculosis isolates were characterized on the basis of the most common INH associated mutations, katG315 and mabA -15C→T, and phenotypic properties (i.e. MIC of INH, resistance associated pattern, and catalase activity). Typing for resistance mutations was performed by Multiplex Allele-Specific PCR and sequencing reaction. Mutations at either codon were detected in 67.5% of isolates: katG315 in 37.2, mabA -15C→T in 27.9 and both of them in 2.4%, respectively. katG sequencing showed a G insertion at codon 325 detected in 2 strains and leading to amino acid change T326D which has not been previously reported. Distribution of each mutation, among the investigated strains, showed that katG S315T was associated with multiple-drug profile, high-level INH resistance and loss or decreased catalase activity; whereas the mabA -15C→T was more prevalent in mono-INH resistant isolates, but it was not only associated with a low-level INH resistance. It seems that determination of catalase activity aids in the detection of isolates for which MICs are high and could, in conjunction with molecular methods, provide rapid detection of most clinical INH-resistant strains.

  9. [Bilateral Granulomatous Renal Masses after Intravesical BCG Therapy for Non-muscle-invasive Bladder Cancer and Carcinoma in Situ of the Upper Urinary Tract: A Case Study].

    PubMed

    Higashioka, Kazuhiko; Miyake, Noriko; Nishida, Ruriko; Chong, Yong; Shimoda, Shinji; Shimono, Nobuyuki

    2015-07-01

    Bacillus Calmette-Guèrin (BCG) is commonly used not only as an infant vaccination, but also as a treatment of and prophylaxis to prevent recurrence in the management of non-muscle-invasive bladder cancer. However, the use of "live" BCG is sometimes complicated by associated infection. We present a case study of a 77-year-old man who developed bilateral renal masses after intravesical BCG therapy was initiated in November 2013, following transurethral resection of non-muscle-invasive bladder cancer. After four courses of BCG (Japan strain, 80 mg per treatment) instillations, a computed tomography examination for febrile episodes showed multiple bilateral renal masses, accompanied by a histological finding of a granulomatous reaction. An acid fast bacterium was cultured from only urine among blood, urine, and microscopic samples. Using the cultured strain, BCG infection was confirmed by the specific gene deletion pattern based on allele-specific polymerase chain reaction analysis. Anti-tuberculosis treatment, including isoniazid (300 mg/day), rifampicin (600 mg/day), and ethambutol (1,000 mg/day), was started for the BCG-related renal granuloma in February 2014. After 3 months, antibiotic therapy was discontinued owing to severe appetite loss, though the masses remained solid. No rapid growth has been detected after anti-BCG therapy. Intravesical BCG therapy is recommended worldwide as one of standard treatments for non-muscle-invasive bladder cancer. We should closely observe patients undergoing this approach for emerging BCG complications.

  10. Low-level laser therapy for the prevention of low salivary flow rate after radiotherapy and chemotherapy in patients with head and neck cancer*

    PubMed Central

    Gonnelli, Fernanda Aurora Stabile; Palma, Luiz Felipe; Giordani, Adelmo José; Deboni, Aline Lima Silva; Dias, Rodrigo Souza; Segreto, Roberto Araújo; Segreto, Helena Regina Comodo

    2016-01-01

    Objective To determine whether low-level laser therapy can prevent salivary hypofunction after radiotherapy and chemotherapy in head and neck cancer patients. Materials and Methods We evaluated 23 head and neck cancer patients, of whom 13 received laser therapy and 10 received clinical care only. An InGaAlP laser was used intra-orally (at 660 nm and 40 mW) at a mean dose of 10.0 J/cm2 and extra-orally (at 780 nm and 15 mW) at a mean dose of 3.7 J/cm2, three times per week, on alternate days. Stimulated and unstimulated sialometry tests were performed before the first radiotherapy and chemotherapy sessions (N0) and at 30 days after the end of treatment (N30). Results At N30, the mean salivary flow rates were significantly higher among the laser therapy patients than among the patients who received clinical care only, in the stimulated and unstimulated sialometry tests (p = 0.0131 and p = 0.0143, respectively). Conclusion Low-level laser therapy, administered concomitantly with radiotherapy and chemotherapy, appears to mitigate treatment-induced salivary hypofunction in patients with head and neck cancer. PMID:27141130

  11. Short-course treatment of latent tuberculosis infection in patients with rheumatic conditions proposed for anti-TNF therapy.

    PubMed

    Valls, Victoria; Ena, Javier

    2015-01-01

    Tuberculosis reactivation is a serious threat in patients treated with anti-tumour necrosis factor therapy. A 6-month regimen with isoniazid is considered as the standard of care, but patient adherence is a major shortcoming. We carried out an open-label, single-arm intervention study to assess the efficacy, the completion rate and the tolerability of a 3-month regimen with isoniazid plus rifampin. Seventy-eight patients with rheumatic conditions proposed for anti-tumour necrosis factor (TNF) therapy and at risk of tuberculosis reactivation were offered to participate in the study. Nine patients were excluded due to deficit of glucose-6-phosphate dehydrogenase (n = 1), salicylate hypersensitivity (n = 1), declining to participate (n = 5) or preferring a 6-month isoniazid regimen (n = 6). Sixty-nine patients were treated with a 3-month regimen with isoniazid and rifampin. No cases of tuberculosis were observed after a mean follow-up of 90 months (range from 66 to 121 months). Sixty (87 %) patients completed the therapy. Nine (13 %) patients discontinued the therapy due to rifampin hypersensitivity (n = 1), symptomatic grade 3-4 hepatotoxicity (n = 2), abdominal discomfort (n = 2), pruritus (n = 1), arthritis (n = 1) and personal concerns (n = 2). A short course treatment with isoniazid and rifampin provided efficacy, good tolerability and good completion rate in patients with rheumatic conditions proposed for anti-TNF therapy.

  12. Relationship Between Nonprescribed Therapy Use for Illness Prevention and Health Promotion and Health-Related Quality of Life

    PubMed Central

    Altizer, Kathryn P.; Nguyen, Ha T.; Neiberg, Rebecca H.; Quandt, Sara A.; Grzywacz, Joseph G.; Lang, Wei; Bell, Ronny A.; Arcury, Thomas A.

    2014-01-01

    Objectives This study describes the nonprescribed therapy use (prayer, over-the-counter medications [OTC's], home remedies, vitamins, herbs and supplements, and exercise) for health promotion among rural elders. It also delineates the association of such therapy use with physical and mental health-related quality of life (HRQoL). Method The sample (N = 200) consisted of African American and White elders from south-central North Carolina. Participants completed baseline interviews and repeated measures of nonprescribed therapy use over a 6-month follow-up. Results Prayer had the highest percentage (80.7%) of use for health promotion followed by OTC (54.3%); vitamins only (49.3%); herbs and supplements (40.5%); exercise (31.9%); and home remedies (5.2%). Exercise was significantly associated with better physical HRQoL (p < .05). However, elders who used nonprescribed therapies had poorer mental HRQoL than nonusers, adjusting for potential confounders. Conclusion This analysis suggests that use of some nonprescribed therapies for health promotion is associated with poorer mental HRQoL. PMID:24781966

  13. Oral Mucositis Prevention By Low-Level Laser Therapy in Head-and-Neck Cancer Patients Undergoing Concurrent Chemoradiotherapy: A Phase III Randomized Study

    SciTech Connect

    Gouvea de Lima, Aline; Villar, Rosangela Correa; Castro, Gilberto de; Antequera, Reynaldo; Gil, Erlon; Rosalmeida, Mauro Cabral; Federico, Miriam Hatsue Honda; Snitcovsky, Igor Moises Longo

    2012-01-01

    Purpose: Oral mucositis is a major complication of concurrent chemoradiotherapy (CRT) in head-and-neck cancer patients. Low-level laser (LLL) therapy is a promising preventive therapy. We aimed to evaluate the efficacy of LLL therapy to decrease severe oral mucositis and its effect on RT interruptions. Methods and Materials: In the present randomized, double-blind, Phase III study, patients received either gallium-aluminum-arsenide LLL therapy 2.5 J/cm{sup 2} or placebo laser, before each radiation fraction. Eligible patients had to have been diagnosed with squamous cell carcinoma or undifferentiated carcinoma of the oral cavity, pharynx, larynx, or metastases to the neck with an unknown primary site. They were treated with adjuvant or definitive CRT, consisting of conventional RT 60-70 Gy (range, 1.8-2.0 Gy/d, 5 times/wk) and concurrent cisplatin. The primary endpoints were the oral mucositis severity in Weeks 2, 4, and 6 and the number of RT interruptions because of mucositis. The secondary endpoints included patient-reported pain scores. To detect a decrease in the incidence of Grade 3 or 4 oral mucositis from 80% to 50%, we planned to enroll 74 patients. Results: A total of 75 patients were included, and 37 patients received preventive LLL therapy. The mean delivered radiation dose was greater in the patients treated with LLL (69.4 vs. 67.9 Gy, p = .03). During CRT, the number of patients diagnosed with Grade 3 or 4 oral mucositis treated with LLL vs. placebo was 4 vs. 5 (Week 2, p = 1.0), 4 vs. 12 (Week 4, p = .08), and 8 vs. 9 (Week 6, p = 1.0), respectively. More of the patients treated with placebo had RT interruptions because of mucositis (6 vs. 0, p = .02). No difference was detected between the treatment arms in the incidence of severe pain. Conclusions: LLL therapy was not effective in reducing severe oral mucositis, although a marginal benefit could not be excluded. It reduced RT interruptions in these head-and-neck cancer patients, which might

  14. Randomized Trial of Behavioral Activation, Cognitive Therapy, and Antidepressant Medication in the Prevention of Relapse and Recurrence in Major Depression

    ERIC Educational Resources Information Center

    Dobson, Keith S.; Hollon, Steven D.; Dimidjian, Sona; Schmaling, Karen B.; Kohlenberg, Robert J.; Gallop, Robert J.; Rizvi, Shireen L.; Gollan, Jackie K.; Dunner, David L.; Jacobson, Neil S.

    2008-01-01

    This study followed treatment responders from a randomized controlled trial of adults with major depression. Patients treated with medication but withdrawn onto pill-placebo had more relapse through 1 year of follow-up compared to patients who received prior behavioral activation, prior cognitive therapy, or continued medication. Prior…

  15. Promoting Positive Interactions in the Classroom: Adapting Parent-Child Interaction Therapy as a Universal Prevention Program

    ERIC Educational Resources Information Center

    Gershenson, Rachel A.; Lyon, Aaron R.; Budd, Karen S.

    2010-01-01

    The adaptation of Parent-Child Interaction Therapy (PCIT), an empirically-supported dyadic parent training intervention, to a preschool setting may provide an opportunity to enhance the well-being of both teachers and children by improving the teacher-child relationship and supplying teachers with effective tools for behavior management. The…

  16. BET 1: Safety and efficacy of colchicine as stand-alone therapy for the prevention of recurrent pericarditis.

    PubMed

    Manspeaker, Andrew; Andrews-Dickert, Rebecca

    2016-08-01

    A short cut review was carried out looking for evidence of the benefits of using colchicine as a single therapy for acute pericarditis. A literature search was performed but no papers were found to provide evidence of the efficacy of colchicine without the concurrent use of Non-steriodal anti-inflammatory drugs (NSAIDs) for this condition. PMID:27440768

  17. Systematic review and meta-analysis: Multi-strain probiotics as adjunct therapy for Helicobacter pylori eradication and prevention of adverse events

    PubMed Central

    Huang, Ying; Wang, Lin; Malfertheiner, Peter

    2015-01-01

    Background Eradication rates with triple therapy for Helicobacter pylori infections have currently declined to unacceptable levels worldwide. Newer quadruple therapies are burdened with a high rate of adverse events. Whether multi-strain probiotics can improve eradication rates or diminish adverse events remains uncertain. Methods Relevant publications in which patients with H. pylori infections were randomized to a multi-strain probiotic or control were identified in PubMed, Cochrane Databases, and other sources from 1 January 1960–3 June 2015. Primary outcomes included eradication rates, incidence of any adverse event and the incidence of antibiotic-associated diarrhea. As probiotic efficacy is strain-specific, pooled relative risks and 95% confidence intervals were calculated using meta-analysis stratified by similar multi-strain probiotic mixtures. Results A total of 19 randomized controlled trials (20 treatment arms, n = 2730) assessing one of six mixtures of strains of probiotics were included. Four multi-strain probiotics significantly improved H. pylori eradication rates, five significantly prevented any adverse reactions and three significantly reduced antibiotic-associated diarrhea. Only two probiotic mixtures (Lactobacillus acidophilus/Bifidobacterium animalis and an eight-strain mixture) had significant efficacy for all three outcomes. Conclusions Our meta-analysis found adjunctive use of some multi-strain probiotics may improve H. pylori eradication rates and prevent the development of adverse events and antibiotic-associated diarrhea, but not all mixtures were effective. PMID:27536365

  18. Novel katG mutations causing isoniazid resistance in clinical M. tuberculosis isolates

    PubMed Central

    Torres, Jessica N; Paul, Lynthia V; Rodwell, Timothy C; Victor, Thomas C; Amallraja, Anu M; Elghraoui, Afif; Goodmanson, Amy P; Ramirez-Busby, Sarah M; Chawla, Ashu; Zadorozhny, Victoria; Streicher, Elizabeth M; Sirgel, Frederick A; Catanzaro, Donald; Rodrigues, Camilla; Gler, Maria Tarcela; Crudu, Valeru; Catanzaro, Antonino; Valafar, Faramarz

    2015-01-01

    We report the discovery and confirmation of 23 novel mutations with previously undocumented role in isoniazid (INH) drug resistance, in catalase-peroxidase (katG) gene of Mycobacterium tuberculosis (Mtb) isolates. With these mutations, a synonymous mutation in fabG1g609a, and two canonical mutations, we were able to explain 98% of the phenotypic resistance observed in 366 clinical Mtb isolates collected from four high tuberculosis (TB)-burden countries: India, Moldova, Philippines, and South Africa. We conducted overlapping targeted and whole-genome sequencing for variant discovery in all clinical isolates with a variety of INH-resistant phenotypes. Our analysis showed that just two canonical mutations (katG 315AGC-ACC and inhA promoter-15C-T) identified 89.5% of resistance phenotypes in our collection. Inclusion of the 23 novel mutations reported here, and the previously documented point mutation in fabG1, increased the sensitivity of these mutations as markers of INH resistance to 98%. Only six (2%) of the 332 resistant isolates in our collection did not harbor one or more of these mutations. The third most prevalent substitution, at inhA promoter position -8, present in 39 resistant isolates, was of no diagnostic significance since it always co-occurred with katG 315. 79% of our isolates harboring novel mutations belong to genetic group 1 indicating a higher tendency for this group to go down an uncommon evolutionary path and evade molecular diagnostics. The results of this study contribute to our understanding of the mechanisms of INH resistance in Mtb isolates that lack the canonical mutations and could improve the sensitivity of next generation molecular diagnostics. PMID:26251830

  19. Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.

    PubMed

    Seng, Kok-Yong; Hee, Kim-Hor; Soon, Gaik-Hong; Chew, Nicholas; Khoo, Saye H; Lee, Lawrence Soon-U

    2015-11-01

    In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤ Cmax ≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

  20. Effects of repeated administration of rifampicin and isoniazid on vitamin D metabolism in mice.

    PubMed

    Sheng, Li; Xue, Ying; He, Xin; Zhu, Yungui; Li, Huande; Wu, Yanqin; Dang, Ruili; Tang, Mimi; Jiang, Pei

    2015-12-01

    Vitamin D deficiency is prevalent in tuberculosis (TB) patients and the anti-TB drugs, especially rifampicin (RIF) and isoniazid (INH), are associated with altered endocrine actions of vitamin D. Although it is well-known that these two drugs can affect a variety of cytochrome P450 (CYP450) activity, their influence on the CYP450 enzymes involved in vitamin D metabolism remains largely unknown. To fill this critical gap, serum vitamin D status and the expression of hepatic CYP2R1 and CYP27A1 and renal CYP27B1 and CYP24A1 were assessed in mice following 3-week exposure to 100 mg/kg/day RIF or (and) 50 mg/kg/day INH. Unexpectedly, we found either RIF or co-treatment the two drugs increased the concentrations of 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), without affecting 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) status. In parallel, enhanced hepatic expressions of 25-hydroxylase enzymes, CYP2R1 and (or) CYP27A1, were found in RIF and RIF+INH groups. However, co-administration of RIF and INH inhibited the expression of CYP27B1, while inducing CYP24A1 expression. Collectively, our data firstly showed that RIF and co-treatment of RIF and INH can both enhance 25-hydroxylation and 24-hydroxylation of vitamin D, providing novel evidence for the involvement of anti-TB drugs in the metabolism of vitamin D.

  1. Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis: Genes, Mutations, and Causalities.

    PubMed

    Vilchèze, Catherine; Jacobs, William R

    2014-08-01

    Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant Mycobacterium tuberculosis strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalase-peroxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD+ to form an INH-NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in katG, encoding the activator of INH. One specific KatG variant, S315T, is found in 94% of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of inhA (c-15t), which results in inhA overexpression and leads to titration of the drug. Mutations in the inhA open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH-resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs' activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in M. tuberculosis clinical isolates.

  2. Isoniazid-induced cell death is precipitated by underlying mitochondrial complex I dysfunction in mouse hepatocytes.

    PubMed

    Lee, Kang Kwang; Fujimoto, Kazunori; Zhang, Carmen; Schwall, Christine T; Alder, Nathan N; Pinkert, Carl A; Krueger, Winfried; Rasmussen, Theodore; Boelsterli, Urs A

    2013-12-01

    Isoniazid (INH) is an antituberculosis drug that has been associated with idiosyncratic liver injury in susceptible patients. The underlying mechanisms are still unclear, but there is growing evidence that INH and/or its major metabolite, hydrazine, may interfere with mitochondrial function. However, hepatic mitochondria have a large reserve capacity, and minor disruption of energy homeostasis does not necessarily induce cell death. We explored whether pharmacologic or genetic impairment of mitochondrial complex I may amplify mitochondrial dysfunction and precipitate INH-induced hepatocellular injury. We found that INH (≤ 3000 μM) did not induce cell injury in cultured mouse hepatocytes, although it decreased hepatocellular respiration and ATP levels in a concentration-dependent fashion. However, coexposure of hepatocytes to INH and nontoxic concentrations of the complex I inhibitors rotenone (3 μM) or piericidin A (30 nM) resulted in massive ATP depletion and cell death. Although both rotenone and piericidin A increased MitoSox-reactive fluorescence, Mito-TEMPO or N-acetylcysteine did not attenuate the extent of cytotoxicity. However, preincubation of cells with the acylamidase inhibitor bis-p-nitrophenol phosphate provided protection from hepatocyte injury induced by rotenone/INH (but not rotenone/hydrazine), suggesting that hydrazine was the cell-damaging species. Indeed, we found that hydrazine directly inhibited the activity of solubilized complex II. Hepatocytes isolated from mutant Ndufs4(+/-) mice, although featuring moderately lower protein expression levels of this complex I subunit in liver mitochondria, exhibited unchanged hepatic complex I activity and were therefore not sensitized to INH. These data indicate that underlying inhibition of complex I, which alone is not acutely toxic, can trigger INH-induced hepatocellular injury.

  3. Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs.

    PubMed

    Lalande, L; Bourguignon, L; Bihari, S; Maire, P; Neely, M; Jelliffe, R; Goutelle, S

    2015-09-01

    Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

  4. Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs.

    PubMed

    Lalande, L; Bourguignon, L; Bihari, S; Maire, P; Neely, M; Jelliffe, R; Goutelle, S

    2015-09-01

    Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains. PMID:26077251

  5. A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy

    PubMed Central

    Thiel, Christoph; Aschmann, Hélène E.; Baier, Vanessa; Blank, Lars M.

    2016-01-01

    Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens. PMID:27480867

  6. Simplified microarray system for simultaneously detecting rifampin, isoniazid, ethambutol, and streptomycin resistance markers in Mycobacterium tuberculosis.

    PubMed

    Linger, Yvonne; Kukhtin, Alexander; Golova, Julia; Perov, Alexander; Lambarqui, Amine; Bryant, Lexi; Rudy, George B; Dionne, Kim; Fisher, Stefanie L; Parrish, Nicole; Chandler, Darrell P

    2014-06-01

    We developed a simplified microarray test for detecting and identifying mutations in rpoB, katG, inhA, embB, and rpsL and compared the analytical performance of the test to that of phenotypic drug susceptibility testing (DST). The analytical sensitivity was estimated to be at least 110 genome copies per amplification reaction. The microarray test correctly detected 95.2% of mutations for which there was a sequence-specific probe on the microarray and 100% of 96 wild-type sequences. In a blinded analysis of 153 clinical isolates, microarray sensitivity for first-line drugs relative to phenotypic DST (true resistance) was 100% for rifampin (RIF) (14/14), 90.0% for isoniazid (INH) (36/40), 70% for ethambutol (EMB) (7/10), and 89.1% (57/64) combined. Microarray specificity (true susceptibility) for first-line agents was 95.0% for RIF (132/139), 98.2% for INH (111/113), and 98.6% for EMB (141/143). Overall microarray specificity for RIF, INH, and EMB combined was 97.2% (384/395). The overall positive and negative predictive values for RIF, INH, and EMB combined were 84.9% and 98.3%, respectively. For the second-line drug streptomycin (STR), overall concordance between the agar proportion method and microarray analysis was 89.5% (137/153). Sensitivity was 34.8% (8/23) because of limited microarray coverage for STR-conferring mutations, and specificity was 99.2% (129/130). All false-susceptible discrepant results were a consequence of DNA mutations that are not represented by a specific microarray probe. There were zero invalid results from 220 total tests. The simplified microarray system is suitable for detecting resistance-conferring mutations in clinical M. tuberculosis isolates and can now be used for prospective trials or integrated into an all-in-one, closed-amplicon consumable.

  7. Treatment Outcomes with Fluoroquinolone-Containing Regimens for Isoniazid-Resistant Pulmonary Tuberculosis

    PubMed Central

    Lee, Hyun; Jeong, Byeong-Ho; Park, Hye Yun; Jeon, Kyeongman; Huh, Hee Jae; Lee, Nam Yong

    2015-01-01

    Resistance to isoniazid (INH) is the most common form of drug resistance in pulmonary tuberculosis (TB). Although fluoroquinolones (FQs) are recommended to strengthen treatment regimens for INH-resistant pulmonary TB, few studies have evaluated the clinical efficacy of FQ-containing regimens in patients with INH-resistant pulmonary TB. A retrospective cohort study of 140 patients with INH-resistant pulmonary TB was performed between 2005 and 2012. We evaluated whether FQ-containing regimens yielded improved treatment outcomes for patients with INH-resistant pulmonary TB. Overall, favorable outcomes were achieved in 128 (91.4%) patients. Unfavorable outcomes occurred in 12 patients (8.6%), including 7 with treatment failure (5.0%) and 5 with relapse after initial treatment completion (3.6%). FQs, such as levofloxacin and moxifloxacin, were given to 75 (53.6%) patients. Favorable treatment outcomes were more frequent for patients who received FQs (97.3% [73/75 patients]) than for those who did not receive FQs (84.6% [55/65 patients]) (P = 0.007). Patients who did not receive FQs were more likely to develop treatment failure (9.2% [6/65 patients] versus 1.3% [1/75 patients]) (P = 0.049) than patients who received FQs. The adjusted proportion of unfavorable outcomes was significantly higher among patients who did not receive FQs (8.8%; 95% confidence interval [CI], 3.3 to 21.5%) than among those who did receive FQs (1.5%; 95% CI, 0.3 to 7.7%) (P = 0.037). These results suggest that the addition of FQs can improve treatment outcomes for patients with INH-resistant pulmonary TB. PMID:26525801

  8. Novel katG mutations causing isoniazid resistance in clinical M. tuberculosis isolates.

    PubMed

    Torres, Jessica N; Paul, Lynthia V; Rodwell, Timothy C; Victor, Thomas C; Amallraja, Anu M; Elghraoui, Afif; Goodmanson, Amy P; Ramirez-Busby, Sarah M; Chawla, Ashu; Zadorozhny, Victoria; Streicher, Elizabeth M; Sirgel, Frederick A; Catanzaro, Donald; Rodrigues, Camilla; Gler, Maria Tarcela; Crudu, Valeru; Catanzaro, Antonino; Valafar, Faramarz

    2015-07-01

    We report the discovery and confirmation of 23 novel mutations with previously undocumented role in isoniazid (INH) drug resistance, in catalase-peroxidase (katG) gene of Mycobacterium tuberculosis (Mtb) isolates. With these mutations, a synonymous mutation in fabG1 (g609a), and two canonical mutations, we were able to explain 98% of the phenotypic resistance observed in 366 clinical Mtb isolates collected from four high tuberculosis (TB)-burden countries: India, Moldova, Philippines, and South Africa. We conducted overlapping targeted and whole-genome sequencing for variant discovery in all clinical isolates with a variety of INH-resistant phenotypes. Our analysis showed that just two canonical mutations (katG 315AGC-ACC and inhA promoter-15C-T) identified 89.5% of resistance phenotypes in our collection. Inclusion of the 23 novel mutations reported here, and the previously documented point mutation in fabG1, increased the sensitivity of these mutations as markers of INH resistance to 98%. Only six (2%) of the 332 resistant isolates in our collection did not harbor one or more of these mutations. The third most prevalent substitution, at inhA promoter position -8, present in 39 resistant isolates, was of no diagnostic significance since it always co-occurred with katG 315. 79% of our isolates harboring novel mutations belong to genetic group 1 indicating a higher tendency for this group to go down an uncommon evolutionary path and evade molecular diagnostics. The results of this study contribute to our understanding of the mechanisms of INH resistance in Mtb isolates that lack the canonical mutations and could improve the sensitivity of next generation molecular diagnostics.

  9. Detecting Novel Genetic Variants Associated with Isoniazid-Resistant Mycobacterium tuberculosis

    PubMed Central

    Chan, Maurice K. L.; Ong, Danny C. T.; Tongyoo, Pumipat; Wong, Sin-Yew; Lee, Ann S. G.

    2014-01-01

    Background Isoniazid (INH) is a highly effective antibiotic central for the treatment of Mycobacterium tuberculosis (MTB). INH-resistant MTB clinical isolates are frequently mutated in the katG gene and the inhA promoter region, but 10 to 37% of INH-resistant clinical isolates have no detectable alterations in currently known gene targets associated with INH-resistance. We aimed to identify novel genes associated with INH-resistance in these latter isolates. Methodology/Principal Findings INH-resistant clinical isolates of MTB were pre-screened for mutations in the katG, inhA, kasA and ndh genes and the regulatory regions of inhA and ahpC. Twelve INH-resistant isolates with no mutations, and 17 INH-susceptible MTB isolates were subjected to whole genome sequencing. Phylogenetically related variants and synonymous mutations were excluded and further analysis revealed mutations in 60 genes and 4 intergenic regions associated with INH-resistance. Sanger sequencing verification of 45 genes confirmed that mutations in 40 genes were observed only in INH-resistant isolates and not in INH-susceptible isolates. The ratios of non-synonymous to synonymous mutations (dN/dS ratio) for the INH-resistance associated mutations identified in this study were 1.234 for INH-resistant and 0.654 for INH-susceptible isolates, strongly suggesting that these mutations are indeed associated with INH-resistance. Conclusion The discovery of novel targets associated with INH-resistance described in this study may potentially be important for the development of improved molecular detection strategies. PMID:25025225

  10. Screening and characterization of mutations in isoniazid-resistant Mycobacterium tuberculosis isolates obtained in Brazil.

    PubMed

    Cardoso, Rosilene Fressatti; Cooksey, Robert C; Morlock, Glenn P; Barco, Patricia; Cecon, Leticia; Forestiero, Francisco; Leite, Clarice Q F; Sato, Daisy N; Shikama, Maria de Lourdes; Mamizuka, Elsa M; Hirata, Rosario D C; Hirata, Mario H

    2004-09-01

    We investigated mutations in the genes katG, inhA (regulatory and structural regions), and kasA and the oxyR-ahpC intergenic region of 97 isoniazid (INH)-resistant and 60 INH-susceptible Mycobacterium tuberculosis isolates obtained in two states in Brazil: São Paulo and Paraná. PCR-single-strand conformational polymorphism (PCR-SSCP) was evaluated for screening mutations in regions of prevalence, including codons 315 and 463 of katG, the regulatory region and codons 16 and 94 of inhA, kasA, and the oxyR-ahpC intergenic region. DNA sequencing of PCR amplicons was performed for all isolates with altered PCR-SSCP profiles. Mutations in katG were found in 83 (85.6%) of the 97 INH-resistant isolates, including mutations in codon 315 that occurred in 60 (61.9%) of the INH-resistant isolates and 23 previously unreported katG mutations. Mutations in the inhA promoter region occurred in 25 (25.8%) of the INH-resistant isolates; 6.2% of the isolates had inhA structural gene mutations, and 10.3% had mutations in the oxyR-ahpC intergenic region (one, nucleotide -48, previously unreported). Polymorphisms in the kasA gene occurred in both INH-resistant and INH-susceptible isolates. The most frequent polymorphism encoded a G(269)A substitution. Although KatG(315) substitutions are predominant, novel mutations also appear to be responsible for INH resistance in the two states in Brazil. Since ca. 90.7% of the INH-resistant isolates had mutations identified by SSCP electrophoresis, this method may be a useful genotypic screen for INH resistance. PMID:15328099

  11. Isoniazid affects multiple components of the type II fatty acid synthase system of Mycobacterium tuberculosis.

    PubMed

    Slayden, R A; Lee, R E; Barry, C E

    2000-11-01

    Genetic and biochemical evidence has implicated two different target enzymes for isoniazid (INH) within the unique type II fatty acid synthase (FAS) system involved in the production of mycolic acids. These two components are an enoyl acyl carrier protein (ACP) reductase, InhA, and a beta-ketoacyl-ACP synthase, KasA. We compared the consequences of INH treatment of Mycobacterium tuberculosis (MTB) with two inhibitors having well-defined targets: triclosan (TRC), which inhibits InhA; and thiolactomycin (TLM), which inhibits KasA. INH and TLM, but not TRC, upregulate the expression of an operon containing five FAS II components, including kasA and acpM. Although all three compounds inhibit mycolic acid synthesis, treatment with INH and TLM, but not with TRC, results in the accumulation of ACP-bound lipid precursors to mycolic acids that were 26 carbons long and fully saturated. TLM-resistant mutants of MTB were more cross-resistant to INH than TRC-resistant mutants. Overexpression of KasA conferred more resistance to TLM and INH than to TRC. Overexpression of InhA conferred more resistance to TRC than to INH and TLM. Co-overexpression of both InhA and KasA resulted in strongly enhanced levels of INH resistance, in addition to cross-resistance to both TLM and TRC. These results suggest that these components of the FAS II complex are not independently regulated and that alterations in the expression level of InhA affect expression levels of KasA. Nonetheless, INH appeared to resemble TLM more closely in overall mode of action, and KasA levels appeared to be tightly correlated with INH sensitivity. PMID:11069675

  12. Rifampin-Isoniazid Oligonucleotide Typing: an Alternative Format for Rapid Detection of Multidrug-Resistant Mycobacterium tuberculosis ▿ †

    PubMed Central

    Hernández-Neuta, Iván; Varela, Andrés; Martin, Anandi; von Groll, Andrea; Jureen, Pontus; López, Beatriz; Imperiale, Belén; Šķenders, Ģirts; Ritacco, Viviana; Hoffner, Sven; Morcillo, Nora; Palomino, Juan Carlos; Del Portillo, Patricia

    2010-01-01

    A reverse line blot DNA hybridization format for rapid detection of multidrug-resistant tuberculosis was developed. Simultaneous detection of rifampin and isoniazid resistance in clinical isolates of Mycobacterium tuberculosis was based on the same amplification/reverse hybridization principle of the widely used spoligotyping. The test involved probing nine DNA regions that are targets of common drug resistance-associated mutations in the genes rpoB, katG, and inhA. Addition of quaternary amine tetramethyl ammonium chloride to the hybridization buffer promoted multiple hybrid formations at a single annealing temperature irrespective of the different GC contents of probes. The assay was standardized using 20 well-documented strains from the Institute of Tropical Medicine (Belgium) and evaluated blindly in a central laboratory with 100 DNA samples that were obtained from cultured clinical isolates and shipped dried from three other countries. Compared with drug susceptibility testing, both sensitivity and specificity for rifampin resistance detection were 93.0% while for isoniazid the values were 87.7% and 97.7%, respectively. Compared with sequencing and GenoType MTBDRplus methods, sensitivity and specificity reached 96.4% and 95.5% for rifampin and 92.7% and 100% for isoniazid. Altogether, 40/45 (89%) multidrug-resistant isolates were correctly identified. Advantages of this in-house development include versatility, capacity to run up to 41 samples by triplicate in a single run, and reuse of the membrane at least 10 times. These features substantially reduce cost per reaction and make the assay an attractive tool for use in reference laboratories of countries that have a high burden of multidrug-resistant tuberculosis but that cannot afford expensive commercial tests because of limited resources. PMID:20881173

  13. Rapid direct detection of multiple rifampin and isoniazid resistance mutations in Mycobacterium tuberculosis in respiratory samples by real-time PCR.

    PubMed

    Marín, Mercedes; García de Viedma, Darío; Ruíz-Serrano, María Jesús; Bouza, Emilio

    2004-11-01

    Rapid detection of resistance in Mycobacterium tuberculosis can optimize the efficacy of antituberculous therapy and control the transmission of resistant M. tuberculosis strains. Real-time PCR has minimized the time required to obtain the susceptibility pattern of M. tuberculosis strains, but little effort has been made to adapt this rapid technique to the direct detection of resistance from clinical samples. In this study, we adapted and evaluated a real-time PCR design for direct detection of resistance mutations in clinical respiratory samples. The real-time PCR was evaluated with (i) 11 clinical respiratory samples harboring bacilli resistant to isoniazid (INH) and/or rifampin (RIF), (ii) 10 culture-negative sputa spiked with a set of strains encoding 14 different resistance mutations in 10 independent codons, and (iii) 16 sputa harboring susceptible strains. The results obtained with this real-time PCR design completely agreed with DNA sequencing data. In all sputa harboring resistant M. tuberculosis strains, the mutation encoding resistance was successfully detected. No mutation was detected in any of the susceptible sputa. The test was applied only to smear-positive specimens and succeeded in detecting a bacterial load equivalent to 10(3) CFU/ml in sputum samples (10 acid-fast bacilli/line). The analytical specificity of this method was proved with a set of 14 different non-M. tuberculosis bacteria. This real-time PCR design is an adequate method for the specific and rapid detection of RIF and INH resistance in smear-positive clinical respiratory samples.

  14. The use of mobile phones to deliver acceptance and commitment therapy in the prevention of mother-child HIV transmission in Nigeria.

    PubMed

    Ishola, A G; Chipps, J

    2015-12-01

    The objective of this study was to determine if introducing acceptance and commitment therapy in the prevention of mother to child HIV transmission (PMTCT) programme using weekly mobile phone messages would result in improved mental health status of HIV-positive, pregnant women in Nigeria. We used a Solomon four-group (two intervention and two control groups) randomised design. The study population was 144 randomly selected, HIV-positive pregnant women attending four randomly selected PMTCT centres in Nigeria. The intervention groups were exposed to one session of acceptance and commitment therapy with weekly value-based health messages sent by mobile phone for three months during pregnancy. The control groups received only post-HIV test counselling. A total of 132 participants (33 per site) were enrolled in the study from the two intervention and two control sites. In the pre-tests, the intervention and control groups did not differ significantly with regard to demographics. Evaluation of the pre- and post-tests of the intervention group indicated significantly higher Action and Acceptance Questionnaire (AAQ-II) scores. The introduction of a mobile phone acceptance and commitment therapy programme may result in greater psychological flexibility in women diagnosed with HIV.

  15. Psycho-Pedagogical Interventions in the Prevention and the Therapy of Learning Difficulties in the Field of Mathematics

    ERIC Educational Resources Information Center

    Anca, Maria; Hategan, Carolina

    2009-01-01

    In the given study dyscalculia is approached in the context of learning difficulties, but also in relation with damaged psychic processes and functions. The practical part of the study describes intervention models from the perspective of dyscalculia prevention and therapymaterialized in personalized intervention programs.

  16. Contribution of dfrA and inhA mutations to the detection of isoniazid-resistant Mycobacterium tuberculosis isolates.

    PubMed

    Ho, Yu Min; Sun, Yong-Jiang; Wong, Sin-Yew; Lee, Ann S G

    2009-09-01

    Screening of 127 isoniazid (INH)-resistant Mycobacterium tuberculosis isolates from Singapore for mutations within the dfrA and inhA genes revealed mutations in 0 and 5 (3.9%) isolates respectively, implying that mutations in dfrA do not contribute to the detection of INH-resistant M. tuberculosis and that mutations within inhA are rare. Thirty-seven (29%) of the 127 isolates had no mutations in any of the genes implicated in INH resistance (katG, kasA, and ndh; inhA and ahpC promoters), suggesting that there are new INH targets yet to be discovered. PMID:19581462

  17. Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model

    NASA Astrophysics Data System (ADS)

    Conde, João; Oliva, Nuria; Zhang, Yi; Artzi, Natalie

    2016-10-01

    Conventional cancer therapies involve the systemic delivery of anticancer agents that neither discriminate between cancer and normal cells nor eliminate the risk of cancer recurrence. Here, we demonstrate that the combination of gene, drug and phototherapy delivered through a prophylactic hydrogel patch leads, in a colon cancer mouse model, to complete tumour remission when applied to non-resected tumours and to the absence of tumour recurrence when applied following tumour resection. The adhesive hydrogel patch enhanced the stability and provided local delivery of embedded nanoparticles. Spherical gold nanoparticles were used as a first wave of treatment to deliver siRNAs against Kras, a key oncogene driver, and rod-shaped gold nanoparticles mediated the conversion of near-infrared radiation into heat, causing the release of a chemotherapeutic as well as thermally induced cell damage. This local, triple-combination therapy can be adapted to other cancer cell types and to molecular targets associated with disease progression.

  18. Rationale and Baseline Characteristics of PREVENT: A Second-Generation Intervention Trial in Subjects At-Risk (Prodromal) of Developing First-Episode Psychosis Evaluating Cognitive Behavior Therapy, Aripiprazole, and Placebo for the Prevention of Psychosis

    PubMed Central

    Bechdolf, Andreas; Müller, Hendrik; Stützer, Hartmut; Wagner, Michael; Maier, Wolfgang; Lautenschlager, Marion; Heinz, Andreas; de Millas, Walter; Janssen, Birgit; Gaebel, Wolfgang; Michel, Tanja Maria; Schneider, Frank; Lambert, Martin; Naber, Dieter; Brüne, Martin; Krüger-Özgürdal, Seza; Wobrock, Thomas; Riedel, Michael; Klosterkötter, Joachim

    2011-01-01

    Antipsychotics, cognitive behavioral therapy (CBT), and omega-3-fatty acids have been found superior to control conditions as regards prevention of psychosis in people at-risk of first-episode psychosis. However, no large-scale trial evaluating the differential efficacy of CBT and antipsychotics has been performed yet. In PREVENT, we evaluate CBT, aripiprazole, and clinical management (CM) as well as placebo and CM for the prevention of psychosis in a randomized, double-blind, placebo-controlled trial with regard to the antipsychotic intervention and a randomized controlled trial with regard to the CBT intervention with blinded ratings. The hypotheses are first that CBT and aripiprazole and CM are superior to placebo and CM and second that CBT is not inferior to aripiprazole and CM combined. The primary outcome is transition to psychosis. By November 2010, 156 patients were recruited into the trial. The subjects were substantially functionally compromised (Social and Occupational Functioning Assessment Scale mean score 52.5) and 78.3% presented with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I comorbid diagnosis. Prior to randomization, 51.5% of the participants preferred to be randomized into the CBT arm, whereas only 12.9% preferred pharmacological treatment. First, assessments of audiotaped treatment sessions confirmed the application of CBT-specific skills in the CBT condition and the absence of those in CM. The overall quality rating of the CBT techniques applied in the CBT condition was good. When the final results of the trial are available, PREVENT will substantially expand the current limited evidence base for best clinical practice in people at-risk (prodromal) of first-episode psychosis. PMID:21860040

  19. Combinatorial RNA Interference Therapy Prevents Selection of Pre-existing HBV Variants in Human Liver Chimeric Mice.

    PubMed

    Shih, Yao-Ming; Sun, Cheng-Pu; Chou, Hui-Hsien; Wu, Tzu-Hui; Chen, Chun-Chi; Wu, Ping-Yi; Enya Chen, Yu-Chen; Bissig, Karl-Dimiter; Tao, Mi-Hua

    2015-01-01

    Selection of escape mutants with mutations within the target sequence could abolish the antiviral RNA interference activity. Here, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy. We previously identified a highly potent shRNA, S1, which, when delivered by an adeno-associated viral vector, effectively inhibits HBV replication in HBV transgenic mice. We applied the "PICKY" software to systemically screen the HBV genome, then used hydrodynamic transfection and HBV transgenic mice to identify additional six highly potent shRNAs. Human liver chimeric mice were infected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, and then treated with a single or combined shRNAs. The presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of serum wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of six potent shRNAs, markedly reduced titers for both wild-type and T472C HBV. Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. Our results demonstrate that combinatorial RNAi therapy can minimize the escape of resistant viral mutants in chronic HBV patients.

  20. Integrative approach in prevention and therapy of basal cellular carcinoma by association of three actives loaded into lipid nanocarriers.

    PubMed

    Badea, Gabriela; Lacatusu, Ioana; Ott, Cristina; Badea, Nicoleta; Grafu, Iulia; Meghea, Aurelia

    2015-06-01

    Basal cell carcinoma (BCC) is one of the commonest malignancies occurred on sun-exposed skin, mainly by UV-B radiation, of lighter-skinned individuals. The aim of the present study was to develop advanced drug delivery formulations used in BCC therapy that overcomes chemotherapy-induced side-effects of skin photosensitivity by an integrative approach of nanoencapsulation in conjunction with combination therapy that uses chemotherapeutic, chemoprotective and sunscreen agents. The combination of anticancer drug together with sunscreen agent is very useful in therapy, especially for individuals who are more exposed to the sun without using a sunscreen. Nanostructured lipid carriers (NLCs) employed as drug delivery systems were co-loaded with 5-fluorouracil (5-FU), a hydrophilic chemotherapeutic drug, and ethylhexyl salicylate (EHS), a lipophilic UV-B sunscreen agent. The NLCs were developed using bioactive squalene (50.8% w/w) from amaranth seed oil as chemoprotective agent. By varying the concentrations of 5-FU and EHS, the co-loaded NLCs presented particle sizes of about 100nm, acceptable physical stability with values smaller than -25mV and appropriate entrapment efficiency that reaches values over 65% for both types of drugs. The UV-B blocking ability of EHS loaded into NLCs were influenced by the concentration of 5-FU. The amaranth oil offered a capacity of 70% in scavenging the free radicals. In vitro drug release showed that NLCs presented sustained release of 5-FU that followed the Fick's law of diffusion. PMID:25828466

  1. Oxidative stress in hemodialysis patients receiving intravenous iron therapy and the role of N-acetylcysteine in preventing oxidative stress.

    PubMed

    Swarnalatha, G; Ram, R; Neela, Prasad; Naidu, M U R; Dakshina Murty, K V

    2010-09-01

    To determine the contribution of injectable iron administered to hemodialysis (HD) patients in causing oxidative stress and the beneficial effect of N-acetylcysteine (NAC) in reducing it, we studied in a prospective, double blinded, randomized controlled, cross over trial 14 adult HD patients who were randomized into two