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Sample records for isoniazid preventive therapy

  1. Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis.

    PubMed Central

    Jabès, D; Della Bruna, C; Rossi, R; Olliaro, P

    1994-01-01

    The ever-increasing incidence of tuberculosis calls for the implementation of control measures, including new efficient, short-term preventive therapies to replace 6 to 12 months of isoniazid therapy. The efficacies of 12-week regimens of rifabutin or isoniazid given daily and the combination of the two drugs administered intermittently were evaluated in mice infected with Mycobacterium tuberculosis after vaccination with the bacillus Calmette-Guérin (BCG) to imitate some features of the natural infection in humans with a low number of persisting bacteria. Rifabutin at 10 mg/kg of body weight per day was highly effective as early as the eighth week of treatment: all spleens were sterilized and the number of bacteria was drastically reduced in the lungs (mean +/- standard deviation log CFU, 0.2 +/- 0.3, compared with 5.9 +/- 0.6 for untreated controls). No bacilli were found in the spleens or lungs of any of the animals treated for 12 weeks. The combination of rifabutin at 10 mg/kg plus isoniazid at 25 mg/kg twice weekly was almost as effective as rifabutin daily: after 8 weeks of treatment only two of six mice harbored a small number of mycobacteria in their spleens and lungs; at week 12, all spleens were sterilized and a total of eight colonies were isolated from the lungs of two of six mice. Daily isoniazid and once-weekly rifabutin plus isoniazid therapies were less effective. Colonies randomly isolated from the spleens and lungs of mice from different experimental groups were also tested for their susceptibilities to the two drugs. The three surviving colonies from rifabutin-treated mice and all colonies from those administered rifabutin plus isoniazid remained fully susceptible to either drug. In contrast, 2 (18%) of the 11 colonies randomly selected from isoniazid-treated mice became resistant to isoniazid (MIC, > 2 micrograms/ml), although they were still susceptible to rifabutin. Three months of treatment with rifabutin, either daily alone or twice a week

  2. Isoniazid preventive therapy for people living with HIV: public health challenges and implementation issues.

    PubMed

    Aït-Khaled, N; Alarcon, E; Bissell, K; Boillot, F; Caminero, J A; Chiang, C-Y; Clevenbergh, P; Dlodlo, R; Enarson, D A; Enarson, P; Ferroussier, O; Fujiwara, P I; Harries, A D; Heldal, E; Hinderaker, S G; Kim, S J; Lienhardt, C; Rieder, H L; Rusen, I D; Trébucq, A; Van Deun, A; Wilson, N

    2009-08-01

    Isoniazid preventive therapy (IPT) is recognised as an important component of collaborative tuberculosis (TB) and human immunodeficiency virus (HIV) activities to reduce the burden of TB in people living with HIV (PLHIV). However, there has been little in the way of IPT implementation at country level. This failure has resulted in a recent call to arms under the banner title of the 'Three I's' (infection control to prevent nosocomial transmission of TB in health care settings, intensified TB case finding and IPT). In this paper, we review the background of IPT. We then discuss the important challenges of IPT in PLHIV, namely responsibility and accountability for the implementation, identification of latent TB infection, exclusion of active TB and prevention of isoniazid resistance, length of treatment and duration of protective efficacy. We also highlight several research questions that currently remain unanswered. We finally offer practical suggestions about how to scale up IPT in the field, including the need to integrate IPT into a package of care for PLHIV, the setting up of operational projects with the philosophy of 'learning while doing', the development of flow charts for eligibility for IPT, the development and implementation of care prior to antiretroviral treatment, and finally issues around procurement, distribution, monitoring and evaluation. We support the implementation of IPT, but only if it is done in a safe and structured way. There is a definite risk that 'sloppy' IPT will be inefficient and, worse, could lead to the development of multidrug-resistant TB, and this must be avoided at all costs.

  3. Implementation of co-trimoxazole prophylaxis and isoniazid preventive therapy for people living with HIV

    PubMed Central

    Vitoria, Marco; Granich, Reuben; Banda, Mazuwa; Fox, Mayada Youssef; Gilks, Charlie

    2010-01-01

    Abstract Objective To measure progress in implementing co-trimoxazole prophylaxis (CTXp) (trimethoprim plus sulfamethoxazole) and isoniazid preventive therapy (IPT) policy recommendations, identify barriers to the development of national policies and pinpoint challenges to implementation. Methods In 2007 we conducted by e-mail a cross-sectional survey of World Health Organization (WHO) HIV/AIDS programme officers in 69 selected countries having a high burden of infection with HIV or HIV-associated tuberculosis (TB). The specially-designed, self-administered questionnaire contained items covering national policies for CTXp and IPT in people living with HIV, current level of implementation and barriers to developing or implementing these policies. Findings The 41 (59%) respondent countries, representing all WHO regions, comprised 85% of the global burden of HIV-associated TB and 82% of the global burden of HIV infection. Thirty-eight countries (93%) had an established national policy for CTXp, but only 66% of them (25/38) had achieved nationwide implementation. For IPT, 21 of 41 countries (51%) had a national policy but only 28% of them (6/21) had achieved nationwide implementation. Despite significant progress in the development of CTXp policy, the limited availability of co-trimoxazole for this indication and inadequate systems to manage drug supply impeded nationwide implementation. Inadequate intensified tuberculosis case-finding and concerns regarding isoniazid resistance were challenges to the development and implementation of national IPT policies. Conclusion Despite progress in implementing WHO-recommended CTXp and IPT policies, these interventions remain underused. Urgent steps are required to facilitate the development and implementation of these policies. PMID:20431788

  4. Routine programmatic delivery of isoniazid preventive therapy to children in Cape Town, South Africa

    PubMed Central

    Hesseling, A. C.; Beyers, N.; Enarson, D. A.; Rusen, I. D.; Lombard, C.; van Wyk, S. S.

    2013-01-01

    Setting: Fourteen primary health care facilities in Cape Town, South Africa. Objective: To determine the proportion and characteristics of infectious adult tuberculosis (TB) cases that identify children aged <5 years who qualify for isoniazid preventive therapy (IPT), and to determine the proportion of children who initiate and complete IPT. Design: A retrospective clinical record review conducted as a stratified cluster survey. Results: Of 1179 records of infectious adult cases, 33.3% had no documentation of contacts. Of the remaining 786 records, 525 contacts aged <5 years were identified, representing 0.7 child contacts per infectious adult case. Older age, male, human immunodeficiency virus (HIV) positive, smear-negative and retreatment TB cases were all associated with no documentation of contacts. Of the 525 child contacts identified, less than half were screened for TB, 141 initiated IPT and 19 completed it. Conclusion: Less than 67% of infectious TB case records had documentation of contacts. Younger, female, HIV-negative and new smear-positive TB cases were more likely to have had contacts identified. Less than 14% of children already initiated on IPT completed 6 months of treatment. PMID:26393029

  5. 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

  6. Bacillus Calmette-Guérin and Isoniazid Preventive Therapy Protect Contacts of Patients with Tuberculosis

    PubMed Central

    Murray, Megan B.; Becerra, Mercedes C.; Galea, Jerome; Lecca, Leonid; Calderon, Roger; Yataco, Rosa; Contreras, Carmen; Zhang, Zibiao; Grenfell, Bryan T.; Cohen, Ted

    2014-01-01

    Rationale: Individuals living with patients with tuberculosis (TB) are at elevated risk of infection and disease, with children at greatest risk. The World Health Organization recommends isoniazid preventive therapy (IPT) for HIV-positive contacts and those younger than 5 years. Despite these recommendations, household-level IPT programs are rarely implemented in high TB burden settings. Evidence is scarce about the age-specific efficacy of interventions, such as IPT and bacillus Calmette-Guérin (BCG) vaccination for preventing TB disease among exposed contacts. Objectives: We estimate the age-specific efficacy of IPT and BCG for preventing TB disease using data from a large observational prospective cohort study of household contacts of patients with TB in Lima, Peru. Methods: We identified all adults (>15 yr) with incident pulmonary TB (index cases) diagnosed at 106 public health centers in Lima from September 2009 to August 2012. Among 14,041 household contacts (of 3,446 index cases) assessed for infection and disease during the yearlong follow-up period, we identified 462 additional TB cases. We estimate risk ratios (RR) for pulmonary TB associated with BCG, IPT, and latent TB infection. Measurements and Main Results: BCG confers protection against coprevalent and incident TB among HIV-negative children younger than 10 years (RR, 0.35; 95% confidence interval, 0.19–0.66). IPT confers protection against incident TB among HIV-negative contacts younger than 30 years (RR, 0.33; 95% confidence interval, 0.20–0.54). Risk of incident TB associated with latent TB infection is greatest for children younger than 5 years and decreases with age. Conclusions: These findings support the use of IPT in older children and young-adult household contacts, in addition to children younger than 5 years. PMID:24592878

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. Assessment of isoniazid preventive therapy in the reduction of tuberculosis among ART patients in Arba Minch Hospital, Ethiopia

    PubMed Central

    Abossie, Ashenafi; Yohanes, Tsegaye

    2017-01-01

    Background Tuberculosis (TB) is the most frequent life-threatening opportunistic disease among people living with HIV and remains a leading cause of mortality, even among persons receiving antiretroviral therapy (ART). Isoniazid preventive therapy (IPT) and cotrimoxazole prophylaxis have been recommended for the benefit of HIV/AIDS-infected individuals to prevent opportunistic infections. The aim of this study was to assess IPT prophylaxis in the reduction of TB among ART patients. Methods The study was a hospital-based retrospective study. A total of 271 study participants’ available information such as demographic data, the type of prophylaxis used, and TB/HIV coinfection status as well as other variables were collected from clinical laboratory and HIV care/ART follow-up clinic. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 20.0. Results TB-infected ART patients were higher among non-IPT group (37 [27.8%]) compared to IPT group (12 [8.7%]). The finding showed that IPT prophylaxis significantly reduces acquiring TB with the relative risk =0.31 (95% confidence interval =0.122, 0.49) in ART patients of this study site where the tuberculosis prevalence is prominent. ART had significant contribution for CD4+ T-cell lymphocyte count improvement in both IPT and non-IPT groups (P<0.05) in this study. Conclusion IPT had significant contributions to reduce the burden of TB in ART patients than non-IPT group. This result highlights the use of IPT for the prevention of TB, especially for all ART patients. Other longitudinal studies are needed to observe the benefits and side effects of IPT prophylaxis in tuberculin skin test-positive individuals. PMID:28392698

  13. 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.

  14. Tuberculosis Contact Screening and Isoniazid Preventive Therapy in a South Indian District: Operational Issues for Programmatic Consideration

    PubMed Central

    Pothukuchi, Madhavi; Nagaraja, Sharath Burugina; Kelamane, Santosha; Satyanarayana, Srinath; Shashidhar; Babu, Sai; Dewan, Puneet; Wares, Fraser

    2011-01-01

    Background Under India's Revised National Tuberculosis Control Programme (RNTCP), all household contacts of sputum smear positive Pulmonary Tuberculosis (PTB) patients are screened for TB. In the absence of active TB disease, household contacts aged <6 years are eligible for Isoniazid Preventive Therapy (IPT) (5 milligrams/kilogram body weight/day) for 6 months. Objectives To estimate the number of household contacts aged <6 years, of sputum smear positive PTB patients registered for treatment under RNTCP from April to June'2008 in Krishna District, to assess the extent to which they are screened for TB disease and in its absence initiated on IPT. Methods A cross sectional study was conducted. Households of all smear positive PTB cases (n = 848) registered for treatment from April to June'2008 were included. Data on the number of household contacts aged <6 years, the extent to which they were screened for TB disease, and the status of initiation of IPT, was collected. Results Households of 825 (97%) patients were visited, and 172 household contacts aged <6 years were identified. Of them, 116 (67%) were evaluated for TB disease; none were found to be TB diseased and 97 (84%) contacts were initiated on IPT and 19 (16%) contacts were not initiated on IPT due to shortage of INH tablets in peripheral health centers. The reasons for non-evaluation of the remaining eligible children (n = 56, 33%) include no home visit by the health staff in 25 contacts, home visit done but not evaluated in 31 contacts. House-hold contacts in rural areas were less likely to be evaluated and initiated on IPT [risk ratio 6.65 (95% CI; 3.06–14.42)]. Conclusion Contact screening and IPT implementation under routine programmatic conditions is sub-optimal. There is an urgent need to sensitize all concerned programme staff on its importance and establishment of mechanisms for rigorous monitoring. PMID:21799875

  15. 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

  16. Risk of Disease After Isoniazid Preventive Therapy for Mycobacterium tuberculosis Exposure in Young HIV-uninfected Children

    PubMed Central

    Tameris, Michele D.; Geldenhuys, Hennie D.; Mulenga, Humphrey; Van Schalkwyk, Amaryl; Hughes, Elizabeth J.; Toefey, Asma; Scriba, Thomas J.; Hussey, Gregory; Mahomed, Hassan; McShane, Helen; Landry, Bernard; Hanekom, Willem A.; Hatherill, Mark

    2015-01-01

    Background: The risk of developing tuberculosis (TB) disease in HIV-uninfected children after isoniazid preventive therapy (IPT) for a positive QuantiFERON-TB Gold In-Tube test (QFT-GIT) is unknown. The aim of this study was to evaluate risk of TB disease after IPT in young HIV-uninfected children with a positive QFT-GIT result, or household TB contact. Methods: HIV-uninfected South African infants aged 4–6 months were screened for enrolment in a TB vaccine trial. Baseline household TB contact and positive QFT-GIT result were exclusion criteria, and these infants were referred for IPT. Outcome data are reported for 36 months after IPT referral. Results: Four thousand seven hundred forty-nine infants were screened. Household TB contact was reported in 131 (2.8%) infants; 279 (6.0%) were QFT-GIT positive, and 138 of these 410 infants (34.0%) started IPT. Forty-four cases of TB disease (11.0%) were recorded within 991 child years of observation. TB disease incidence was 4.8 versus 3.6 per 100 child years in household exposed versus QFT-GIT-positive children [incidence rate ratio: 1.35; 95% confidence interval (CI): 0.67–2.88] and 2.4 versus 5.5 per 100 child years in children who received versus did not receive IPT, respectively (incidence rate ratio: 0.44; 95% CI: 0.17–0.96). Adjusted hazard ratio (Cox regression) for TB disease was 0.48 (95% CI: 0.21–1.05) for those who received IPT. Conclusion: In young HIV-uninfected children, the effect of IPT on risk of TB disease is similar, whether TB exposure was defined by household contact history or by positive QFT-GIT result. International IPT guidelines for HIV-uninfected children with a positive QFT-GIT result should be updated. PMID:26252568

  17. A Qualitative Evaluation of the Acceptability of an Interactive Voice Response System to Enhance Adherence to Isoniazid Preventive Therapy Among People Living with HIV in Ethiopia.

    PubMed

    Daftary, Amrita; Hirsch-Moverman, Yael; Kassie, Getnet M; Melaku, Zenebe; Gadisa, Tsigereda; Saito, Suzue; Howard, Andrea A

    2016-05-24

    Interactive voice response (IVR) is increasingly used to monitor and promote medication adherence. In 2014, we evaluated patient acceptability toward IVR as part of the ENRICH Study, aimed to enhance adherence to isoniazid preventive therapy for tuberculosis prevention among HIV-positive adults in Ethiopia. Qualitative interviews were completed with 30 participants exposed to 2867 IVR calls, of which 24 % were completely answered. Individualized IVR options, treatment education, and time and cost savings facilitated IVR utilization, whereas poor IVR instruction, network and power malfunctions, one-way communication with providers, and delayed clinic follow-up inhibited utilization. IVR acceptability was complicated by HIV confidentiality, mobile phone access and literacy, and patient-provider trust. Incomplete calls likely reminded patients to take medication but were less likely to capture adherence or side effect data. Simple, automated systems that deliver health messages and triage clinic visits appear to be acceptable in this resource-limited setting.

  18. Isoniazid

    MedlinePlus

    ... a solution (liquid) to take by mouth without food. Isoniazid is usually is taken once a day; ... You will need to avoid eating foods beverages that contain very high amounts of tyramine or histamine during your treatment with isoniazid. These foods and beverages include certain cheeses, ...

  19. Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention

    PubMed Central

    Podany, Anthony T.; Bao, Yajing; Swindells, Susan; Chaisson, Richard E.; Andersen, Janet W.; Mwelase, Thando; Supparatpinyo, Khuanchai; Mohapi, Lerato; Gupta, Amita; Benson, Constance A.; Kim, Peter; Fletcher, Courtney V.

    2015-01-01

    Background. Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and isoniazid in human immunodeficiency virus (HIV)–infected individuals receiving a 4-week regimen to prevent tuberculosis. Methods. Participants receiving daily rifapentine and isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8. Results. Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29–44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42–13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04–15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97–1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8. Conclusions. The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression. Clinical Trials Registration. NCT 01404312. PMID:26082504

  20. Transfer of isoniazid from circulation to breast milk in lactating women on chronic therapy for tuberculosis

    PubMed Central

    Singh, Neera; Golani, Anil; Patel, Zarine; Maitra, Anurupa

    2008-01-01

    Aim To determine milk to plasma (M : P) ratios and infant dose (absolute and relative) for isoniazid in lactating women on antituberculosis therapy. Methods Concentrations of isoniazid in plasma and milk were measured in exclusively breast feeding women taking 300 mg day−1 as treatment for tuberculosis. Results Peak plasma and milk concentrations of isoniazid were observed at 1 h. A mean M : PAUC value of 0.89 (95% CI 0.7, 1.1) was calculated for isoniazid from seven women over 24 h. The mean absolute infant dose was estimated to be 89.9 μg kg day−1 (95% CI 65.6, 114) and the relative infant dose was 1.2% of the weight adjusted maternal dose. Conclusions The mean relative dose of isoniazid (1.2%) transmitted to the infant via breast milk is below the 10% notional level of concern. These data suggest that isoniazid therapy is safe during breastfeeding. What is already known about this subject Isoniazid is the most widely used first line antituberculosis drug.It is considered safe during lactation, but limited data are available on the transfer of isoniazid from circulation to milk in lactating women, which can provide an assessment of extent of exposure to the nursling. What this study adds The study documents the transfer pattern and milk to plasma (M : P) ratio of isoniazid at a steady state.Peak plasma and milk concentrations of isoniazid were reached within 1 h and the projected exposure of the drug to the infant is much lower than the prophylactic dose, supporting its safety during breast feeding. PMID:18093257

  1. Intensified tuberculosis case finding, implementation of isoniazid preventive therapy and associated factors among people living with human immunodeficiency virus at public health facilities of Harari Region, Eastern Ethiopia: A cross-sectional study

    PubMed Central

    Geleto, Ayele; Abate, Degu; Egata, Gudina

    2017-01-01

    Objective: Globally, the number of people living with human immunodeficiency virus (PLHIV) particularly in sub-Saharan Africa is growing. This has been resulted in increased number of tuberculosis (TB) new cases. To control burden of TB among PLHIV, a number of collaborative TB/HIV activities were recommended. However, data about collaborative TB/HIV services in the study area is scarce. The objective of this study is to assess intensified TB case finding, implementation of isoniazid preventive therapy (IPT) and associated factors among PLHIV. Methods: A facility based cross-sectional study design was employed among 419 randomly selected PLHIV from public health facilities of Harari region. Systematic sampling method was used to obtain sample from each health facilities. Interviewer-administered questionnaire was used to collect data. Data were entered into EpiData and analyzed by SPSS statistical software. Multivariate logistic regression analysis was conducted to determine the presence of association between variables using odds ratio with 95% confidence interval and association was declared significant at P ≤ 0.05. Results: One hundred fifteen (75.2%) of the respondents reported that they offered screening for TB during their HIV chronic cares and 94 (29.8%) of them were found to be positive for active TB. Female sex [AOR 2.51; 95%CI (1.52, 6.14)], educated patients [AOR 0.52; 95%CI (0.21, 0.83)], CD4 count greater than 350 cells/dl3 [AOR 0.62; 95%CI(0.22,0.82)], Antiretroviral Therapy (ART) initiation [AOR 0.50; 95%CI (0.35, 0.88)] and missing dose of ART [AOR 2.57; 95%CI (1.21, 5.32)] were significantly associated with TB infection. Nearly four-fifth (78.7 %) of the study participants were provided IPT. Conclusions: Screening of TB among PLHIV and implementation of IPT in the region is lower when compared to the findings of other studies conducted in different parts of the country and needs to be improved through implementation of national and international

  2. Two controlled studies of the efficacy of isoniazid alone in preventing relapse in patients with bacteriologically quiescent pulmonary tuberculosis at the end of one year of chemotherapy*

    PubMed Central

    Nazareth, O.; Devadatta, S.; Fox, Wallace; Menon, N. K.; Radhakrishna, S.; Rajappa, D.; Ramakrishnan, C. V.; Somasundaram, P. R.; Stott, H.; Subbammal, S.; Velu, S.

    1971-01-01

    An earlier report showed that, in patients with bacteriologically quiescent pulmonary tuberculosis at the end of 1 year of chemotherapy, isoniazid alone in a single daily dose of 150-200 mg, given as maintenance therapy in the second year, did not markedly prevent relapse over a 4-year period of follow-up in patients who had had residual cavitation (the ”open-negative” syndrome) at 1 year, but was highly effective in patients who had not. As a result of these findings, two controlled studies, reported here, were undertaken. The first study was undertaken in patients with bacteriologically quiescent disease and residual cavitation at 1 year, and investigated the value of isoniazid in a higher daily dose (400 mg) throughout the second year; this is known to be the optimum therapeutic dose when isoniazid is prescribed alone for 1 year in the initial treatment of the disease. The second study was carried out in patients with bacteriologically quiescent disease and no residual cavitation at 1 year, and sought to determine the value of a shorter duration (6 months) of chemotherapy in the second year with a daily dose of 300 mg of isoniazid. Neither of the two isoniazid regimens was highly satisfactory, although both appeared to have had some effect in preventing relapse during the 4-year period of follow-up. PMID:4947494

  3. Isoniazid toxicity and TB development during biological therapy of patients with psoriasis in Colombia.

    PubMed

    Cataño, Juan; Morales, Milena

    2016-10-01

    Background The use of biological therapy has been linked with an increased risk of tuberculosis (TB) reactivation. Objective The aim of this study was to present the follow-up results for Isoniazid (INH) chemoprophylaxis in patients with psoriasis receiving different biological therapies. Methods In this prospective observational study, patients with latent tuberculosis infection (LTBI) were given INH chemoprophylaxis between two and nine months prior to the beginning of biological therapy. All patients were followed up monthly for any signs or symptoms of active TB or INH toxicity. Results A total of 101 patients, 44.5% females, with a mean age of 46.9 ± 11.5 years (20-73) were enrolled. LTBI was identified in 100 patients (99%), of whom 81.2% completed nine months of chemoprophylaxis. Three patients (2.9%) developed active TB and 17 patients (16.8%) developed intolerance or toxicity related to INH. Conclusions Chemoprophylaxis with INH seems to be effective and safe for the prevention of most TB reactivations in individuals with LTBI receiving biological therapy, but toxicity must be monitored during follow-up.

  4. Combined Streptomycin-Isoniazid-Rifampin Therapy in the Treatment of Johne's Disease in a Goat

    PubMed Central

    Slocombe, R. F.

    1982-01-01

    Johne's disease (paratuberculosis) is an insidious, invariably fatal, chronic disease of ruminants. An increasing role for the goat as a companion animal as well as its commercial use stimulated interest in attempting to treat Johne's disease in this species. The disease tends to differ both clinically and pathologically in goats compared to cattle because the former species often has less severe intestinal involvement. It was, therefore, speculated that response to therapy may differ between cattle and goats. In addition, the combination drug regime of isoniazid, rifampin and streptomycin, widely accepted for human mycobacterial infections, has not been previously employed for treatment of Mycobacterium paratuberculosis. The clinical course and pathological findings of a case of naturally occurring Johne's disease subsequent to a combined drug regime of isoniazid, rifampin and streptomycin is discussed. ImagesFigure 1.Figure 2.Figure 3a.Figure 3b. PMID:17422141

  5. Isoniazid Therapy for Mycobacterium tuberculosis Infection in HIV Clinics, Los Angeles, California

    PubMed Central

    Shin, Sanghyuk S.; Chang, Alicia H.; Ghosh, Jo Kay C.; Dubé, Michael P.; Bolan, Robert; Yang, Otto O.; Kerndt, Peter R.

    2016-01-01

    Setting Publicly-funded HIV clinics in Los Angeles County, California, USA. Objective HIV-infected persons are a high priority group for targeted testing and treatment for Mycobacterium tuberculosis infection in the United States. We describe rates of isoniazid initiation and completion among HIV-1 and M. tuberculosis co-infected persons in Los Angeles County. Design We conducted a cross-sectional study using routinely collected surveillance data from publicly-funded HIV clinics. We examined differences in isoniazid treatment initiation and completion between four clinic categories: the three largest clinics (Clinics A, B, and C) and “Other” clinics (pooled data for remaining 10 clinics). Results During 2010–2013, 802 (5.3%) of 15,029 HIV-1-infected persons tested positive for M. tuberculosis infection. Isoniazid was initiated in 581 (72.4%) persons, of whom 457 (78.7%) completed therapy. We found significant differences between clinics for treatment initiation (range: 59.1% – 93.4%) and completion (range: 58.8% – 82.3%). Overall, 57% (457/802) of HIV and M. tuberculosis co-infected persons completed the recommended treatment (range across clinics: 34.8% – 76.3%). Conclusion We identified significant gaps in treatment for M. tuberculosis infection among HIV-infected persons in Los Angeles County. Interventions are needed to improve initiation and completion of treatment for M. tuberculosis infection in this population. PMID:27287651

  6. [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.

  7. Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa

    PubMed Central

    Szakacs, Tom A; Wilson, Douglas; Cameron, D William; Clark, Michael; Kocheleff, Paul; Muller, F James; McCarthy, Anne E

    2006-01-01

    Background Tuberculosis (TB) is the most common opportunistic infection in HIV-infected adults in developing countries. Isoniazid (INH) is recommended for treatment of latent TB infection, however non-adherence is common. The purpose of this study was to apply in-house prepared isoniazid (INH) urine test strips in a clinical setting, and identify predictors of positive test results in an adherence questionnaire in HIV-infected adults taking INH for prevention of TB. Methods Cross-sectional study of adherence using a questionnaire and urine test strips for detection of INH metabolites at two hospitals in Pietermaritzburg, South Africa. Participants were aged at least 18 years, HIV positive, and receiving INH for prevention of tuberculosis disease. Univariate and multivariate analyses are used to identify factors relevant to adherence. Results 301 consecutive patients were recruited. 28% of participants had negative urine tests. 32 (37.2%, 95% CI25.4, 45.0) of the 86 patients who received INH from peripheral pharmacies said the pharmacy had run out of INH at some time, compared with central hospital pharmacies (p = 0.0001). In univariate analysis, a negative test was associated with self-reported missed INH doses (p = 0.043). Each 12-hour increment since last reported dose increased the likelihood of a negative test by 34% (p = 0.0007). Belief in INH safety was associated with a positive test (p = 0.021). In multivariate analysis, patients who believed INH is important for prevention of TB disease were more likely to be negative (p = 0.0086). Conclusion Adequate drug availability at peripheral pharmacies remains an important intervention for TB prevention. Key questions may identify potentially non-adherent patients. In-house prepared urine tests strips are an effective and cheap method of objectively assessing INH adherence, and could be used an important tool in TB control programs. PMID:16772037

  8. Isoniazid preventive treatment among child contacts of adults with smear-positive tuberculosis in The Gambia

    PubMed Central

    Sillah, A.; Togun, T.; Kandeh, S.; Cole, F.; Jallow, A.; Able-Thomas, A.; Hoelscher, M.; Heinrich, N.; Hill, P. C.; Kampmann, B.

    2016-01-01

    Setting: Greater Banjul area of The Gambia. Objectives: To evaluate uptake, adherence and completion of treatment among tuberculosis (TB) exposed children in The Gambia when isoniazid preventive treatment (IPT) is delivered at home Design: Child (age <5 years) contacts of adults with smear-positive TB were prospectively enrolled. Following symptom screening, tuberculin skin testing and clinical evaluation where indicated, those without disease were placed on daily isoniazid, provided monthly at home. Adherence was assessed by pill counts and IsoScreen™ urine test. Results: Of 404 contacts aged <5 years, 368 (91.1%) were offered IPT. Of the 328 (89.4%) for whom consent was received and who commenced IPT, 18 (5.5%) dropped out and 310 (94.5%) remained on IPT to the end of the 6-month regimen. Altogether, 255/328 children (77.7%, 95%CI 73.2–82.2) completed all 6 months, with good adherence. The IsoScreen test was positive in 85.3% (435/510) of all tests among those defined as having good adherence by pill count and in 16% (8/50) of those defined as having poor adherence (P < 0.001). A cascade of care analysis showed an overall completion rate with good adherence of 61% for all child contacts. Conclusion: Home-delivered IPT among child contacts of adults with smear-positive TB in The Gambia achieved verifiable high uptake and adherence rates. System rather than patient factors are likely to determine the success of IPT at national level. PMID:28123958

  9. Isoniazid preventive treatment among child contacts of adults with smear-positive tuberculosis in The Gambia.

    PubMed

    Egere, U; Sillah, A; Togun, T; Kandeh, S; Cole, F; Jallow, A; Able-Thomas, A; Hoelscher, M; Heinrich, N; Hill, P C; Kampmann, B

    2016-12-21

    Setting: Greater Banjul area of The Gambia. Objectives: To evaluate uptake, adherence and completion of treatment among tuberculosis (TB) exposed children in The Gambia when isoniazid preventive treatment (IPT) is delivered at home Design: Child (age <5 years) contacts of adults with smear-positive TB were prospectively enrolled. Following symptom screening, tuberculin skin testing and clinical evaluation where indicated, those without disease were placed on daily isoniazid, provided monthly at home. Adherence was assessed by pill counts and IsoScreen(™) urine test. Results: Of 404 contacts aged <5 years, 368 (91.1%) were offered IPT. Of the 328 (89.4%) for whom consent was received and who commenced IPT, 18 (5.5%) dropped out and 310 (94.5%) remained on IPT to the end of the 6-month regimen. Altogether, 255/328 children (77.7%, 95%CI 73.2-82.2) completed all 6 months, with good adherence. The IsoScreen test was positive in 85.3% (435/510) of all tests among those defined as having good adherence by pill count and in 16% (8/50) of those defined as having poor adherence (P < 0.001). A cascade of care analysis showed an overall completion rate with good adherence of 61% for all child contacts. Conclusion: Home-delivered IPT among child contacts of adults with smear-positive TB in The Gambia achieved verifiable high uptake and adherence rates. System rather than patient factors are likely to determine the success of IPT at national level.

  10. Empiric Tuberculosis Therapy versus Isoniazid in Advanced HIV-infected Adult Outpatients Initiating Antiretroviral Therapy: a Multi-Country Randomized Controlled Trial

    PubMed Central

    Hosseinipour, Mina C.; Bisson, Gregory P.; Miyahara, Sachiko; Sun, Xin; Moses, Agnes; Riviere, Cynthia; Kirui, F.K.; Badal-Faesen, Sharla; Lagat, David; Nyirenda, Mulinda; Naidoo, K; Hakim, James; Mugyenyi, Peter; Henostroza, German; Leger, P.D; Lama, Javier.R; Mohapi, Lerato; Alave, Jorge; Mave, V; Veloso, Valdilea.G; Pillay, Sandy; Kumarasamy, N.; Bao, Jing; Hogg, Evelyn; Jones, Lynne; Zolopa, Andrew; Kumwenda, Johnstone; Gupta, Amita

    2016-01-01

    Summary Background Mortality within the first 6 months after initiating antiretroviral therapy (ART) is common in resource-limited settings and is often due to tuberculosis (TB) among patients with advanced HIV disease. Isoniazid preventive therapy (IPT) is recommended in HIV-infected adults, but sub-clinical TB can be difficult to diagnose. We hypothesized that empiric TB treatment would reduce early mortality compared to IPT in high-burden settings. Methods We conducted a multi-country randomized clinical trial comparing empiric TB therapy (Empiric) vs. isoniazid preventive therapy (IPT) in HIV-infected outpatients initiating ART with CD4 counts <50 cells/mm3. Individuals were screened for TB using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available. The primary endpoint was survival (death or unknown status) at 24 weeks post randomization. Kaplan Meier estimates of the endpoint rates across arms were compared by the z-test. Registered at ClinicalTrials.gov (NCT01380080). Findings From October 31, 2011 until June 9, 2014, we randomized 850 participants (424 in Empiric arm and 426 in IPT arm); the median CD4 count at baseline was 18 cells/mm3 (IQR: 9, 32). At week 24, each arm had 22 primary endpoints, for rates of 5.2% in each arm (95% CI: 3.5% to 7.8% for Empiric and 3.4% to 7.8% for IPT; absolute risk difference of -0.06% (95% CI: −3.05% to 2.94%). Grade 3 or 4 signs or symptoms occurred in 50 (12%) in the Empiric arm and 46 (11%) in the IPT arm. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) in the Empiric arm and 97 (23%) in the IPT arm. Incident TB was more common in the Empiric arm (31 vs. 18 events, p=0.01). Interpretation Empiric TB therapy did not reduce mortality at 24 weeks in outpatient adults initiating ART with advanced HIV disease. The low mortality rate of the trial supports implementation of systematic TB screening and IPT in outpatients with advanced HIV disease. PMID:27025337

  11. Analysis of Rifapentine for Preventive Therapy in the Cornell Mouse Model of Latent Tuberculosis

    PubMed Central

    Miyazaki, Eishi; Chaisson, Richard E.; Bishai, William R.

    1999-01-01

    Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously with Mycobacterium tuberculosis and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection. PMID:10471552

  12. 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

  13. Weekly Rifapentine/Isoniazid or Daily Rifampin/Pyrazinamide for Latent Tuberculosis in Household Contacts

    PubMed Central

    Schechter, Mauro; Zajdenverg, Roberto; Falco, Gisely; Barnes, Grace Link; Faulhaber, José Cláudio; Coberly, Jacqueline S.; Moore, Richard D.; Chaisson, Richard E.

    2006-01-01

    Rationale: Treatment of latent tuberculosis (TB) infection with weekly rifapentine and isoniazid is a potentially effective alternative to current therapies. Objectives: To compare the efficacy of weekly rifapentine/isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil. Methods: Contacts of patients with TB were randomized to rifapentine 900 mg/isoniazid 900 mg once weekly for 12 wk or rifampin 450–600 mg/pyrazinamide 750–1,500 mg daily for 8 wk and followed for at least 2 yr. Measurements: TB rates, adverse events, and adherence to therapy. Main Results: A total of 399 household contacts were enrolled, 206 in the rifapentine/isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/isoniazid (p < 0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, −1.6 to 3.7%). Conclusions: Rifapentine/isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection. PMID:16474028

  14. Contribution of Efflux to the Emergence of Isoniazid and Multidrug Resistance in Mycobacterium tuberculosis

    PubMed Central

    Machado, Diana; Couto, Isabel; Perdigão, João; Rodrigues, Liliana; Portugal, Isabel; Baptista, Pedro; Veigas, Bruno; Amaral, Leonard; Viveiros, Miguel

    2012-01-01

    Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment. PMID:22493700

  15. Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis.

    PubMed

    Machado, Diana; Couto, Isabel; Perdigão, João; Rodrigues, Liliana; Portugal, Isabel; Baptista, Pedro; Veigas, Bruno; Amaral, Leonard; Viveiros, Miguel

    2012-01-01

    Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment.

  16. 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.

  17. 3D-printed hierarchical scaffold for localized isoniazid/rifampin drug delivery and osteoarticular tuberculosis therapy.

    PubMed

    Zhu, Min; Li, Kun; Zhu, Yufang; Zhang, Jianhua; Ye, Xiaojian

    2015-04-01

    After surgical treatment of osteoarticular tuberculosis (TB), it is necessary to fill the surgical defect with an implant, which combines the merits of osseous regeneration and local multi-drug therapy so as to avoid drug resistance and side effects. In this study, a 3D-printed macro/meso-porous composite scaffold is fabricated. High dosages of isoniazid (INH)/rifampin (RFP) anti-TB drugs are loaded into chemically modified mesoporous bioactive ceramics in advance, which are then bound with poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) through a 3D printing procedure. The composite scaffolds show greatly prolonged drug release time compared to commercial calcium phosphate scaffolds either in vitro or in vivo. In addition, the drug concentrations on the periphery tissues of defect are maintained above INH/RFP minimal inhibitory concentrations even up to 12 weeks post-surgery, while they are extremely low in blood. Examinations of certain serum enzymes suggest no harm to hepatic or renal functions. Micro-CT evaluations and histology results also indicate partly degradation of the composite scaffolds and new bone growth in the cavity. These results suggest promising applications of our hierarchical composite scaffold in bone regeneration and local anti-TB therapy after osteoarticular TB debridement surgery.

  18. Isoniazid-induced pellagra.

    PubMed

    Bilgili, Serap Gunes; Karadag, Ayse Serap; Calka, Omer; Altun, Faruk

    2011-12-01

    Pellagra is characterized by dermatitis, diarrhea, dementia and eventually death occurring as a result of niacin or its precursor tryptophan deficiency. Although pellagra is a well-known complication of isoniazid (INH) therapy, the clinical diagnosis may be missed or delayed that may cause life-threatening consequences. Due to the diversity of pellagra-related signs and symptoms, the diagnosis can be made with an appropriate index of suspicion. We report a 7-year-old boy presenting with INH-induced pellagra that resolved after the administration of the niacin therapy.

  19. Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study

    PubMed Central

    Sterling, Timothy R.; Moro, Ruth N.; Borisov, Andrey S.; Phillips, Elizabeth; Shepherd, Gillian; Adkinson, Newton Franklin; Weis, Stephen; Ho, Christine; Villarino, Margarita Elsa

    2015-01-01

    Background. Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome. Methods. We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study. Results. Among 7552 persons who received ≥1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1). Conclusions. SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear. Clinical Trials Registration. NCT00023452. PMID:25904367

  20. Acute isoniazid intoxication: an uncommon cause of convulsion, coma and acidosis.

    PubMed

    Uzman, Sinan; Uludağ Yanaral, Tümay; Toptaş, Mehmet; Koç, Alparslan; Taş, Aytül; Bican, Gülşen

    2013-01-01

    Despite the widespread use, suicidal ingestion of isoniazid is a rare condition in Turkey. We reported a case of acute isoniazid intoxication associated with alcohol intake presenting with convulsion, coma and metabolic acidosis. The patient was treated successfully with intravenous pyridoxine administration. Early recognation and appropriate treatment in the intensive care unit is very important to prevent mortality in patients with acute isoniazid toxicity.

  1. Effect of secondary preventive therapy on recurrence of tuberculosis in HIV-infected individuals: a systematic review.

    PubMed

    Bruins, Wassilis Sc; van Leth, Frank

    2017-03-01

    Human immunodeficiency virus (HIV)-infected individuals successfully treated for tuberculosis (TB) remain at risk of recurrence of the disease, especially in high TB incidence settings. We performed a systematic review, investigating whether secondary preventive therapy (sPT) with anti-TB drugs (preventive therapy in former TB patients with treatment success) is an effective strategy to prevent recurrence of TB in this patient group. We searched the databases PubMed, Cochrane Library, EMBASE, Web of Science and Google Scholar using the keywords HIV-infections, HIV, human immunodeficiency virus, AIDS, isoniazid, isoniazid preventive therapy (IPT), tuberculosis, TB, recurrence and recurrent disease, resulting in 253 potential publications. We identified eight publications for full text assessment, after which four articles qualified for inclusion in this systematic review. The quality of the included articles was rated using the GRADE system. All but one study were rated as having a high quality. In all included studies, sPT significantly decreased the incidence of recurrent TB in HIV-infected individuals to a substantial degree in comparison to non-treatment or placebo. Relative reductions varied from 55.0% to 82.1%. These data showed that the use of sPT to prevent recurrent TB in HIV-infected individuals was highly beneficial. These findings need to be confirmed in prospective studies with an adequate assessment of the effect of antiretroviral therapy (ART) and the occurrence of drug resistance.

  2. Hepatocellular carcinoma: Therapy and prevention

    PubMed Central

    Blum, Hubert E

    2005-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. Despite these scientific advances and the implementation of measures for the early detection of HCC in patients at risk, patient survival has not improved during the last three decades. This is due to the advanced stage of the disease at the time of clinical presentation and limited therapeutic options. The therapeutic options fall into five main categories: surgical interventions including tumor resection and liver transplantation, percutaneous interventions including ethanol injection and radiofrequency thermal ablation, transarterial interventions including embolization and chemoembolization, radiation therapy and drugs as well as gene and immune therapies. These therapeutic strategies have been evaluated in part in randomized controlled clinical trials that are the basis for therapeutic recommendations. Though surgery, percutaneous and transarterial interventions are effective in patients with limited disease (1-3 lesions, <5 cm in diameter) and compensated underlying liver disease (cirrhosis Child A), at the time of diagnosis more than 80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce the morbidity and mortality of HCC, early diagnosis and the development of novel systemic therapies for advanced disease, including drugs, gene and immune therapies as well as primary HCC prevention are of paramount importance. Furthermore, secondary HCC prevention after successful therapeutic interventions needs to be improved in order to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses, should allow to further

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

    PubMed

    2013-10-04

    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.

  4. 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.

  5. 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

  6. Supervised preventive therapy for latent tuberculosis infection in illegal immigrants in Italy.

    PubMed

    Matteelli, A; Casalini, C; Raviglione, M C; El-Hamad, I; Scolari, C; Bombana, E; Bugiani, M; Caputo, M; Scarcella, C; Carosi, G

    2000-11-01

    In a multicenter, prospective, randomized, open-label study of isoniazid-preventive therapy (IPT) for latent tuberculosis infection, illegal immigrants from countries where tuberculosis is highly endemic were enrolled at two clinical sites in Northern Italy. Of 208 eligible subjects, 82 received supervised IPT at a dose of 900 mg twice weekly for 6 mo (Regimen A), 73 received unsupervised IPT 900 mg twice weekly for 6 mo (Regimen B), and 53 received unsupervised IPT 300 mg daily for 6 mo (Regimen C). Supervised IPT was delivered at either one tuberculosis clinic or one migrant clinic. The probability of completing a 26-wk regimen was 7, 26, and 41% in Regimens A, B, and C, respectively (p < 0.005, Log- rank test calculated using Kaplan-Meier plots). The mean time to dropout was 3. 8, 6, and 6.2 wk in Regimens A, B, and C, respectively (p = 0.003 for regimen A versus either Regimens B or C). Treatment was stopped in five subjects (2.4%) because of adverse events. The rate of completion of preventive therapy for latent tuberculosis infection among illegal immigrants was low. Supervised, clinic-based administration of IPT significantly reduced adherence. Alternative strategies to implement preventive therapy in illegal immigrants are clearly required.

  7. 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.

  8. 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

  9. 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).

  10. 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.

  11. Isoniazid mediates the CYP2B6*6 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of CYP2A6.

    PubMed

    Court, Michael H; Almutairi, Fawziah E; Greenblatt, David J; Hazarika, Suwagmani; Sheng, Hongyan; Klein, Kathrin; Zanger, Ulrich M; Bourgea, Joanne; Patten, Christopher J; Kwara, Awewura

    2014-07-01

    Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the CYP2B6*6/*6 genotype (but not the CYP2B6*1/*1 genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [Ki] = 368 μM) and pyrazinamide (Ki = 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [KI] = 30 μM; maximal rate constant of inactivation [kinact] = 0.023 min(-1)) and recombinant CYP2A6 (KI = 15 μM; kinact = 0.024 min(-1)) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through

  12. Targeted Therapy for Breast Cancer Prevention

    PubMed Central

    den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

    2013-01-01

    With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

  13. Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis

    PubMed Central

    Gerona, Roy; Wen, Anita; Chin, Aaron T.; Koss, Catherine A.; Bacchetti, Peter; Metcalfe, John; Gandhi, Monica

    2016-01-01

    Background Tuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV. Methods A large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay’s suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested. Results Our LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10–25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05–50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range. Conclusions An LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to

  14. Preventive therapies: weighing the pros and cons.

    PubMed Central

    Laupacis, A

    1996-01-01

    The author comments on three issues raised by Dr. Kenneth G. Marshall in his series on the benefits and harms of preventive therapies, which begins in this issue on page 1493. First, because the method by which the results of clinical trials are presented markedly affects the perception of those results some measure of absolute benefit and harm must be used when the results of clinical trials are presented. Second, there is increasing interest in decision aids as a means of helping patients to understand evidence and make therapeutic choices. It is important that these aids undergo rigorous testing before they are adopted for common use. Third, evidence-based clinical practice guidelines are a welcome resource for busy clinicians. However, physicians and patients should bear in mind that interpretations of the available evidence can vary, leading to different conclusions about the appropriateness of preventive therapies. PMID:8625001

  15. Screening and preventive therapy for tuberculosis.

    PubMed

    Marais, Ben J; Ayles, Helen; Graham, Stephen M; Godfrey-Faussett, Peter

    2009-12-01

    The tuberculosis (TB) epidemic is well controlled in most developed countries and the focus in these areas has shifted to TB eradication. Transmission within nonendemic areas is limited and most cases of TB result from reactivation of distant (latent) infection. With adequate resources, wide-scale use of preventive therapy can assist to eliminate the pool of latent infection that is required for TB eradication. In contrast, TB control remains poor in many developing countries, especially those worst affected by poverty and the human immunodeficiency virus (HIV) epidemic. In this review the authors critically assess the approach to TB preventive therapy in children and adults, focus on the underlying treatment rationale, discuss available data and identify issues of concern.

  16. Isoniazid or Moxifloxacin in Rifapentine-based Regimens for Experimental Tuberculosis?

    PubMed Central

    Rosenthal, Ian M.; Zhang, Ming; Almeida, Deepak; Grosset, Jacques H.; Nuermberger, Eric L.

    2008-01-01

    Rationale: Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard, daily, short-course regimen of rifampin, isoniazid, and pyrazinamide produces stable cure in 12 weeks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and isoniazid to rifapentine-based regimens. Objectives: We compared bactericidal activity and treatment-shortening potential between regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily. Methods: Using a mouse model of tuberculosis, we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure. Measurements and Main Results: After 4 weeks of treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, isoniazid, and pyrazinamide. By 8 weeks of treatment, all mice receiving the moxifloxacin-containing regimens were lung culture negative, whereas those mice receiving the isoniazid-containing regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment. Conclusions: These results suggest that regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis. PMID:18723432

  17. Safety and Adherence for 12 Weekly Doses of Isoniazid and Rifapentine for Pediatric Tuberculosis Infection.

    PubMed

    Cruz, Andrea T; Starke, Jeffrey R

    2016-07-01

    Traditional treatment of tuberculosis infection (TBI) is efficacious, but adherence is low. Eighty children with TBI received a 12-dose once-weekly isoniazid/rifapentine regimen; 79 (99%) completed therapy, 94% reported no adverse events, 1 child had mildly elevated transaminases but 1 adolescent later developed pulmonary TB. Isoniazid/rifapentine is safe, is well tolerated and has much higher completion rates than traditional TBI regimens.

  18. 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.

  19. 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

  20. 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 ...

  1. 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

  2. Cytoprotective effects of taurine against toxicity induced by isoniazid and hydrazine in isolated rat hepatocytes.

    PubMed

    Heidari, Reza; Babaei, Hossein; Eghbal, Mohammad Ali

    2013-06-01

    Isoniazid is one of the most commonly used drugs to treat tuberculosis. Its administration is associated with a high incidence of hepatotoxicity. The aim of this study was to establish the protective effects of taurine against cytotoxicity induced by isoniazid and its suspected toxic metabolite hydrazine in isolated rat hepatocytes by measuring reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial depolarisation, reduced glutathione (GSH), and oxidised glutathione (GSSG). Isoniazid caused no significant ROS formation in normal hepatocytes, but in glutathione-depleted cells it was considerable. Hydrazine caused ROS formation and lipid peroxidation in both intact and glutathione-depleted cells. Both isoniazid and hydrazine caused mitochondrial membrane depolarisation. Hydrazine lowered cellular GSH reserve and increased GSSG. Taurine (200 μmol L(-1)) and N-acetylcysteine (200 μmol L(-1)) effectively countered the toxic effects of isoniazid and/or hydrazine by decreasing ROS formation, lipid peroxidation, and mitochondrial damage. Taurine prevented depletion of GSH and lowered GSSG levels in hydrazine-treated cells. This study suggests that the protective effects of taurine against isoniazid and its intermediary metabolite hydrazine cytotoxicity in rat hepatocytes could be attributed to antioxidative action.

  3. Completion Rate and Side-Effect Profile of Three-Month Isoniazid and Rifapentine Treatment for Latent Tuberculosis Infection in an Urban County Jail.

    PubMed

    Juarez-Reyes, Maria; Gallivan, Mark; Chyorny, Alexander; O'Keeffe, Linda; Shah, Neha S

    2016-01-01

    In an urban jail population, 3 months of isoniazid and rifapentine (3HP) was associated with an 85% latent tuberculosis infection treatment completion rate compared with 18% in a standard 9-month isoniazid treatment group. Among the 91 patients who started 3HP therapy, there were 2 treatment discontinuations from adverse drug reactions.

  4. Completion Rate and Side-Effect Profile of Three-Month Isoniazid and Rifapentine Treatment for Latent Tuberculosis Infection in an Urban County Jail

    PubMed Central

    Juarez-Reyes, Maria; Gallivan, Mark; Chyorny, Alexander; O'Keeffe, Linda; Shah, Neha S.

    2016-01-01

    In an urban jail population, 3 months of isoniazid and rifapentine (3HP) was associated with an 85% latent tuberculosis infection treatment completion rate compared with 18% in a standard 9-month isoniazid treatment group. Among the 91 patients who started 3HP therapy, there were 2 treatment discontinuations from adverse drug reactions. PMID:26885547

  5. [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.

  6. Using Rational-Emotive Therapy to Prevent Classroom Problems.

    ERIC Educational Resources Information Center

    Webber, Jo; Coleman, Maggie

    1988-01-01

    Teachers are encouraged to utilize rational-emotive therapy to prevent and deal with classroom behavior problems. Rational-emotive therapy is defined, the ABC model of rational thinking briefly explained, types of irrational thinking identified, and suggestions for becoming a rational thinker are offered. Classroom examples are given. (DB)

  7. 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

  8. Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model

    SciTech Connect

    Tafazoli, Shahrzad; Mashregi, Mariam; O'Brien, Peter J.

    2008-05-15

    Isoniazid is an anti-tuberculosis drug that can cause hepatotoxicity in 20% of patients that is usually associated with an inflammatory response. Hepatocytes when exposed to non-toxic levels of H{sub 2}O{sub 2}, to simulate H{sub 2}O{sub 2} formation by inflammatory cells, became twice as sensitive to isoniazid toxicity. Isoniazid cytotoxicity was prevented by 1-aminobenzotriazole, a non-selective P450 inhibitor or by bis-p-nitrophenyl phosphate (BNPP), an esterase inhibitor. Moreover, the cytotoxicity of hydrazine, the metabolite formed by amidase-catalyzed hydrolysis of isoniazid, was increased 16-fold by a non-toxic H{sub 2}O{sub 2}-generating system. The acetylhydrazine metabolite was found to be much less cytotoxic than hydrazine in this hepatocyte inflammation model. Hydrazine, therefore, seems to be the isoniazid reactive metabolite in this inflammation model. The molecular mechanism of hydrazine-induced cytotoxicity was attributed to oxidative stress as reactive oxygen species (ROS) and protein carbonyl formation occurred before the onset of hepatocyte toxicity. Hydrazine toxicity also involved significant production of endogenous H{sub 2}O{sub 2} which resulted in lysosomal membrane damage and leads to a collapse in mitochondrial membrane potential. These results implicated H{sub 2}O{sub 2}, a cellular mediator of inflammation, as a potential risk factor for the manifestation of adverse drug reactions, particularly those caused by hydrazine containing drugs.

  9. Medical and dietary therapy for kidney stone prevention.

    PubMed

    Gul, Zeynep; Monga, Manoj

    2014-12-01

    The prevalence of kidney stone disease is increasing, and newer research is finding that stones are associated with several serious morbidities. These facts suggest that emphasis needs to be placed not only on stone treatment but also stone prevention. However, there is a relative dearth of information on dietary and medical therapies to treat and avoid nephrolithiasis. In addition, studies have shown that there are many misconceptions among both the general community and physicians about how stones should be managed. This article is meant to serve as a review of the current literature on dietary and drug therapies for stone prevention.

  10. 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

  11. Pharmacokinetics of rifampin and isoniazid in tuberculosis-HIV-coinfected patients receiving nevirapine- or efavirenz-based antiretroviral treatment.

    PubMed

    Bhatt, N B; Barau, C; Amin, A; Baudin, E; Meggi, B; Silva, C; Furlan, V; Grinsztejn, B; Barrail-Tran, A; Bonnet, M; Taburet, A M

    2014-06-01

    This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of

  12. Pharmacokinetics of Rifampin and Isoniazid in Tuberculosis-HIV-Coinfected Patients Receiving Nevirapine- or Efavirenz-Based Antiretroviral Treatment

    PubMed Central

    Bhatt, N. B.; Barau, C.; Amin, A.; Baudin, E.; Meggi, B.; Silva, C.; Furlan, V.; Grinsztejn, B.; Barrail-Tran, A.; Bonnet, M.

    2014-01-01

    This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4+ T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of

  13. Homocysteine-lowering therapy: a role in stroke prevention?

    PubMed

    Spence, J David

    2007-09-01

    On the basis of the results of several recent clinical trials, many researchers have concluded that vitamin therapy designed to lower total homocysteine concentrations is not effective in reducing the risk of cardiovascular events. However, whereas almost all myocardial infarctions are due to plaque rupture, stroke has many more pathophysiological mechanisms, and thrombosis-which is increased by raised total homocysteine concentrations-has an important role in many of these processes. Thus, stroke and myocardial infarction could respond differently to vitamin therapy. A detailed assessment of the results of the recent HOPE-2 trial and a reanalysis of the VISP trial restricted to patients capable of responding to vitamin therapy suggest that higher doses of vitamin B12 and perhaps new approaches to lowering total homocysteine besides routine vitamin therapy with folate, vitamin B6, and vitamin B12 could reduce the risk of stroke. Thus, therapy to lower homocysteine could still help to prevent stroke, if not other vascular outcomes.

  14. The effects of isoniazid on hippocampal NMDA receptors: protective role of erdosteine.

    PubMed

    Cicek, Ekrem; Sutcu, Recep; Gokalp, Osman; Yilmaz, H Ramazan; Ozer, M Kaya; Uz, Efkan; Ozcelik, Nurten; Delibas, Namik

    2005-09-01

    Isoniazid (INH) has neurotoxic effects such as seizure, poor concentration, subtle reduction in memory, anxiety, depression and psychosis. INH-induced toxic effects are thought to be through increased oxidative stress, and these effects have been shown to be prevented by antioxidant therapies in various organs. Increased oxidative stress may be playing a role in these neurotoxic effects. N-methyl D-aspartat receptors (NMDA) are a member of the ionotropic group of glutamate receptors. These receptors are involved in a wide variety of processes in the central nervous system including synaptogenesis, synaptic plasticity, memory and learning. Erdosteine is a potent antioxidant and mucolytic agent. We aimed to investigate adverse effects of INH on rat hippocampal NMDAR receptors, and to elucidate whether erdosteine prevents possible adverse effects of INH. In the present study, compared to control group, NMDAR2A (NR2A) receptors were significantly decreased and malondialdehyde (MDA), end product of lipid peroxidation, production was significantly increased in INH-treated group. On the other hand, administration of erdosteine to INH-treated group significantly increased NR2A receptors and decreased MDA production. In conclusion, decreasing NR2A receptors in hippocampus and increasing lipid peroxidation correlates with the degree of oxidative effects of INH and erdosteine protects above effect of INH on NR2A receptors and membrane damage due to lipid peroxidation by its antioxidant properties.

  15. 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

  16. Comparison of three composite compliance indices in a trial of self-administered preventive therapy for tuberculosis in HIV-infected Ugandan adults. Uganda-Case Western Reserve University Research Collaboration.

    PubMed

    Pekovic, V; Mayanja, H; Vjecha, M; Johnson, J; Okwera, A; Nsubuga, P; Mugerwa, R; Ellner, J; Whalen, C

    1998-07-01

    Compliance with tuberculosis preventive therapy in a randomized placebo-controlled trial in 2736 HIV-infected Ugandans was measured using urinary isoniazid metabolite testing, clinic attendance, and self-report. Overall, 77% of urine tests were positive, subjects kept 85% of their scheduled visits while on therapy, and 69% reportedly never forgot to take their medication. Different strategies were used for constructing three composite compliance indices in active arms: (1) an unweighted index of the summed scores on scaled compliance measures; (2) a weighted index using weights obtained from a survey of experts on tuberculosis; and (3) a statistically weighted index using principal components analysis. Composite indices were evaluated for reliability, validity, and practical utility. Understanding of the regimen, study arm, subsequent follow-up, tuberculosis status, and urine spot-check result were associated with composite compliance scores. The unweighted index in this study performed as well as the weighted indices.

  17. NF-κB in Carcinoma Therapy and Prevention

    PubMed Central

    Brown, Matthew; Cohen, Jonah; Arun, Pattatheyil; Chen, Zhong; Van Waes, Carter

    2008-01-01

    Background Nuclear factor-κB (NF-κB) includes a family of signal-activated transcription factors which normally regulate responses to injury and infection, but which are aberrantly activated in many carcinomas. Objective To review the activation and role of NF-κB in pathogenesis and as a target for treatment and prevention in carcinoma. Methods Evidence from experimental, epidemiologic, pre-clinical studies and clinical trials cited in the literature are reviewed. Results/conclusion Cumulative evidence implicates NF-κB in cell survival, inflammation, angiogenesis, spread and therapeutic resistance during tumor development, progression and metastasis of carcinomas. Non-specific natural and synthetic agents that inhibit NF-κB have demonstrated activity and safety in prevention or therapy. NF-κB activating kinases and the proteasome are under investigation for targeted prevention and therapy of carcinoma. PMID:18694378

  18. Extended therapy for primary and secondary prevention of venous thromboembolism.

    PubMed

    Conway, Susan E; Marcy, Todd R

    2010-08-01

    Clinical practice guidelines currently suggest extended anticoagulation therapy for primary and secondary prevention of venous thromboembolism (VTE). The optimal duration of anticoagulation has been an active area of clinical investigation for patients undergoing orthopedic surgeries and those diagnosed with a first episode of unprovoked VTE. Practice guidelines, VTE incidence, clinical predictors/mediators, and clinical trial evidence is reviewed to help pharmacists and other health care providers make an informed, patient-specific decision on the optimal duration of anticoagulation therapy. Extended anticoagulation up to 5 weeks following orthopedic surgery for primary VTE prevention and indefinitely following a first episode of unprovoked VTE for secondary VTE prevention should be considered only if the risk of bleeding is not high and the cost and burden of anticoagulation is acceptable to the patient. The optimal duration of anticoagulation therapy for primary or secondary prevention of VTE should include the health care provider and patient making a decision based on evaluation of individual benefits, risks, and preferences.

  19. Update on Antithrombotic Therapy for Stroke Prevention in Atrial Fibrillation

    PubMed Central

    Ovbiagele, Bruce

    2010-01-01

    Opinion statement Atrial fibrillation (AF) is the most common cardiac arrhythmia in the elderly, affecting 1 in 20 adults over the age of 70 years. Stroke is a major yet highly preventable complication of AF, and the strokes related to AF often are disabling and fatal. Warfarin is the treatment of choice in high-risk patients with AF, and its superior efficacy over aspirin for preventing stroke in these patients is widely recognized. However, several eligible patients with AF are not being treated with warfarin or are being treated inadequately, largely because of concerns regarding the attendant strict monitoring, drug interactions, and risk of major bleeding. As such, alternative antithrombotic therapies that can rival or exceed the efficacy of warfarin, yet compare favorably with its administration and side effect profile, are being sought. One such strategy, the use of a combination antiplatelet regimen, for stroke prevention in high-risk patients with nonvalvular AF was investigated recently in two clinical trials. This article reviews the role of combination antiplatelet regimens in stroke prevention for patients with AF. Other therapies discussed include oral anticoagulation, single antiplatelet therapies, oral anticoagulation plus antiplatelet treatment, direct thrombin inhibitors, and factor Xa inhibitors. PMID:20461116

  20. 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

  1. 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.

  2. Spectrophotometric determination of isoniazid in presence of its hydrazones.

    PubMed

    Devani, M B; Shishoo, C J; Patel, M A; Bhalara, D D

    1978-05-01

    A spectrophotometric determination of isoniazid in the presence of its hydrazones was developed. The method involves the reaction between isoniazid and 2,3-dichloro-1,4-naphthoquinone in the presence of ammonia in an ethanolic medium. The colored product has an absorbance maxium at 640 nm. The Lambert-Beer law is obeyed in the 1--14-microgram/ml range. The proposed method was applied to the analysis of isoniazid tablets. In commercial tablets, hydrazone formation due to the reaction between isoniazid and lactose was detected by TLC. The analysis of lactose-containing isoniazid tablets showed 10--22% lower recovery than that obtained by the official method. Hydrazone formation in tablets probably interferes with isoniazid bioavailability.

  3. 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

  4. ICD Therapy for Primary Prevention in Hypertrophic Cardiomyopathy

    PubMed Central

    Trivedi, Amar

    2016-01-01

    Hypertrophic cardiomyopathy (HCM) is a common and heterogeneous disorder that increases an individual’s risk of sudden cardiac death (SCD). This review article discusses the relevant factors that are involved in the challenge of preventing SCD in patients with HCM. The epidemiology of SCD in patients is reviewed as well as the structural and genetic basis behind ventricular arrhythmias in HCM. The primary prevention of SCD with implantable cardioverter-defibrillator (ICD) therapy is the cornerstone of modern treatment for individuals at high risk of SCD. The focus here is on the current and emerging predictors of SCD as well as risk stratification recommendations from both North American and European guidelines. Issues related to ICD implantation, such as programming, complications and inappropriate therapies, are discussed. The emerging role of the fully subcutaneous ICD and the data regarding its implantation are reviewed. PMID:28116084

  5. Isoniazid-Resistant Tuberculosis in Children: A Systematic Review

    PubMed Central

    Yuen, Courtney M.; Tolman, Arielle W.; Cohen, Ted; Parr, Jonathan B.; Keshavjee, Salmaan; Becerra, Mercedes C.

    2013-01-01

    Background Isoniazid resistance is an obstacle to the treatment of tuberculosis disease and latent tuberculosis infection in children. We aim to summarize the literature describing the risk of isoniazid-resistant tuberculosis among children with tuberculosis disease. Methods We did a systematic review of published reports of children with tuberculosis disease who had isolates tested for susceptibility to isoniazid. We searched PubMed, Embase and LILACS online databasesuptoJanuary 12, 2012. Results Our search identified 3,403 citations, of which 95 studies met inclusion criteria. These studies evaluated 8,351 children with tuberculosis disease for resistance to isoniazid. The median proportion of children found to have isoniazid-resistant strains was 8%; the distribution was right-skewed (25th percentile: 0% and 75th percentile: 18%). Conclusions High proportions of isoniazid resistance among pediatric tuberculosis patients have been reported in many settings suggesting that diagnostics detecting only rifampin resistance are insufficient to guide appropriate treatment in this population. Many children are likely receiving sub-standard tuberculosis treatment with empirical isoniazid-based regimens, and treating latent tuberculosis infection with isoniazid may not be effective in large numbers of children. Work is needed urgently to identify effective regimens for the treatment of children sick with or exposed to isoniazid-resistant tuberculosis and to better understand the scope of this problem. PMID:23348808

  6. A rare case of isoniazid-induced erythroderma.

    PubMed

    Garg, Yashika; Gore, Rajeshwari; Jain, Sourabh; Kumar, Arun

    2015-01-01

    Tuberculosis is a common infectious disease in developing countries. Isoniazid is established the first-line antitubercular drug and an essential component of all antitubercular regimens. Erythroderma caused by isoniazid is an uncommon but serious adverse drug reaction. We report here a case of a 63-year-old female patient who presented with generalized redness and scaling with itching after 8 weeks of antitubercular treatment (ATT). ATT was stopped immediately, and antihistaminics were started. The patient improved over a period of 2 weeks. On sequential rechallenge, she developed similar lesions all over the body with isoniazid, hence confirming the diagnosis of isoniazid-induced erythroderma.

  7. 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.

  8. Cognitive Therapy to Prevent Depressive Relapse in Adults

    PubMed Central

    2015-01-01

    The high prevalence, frequent relapse, and recurrence of major depressive disorder (MDD) increase its personal and societal costs. Cognitive therapy (CT) aims to decrease depressive symptoms and prevent relapse/recurrence. We review prevention evidence for acute, continuation, and maintenance CTs for patients whose depression is active, remitted, and recovered, respectively. Evidence suggests that patients relapse less often after discontinuing acute phase CT versus discontinuing pharmacotherapy. Continuation CT further decreases relapse relative to inactive controls and similarly to active pharmacotherapy. Maintenance CT may decrease recurrence but needs rigorous evaluation. Post-acute CT’s preventive effects appear greater for higher-risk patients (e.g., with residual depressive symptoms, unstable acute-phase treatment response, childhood trauma, more prior depressive episodes), although risks may vary by specific CTs. PMID:25729758

  9. Influence of endothelium in dose-dependent inhibition and potentiation by isoniazid of isosorbide dinitrate relaxation of rat aorta.

    PubMed

    Vidrio, H; Fernández, G

    2001-05-01

    The influence of in vivo administration of isoniazid on the relaxant effect of isosorbide dinitrate was determined by pretreating rats with various doses of isoniazid and obtaining concentration-response curves to isosorbide dinitrate in aortic rings from these animals. In rings with endothelium, isoniazid potentiated responses to isosorbide dinitrate at doses of 10, 30, and 100 mg/kg; 3 and 300 mg/kg were without effect. In endothelium-denuded preparations, potentiation was present only at 10 mg/kg; 3 and 300 mg/kg inhibited relaxation. Other experiments indicated that isoniazid potentiation was prevented by pyridoxine, was reproduced with theophylline, and did not occur with 3-morpholinosydnonimine or papaverine. These results were deemed compatible with the hypothesis that isoniazid inhibits transsulfuration of homocysteine and causes its accumulation in vascular smooth muscle and endothelial cells, where it functions as a thiol intermediate and leads to enhanced bioactivation of isosorbide dinitrate. Potentiation appeared to occur only with moderate increases of homocysteine.

  10. 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.

  11. Ozone therapy in the management and prevention of caries.

    PubMed

    Almaz, Merve Erkmen; Sönmez, Işıl Şaroğlu

    2015-01-01

    The purpose of this article was to assess the effectiveness of ozone therapy in the management and prevention of caries, reviewing clinical and in vitro studies. Ozone has proven to be effective against gram-negative and gram-positive bacteria, viruses, and fungi. In dentistry, most of the published articles are based on ozone's antimicrobial effects and the treatment of caries. Most of the clinical studies reported ozone to be a promising alternative to conventional methods for caries management. However, a few studies have shown ozone to be insufficient for preventing caries and reducing microorganisms in open occlusal carious lesions. Ozone might be a useful tool to reduce and control oral infectious microorganisms in dental plaque and dental cavity. However, the results of in vitro studies are controversial; while some researchers reported that ozone therapy had a minimal or no effect on the viability of microorganisms, others suggested ozone to be highly effective in killing both gram-positive and gram-negative oral microorganisms. Therefore, more evidence is required before ozone can be accepted as an alternative to present methods for the management and prevention of caries.

  12. Emerging Therapies for the Prevention of Acute Respiratory Distress Syndrome

    PubMed Central

    Ruthman, Carl A.; Festic, Emir

    2015-01-01

    The development of the acute respiratory distress syndrome (ARDS) carries significant risk of morbidity and mortality. To date, pharmacologic therapy has been largely ineffective for patients with ARDS. We present our personal review aimed at outlining current and future directions for the pharmacologic prevention of ARDS. Several available risk-stratification or prediction scores strategies for identification of patients at risk of ARDS have been reported. Although not ready for the clinical everyday use, they are and will be instrumental in the ongoing and future trials of pharmacoprevention of ARDS. Several systemic medications established the potential role in ARDS prevention based on the preclinical studies and observational data. Due to potential for systemic adverse effects to neutralize any pharmacologic benefits of systemic therapy, inhaled medications appear particularly attractive candidates for ARDS prevention. This is because of their direct delivery to the site of the proposed action (lungs), while pulmonary epithelial surface is still functional. We postulate that overall morbidity and mortality rates from ARDS in the future will be contingent upon decreasing the overall incidence of ARDS through effective identification of those at risk and early application of proven supportive care and pharmacologic interventions. PMID:26002528

  13. Effect of isoniazid on antigen-specific interferon-γ secretion in latent tuberculosis

    PubMed Central

    Torres, Martha; Cruz-Hervert, Pablo; Guio, Heinner; Carranza, Claudia; Ferreyra-Reyes, Leticia; Canizales, Sergio; Molina, Susana; Ferreira-Guerrero, Elizabeth; Téllez, Norma; Montero-Campos, Rogelio; Delgado-Sánchez, Guadalupe; Mongua-Rodriguez, Norma; Sifuentes-Osornio, Jose; Ponce-de Leon, Alfredo; Sada, Eduardo; Young, Douglas B.; Wilkinson, Robert J.

    2015-01-01

    Treatment of persons with latent tuberculosis (TB) infection at greatest risk of reactivation is an important component of TB control and elimination strategies. Biomarkers evaluating the effectiveness of treatment of latent TB infection have not yet been identified. This information would enhance control efforts and assist the evaluation of new treatment regimes. We designed a two-group, two-arm, randomised clinical study of tuberculin skin test-positive participants: 26 with documented contact with TB patients and 34 with non-documented contact. Participants in each group were randomly assigned to the immediate- or deferred-isoniazid treatment arms. Assays of in vitro interferon (IFN)-γ secretion in response to recombinant Rv1737 and overlapping synthetic peptide pools from various groups of immunodominant proteins were performed. During isoniazid therapy, a significant increase from baseline in the proportion of IFN-γ responders to the 10-kDa culture filtrate protein, Rv2031, Rv0849, Rv1986, Rv2659c, Rv2693c and the recombinant Rv1737 protein was observed (p⩽0.05). The peptide pool of Rv0849 and Rv1737 recombinant proteins induced the highest percentage of IFN-γ responders after isoniazid therapy. The in vitro IFN-γ responses to these proteins might represent useful markers to evaluate changes associated with treatment of latent TB infection. PMID:25359354

  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. 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

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

    PubMed Central

    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.

    2016-01-01

    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

  17. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection.

    PubMed

    2011-12-09

    Preventing tuberculosis (TB) by treating latent Mycobacterium tuberculosis infection (LTBI) is a cornerstone of the U.S. strategy for TB elimination. Three randomized controlled trials have shown that a new combination regimen of isoniazid (INH) and rifapentine (RPT) administered weekly for 12 weeks as directly observed therapy (DOT) is as effective for preventing TB as other regimens and is more likely to be completed than the U.S. standard regimen of 9 months of INH daily without DOT. This report provides CDC recommendations for using the INH-RPT regimen. The new regimen is recommended as an equal alternative to the 9-month INH regimen for otherwise healthy patients aged≥12 years who have LTBI and factors that are predictive of TB developing (e.g., recent exposure to contagious TB). The new regimen also can be considered for other categories of patients when it offers practical advantages. Although the INH-RPT regimen was well tolerated in treatment trials, monitoring for adverse effects is recommended. Severe adverse effects should be reported to the Food and Drug Administration (FDA) and CDC.

  18. [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

  19. Boron neutron capture therapy for the prevention of restenosis

    SciTech Connect

    Yanch, J.C.; Delfaus, M.L.

    1997-12-01

    The potential application of boron neutron capture therapy (BNCT) for the prevention of restenosis following angioplasty is under investigation at Massachusetts Institute of Technology`s Laboratory for Accelerator Beam Applications. The process of Percutaneous transluminal coronary angioplasty involves the insertion of a balloon dilation catheter into the occluded artery. The balloon is then inflated for several minutes to dilate the artery. The blockage is decreased, and blood flow through the artery is improved. This procedure is, initially, very successful. However, 30 to 60% of patients treated also show restenosis within 6 months. Although many physiological processes may contribute to restenosis, the primary mechanism is thought to be abnormal proliferation of the smooth muscle cells in the treated artery.

  20. The role of Fc Receptors in HIV Prevention and Therapy

    PubMed Central

    Boesch, Austin W.; Brown, Eric; Ackerman, Margaret E.

    2016-01-01

    Over the past decade, a wealth of experimental evidence has accumulated supporting the importance of Fc receptor (FcR) ligation in antibody-mediated pathology and protection in many disease states. Here we present the diverse evidence base that has accumulated as to the importance of antibody effector functions in the setting of HIV prevention and therapy, including clinical correlates, genetic associations, viral evasion strategies, and a rapidly growing number of compelling animal model experiments. Collectively, this work identifies antibody interactions with FcR as important to both therapeutic and prophylactic strategies involving both passive and active immunity. These findings mirror those in other fields as investigators continue to work toward identifying the right antibodies and the right effectors to be present at the right sites at the right time. PMID:26497529

  1. 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

  2. Photodynamic therapy for the prevention of restenosis after angioplasty

    NASA Astrophysics Data System (ADS)

    Asahara, Takayuki; Usui, Mikio; Amemiya, Takashi; Oike, Yasuhisa; Shiraishi, Hiromori; Miyagi, Manabu; Nakajima, Hitoshi; Kato, Tomitsugu; Naito, Yuichi; Ibukiyama, Chiharu

    1993-06-01

    The purpose of this study was to evaluate whether photodynamic therapy (PDT) can destroy the proliferating smooth muscle cells and therefore suppress the occurrence of restenosis after angioplasty. PDT following administration of hematoporphyrin derivatives (HpD) 24 hours before irradiation was performed on 30 rabbits immediately (0D), 3 days (3D), 1 week (1W) and 2 weeks (2W) after balloon injury. HpD accumulation of each group was investigated simultaneously. Irradiation of 27 J/10 mm2 from an Hg-Xe flash lamp light transmitted through an 800 micrometers quartz fiber with a diffusing tip was used. All rabbits were sacrificed 4 weeks after balloon injury. The results were expressed in terms of intima:media thickness ratio at the site of fiber contact (I/M) and intima:media area ratio of the cross section (IA/MA). Inhibition of intimal thickening evaluated on the basis of the I/M ratio was recognized in the 3D-, 1W-, and 2W-PDT group. The most effective photoradiation was at the 1W-PDT (I/M equals 0.78 +/- 0.67), but in 2W-PDT intimal necrosis resulting in a small amount of thickness was observed with less media necrosis. ThreeD and 0D PDT effects reduced with media necrosis. We conclude that PDT after angioplasty would be an ideal preventional therapy of restenosis.

  3. 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.

  4. Liver regeneration microenvironment of hepatocellular carcinoma for prevention and therapy

    PubMed Central

    Li, Hanmin; Zhang, Lisheng

    2017-01-01

    Research on liver cancer prevention and treatment has mainly focused on the liver cancer cells themselves. Currently, liver cancers are no longer viewed as only collections of genetically altered cells but as aberrant organs with a plastic stroma, matrix, and vasculature. Improving the microenvironment of the liver to promote liver regeneration and repair by affecting immune function, inflammation and vasculature can regulate the dynamic imbalance between normal liver regeneration and repair and abnormal liver regeneration, thus improving the microenvironment of liver regeneration for the prevention and treatment of liver cancer. This review addresses the basic theory of the liver regeneration microenvironment, including the latest findings on immunity, inflammation and vasculature. Attention is given to the potential design of molecular targets in the microenvironment of hepatocellular carcinoma (HCC). In an effort to improve the liver regeneration microenvironment of HCC, researchers have extensively utilized the enhancement of immunity, anti-inflammation and the vasculature niche, which are discussed in detail in this review. In addition, the authors summarize the latest pro-fibrotic transition characteristics of the vascular niche and review potential cell therapies for liver disease. PMID:27655683

  5. Preventing restenosis in atherosclerotic miniswine with photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Hsiang, York N.; Crespo, M. T.; To, Eleanor C.; Sobeh, Mohammed S.; Greenwald, Stephen E.; Bower, Robert D.

    1995-05-01

    The purpose of this study was to determine whether the addition of Photodynamic Therapy (PDT) using the photosensitizer Photofrin* (P*) following balloon angioplasty (BA) could prevent restenosis in an atherosclerotic animal model. Bilateral iliac atherosclerosis was created in 21 Yucatan miniswine. Six weeks later, P* 2.5 mg/kg was given IV 24 hours prior to BA (4 mm X 20 mm, 1 inflation). Following BA, swine were randomly allocated to receive PDT via a fiberoptic probe with laser energy or the same probe without laser energy. The fiberoptic probe had a 1 cm cylindrical diffusing tip and was passed co-axially through a custom catheter to ensure central location of the probe. A continuous wave argon ion-pumped dye laser tuned to 630 nm was used to provide a fluence of 100 J/cm2. Four weeks later, swine were sacrificed and vessels perfusion-fixed in-situ with glutaraldehyde and analyzed by ocular micrometry. Five occlusions occurred, all in the PDT + BA group. Percentage intimal thickness (mean +/- SD) was 51.0 +/- 29.5 in the BA group and 71.2 +/- 35.2 in the BA + PDT group (p equals 0.21). These results suggest that the addition of PDT following BA does not prevent restenosis.

  6. 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

  7. Porcine Neonatal Coccidiosis: Evaluation of Monensin as Preventive Therapy

    PubMed Central

    Doré, Monique; Morin, Michel

    1987-01-01

    In this study, we evaluated the efficacy of monensin as a preventive therapy for porcine neonatal coccidiosis. Fifteen three-day-old piglets were given 50,000 sporulated oocysts of Isospora suis and eight of them received 15 mg/kg of monensin orally every other day. Seven piglets served as normal controls. Fecal samples were collected and checked for oocyst shedding. At 18 days of age, piglets were euthanized and necropsied. The onset of clinical signs was delayed in the treated group, but all inoculated piglets displayed anorexia, soft stool, or diarrheic feces. Treated piglets shed large numbers of oocysts in their feces (up to 201,200 oocysts per gram of feces). All infected piglets had lesions of villous atrophy in the jejunum and most of them were in the late atrophic or villous regrowth stages. The results of this study suggest that monensin does not prevent clinical signs, oocyst shedding, and intestinal lesions caused by I. suis in neonatal piglets. PMID:17422909

  8. [Animal welfare in prevention and therapy of laminitis].

    PubMed

    Winkelsett, S; Vervuert, I

    2008-03-01

    Laminitis is a systemic disease which is manifested as a non infectious condition in the foot. The management of feeding and housing conditions is necessary to treat the endocrinological and metabolic disturbances of laminitic horses. The Equine Metabolic Syndrome (EMS) is predisposing for developing laminitis, and it is characterised by obesity, insulin resistance, hypertension and dyslipidaemia. A genetical predisposition is supposed and EMS is accompanied by a lack of exercise and inadequate energy intake. Laboratory examinations are of great importance for diagnosis. Analyses of insulin, glucose and ACTH are of interest. Several approaches to treat laminitis are available, including pharmacological and orthopaedic strategies as well as the management of the feeding and housing conditions. However, the prophylaxis to prevent laminitis has to be emphasised. Predisposed horses should be detected and adequately treated; especially weight reduction in obese horses is in the focus of interest. Horses in the acute stage of laminitis have to be stabled. Furthermore redistributing weight from the most stressed wall is necessary to prevent pain and to minimise laminar damage and displacement of the distal phalanx. In cases of displacement of the distal phalanx a close communication between the veterinarian and the authorised farrier is necessary, in these cases treatment should be supported by x-ray diagnosis. Horses have to be treated with NSAISs to ensure a proper therapy to consider animal welfare. Horses have to be fed with hay and supplemented with minerals and vitamins. Feeding exclusively straw and feed restriction has to be avoided.

  9. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex.

    PubMed

    Rodrigues, Liliana; Machado, Diana; Couto, Isabel; Amaral, Leonard; Viveiros, Miguel

    2012-06-01

    Resistance to isoniazid (INH), one of the main drugs used in tuberculosis (TB) therapy, is mostly due to chromosomal mutations in target genes. However, approximately 20-30% of INH resistant Mycobacterium tuberculosis isolates do not have mutations in any of the genes associated with INH resistance. This suggests that other mechanism(s) may be involved, namely efflux pump systems capable of extruding the drug to the exterior of the cell. In a previous work, we have induced clinical INH susceptible M. tuberculosis isolates and the H37Rv reference strain to high-level resistance to INH, by gradual exposure to increasing concentrations of this drug. In the present study, we have characterized these strains and Mycobacterium bovis BCG induced to INH resistance with respect to their efflux activity and its contribution to INH resistance using the following approach: determination of the susceptibility to INH in the presence and absence of the efflux inhibitors (EIs) chlorpromazine, thioridazine and verapamil; evaluation of efflux activity by a semi-automated fluorometric method; and quantification of the expression level of genes coding for efflux pumps by real-time RT-qPCR. The EIs decreased INH resistance in the INH induced strains, in particular verapamil promoted a reversal of resistance in some of the strains tested. The induced strains presented an increased efflux activity that was inhibited by the EIs and showed overexpression of the efflux pump genes efpA, mmpL7, mmr, p55 and the Tap-like gene Rv1258c. Altogether, these results correlate efflux activity with INH resistance and demonstrate that efflux pumps play an important role in acquired INH resistance in M. tuberculosis complex. The development of EIs that can restore the antimicrobial activity of the antibiotic subject to efflux is an approach that can be useful in order to prevent the emergence of this resistance and guide the development of new effective anti-TB therapeutical approaches.

  10. Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

    PubMed Central

    Hassan, Hozeifa M.; Guo, Hongli; Yousef, Bashir A.; Ping-Ping, Ding; Zhang, Luyong; Jiang, Zhenzhou

    2017-01-01

    Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity. PMID:28360859

  11. Biowaiver monographs for immediate release solid oral dosage forms: isoniazid.

    PubMed

    Becker, C; Dressman, J B; Amidon, G L; Junginger, H E; Kopp, S; Midha, K K; Shah, V P; Stavchansky, S; Barends, D M

    2007-03-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing isoniazid as the only active pharmaceutical ingredient (API) are reviewed. Isoniazid's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Isoniazid is "highly soluble" but data on its oral absorption and permeability are inconclusive, suggesting this API to be on the borderline of BCS Class I and III. For a number of excipients, an interaction with the permeability is extreme unlikely, but lactose and other deoxidizing saccharides can form condensation products with isoniazid, which may be less permeable than the free API. A biowaiver is recommended for IR solid oral drug products containing isoniazid as the sole API, provided that the test product meets the WHO requirements for "very rapidly dissolving" and contains only the excipients commonly used in isoniazid products, as listed in this article. Lactose and/or other deoxidizing saccharides containing formulations should be subjected to an in vivo BE study.

  12. [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.

  13. 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.

  14. 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.

  15. 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.

  16. [Gender aspects of malnutrition and associated sequelae. Prevention and therapy].

    PubMed

    Lechleitner, M; Hoppichler, F

    2013-08-01

    Malnutrition is related to a range of secondary complications. The prevalence of many of these sequelae is higher in elderly women than in men, thus resulting in a higher level of impairment and reduced quality of life. Multiple factors lead to the development of malnutrition and socioeconomic causes, such as poverty among the elderly and isolation, are more common in elderly women. The age-associated loss of muscle mass is more pronounced in women than in men and the risk of developing sarcopenia and frailty is increased. The prevalence of sarcopenic obesity is higher in women than in men. Malnutrition increases the risk of osteoporosis and about 80 % of all osteoporosis patients are women. Furthermore, low serum levels of vitamin D correlate more closely to a poorer cognitive outcome in elderly women than they do in men. The prevention, early diagnosis and therapy of malnutrition is of great clinical importance, particularly to preserve physical functional capacity and thus quality of life in elderly women.

  17. 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

  18. 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

  19. Protective effect of methanolic extract of Annona squamosa Linn in isoniazid-rifampicin induced hepatotoxicity in rats.

    PubMed

    Thattakudian Sheik Uduman, Mohamed Saleem; Sundarapandian, Ramkanth; Muthumanikkam, Azagusundharam; Kalimuthu, Gnanaprakash; Parameswari S, Angala; Vasanthi Srinivas, Thiruvengada Rajan; Karunakaran, Gauthaman

    2011-04-01

    The present study was made to investigate the protective effect of methanolic extract of Annona squamosa on isoniazid-rifampicin-induced hepatotoxicity in rats. Rats were divided into five different groups (n=6), group 1 served as a control, Group 2 received isoniazid (100 mg/kg, i.p.) and co-administered with rifampicin (100 mg/kg, i.p.), in sterile water, group 3 and 4 served as extract treatment groups and received 250 & 500 mg/kg bw, p.o methanolic extract of Annona squamosa and group 5 served as standard group and received silymarin 2.5 mg/kg bw, p.o. All the treatment protocols followed 21 days and after rats were sacrificed blood and liver were used for biochemical and histological studies, respectively. Administration of isoniazid and rifampicin caused a significant elevation in the levels of liver marker enzymes and thiobarbituric acid reactive substances (TBARS, oxidative stress markers) in experimental rats. Administration of methanolic extracts of Annona squamosa significantly prevented isoniazid-rifampicin-induced elevation in the levels of serum diagnostic liver marker enzymes (alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP) and gamma glutamate transpeptidase (γ-GT)), serum bilirubin, and TBARS level in experimental groups of rats. Moreover, total protein and reduced glutathione (GSH) levels were significantly increased in treatment group. The effect of extract was compared with a standard drug, silymarin. The changes in biochemical parameters were supported by histological profile. It is to be concluded that the methanolic extract of Annona squamosa protects against isoniazid and rifampicin-induced oxidative liver injury in rats.

  20. 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.

  1. Prevention of transmitted infections in a pet therapy program: An exemplar.

    PubMed

    Hardin, Pam; Brown, Janice; Wright, Mary Ellen

    2016-07-01

    The focus of the patient experience in health care delivery has afforded the opportunity to integrate pet therapy as a part of patient care. The purpose of this article is to present the implementation of a pet therapy program that includes guidelines for the prevention of transmitted infections. Consideration of infection prevention strategies has resulted in a 16-year program with no documented incidences of transmitted infections, averaging 20,000 pet therapy interactions per year.

  2. Isoniazid hepatotoxicity with clinical and histopathology correlate.

    PubMed

    Gourishankar, Anand; Navarro, Fernando; Debroy, Ashish N; Smith, Kim C

    2014-01-01

    A fifteen-year-old girl was treated with isoniazid (INH) for latent tuberculosis infection (LTBI), and subsequently developed epigastric pain, vomiting, and jaundice after three months of treatment. Acute fulminant hepatic failure was diagnosed. INH was stopped, and she received N-acetyl cysteine and Vitamin K. Liver biopsy showed moderate to severe lymphocytic and plasmacytic portal and lobular inflammation, prominent ductal proliferation, moderate cholestasis (predominantly hepatocellular and canalicular), hepatocellular damage, and stage 3 bridging fibrosis. She was treated with steroids and azathioprine for probable autoimmune hepatitis (AIH). She received six months of rifampicin treatment for LTBI. Liver biopsy two years later showed mild portal inflammation, predominantly lymphocytitic, mild portal fibrosis without bridging, irregular bile ducts without cholestasis, and no significant hepatocellular damage; overall the later biopsy demonstrated significant improvement. This case illustrates overlapping morphologic presentation in INH hepatotoxicity with hepatocellular injury and plasma cell infiltrate (due to probable AIH), as well as cholestatic features. Although her follow-up liver biopsy indicated lymphocytic inflammation, she is now asymptomatic with normal hepatic transaminases.

  3. 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…

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. A programmed release multi-drug implant fabricated by three-dimensional printing technology for bone tuberculosis therapy.

    PubMed

    Wu, Weigang; Zheng, Qixin; Guo, Xiaodong; Sun, Jianhua; Liu, Yudong

    2009-12-01

    In the world, bone tuberculosis is still very difficult to treat and presents a challenge to clinicians. In this study, we utilized 3D printing technology to fabricate a programmed release multi-drug implant for bone tuberculosis therapy. The construction of the drug implant was a multi-layered concentric cylinder divided into four layers from the center to the periphery. Isoniazid and rifampicin were distributed individually into the different layers in a specific sequence of isoniazid-rifampicin-isoniazid-rifampicin. The drug release assays in vitro and in vivo showed that isoniazid and rifampicin were released orderly from the outside to the center to form the multi-drug therapeutic alliance, and the peak concentrations of drugs were detected in sequence at 8 to 12 day intervals. In addition, no negative effect on the proliferation of rabbit bone marrow mesenchymal stem cells was detected during the cytocompatibility assay. Due to its ideal pharmacologic action and cytocompatibility, the programmed release multi-drug implant with a complex construction fabricated by 3D printing technology could be of interest in prevention and treatment of bone tuberculosis.

  10. Differentiated thyroid cancer-personalized therapies to prevent overtreatment.

    PubMed

    Luster, Markus; Weber, Theresia; Verburg, Frederik A

    2014-09-01

    The concept of individualized therapy is rapidly gaining recognition in the management of patients with differentiated thyroid cancer (DTC). This Review provides an overview of the most important elements of this paradigm shift in DTC management and discusses the implications for clinical practice. In the majority of patients with DTC who have an inherently good prognosis, the extent of surgery, the dosage of (131)I therapy and the use of levothyroxine therapy are all aspects suitable for individualization, on the basis of both the stage of disease and the response to treatment. In individuals with advanced disease, newer imaging techniques, advances in (131)I therapy and the use of targeted molecular therapies (such as multitargeted kinase inhibitors) have provided new options for the personalized care of patients, for whom until recently no effective therapies were available. Individualized therapies could reduce adverse effects, including the sometimes debilitating hypothyroidism that used to be required before initiation of (131)I treatment, and major salivary gland damage, a common and unpleasant side effect of (131)I therapy. Highly individualized interdisciplinary treatment of patients with DTC might lead to improved outcomes with reduced severity and frequency of complications and adverse effects. However, in spite of ongoing research, personalized therapies remain in their infancy.

  11. Thermodynamics of inclusion complexes between cyclodextrins and isoniazid

    NASA Astrophysics Data System (ADS)

    Terekhova, I. V.; Kumeev, R. S.

    2010-01-01

    Complex formation of α- and β-cyclodextrins with isoniazid, a antituberculous pharmaceutical, is studied using such methods as calorimetry and 1H NMR at 298.15 K. On the basis of the obtained experimental data, it is shown that α- and β-cyclodextrins form 1 : 1 inclusion complexes with isoniazid, which are characterized by low stability in aqueous solution. Along with this, deeper penetration of isoniazid into the cavity of β-cyclodextrin, accompanied by more intensive dehydration of the reagents, is observed. The results are interpreted in terms of influence of structure of reagents and their state in solution on the binding mode, driving forces, and thermodynamic parameters of the complex formation.

  12. 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.

  13. Hepatoprotective activity of chitosan against isoniazid and rifampicin-induced toxicity in experimental rats.

    PubMed

    Santhosh, Sethumadhavan; Sini, Theruvathil K; Anandan, Rangasamy; Mathew, Paruthapara T

    2007-10-15

    Tuberculosis is a dangerous disease and its death toll is increasing year by year. Intake of isoniazid and rifampicin, the most common antitubercular drugs, lead to fatal hepatotoxic condition. We have studied the protective effect of chitosan supplementation against the hepatotoxicity induced by antitubercular drugs with respect to the changes in the levels of protein, albumin-globulin ratio, urea and bilirubin in the serum and diagnostic marker enzymes (alanine amino transferase, aspartate amino transferase, acid phosphatase and alkaline phosphatase), protein, glycoprotein conjugates (hexose, hexosamine and sialic acid), lipid peroxidation and reduced glutathione in the liver tissue of normal and experimental groups of rats. Co-administration of chitosan was found to significantly prevent the antitubercular drugs-induced alterations in the levels of diagnostic marker enzymes, bilirubin and albumin/globulin ratio in experimental groups of rats. Isoniazid and rifampicin-induced lipid peroxidation was also found to be prevented by the administration of chitosan. Further, chitosan administration increased the levels of urea and protein (in serum and liver) in experimental groups compared to hepatotoxicity-induced group of rats. Levels of glycoconjugates were also maintained to near normal level by chitosan co-administration. From the results obtained, it can be concluded that chitosan is beneficial against antitubercualr drugs-induced hepatoxicity.

  14. 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

  15. Isoniazid Induced Lupus Presenting as Oral Mucosal Ulcers with Pancytopenia

    PubMed Central

    Ankale, Padmaraj; Sinha, Kanishk; Iyer, Aparna; Jayalakshmi, T.K

    2016-01-01

    Drug Induced Lupus Erythematous (DILE) is a rare adverse reaction to a large variety of drugs including Isoniazid (INH), with features resembling idiopathic Systemic Lupus Erythematosus (SLE). Diagnosis require identification of a temporal relationship between drug administered and symptom. It is an idiosyncratic reaction, with no pre-existing lupus. Our case highlights a rare presentation of isoniazid induced lupus with profound pancytopenia and mucosal ulcers, thus posing a diagnostic challenge. The patient was on multidrug treatment for pulmonary and knee joint tuberculosis. DILE was diagnosed on basis of strongly positive Anti Nuclear Antibodies (ANA), anti ds DNA and antihistone antibodies with clinical response to cessation of INH. PMID:27891378

  16. 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

  17. [The role of Lactobacillus acidophilus in the prevention and adjuvant therapy of certain infectious diseases].

    PubMed

    Halmy, C; Halmy, L

    1998-09-27

    Authors call attention to the role of lactic acid bacteria in the prevention and adjuvant therapy of certain infective diseases. It has special importance in the prevention and adjuvant therapy of new-born and childhood enteritis, different urogenital inflammations and antibiotic associated diarrhoea. Administration of lactic acid bacteria create eubiosis between the human organism and the world of bacteria, that is, eubacteriosis is developed instead of a pathogen flora, assuring normal physiologic functions for the well-being of the organism.

  18. Isoniazid Hair Concentrations in Children with Tuberculosis: A Proof of Concept Study

    PubMed Central

    Mave, Vidya; Chandanwale, Ajay; Kinikar, Aarti; Khadse, Sandhya; Kagal, Anju; Gupte, Nikhil; Suryavanshi, Nishi; Nimkar, Smita; Koli, Hari; Khwaja, Sultanat; Bharadwaj, Renu; Joshi, Samir; Horng, Howard; Benet, Leslie Z.; Ramachandran, Geetha; Dooley, Kelly E.; Gupta, Amita; Gandhi, Monica

    2016-01-01

    Assessing treatment adherence and quantifying tuberculosis drug exposure among children is challenging. We undertook a “proof of concept” study to assess the drug concentrations of isoniazid in hair as a therapeutic drug monitoring tool. Children <12 years of age initiated on thrice-weekly treatment including isoniazid (10 mg/kg) for newly diagnosed tuberculosis were enrolled. Isoniazid concentrations in hair were measured using liquid chromatography-tandem mass spectrometry at 1, 2, 4 and 6 months after tuberculosis treatment initiation. We found that isoniazid hair concentrations in all children on thrice weekly isoniazid were detectable and displayed variability across a dynamic range. PMID:27155191

  19. 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

    2016-11-03

    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

  20. Validation of microscopic observation drug susceptibility testing for rapid, direct rifampicin and isoniazid drug susceptibility testing in patients receiving tuberculosis treatment.

    PubMed

    Coronel, J; Roper, M H; Herrera, C; Bonilla, C; Jave, O; Gianella, C; Sabogal, I; Huancaré, V; Leo, E; Tyas, A; Mendoza-Ticona, A; Caviedes, L; Moore, D A J

    2014-06-01

    Drug susceptibility testing (DST) is often needed in patients clinically failing tuberculosis (TB) therapy. Most studies of phenotypic direct drug susceptibility tests, such as microscopic observation drug susceptibility (MODS) tests, have been performed in patients not receiving TB treatment. The effect of ongoing TB treatment on the performance of MODS direct DST has not been previously explored, but patients failing such therapy constitute an important target group. The aim of this study was to determine the performance of MODS direct rifampicin and isoniazid DST in patients clinically failing first-line TB treatment, and to compare MODS direct DST with indirect proportion method DST. Sputa from 264 TB patients were cultured in parallel in Lowenstein-Jensen (LJ) and MODS assays; strains were tested for rifampicin and isoniazid susceptibility by the proportion method at the national reference laboratory. Ninety-three samples were culture-positive by LJ and MODS (concordance of 96%; kappa 0.92). With conventional MODS plate DST reading (performed on the same day as the sample is classified as culture-positive), the isoniazid DST concordance was 96.8% (kappa 0.89), and the concordance for rifampicin susceptibility testing was 92.6% (kappa 0.80). Reading of MODS DST plates 1 week after cultures had been determined to be culture-positive improved overall performance marginally-the isoniazid DST concordance was 95.7% (kappa 0.85); and the rifampicin DST concordance was 96.8% (kappa 0.91). Sensitivity for detection of multidrug-resistant TB was 95.8%. MODS testing provided reliable rifampicin and isoniazid DST results for samples obtained from patients receiving TB therapy. A modified DST reading schedule for such samples, with a final reading 1 week after a MODS culture turns positive, marginally improves the concordance with reference DST.

  1. Understanding and Prevention of “Therapy-” Induced Dyskinesias

    PubMed Central

    Aviles-Olmos, Iciar; Kefalopoulou, Zinovia; Foltynie, Thomas

    2012-01-01

    L-dopa is the most effective, currently available treatment for Parkinson's disease (PD), but it leads to the development of involuntary movements known as L-dopa-induced dyskinesia (LID) in the majority of patients after long-term use. Both gene and cell therapy approaches are the subject of multiple ongoing studies as potential ways of relieving symptoms of PD without the complication of dyskinesia. However, the spectre of dyskinesia in the absence of L-dopa, the so-called “off-phase” or graft-induced dyskinesia (GID), remains a major obstacle particularly in the further development of cell therapy in PD, but it is also a concern for proponents of gene therapy approaches. LID results from nonphysiological dopamine release, supersensitivity of dopamine receptors, and consequent abnormal signalling through mechanisms of synaptic plasticity. Restoration of physiological circuitry within the basal ganglia loops is ultimately the aim of all cell and gene therapy approaches but each using distinctive strategies and accompanied by risks of exacerbation of LID or development of “off-phase”/GID. In this paper we discuss the details of what is understood regarding the development of dyskinesias with relevance to cell and gene therapy and potential strategies to minimize their occurrence. PMID:22685687

  2. 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…

  3. 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,"…

  4. 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…

  5. Preventing Ototoxic Synergy of Prior Noise Trauma During Aminoglycoside Therapy

    DTIC Science & Technology

    2015-12-01

    for patients with cystic fibrosis, or Gram positive infections like tuberculosis and protozoal infections . Despite their wide use, broad-spectrum...trauma, combat injury, otoprotection, aminoglycoside antibiotic, bacterial infection , ototoxicity, auditory function, hearing loss 16. SECURITY...preventing life-threatening infections . However, aminoglycosides are also toxic to the cochlea, leading to hearing loss and further degradation from

  6. Preventing Ototoxic Synergy of Prior Noise Trauma During Aminoglycoside Therapy

    DTIC Science & Technology

    2014-12-01

    patients with cystic fibrosis, or Gram positive infections like tuberculosis and protozoal infections . Despite their wide use, broad-spectrum...activity for treating or preventing life-threatening infections . However, aminoglycosides are also toxic to the cochlea, leading to hearing loss and... infection , ototoxicity, auditory function, hearing loss 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a

  7. [Antiretroviral therapy: useful from prevention to HIV treatment].

    PubMed

    Tshikung, Olivier Nawej; Calmy, Alexandra

    2016-01-13

    In 2015, the publication of important studies allowed the development of new guidelines, notably by WHO and the European AIDS ClinicalSociety (EACS), for HIV preventive treatment (pre-exposure prophylaxis), as well as for the start of antiretroviral treatment. The START and TEMPRANO studies have extended the treatment to all HIV-infected patients, irrespective of the level of immunosuppression and therefore the CD4 count. In addition, innovative screening methods, such as self-tests, are now available in all French pharmacies since 15 September 2015. The latest developments in 2015 concerning the prevention, screening, and treatment of HIV are discussed in this article and will certainly have an impact on the care of patients in Switzerland.

  8. [Non-withdrawal-related delirium : Evidence on prevention and therapy].

    PubMed

    Haussmann, R; Bauer, M; Donix, M

    2016-05-01

    Delirium is a severe and common yet under-diagnosed disorder in the clinical routine. Multiple factors may contribute to the development of delirium, which is associated with increased mortality and high healthcare costs. Treatment of delirium is often provided with delay and limited to pharmacological interventions. This article summarizes the key symptoms for delirium as well as risk factors and highlights the pharmacological and non-pharmacological options for treatment and prevention.

  9. Paediatric human metapneumovirus infection: epidemiology, prevention and therapy.

    PubMed

    Principi, Nicola; Esposito, Susanna

    2014-03-01

    Since its discovery in 2001, human metapneumovirus (hMPV) has been identified as one of the most frequent causes of upper and lower respiratory tract infections. Although a considerable number of hMPV infections are diagnosed in adults and the elderly, the highest incidence of infection is among children as seropositivity for hMPV approaches 100% by 5-10 years of age. Most of the diseases due to hMPV are mild or moderate, tend to resolve spontaneously, and only require outpatient treatment. However, some may be severe enough to require hospitalisation or, albeit rarely, admission to a paediatric intensive care unit because of acute respiratory failure. Mortality is exceptional, but may occur. The most severe diseases generally affect younger patients, prematurely born children, and children who acquire nosocomial hMPV infection and those with a severe chronic underlying disease. Global hMPV infection has a major impact on national health systems, which is why various attempts have recently been made to introduce effective preventive and therapeutic measures; however, although some are already in the phase of development (including vaccines and monoclonal antibodies), there is currently no substantial possibility of prevention and, despite its limitations, ribavirin is still the only possible treatment. Given the risk of severe disease in various groups of high-risk children and the frequency of infection in the otherwise healthy paediatric population, there is an urgent need for further research aimed at developing effective preventive and therapeutic measures against hMPV.

  10. 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. |

  11. 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

  12. Anithrombotic prevention in vascular disease: bases for a new strategy in antithrombotic therapy

    PubMed Central

    Altman, Raul

    2007-01-01

    A tendency toward bleeding often undercuts the beneficial preventive effect of higher doses of a single antithrombotic drug or combined antithrombotic therapy. Although high doses of antithrombotic drugs may be necessary for optimal prevention, such therapy can also elicit more frequent bleeding. Although major bleeding could be a reversible event is likely to lead clinicians to discontinue antithrombotic therapy which in turn could increase the risk of myocardial infarction, stroke, and cardiovascular death. Thus, to prevent thrombotic events without frequent bleeding complications, the preferred approach might be to use anti-inflammatory drugs in addition to the first-line antithrombotic drugs to reduce inflammation and thrombin formation in atheroma. Although some preliminary data have been already published, to confirm the potential benefit of anti-inflammatory drugs in acute coronary syndromes large prospective double-bind randomized trials are necessary. PMID:17727726

  13. 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

  14. 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.

  15. 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

  16. 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.

  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. Liver disorders in patients receiving chlorpromazine or isoniazid.

    PubMed

    Derby, L E; Gutthann, S P; Jick, H; Dean, A D

    1993-01-01

    Based on information derived from computers and clinical records obtained from general practitioners in the United Kingdom, we estimated the frequency of liver toxicity associated with two known hepatotoxins, chlorpromazine and isoniazid. Among the cohort of 10,502 users of chlorpromazine, 14 had illnesses compatible with drug-induced liver disease, a frequency of 1.3/1000 users (95% Cl 0.8, 2.2). Four presumed cases of the disorder occurred among 921 users of isoniazid, for a frequency of 4/1000 users (95% Cl 1.7, 11.1). This study provides population-based quantification of the frequency of liver disorders associated with the use of these two agents.

  19. Chlorhexidine, fluoride varnish, and xylitol chewing gum: underutilized preventive therapies?

    PubMed

    Anusavice, K J

    1998-01-01

    The successful implementation of a preventive dentistry program depends, to a large extent, on the compliance of the patient. The scheduled program would include: recall appointments, all instructions relative to oral hygiene, use of nightly fluoride rinses, and control of diet. To ensure that high-risk patients who have cariogenic bacteria are adequately treated, chlorhexidine rinses may be required on a periodic basis. The patient's level of risk must determine all treatment decisions. For low-risk patients, the times between recall appointments can be extended when evidence of caries arrest and remineralization can be documented. High-risk patients should be recalled at least every three months, until evidence of lesion arrest and/or remineralization has been documented. For patients with extremely low saliva flow rates, the combined chlorhexidine and fluoride method may be required. If the caries risk is still judged to be high according to bacteria counts and/or evidence of further lesion development or progression, more frequent applications of chlorhexidine may be required. Because fluoride varnish is generally more effective on smooth surfaces than on fissure sites, moderate caries-risk patients should receive fluoride varnish on smooth surfaces, and sealants, when indicated, on fissure sites. As the caries risk of the patient is reduced to a low-risk level, less frequent use of fluoride-containing or fluoride releasing products is indicated, and there can be longer periods between recall examinations. Three applications of fluoride varnish, applied to a single week, appear to provide greater caries protection than two applications per year. Attempts should be made to ensure that the varnish is applied immediately after cleaning the teeth and protected as long as possible after the varnish has been applied (preferably at least 10 hours). Fluoride varnish appears to be as effective as topical fluoride gel and may be safer. Thus, a greater frequently of

  20. Aspirin therapy and primary prevention of cardiovascular disease in diabetes mellitus.

    PubMed

    Younis, Naveed; Williams, Steve; Soran, Handrean

    2009-11-01

    The benefits of aspirin therapy in reducing the subsequent risk of myocardial infarction, stroke and death is well documented in individuals with cardiovascular disease including those with diabetes mellitus (DM). The evidence for aspirin use in primary prevention of cardiovascular events in DM is debatable and meta-analyses do not suggest a proven benefit. Despite the lack of evidence, low-dose aspirin therapy has been recommended by many current diabetes guidelines. This article reviews the results of two recently published large randomized clinical trials that have looked at primary prevention of cardiovascular events using aspirin in patients with DM.

  1. Metformin: On Ongoing Journey across Diabetes, Cancer Therapy and Prevention

    PubMed Central

    Pulito, Claudio; Sanli, Toran; Rana, Punam; Muti, Paola; Blandino, Giovanni; Strano, Sabrina

    2013-01-01

    Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide. PMID:24958265

  2. In vitro postantibiotic effects of rifapentine, isoniazid, and moxifloxacin against Mycobacterium tuberculosis.

    PubMed

    Chan, Chiu-Yeung; Au-Yeang, Carrie; Yew, Wing-Wai; Leung, Chi-Chiu; Cheng, Augustine F B

    2004-01-01

    Postantibiotic effects (PAEs) of rifapentine, isoniazid, and moxifloxacin against Mycobacterium tuberculosis ATCC 27294 were studied using a radiometric culture system. Rifapentine at 20 mg/liter gave the longest PAE (104 h) among the drugs used alone. The combinations of rifapentine plus isoniazid, rifapentine plus moxifloxacin, and isoniazid plus moxifloxacin gave PAEs of 136.5, 59.0, and 8.3 h, respectively.

  3. In Vitro Postantibiotic Effects of Rifapentine, Isoniazid, and Moxifloxacin against Mycobacterium tuberculosis

    PubMed Central

    Chan, Chiu-Yeung; Au-Yeang, Carrie; Yew, Wing-Wai; Leung, Chi-Chiu; Cheng, Augustine F. B.

    2004-01-01

    Postantibiotic effects (PAEs) of rifapentine, isoniazid, and moxifloxacin against Mycobacterium tuberculosis ATCC 27294 were studied using a radiometric culture system. Rifapentine at 20 mg/liter gave the longest PAE (104 h) among the drugs used alone. The combinations of rifapentine plus isoniazid, rifapentine plus moxifloxacin, and isoniazid plus moxifloxacin gave PAEs of 136.5, 59.0, and 8.3 h, respectively. PMID:14693563

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. [Drug therapy for prevention of falls and fractures].

    PubMed

    Ringe, Johann D

    2006-06-01

    The primary goal in the practical management of osteoporosis is to prevent first or subsequent fractures and thereby to avoid acute or chronic pain and progressive skeletal deformity. Therapeutic strategies should always take the complex pathogenetic mechanisms of fractures into account, especially the fact that mechanical impacts and falls play an important role in the majority of fracture events. Accordingly, recommendations to patients and the selection of drugs should aim at both, falls and fractures. In this context there is an increasing interest in the dual effects of vitamin D on bone and muscle. Controlled studies proved that adequate vitamin D supplementation is able to improve muscle strength, coordination and body sway and thereby reduce the risk of falls and fractures. Alendronate has been studied extensively by large trials of high quality and its efficacy to reduce the risk of vertebral and nonvertebral fractures is in line with the criteria of evidence-based medicine. The innovative combination of 70 mg alendronate with 2,800 IU vitamin D in a once-weekly tablet guarantees a basic supply with this important prohormone for bone and muscle. Due to a regular combined intake an improved compliance can be anticipated which will be followed by better therapeutic results in osteoporosis patients with increased fracture risk.

  9. Luteolin, a flavonoid with potentials for cancer prevention and therapy

    PubMed Central

    Lin, Yong; Shi, Ranxin; Wang, Xia; Shen, Han-Ming

    2008-01-01

    Luteolin, 3′,4′,5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3′-kinase (PI3K)/Akt, nuclear factor kappa B (NF-κB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to luteolin. In this review, we summarize the progress of recent research on luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of luteolin. PMID:18991571

  10. Antiretroviral Therapy as Prevention of … Pneumococcal Infections?

    PubMed Central

    Leporrier, Jérémie; Delbos, Valérie; Unal, Guillemette; Honoré, Patricia; Etienne, Manuel; Bouchaud, Olivier; Caron, François

    2016-01-01

    Background. Despite antiretroviral therapy, it is generally believed that the risk for pneumococcal infections (PnIs) is high among patients infected with human immunodeficiency virus (HIV). However, most studies in this field have been conducted before 2010, and the proportion of virologically suppressed patients has drastically increased in these latter years thanks to larger indications and more effective antiretroviral regimens. This study aimed to re-evaluate the current risk of PnI among adult patients infected with HIV. Methods. The incidence of PnI was evaluated between 1996 and 2014 in 2 French regional hospitals. The 80 most recent cases of PnI (2000–2014) were retrospectively compared with 160 controls (HIV patients without PnI) to analyze the residual risk factors of PnI. Results. Among a mean annual follow-up cohort of 1616 patients, 116 PnIs were observed over 18 years. The risk factors of PnI among patients infected with HIV were an uncontrolled HIV infection or “classic” risk factors of PnI shared by the general population such as addiction, renal or respiratory insufficiency, or hepatitis B or C coinfection. Pneumococcal vaccination coverage was low and poorly targeted, because only 5% of the cases had been previously vaccinated. The incidence of invasive PnIs among HIV patients with a nonvirologically suppressed infection or comorbidities was 12 times higher than that reported in the general population at the country level (107 vs 9/100000 patients), whereas the incidence among virologically suppressed HIV patients without comorbidities was lower (7.6/100000 patients). Conclusions. Human immunodeficiency virus infection no longer per se seems to be a significant risk factor for PnI, suggesting a step-down from a systematic to an “at-risk patient” targeted pneumococcal vaccination strategy. PMID:28018929

  11. Current recommendations for prevention and therapy of extravasation reactions in dermato-oncology.

    PubMed

    Kähler, Katharina C; Mustroph, Dieter; Hauschild, Axel

    2009-01-01

    Despite the introduction of many targeted therapies, a wide variety of cytostatic agents are still frequently used in dermato-oncology. In order to avoid further morbidity in tumor patients, prevention of extravasation reactions is of highest importance. The optimal management of extravasation requires an early diagnosis, the application of specific antidotes and a well-trained oncology team.

  12. Antithrombotic Therapy for Secondary Prevention in Patients With Diabetes Mellitus and Coronary Artery Disease.

    PubMed

    Park, Yongwhi; Franchi, Francesco; Rollini, Fabiana; Angiolillo, Dominick J

    2016-01-01

    Diabetes mellitus (DM) is a key risk factor for recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). The prothrombotic milieu that characterizes patients with DM underscores the importance of oral antithrombotic therapy for secondary prevention of recurrent events in these patients. Indeed, dual antiplatelet therapy (DAPT) with aspirin and the P2Y12inhibitor clopidogrel, which has represented the mainstay of treatment for many years, has significantly reduced the incidence of recurrent atherothrombotic events. However, recurrence rates in DM patients still remain high despite this treatment regimen, which may be partly related to inadequate platelet inhibition induced by standard DAPT with aspirin and clopidogrel. This underpins the need for more potent antithrombotic treatment regimens for secondary prevention of atherothrombotic events in DM patients following ACS or PCI. The development of antiplatelet therapies associated with more potent oral platelet P2Y12receptor inhibition, including prasugrel and ticagrelor, as well as platelet inhibitors blocking alternative pathways, such as thrombin-mediated platelet inhibition with vorapaxar, may represent potential treatment options in DM patients. Moreover, with the introduction of the target-specific oral anticoagulants, there has been a reappraisal of the use of anticoagulation in addition to antiplatelet therapy for secondary prevention in patients with ACS. This review provides an update on the recent advances and limitations of oral antithrombotic agents used for secondary prevention in DM patients following ACS or PCI.

  13. 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…

  14. Preventing Relapse/Recurrence in Recurrent Depression With Cognitive Therapy: A Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Bockting, Claudi L. H.; Schene, Aart H.; Spinhoven, Philip; Koeter, Maarten W. J.; Wouters, Luuk F.; Huyser, Jochanan; Kamphuis, Jan H.

    2005-01-01

    This article reports on the outcome of a randomized controlled trial of cognitive group therapy (CT) to prevent relapse/recurrence in a group of high-risk patients diagnosed with recurrent depression. Recurrently depressed patients (N = 187) currently in remission following various types of treatment were randomized to treatment as usual,…

  15. Overview of the methods and therapies for the primary prevention of variceal bleeding.

    PubMed

    Tripathi, Dhiraj

    2010-08-01

    Patients with cirrhosis develop varices at a rate of 5% per year, and a third of patients with high-risk varices will bleed. The mortality associated with variceal haemorrhage is typically 20%, and still exceeds that of myocardial infarction. Current options to prevent the first variceal bleed include noncardioselective beta-blockers or variceal band ligation. In patients with medium-to-large esophageal varices, both therapies reduce the risk of bleeding by 50% or more. The choice of therapy should take into account patient choice and local availability; although for most patients drug therapy is the preferred first-line treatment. There has been recent interest in carvedilol, with promising initial data. Further studies are necessary before universal recommendation. There is no role for drug therapy in patients without varices, and the use of beta-blockers for patients with small varices is controversial.

  16. 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.

  17. Cancer prevention and treatment using combination therapy with plant- and animal-derived compounds.

    PubMed

    Uzoigwe, Jacinta; Sauter, Edward R

    2012-11-01

    Compounds naturally occurring in plants and animals play an essential role in the prevention and treatment of various cancers. There are more than 100 plant- and animal-based natural compounds currently in clinical use. Similar to synthetic compounds, these natural compounds are associated with dose-related toxicity that limits efficacy. Scientists have investigated combination therapy with compounds that have different toxicities in order to optimize efficacy. These combination therapies may work additively or synergistically, there may be no effect or they may promote tumor formation. Combination therapy with agents that have similar mechanisms of action may increase toxicity. In this article, combination therapies that have been investigated, their rationale, mechanism of action and findings are reviewed. When the data warrant it, combined (pharmacologic and natural; two or more natural) interventions that appear to increase efficacy (compared with monotherapy) while minimizing toxicity have been highlighted.

  18. Isoniazid-induced seizures with secondary rhabdomyolysis and associated acute renal failure in a dog.

    PubMed

    Haburjak, J J; Spangler, W L

    2002-04-01

    Isoniazid-induced seizures resulted in rhabdomyolysis and associated acute renal tubular necrosis in a dog. Rhabdomyolysis and myoglobinuric renal failure, although recognised in the dog, are reported infrequently as a consequence of seizures. The clinical presentation of isoniazid toxicity in a dog is described.

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

    PubMed Central

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

    2009-01-01

    Objective To describe the elements of a manualized cognitive behavior psychotherapy 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 CBT-SP was developed using a risk reduction, relapse prevention approach and theoretically grounded in principles of cognitive behavior therapy, dialectical behavioral therapy and targeted therapies for suicidal, depressed youth. CBT-SP consists of acute and continuation phases, each lasting about 12 sessions, and includes a chain analysis of the suicidal event, safety plan development, skill building, psychoeducation, family intervention, and relapse prevention. Results CBT-SP was administered to 110 depressed, recent suicide attempters aged 13–19 years (mean 15.8±1.6) across five academic sites. Twelve or more sessions were completed by 72.4% of the sample. Conclusions A specific intervention for adolescents at high risk for repeated suicide attempts has been developed and manualized, and further testing of its efficacy appears feasible. PMID:19730273

  20. Preventive therapy for latent tuberculosis infection-the promise and the challenges.

    PubMed

    Fox, G J; Dobler, C C; Marais, B J; Denholm, J T

    2017-03-01

    Around one third of the world's population may harbour latent tuberculosis infection (LTBI), an asymptomatic immunological state that confers a heightened risk of subsequently developing tuberculosis (TB). Effectively treating LTBI will be essential if the End TB Strategy is to be realized. This review evaluates the evidence in relation to the effectiveness of preventive antibiotic therapy to treat LTBI due to both drug-susceptible and drug-resistant bacteria. Current national and international preventive therapy guidelines are summarized, as well as ongoing randomized trials evaluating regimens to prevent drug-resistant TB. Populations that may benefit most from screening and treatment for LTBI include close contacts of patients with TB (particularly children under 5 years of age) and individuals with substantial immunological impairment. The risks and benefits of treatment must be carefully balanced for each individual. Electronic decision support tools offer one way in which clinicians can help patients to make informed decisions. Modelling studies indicate that the expanded use of preventive therapy will be essential to achieving substantial reductions in the global TB burden. However, the widespread scale-up of screening and treatment will require careful consideration of cost-effectiveness, while ensuring the drivers of ongoing disease transmission are also addressed.

  1. Matrix metalloproteinase inhibitor therapy to prevent complications as well as therapy for Ehler-Danlos syndrome.

    PubMed

    Sastry, P S R K

    2002-09-01

    Matrixmetalloproteinase inhibitors have been developed as anti-cancer agents. Their usage in pancreatic cancer and other such malignancies is under trial at present. An interesting undesired-effect of one of these agents is contracture of the hand. Ehler-Danlos syndrome is an inherited group of diseases with varying types. At present there is no known treatment or prevention for the complications associated with this inherited condition. Sometimes it is the adverse events of a drug, which provides an insight into its efficacy for another indication. It is hereby being hypothesized that the matrixmetalloproteinase inhibitors especially marimastat may be an effective drug for treatment of Ehler-Danlos syndrome and/or prevention of its major complications.

  2. Experimental and theoretical NMR determination of isoniazid and sodium p-sulfonatocalix[n]arenes inclusion complexes.

    PubMed

    de Assis, João V; Teixeira, Milena G; Soares, Cássia G P; Lopes, Juliana F; Carvalho, Guilherme S L; Lourenço, Maria C S; de Almeida, Mauro V; de Almeida, Wagner B; Fernandes, Sergio A

    2012-10-09

    In this work the inclusion complex formation of isoniazid with sodium p-sulfonatocalix[n]arenes is reported aiming to improve the physicochemical and biopharmaceutical properties of isoniazid a first line antibuberculosis drug. The architectures of the complexes were proposed according to NMR data Job plot indicating details on the insertion of the isoniazid in the calix[n]arenes cavities. DFT theoretical NMR calculations were also performed for sodium p-sulfonatocalix[4]arene complex with isoniazid, with various modes of complexation being considered, to provide support for the experimental proposal. A comparison between experimental and theoretical ¹H NMR chemical shifts profiles allowed for the inclusion complex characterization confirming the isoniazid inclusion mode which is preferentially through the hydrazide moiety. The remarkable agreement between experimental and theoretical NMR profiles adds support to their use in the structural characterization of inclusion compounds. Antibacterial activity was evaluated and the results indicated the inclusion complexes as a potential strategy for tuberculosis treatment.

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

    PubMed Central

    de Cates, Angharad N; Farr, Matthew RB; Rees, Karen; Casas, Juan P; Huffman, Mark

    2014-01-01

    This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of fixed-dose combination therapy on optimising CVD risk factors and reducing CVD fatal and non-fatal events for both primary and secondary prevention of CVD. Details of CVD events and risk factors included are listed in the methods. We will also determine any adverse events associated with taking fixed-dose combination therapy. This will include studies conducted in both developed and developing regions of the world. PMID:25267903

  4. [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.

  5. Developing a HER3 Vaccine to Prevent Resistance to Endocrine Therapy

    DTIC Science & Technology

    2013-10-01

    an activated HER3 protein pathway signature that is more likely to respond to the anti-tumor effects of a HER3 vaccine . In the BT474 luminal B ...AD______________ AWARD NUMBER: W81XWH-12-1-0574 TITLE: Developing a HER3 Vaccine to...9/29/2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Developing a HER3 Vaccine to Prevent Resistance to Endocrine Therapy 5b

  6. Development of a Lubricant Therapy to Prevent Development of Osteoarthritis after Acute Injury of Synovial Joints

    DTIC Science & Technology

    2015-10-01

    AD______________ AWARD NUMBER: W81XWH-14-1-0562 TITLE: Development of a Lubricant Therapy to Prevent Development of Osteoarthritis after Acute...Injury of Synovial Joints PRINCIPAL INVESTIGATOR: Robert L. Sah RECIPIENT: Dr. Prem Yadav, Ph.D. REPORT DATE: October 2015 TYPE OF REPORT...PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2015 2. REPORT TYPE Annual 3. DATES COVERED 30 Sep 2014 - 29 Sep 2015 4

  7. 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

  8. Influence of rifampicin and isoniazid on the kinetics of phenytoin.

    PubMed Central

    Kay, L; Kampmann, J P; Svendsen, T L; Vergman, B; Hansen, J E; Skovsted, L; Kristensen, M

    1985-01-01

    Clearance of phenytoin after i.v. injection of 100 mg was studied in six patients before and after 2 weeks daily treatment with 450 mg rifampicin, and in 14 patients with tuberculosis receiving standard treatment with 450 mg rifampicin, 300 mg isoniazid, and 1200 mg ethambutol daily. Acetylator status was measured by urinary acetylated sulphadimidine. Clearance of phenytoin in patients receiving only rifampicin increased from 46.7 ml min-1 +/- 20.6 ml min-1 to 97.8 ml min-1 +/- 33.4 ml min-1 (P less than 0.01), while clearance in patients on three drugs increased from 47.1 +/- 23.4 ml min-1 to 81.3 ml min-1 +/- 41.6 ml min-1 (P less than 0.01). No significant differences were observed between the six fast acetylators and the eight slow acetylators. Phenytoin kinetics were unchanged after further 3 months of combined treatment. Rifampicin is a strong inducer of the elimination of phenytoin. Combined treatment with isoniazid has no counter-acting effect in either fast or slow acetylators. PMID:4074601

  9. 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.

  10. Factors Influencing the Prescription of Cardiovascular Preventive Therapies in Patients with Peripheral Arterial Disease

    PubMed Central

    Gauvin, Valerie; Turcotte, Stephane; Milot, Alain; Douville, Yvan

    2016-01-01

    Background Guidelines recommend that patients with peripheral arterial disease should be medically treated to reduce the occurrence of serious cardiovascular events. Despite these recommendations, studies conducted in the early 2000s reported that medical therapies for secondary cardiovascular prevention are not given systematically to patients with peripheral arterial disease (PAD). We identified factors associated with the prescription of preventive therapies in patients with symptomatic PAD. Methods and Findings Consecutive patients with symptomatic peripheral arterial disease (n = 362) treated between 2008 and 2010 in one tertiary care center (CHU de Quebec, Canada) were considered. Data were collected from the medical charts. The main outcome was the combined prescription of three therapies: 1) statins, 2) antiplatelets, 3) angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. The mean age was 70 years and 43% had a pre-existing coronary artery disease. Antiplatelet therapy was the most prescribed drug (83%). A total of 52% of the patients received the three combined therapies. Less than 10% of patients had a known contraindication to one class of medication. Having at least three cardiovascular risk factors (Odds Ratio (OR) = 4.51; 95% CI: 2.76–7.37) was the factor most strongly associated with the prescription of the combined therapies. Pre-existing coronary artery disease (OR = 2.28; 95% CI: 1.43–3.65) and history of peripheral vascular surgery (OR = 2.30; 95% CI: 1.37–3.86) were two factors independently associated with the prescription of the combined therapies. However, peripheral arterial disease patients with chronic critical limb ischemia were less likely to receive the combined therapies (OR = 0.53; 95% CI: 0.32–0.87) than those with claudication. The retrospective nature of this study, not allowing for an exhaustive report of the contraindication to medication prescription, is the main limitation. Conclusion About half

  11. Epithelial cell culture models for the prevention and therapy of clinical breast cancer (Review)

    PubMed Central

    2012-01-01

    Clinical breast cancer progresses via a multi-step carcinogenic process wherein genetic, molecular, endocrine and dietary factors play significant roles in the pathogenesis, prevention and therapy of the disease. Preclinical cell culture models, expressing clinically relevant genetic and endocrine defects and exhibiting quantifiable cancer risk, may provide facile, clinically translatable approaches to identify molecular targets and susceptible mechanistic pathways for the efficacy of novel interventional approaches. This review summarizes laboratory investigations focused on i) developing murine and human mammary tissue-derived cell culture models; ii) optimizing mechanism-based quantitative endpoint biomarker assays specific for carcinogenic risk and preventive/therapeutic efficacy; and iii) providing quantifiable proof-of-principle evidence for validation of the present cell culture approaches, capable of prioritizing efficacious lead compounds for subsequent in vivo animal studies and clinical trials for the prevention/therapy of breast cancer. Epithelial cell culture models are developed and characterized where the carcinogenic process is initiated by the targeted expression of clinically relevant oncogenes. The cell culture systems from mouse mammary tissue are in vitro approaches that complement the Ras and Myc transgenic mouse models. The human mammary tissue-derived systems are in vitro models for chemoendocrine, therapy-resistant, clinical, pre-invasive ER-/PR-/HER-2+ comedo ductal carcinoma in situ, ER+/PR+ chemoendocrine therapy-responsive breast cancer and ER-/PR-/HER-2- triple-negative chemoendocrine, therapy-resistant breast cancer. The oncogene-initiated phenotypes exhibit loss of homeostatic growth control, downregulation of cell apoptosis and gain of carcinogenic risk in vitro, as well as transplantable tumor development in vivo. Numerous mechanistically distinct, synthetic pharmacological agents, as well as naturally occurring dietary compounds

  12. 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.

  13. 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

  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. Safety of Dual Antiplatelet Therapy After Carotid Endarterectomy for Prevention of Restenosis: A Single Center Experience

    PubMed Central

    Barboza, Miguel A.; Chang, José; Hernández, Alvaro; Martínez, Emmanuel; Fernández, Huberth; Quirós, Gerardo; Salazar, Johanna; Ramos-Esquivel, Allan; Maud, Alberto

    2016-01-01

    Introduction The incidence of recurrent carotid stenosis after carotid endarterectomy varies from 1% to 37% with only 0–8% symptomatic restenosis. Safety of short-term (30 days) dual-antiplatelet therapy has not been established in this type of procedure. Aims To investigate the safety of dual antiplatelet therapy after carotid endarterectomy to prevent restenosis. Methods We retrospectively identified all the patients who underwent carotid endarterectomy (symptomatic or asymptomatic) treated at our center between July 2010 and July 2013 according to local protocols. All patients received a dose of 100 mg of aspirin daily immediately after carotid endarterectomy, with subsequent 100 mg of aspirin daily for the rest of the study period, and some patients received 75 mg of Clopidogrel for 30 days starting immediately after surgical procedure (dual therapy group), assigned according to medical criteria. Duplex carotid ultrasound and clinical assessments were performed at 30 days and 1 year after the procedure. Results A total of 44 patients (71.2 ± 7.9 years old; 77.2% symptomatic) were analyzed; 35 of them with dual therapy (79.54%). At 30 days, two patients from the mono-therapy group developed restenosis (22.2%), compared to none in dual therapy group (p=0.04). At one year follow-up, only one patient from the dual group showed restenosis (p=0.10). No deaths, major bleeding or new strokes were reported in both groups. Conclusions Short-term dual antiplatelet therapy with aspirin and clopidogrel after carotid endarterectomy might be associated with a lower incidence of restenosis. This observation must be validated in a prospective trial. PMID:27829964

  16. The role of fluticasone propionate/salmeterol combination therapy in preventing exacerbations of COPD

    PubMed Central

    Yawn, Barbara P; Raphiou, Ibrahim; Hurley, Judith S; Dalal, Anand A

    2010-01-01

    Exacerbations contribute significantly to the morbidity of COPD, leading to an accelerated decline in lung function, reduced functional status, reduced health status and quality of life, poorer prognosis and increased mortality. Prevention of exacerbations is thus an important goal of COPD management. In patients with COPD, treatment with a combination of the inhaled corticosteroid fluticasone propionate (250 μg) and the long-acting β2-agonist salmeterol (50 μg) in a single inhaler (250/50 μg) is an effective therapy option that has been shown to reduce the frequency of exacerbations, to improve lung function, dyspnea and health status, and to be relatively cost-effective as a COPD maintenance therapy. Importantly, results of various studies suggest that fluticasone propionate and salmeterol have synergistic effects when administered together that improve their efficacy in controlling symptoms and reducing exacerbations. The present non-systematic review summarizes the role of fluticasone propionate/salmeterol combination therapy in the prevention of exacerbations of COPD and its related effects on lung function, survival, health status, and healthcare costs. PMID:20631816

  17. Targeting the NFκB signaling pathways for breast cancer prevention and therapy.

    PubMed

    Wang, Wei; Nag, Subhasree A; Zhang, Ruiwen

    2015-01-01

    The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

  18. Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease.

    PubMed

    Sun, Baodong; Kulis, Michael D; Young, Sarah P; Hobeika, Amy C; Li, Songtao; Bird, Andrew; Zhang, Haoyue; Li, Yifan; Clay, Timothy M; Burks, Wesley; Kishnani, Priya S; Koeberl, Dwight D

    2010-02-01

    Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene therapy with a low dose adeno-associated virus (AAV) vector (2 x 10(10) particles) containing a liver-specific regulatory cassette significantly lowered immunoglobin G (IgG), IgG1, and IgE antibodies to GAA in Pompe disease mice, when compared with mock-treated mice (P < 0.05). AAV-LSPhGAApA had the same effect on GAA-antibody production whether it was given prior to, following, or simultaneously with the initial GAA injection. Mice given AAV-LSPhGAApA had significantly less decrease in body temperature (P < 0.001) and lower anaphylactic scores (P < 0.01) following the GAA challenge. Mouse mast cell protease-1 (MMCP-1) followed the pattern associated with hypersensitivity reactions (P < 0.05). Regulatory T cells (Treg) were demonstrated to play a role in the tolerance induced by gene therapy as depletion of Treg led to an increase in GAA-specific IgG (P < 0.001). Treg depleted mice were challenged with GAA and had significantly stronger allergic reactions than mice given gene therapy without subsequent Treg depletion (temperature: P < 0.01; symptoms: P < 0.05). Ubiquitous GAA expression failed to prevent antibody formation. Thus, immunomodulatory gene therapy could provide adjunctive therapy in lysosomal storage disorders treated by enzyme replacement.

  19. Immunomodulatory Gene Therapy Prevents Antibody Formation and Lethal Hypersensitivity Reactions in Murine Pompe Disease

    PubMed Central

    Sun, Baodong; Kulis, Michael D; Young, Sarah P; Hobeika, Amy C; Li, Songtao; Bird, Andrew; Zhang, Haoyue; Li, Yifan; Clay, Timothy M; Burks, Wesley; Kishnani, Priya S; Koeberl, Dwight D

    2009-01-01

    Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has been effective in most patients with Pompe disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene therapy with a low dose adeno-associated virus (AAV) vector (2 × 1010 particles) containing a liver-specific regulatory cassette significantly lowered immunoglobin G (IgG), IgG1, and IgE antibodies to GAA in Pompe disease mice, when compared with mock-treated mice (P < 0.05). AAV-LSPhGAApA had the same effect on GAA-antibody production whether it was given prior to, following, or simultaneously with the initial GAA injection. Mice given AAV-LSPhGAApA had significantly less decrease in body temperature (P < 0.001) and lower anaphylactic scores (P < 0.01) following the GAA challenge. Mouse mast cell protease-1 (MMCP-1) followed the pattern associated with hypersensitivity reactions (P < 0.05). Regulatory T cells (Treg) were demonstrated to play a role in the tolerance induced by gene therapy as depletion of Treg led to an increase in GAA-specific IgG (P < 0.001). Treg depleted mice were challenged with GAA and had significantly stronger allergic reactions than mice given gene therapy without subsequent Treg depletion (temperature: P < 0.01; symptoms: P < 0.05). Ubiquitous GAA expression failed to prevent antibody formation. Thus, immunomodulatory gene therapy could provide adjunctive therapy in lysosomal storage disorders treated by enzyme replacement. PMID:19690517

  20. Anticoagulation therapy prevents portal-splenic vein thrombosis after splenectomy with gastroesophageal devascularization

    PubMed Central

    Lai, Wei; Lu, Shi-Chun; Li, Guan-Yin; Li, Chuan-Yun; Wu, Ju-Shan; Guo, Qing-Liang; Wang, Meng-Long; Li, Ning

    2012-01-01

    AIM: To compare the incidence of early portal or splenic vein thrombosis (PSVT) in patients treated with irregular and regular anticoagulantion after splenectomy with gastroesophageal devascularization. METHODS: We retrospectively analyzed 301 patients who underwent splenectomy with gastroesophageal devascularization for portal hypertension due to cirrhosis between April 2004 and July 2010. Patients were categorized into group A with irregular anticoagulation and group B with regular anticoagulation, respectively. Group A (153 patients) received anticoagulant monotherapy for an undesignated time period or with aspirin or warfarin without low-molecular-weight heparin (LMWH) irregularly. Group B (148 patients) received subcutaneous injection of LMWH routinely within the first 5 d after surgery, followed by oral warfarin and aspirin for one month regularly. The target prothrombin time/international normalized ratio (PT/INR) was 1.25-1.50. Platelet and PT/INR were monitored. Color Doppler imaging was performed to monitor PSVT as well as the effectiveness of thrombolytic therapy. RESULTS: The patients’ data were collected and analyzed retrospectively. Among the patients, 94 developed early postoperative mural PSVT, including 63 patients in group A (63/153, 41.17%) and 31 patients in group B (31/148, 20.94%). There were 50 (32.67%) patients in group A and 27 (18.24%) in group B with mural PSVT in the main trunk of portal vein. After the administration of thrombolytic, anticoagulant and anti-aggregation therapy, complete or partial thrombus dissolution achieved in 50 (79.37%) in group A and 26 (83.87%) in group B. CONCLUSION: Regular anticoagulation therapy can reduce the incidence of PSVT in patients who undergo splenectomy with gastroesophageal devascularization, and regular anticoagulant therapy is safer and more effective than irregular anticoagulant therapy. Early and timely thrombolytic therapy is imperative and feasible for the prevention of PSVT. PMID:22807615

  1. Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus.

    PubMed

    Peura, David A; Wilcox, C Mel

    2014-01-01

    Aspirin, used at low doses (75-325 mg daily), prevents aggregation of platelets and is prescribed for patients as pharmacologic prevention of cardiovascular disease. Despite the well-documented beneficial effects of aspirin, prolonged use is associated with damage to the gastrointestinal (GI) mucosa in the upper and lower GI tract. Patient risk of hemorrhage and peptic ulcer formation is increased with older age, previous ulcer history, Helicobacter pylori infection, and concomitant use of nonsteroidal anti-inflammatory drugs, corticosteroids, or antithrombotic agents. As termination of aspirin therapy can precipitate a cardiovascular event, patients at risk need co-therapy with gastroprotective agents, such as proton pump inhibitors (PPIs), to reduce the GI side effects of aspirin treatment. Fixed-dose combinations of low-dose aspirin and gastroprotective agents have been designed to increase medication compliance, improve clinical outcomes, and reduce the overall cost of therapy. Prolonged use of PPIs may, however, lead to serious adverse effects or, in some cases, reduce the cardioprotective effects of aspirin. Hence, physicians need to carefully consider the benefits and risks associated with the condition of each patient to optimize clinical outcomes of combination therapy. A growing body of clinical evidence indicates that aspirin may decrease the risk of colorectal and other GI cancers, as well as reduce progression from Barrett's esophagus (BE) to esophageal adenocarcinoma. Furthermore, PPIs have recently been shown to reduce neoplastic transformation in patients with BE. Thus, the use of a fixed-dose aspirin/PPI combination could potentially provide chemopreventive benefit to patients with BE, and, at the same time, treat the underlying gastroesophageal reflux responsible for the condition.

  2. 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

  3. 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.

  4. [Preventive and cessation therapy of mental disorders in patients with the acute coronary syndrome].

    PubMed

    Medvedev, V E; Epifanov, A V; Zverev, K V

    2012-01-01

    An open prospective trial of 93 inpatients divided into two main groups (61 patients) - with mental disorders (31) and without mental disorders (30) and a comparison group (32 patients) was carried out. All patients survived the acute coronary syndrome (myocardial infarction, unstable angina). The efficacy and safety of both preventive and cessation therapy with pantogam active in mean doses 1.8 and 1.2 g /daily, respectively, was demonstrated in respect of heterogeneous depressive, anxiety and somatoform disorders of the neurotic level.

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

    PubMed

    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.

  6. Hypoglycaemia due to interaction of glimepiride with isoniazid in a patient with type 2 diabetes mellitus.

    PubMed

    Boglou, Panagiotis; Steiropoulos, Paschalis; Papanas, Nikolaos; Bouros, Demosthenes

    2013-04-16

    Hypoglycaemia is a well-recognised untoward effect of sulfonylureas. We report a case of severe hypoglycaemia after isoniazid initiation in a type 2 diabetic patient. An oral glucose tolerance test revealed high serum insulin and C peptide, suggesting hyperinsulinaemia, and it was used to ascertain the relationship between insulin, glucose and C peptide levels. Insulin and C peptide elevation was attributed to the interaction between the two drugs. As a cytochrome inhibitor, isoniazid increased serum glimepiride concentration, resulting in hyperinsulinaemia. The diagnosis of occult insulinoma or nesidioblastosis was ruled out by CT and MRI, as we could not perform more sensitive, still invasive, diagnostic procedures. After isoniazid withdrawal, hypoglycaemia regressed and glimepiride was reinitiated. In conclusion, this case illustrates the need of caution when prescribing isoniazid in patients with type 2 diabetes mellitus receiving glimepiride to avoid hypoglycaemia.

  7. Enhanced bradycardia induced by beta-adrenoceptor antagonists in rats pretreated with isoniazid.

    PubMed

    Vidrio, H; Sánchez-Salvatori, M A; Medina, M

    1998-12-01

    High doses of isoniazid increase hypotension induced by vasodilators and change the accompanying reflex tachycardia to bradycardia, an interaction attributed to decreased synthesis of brain gamma-aminobutyric acid (GABA). In the present study, the possible enhancement by isoniazid of bradycardia induced by beta-adrenoceptor antagonists was determined in rats anaesthetised with chloralose-urethane. Isoniazid significantly increased bradycardia after propranolol, pindolol, labetalol and atenolol, as well as after clonidine, but not after hexamethonium or carbachol. Enhancement was not observed in rats pretreated with methylatropine or previously vagotomised. These results are compatible with interference by isoniazid with GABAergic inhibition of cardiac parasympathetic tone. Such interference could be exerted centrally, possibly at the nucleus ambiguus, or peripherally at the sinus node.

  8. Gene therapy based in antimicrobial peptides and proinflammatory cytokine prevents reactivation of experimental latent tuberculosis.

    PubMed

    Ramos-Espinosa, Octavio; Hernández-Bazán, Sujhey; Francisco-Cruz, Alejandro; Mata-Espinosa, Dulce; Barrios-Payán, Jorge; Marquina-Castillo, Brenda; López-Casillas, Fernando; Carretero, Marta; Del Río, Marcela; Hernández-Pando, Rogelio

    2016-10-01

    Mycobacterium tuberculosis (Mtb) latent infection can lead to reactivation. The design of new strategies to prevent it is an important subject. B6D2F1 mice were infected intratracheally with a low dose of Mtb H37Rv to induce chronic infection. After 7 months, mice were treated with one dose of recombinant adenoviruses encoding TNFα, β defensin-3 and LL37. Immunosupression was induced 1 month later with corticosterone. In comparison with the control group, mice treated with adenoviruses showed significantly less bacterial load and pneumonia, the adenoviruses encoding TNFα and LL37 being the most efficient. Gene therapy based in a proinflammatory cytokine or antimicrobial peptides is a potentially useful system to prevent reactivation of latent tuberculosis.

  9. 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.

  10. [Botulism in dairy cattle in 2008: symptoms, diagnosis, pathogenesis, therapy, and prevention].

    PubMed

    Holzhauer, M; Roest, H I J; de Jong, M G; Vos, J H

    2009-07-01

    Botulism affects about 20 dairy herds a year in the Netherlands. This article describes the dramatic outcome of botulism in a dairy herd. The main clinical symptoms in this herd were increased lying down, slight ataxia of the hind legs, and a high mortality (98%). The diagnosis is difficult to establish in adult cattle, and for this reason the clinical and laboratory findings, differential diagnosis, therapy, and preventive measures are discussed. On the basis of this outbreak, previous experience with botulism, and cases described in literature, it is suggested that presence of 'free-range" poultry could contaminate grazing pastures with botulism neurotoxins, causing clinical problems in cattle. If there is an increased risk of contamination of the pasture and/or silage with botulinum neurotoxins, vaccination should be considered to prevent substantial economic and emotional damage.

  11. 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

  12. 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

  13. 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.

  14. Metabolomics of urine for the assessment of microvesicular lipid accumulation in the liver following isoniazid exposure

    PubMed Central

    Burgess, Jason P.; Snyder, Rodney W.; Popp, James A.; Fennell, Timothy R.

    2010-01-01

    This study was conducted to develop a noninvasive marker of hepatic microvesicular lipid accumulation (MVLA), a histopathological effect currently diagnosed in humans following liver biopsy. MVLA is detected in animal studies of chemicals and drugs and occurs in some humans exposed to chemicals or pharmaceuticals. Because MVLA is a reversible histopathology, early detection of MVLA using a noninvasive method, could aid clinicians in the treatment of patients taking drugs that are known to induce this injury. Isoniazid (INH) was selected as a model compound for this investigation, because MVLA occurs in tuberculosis (TB) patients treated with a combination therapy, which includes INH. This study used male rats dosed daily with INH at 0, 10, or 300 mg/kg/day for up to 8 days. Urine, blood, and liver were obtained following 1 and 8 days. NMR metabolomics of urine revealed markers that correlated (100%) with the findings of MVLA in the right, left, and median liver lobes in 4/9 rats administered the high dose of INH for 8 days. Metabolomics of liver extracts also revealed markers that correlated with the MVLA injury. Serum enzymes that are clinically used to assess liver injury were not consistently correlated to the findings of MVLA. Metabolite changes consistent with the presence of MVLA correlated with interruptions in inositol, carbohydrate, glycerolipid, and glyoxylate metabolism. This study reveals markers that could find pre-clinical use, provides insights into mechanisms involved in MVLA, and demonstrates the need for the validation of noninvasive MVLA markers in human patients. PMID:21057652

  15. Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice.

    PubMed

    Lu, Yuanqing; Tang, Mei; Wasserfall, Clive; Kou, Zhongchen; Campbell-Thompson, Martha; Gardemann, Thomas; Crawford, James; Atkinson, Mark; Song, Sihong

    2006-06-01

    An imbalance of the immune-regulatory pathways plays an important role in the development of type 1 diabetes. Therefore, immunoregulatory and antiinflammatory strategies hold great potential for the prevention of this autoimmune disease. Studies have demonstrated that two serine proteinase inhibitors, alpha1-antitrypsin (AAT) and elafin, act as potent antiinflammatory agents. In the present study, we sought to develop an efficient gene therapy approach to prevent type 1 diabetes. Cohorts of 4-week-old female nonobese diabetic (NOD) mice were injected intramuscularly with rAAV1-CB-hAAT, rAAV1-CB-hElafin, or saline. AAV1 vector mediated sustained high levels of transgene expression, sufficient to overcome a humoral immune response against hAAT. AAT gene therapy, contrary to elafin and saline, was remarkably effective in preventing type 1 diabetes. T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice. Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction. This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model. These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes.

  16. 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

  17. Mutations in catalase-peroxidase KatG from isoniazid resistant Mycobacterium tuberculosis clinical isolates: insights from molecular dynamics simulations.

    PubMed

    Pimentel, Arethusa Lobo; de Lima Scodro, Regiane Bertin; Caleffi-Ferracioli, Katiany Rizzieri; Siqueira, Vera Lúcia Dias; Campanerut-Sá, Paula Aline Zanetti; Lopes, Luciana Dias Ghiraldi; de Almeida, Aryadne Larissa; Cardoso, Rosilene Fressatti; Seixas, Flavio Augusto Vicente

    2017-04-01

    The current multidrug therapy for tuberculosis (TB) is based on the use of isoniazid (INH) in combination with other antibiotics such as rifampin, ethambutol and pyrazinamide. Literature reports have shown that Mycobacterium tuberculosis, the causative agent of TB, has become resistant to this treatment by means of point mutations in the target enzymes of these drugs, such as catalase-peroxidase (KatG). By means of equilibrium molecular dynamics in the presence of the ligand, this work evaluated ten point mutations described in the enzyme KatG that are related to resistance to INH . The results showed that the resistance mechanism is related to stereochemical modifications at the N-terminal domain of the protein, which restrict INH access to its catalytic site, not involving mechanisms of electrostatic nature. These results show insights that can be useful for the identification of new anti-TB drugs which may be able to circumvent this mechanism of resistance.

  18. [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.

  19. 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.

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

    PubMed

    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.

  1. 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.

  2. Reduced Emergence of Isoniazid Resistance with Concurrent Use of Thioridazine against Acute Murine Tuberculosis

    PubMed Central

    Dutta, Noton K.; Pinn, Michael L.

    2014-01-01

    The repurposing of existing drugs is being pursued as a means by which to accelerate the development of novel regimens for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). In the current study, we assessed the activity of the antipsychotic drug thioridazine (TRZ) in combination with the standard regimen in a well-validated murine TB model. Single-dose and steady-state pharmacokinetic studies were performed in BALB/c mice to establish human-equivalent doses of TRZ. To determine the bactericidal activity of TRZ against TB in BALB/c mice, three separate studies were performed, including a dose-ranging study of TRZ monotherapy and efficacy studies of human-equivalent doses of TRZ with and without isoniazid (INH) or rifampin (RIF). Therapeutic efficacy was assessed by the change in mycobacterial load in the lung. The human-equivalent dose of thioridazine was determined to be 25 mg/kg of body weight, which was well tolerated in mice. TRZ was found to accumulate at high concentrations in lung tissue relative to serum levels. We observed modest synergy during coadministration of TRZ with INH, and the addition of TRZ reduced the emergence of INH-resistant mutants in mouse lungs. In conclusion, this study further illustrates the opportunity to reevaluate the contribution of TRZ to the sterilizing activity of combination regimens to prevent the emergence of drug-resistant M. tuberculosis. PMID:24798290

  3. Testing of susceptibility of Mycobacterium tuberculosis to isoniazid and rifampin by mycobacterium growth indicator tube method.

    PubMed Central

    Walters, S B; Hanna, B A

    1996-01-01

    We tested isolates of Mycobacterium tuberculosis recovered from 117 patients for their susceptibilities to isoniazid (INH) and rifampin (RIF) by the Centers for Disease Control and Prevention's disk modification of the indirect method of proportions (MOP) test and a three-tube mycobacteria growth indicator tube (MGIT; BBL) antimycobacterial susceptibility test (AST). Sixty-seven of the M. tuberculosis isolates were recovered from Lowenstein-Jensen (BBL) subcultures, and 50 of the isolates were recovered from MGIT cultures of samples from various body sites. For the MGIT AST method, 0.5 ml of test organism suspension was inoculated into an MGIT with 0.1 micrograms of INH per ml, an MGIT with 1.0 micrograms of RIF per ml, and growth control MGIT. The tubes were incubated at 37 degrees C and were examined daily. The MGIT AST results were interpreted as follows: susceptible if the tubes containing INH or RIF did not fluoresce within 2 days of the time that the positive growth control fluoresced and resistant if the tubes containing INH or RIF did fluoresce within 2 days of the time that the positive growth control fluoresced. The mean time fluorescence for the positive growth control was 5.5 days. The two methods were in agreement for 114 of the 117 isolates from patients, while for 3 isolates there were minor discordant results. PMID:8735121

  4. Preoperative zoledronic acid therapy prevent hungry bone syndrome in patients with primary hyperparathyroidism

    PubMed Central

    Mayilvaganan, Sabaretnam; Vijaya Sarathi, H. A.; Shivaprasad, C.

    2017-01-01

    Background: Hungry bone syndrome is a common complication of surgery for primary hyperparathyroidism in India which often leads to prolonged hospitalization. There are varying reports on the use and efficacy of bisphosphonates in the prevention of hungry bone syndrome. Methods: We retrospectively analyzed the effect of preoperative bisphosphonate therapy on rates of hungry bone syndrome in our patients with primary hyperparathyroidism. A total of 19 patients underwent surgery for primary hyperparathyroidism at our institute between January 2013 and June 2015 among whom eight did not receive preoperative bisphosphonates and 11 received intravenous zoledronic acid 4 mg, 24–48 h preoperatively. Results: There was no significant difference between the two groups with respect to age, gender, duration of symptoms, preoperative serum calcium, phosphorus, parathyroid hormone, alkaline phosphatase, and the presence of radiological evidence of hyperparathyroid bone disease also did not differ between the groups. Three out of the eight patients who did not receive preoperative zoledronic acid therapy had hungry bone syndrome but none in the zoledronic acid group. The prevalence of hungry bone syndrome tended to be lower in the zoledronic acid group (P = 0.058). The need for intravenous calcium and duration of postoperative hospital stay were significantly lesser in the zoledronic acid group. Conclusion: Preoperative intravenous zoledronic acid significantly reduces the need for intravenous calcium therapy and duration of postoperative hospital stay and seems a promising option to reduce the rate of hungry bone syndrome in patients with primary hyperparathyroidism. PMID:28217502

  5. 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.

  6. Cell-based therapy for prevention and reversal of myocardial remodeling.

    PubMed

    Karantalis, Vasileios; Balkan, Wayne; Schulman, Ivonne H; Hatzistergos, Konstantinos E; Hare, Joshua M

    2012-08-01

    Although pharmacological and interventional advances have reduced the morbidity and mortality of ischemic heart disease, there is an ongoing need for novel therapeutic strategies that prevent or reverse progressive ventricular remodeling following myocardial infarction, the process that forms the substrate for ventricular failure. The development of cell-based therapy as a strategy to repair or regenerate injured tissue offers extraordinary promise for a powerful anti-remodeling therapy. In this regard, the field of cell therapy has made major advancements in the past decade. Accumulating data from preclinical studies have provided novel insights into stem cell engraftment, differentiation, and interactions with host cellular elements, as well as the effectiveness of various methods of cell delivery and accuracy of diverse imaging modalities to assess therapeutic efficacy. These findings have in turn guided rationally designed translational clinical investigations. Collectively, there is a growing understanding of the parameters that underlie successful cell-based approaches for improving heart structure and function in ischemic and other cardiomyopathies.

  7. Prevention of trismus with different pharmacological therapies after surgical extraction of impacted mandibular third molar.

    PubMed

    Selimović, Edin; Ibrahimagić-Šeper, Lejla; Šišić, Ibrahim; Sivić, Suad; Huseinagić, Senad

    2017-02-01

    Aim To assess prevention and reduction of trismus after surgically extracted impacted mandibular third molars with individual and combined therapy with corticosteroids and anti-inflammatory analgesics. Methods The research included 60 randomly selected patients (3 groups) attended to the Dental Oral Surgery of the Public Institution Healthcare Center Zenica during the period January-December 2008. Patients of both genders, 18-45 years of age, were presented without pain and other inflammatory symptoms at the time of surgery. According to a scheme established in the research protocol, two medications were administered orally: methylprednisolone(corticosteroid) 32 mg and meloxicam (non-steroidal anti-inflammatory analgesic, NSAID) 15 mg as a single drug, or a combination of both drugs. The level of trismus is assessed on the basis of differences of preoperative and postoperative values of interincisal spaces when fully opening the mouth on the second and the seventh post-operative day. The differences between groups of patients were evaluated by means of Tukey's HSD test. Results On the second and on the seventh post-operative day significantly better results were registered in the group that received only corticosteroids and in the group that received both, corticosteroids and NSAIDs compared to the group that received only NSAIDs. A tendency of trismus reduction was present in all patient groups for the second and seventh day after surgery. Conclusion Prevention and control of postoperative trismus after surgical extraction of impacted mandibular third molars with combined therapy is effective and superior comparing to individual therapy with meloxicam-or methylprednisolone alone.

  8. Donor-derived tuberculosis (TB): isoniazid-resistant TB transmitted from a lung transplant donor with inadequately treated latent infection.

    PubMed

    Jensen, T O; Darley, D R; Goeman, E E; Shaw, K; Marriott, D J; Glanville, A R

    2016-10-01

    Donor-derived tuberculosis (TB) is an increasingly recognized complication of solid organ transplantation. We report a case of isoniazid-resistant pulmonary TB in a lung transplant recipient. The patient acquired the infection from the lung donor who was previously empirically treated with isoniazid for latent TB. The case highlights the caveat that, while adequate treatment of latent TB with isoniazid is presumed, meticulous screening of donors is required.

  9. 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.

  10. 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.

  11. 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.

  12. Flow-injection chemiluminescence sensor for determination of isoniazid in urine sample based on molecularly imprinted polymer

    NASA Astrophysics Data System (ADS)

    Xiong, Yan; Zhou, Houjiang; Zhang, Zhujun; He, Deyong; He, Chao

    2007-02-01

    In this paper, molecularly imprinted polymer (MIP) of isoniazid is synthesized through thermal radical copolymerization of metharylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) in the presence of isoniazid template molecules. A novel flow injection chemiluminescence sensor for isoniazid determination is developed by packing the isoniazid-MIP into the flow cell as recognition elements. Isoniazid could be selectively adsorbed by the MIPs and the adsorbed isoniazid was sensed by its great enhancing effect on the weak CL reaction between luminol and periodate which were mixed in the flow cell. The enhanced CL intensity is linear in the range 2 × 10 -9 to 2 × 10 -7 g/mL and the detection limit is 7 × 10 -10 g/mL (3 σ) isoniazid with a relative standard deviation 2.8% ( n = 9) for 8 × 10 -8 g/mL. The sensor is reversible and reusable. It has a great improvement in sensitivity and selectivity for CL analysis. As a result, the sensor has been successfully applied to determination of isoniazid in human urine. At the same time, the binding characteristic of the polymer to isoniazid was evaluated by batch method and the dynamic method, respectively.

  13. Neonatal Thymulin Gene Therapy Prevents Ovarian Dysgenesis and Attenuates Reproductive Derangements in Nude Female Mice

    PubMed Central

    Reggiani, Paula C.; Barbeito, Claudio G.; Zuccolilli, Gustavo O.; Cónsole, Gloria M.; Flamini, Alicia M.; Dardenne, Mireille

    2012-01-01

    Congenitally athymic (nude) female mice show severe ovarian dysgenesis after puberty, which seems to be consequential to a number of neuroendocrine derangements described in these mutants. Thus, considerable evidence suggests that thymulin, a thymic peptide, may be involved in thymus-pituitary communication. In order to clarify the relevance of thymulin for the maturation of the female reproductive system, we assessed at hypothalamic, pituitary, ovarian, and uterine level the preventive action of neonatal thymulin gene therapy (NTGT) on the changes that typically occur after puberty in congenitally athymic female mice. We injected (im) an adenoviral vector harboring a synthetic DNA sequence encoding a biologically active analog of thymulin, methionine-serum thymic factor, in newborn nude mice (which are thymulin deficient) and killed the animals at 70–71 d of age. NTGT in the athymic mice restored the serum thymulin levels. Morphometric analysis revealed that athymic nudes have reduced numbers of brain GnRH neurons and pituitary gonadotropic cells as compared with heterozygous controls. NTGT prevented these changes and also rescued the premature ovarian failure phenotype typically observed in athymic nude mice (marked reduction in the number of antral follicles and corpora lutea, increase in atretic follicles). Serum estrogen, but not progesterone, levels were low in athymic nudes, a reduction that was partially prevented by NTGT. Little to no morphological changes were observed in the endometrium of female nudes. The delay in the age of vaginal opening that occurs in athymic nudes was significantly prevented by NTGT. Our results suggest that thymulin plays a relevant physiologic role in the thymus-hypothalamo-pituitary-gonadal axis. PMID:22700775

  14. Neonatal thymulin gene therapy prevents ovarian dysgenesis and attenuates reproductive derangements in nude female mice.

    PubMed

    Reggiani, Paula C; Barbeito, Claudio G; Zuccolilli, Gustavo O; Cónsole, Gloria M; Flamini, Alicia M; Dardenne, Mireille; Goya, Rodolfo G

    2012-08-01

    Congenitally athymic (nude) female mice show severe ovarian dysgenesis after puberty, which seems to be consequential to a number of neuroendocrine derangements described in these mutants. Thus, considerable evidence suggests that thymulin, a thymic peptide, may be involved in thymus-pituitary communication. In order to clarify the relevance of thymulin for the maturation of the female reproductive system, we assessed at hypothalamic, pituitary, ovarian, and uterine level the preventive action of neonatal thymulin gene therapy (NTGT) on the changes that typically occur after puberty in congenitally athymic female mice. We injected (im) an adenoviral vector harboring a synthetic DNA sequence encoding a biologically active analog of thymulin, methionine-serum thymic factor, in newborn nude mice (which are thymulin deficient) and killed the animals at 70-71 d of age. NTGT in the athymic mice restored the serum thymulin levels. Morphometric analysis revealed that athymic nudes have reduced numbers of brain GnRH neurons and pituitary gonadotropic cells as compared with heterozygous controls. NTGT prevented these changes and also rescued the premature ovarian failure phenotype typically observed in athymic nude mice (marked reduction in the number of antral follicles and corpora lutea, increase in atretic follicles). Serum estrogen, but not progesterone, levels were low in athymic nudes, a reduction that was partially prevented by NTGT. Little to no morphological changes were observed in the endometrium of female nudes. The delay in the age of vaginal opening that occurs in athymic nudes was significantly prevented by NTGT. Our results suggest that thymulin plays a relevant physiologic role in the thymus-hypothalamo-pituitary-gonadal axis.

  15. Transdermal delivery of isoniazid and rifampin in guinea pigs by electro-phonophoresis.

    PubMed

    Chen, Suting; Han, Yi; Yu, Daping; Huo, Fengmin; Wang, Fen; Li, Yunxu; Dong, Lingling; Liu, Zhidong; Huang, Hairong

    2017-11-01

    Electro-phonophoresis (EP) has been used as a drug delivery approach in clinical fields. The objective of the present study is to evaluate the skin permeability of isoniazid and rifampin in guinea pigs by EP to provide reference basis for clinical applications of such transdermal delivery system in the treatment of patients with superficial tuberculosis. Isoniazid and rifampin solutions were delivered transdermally with or without EP in health guinea pigs for 0.5 h. Local skin and blood samples were collected serially at 0, 1/2, 1, 2, 4, 6 and 24 h after dosing. Drug concentrations in local skin and blood were evaluated by high-performance liquid chromatography. Isoniazid concentrations in local skin of guinea pigs receiving isoniazid through EP transdermal delivery were significantly higher than in animals receiving only isoniazid with transdermal patch. However, for rifampin, patches alone group presented almost uniform concentration versus time curve with that of EP group, and both groups had concentrations much higher than the therapeutic concentration of the drug over sustainable time. After EP transdermal delivery, the mean peak concentrations of isoniazid and rifampin in skin were 771.0 ± 163.4 μg/mL and 81.2 ± 17.3 μg/mL respectively. Neither isoniazid nor rifampin concentration in blood could be detected (below the lower detection limit of 1 μg/mL) at any time point. The present study showed that application of EP significantly enhanced INH penetration through skin in guinea pigs, while RIF patch alone obtained therapeutic concentration in local skin. Our work suggests several possible medication approaches for efficient treatment of superficial tuberculosis.

  16. Mechanisms involved in the intrinsic isoniazid resistance of Mycobacterium avium.

    PubMed

    Mdluli, K; Swanson, J; Fischer, E; Lee, R E; Barry, C E

    1998-03-01

    Isoniazid (INH), which acts by inhibiting mycolic acid biosynthesis, is very potent against the tuberculous mycobacteria. It is about 100-fold less effective against Mycobacterium avium. This difference has often been attributed to a decreased permeability of the cell wall. We measured the rate of conversion of radiolabelled INH to 4-pyridylmethanol by whole cells and cell-free extracts and estimated the permeability barrier imposed by the cell wall to INH influx in Mycobacterium tuberculosis and M. avium. There was no significant difference in the relative permeability to INH between these two species. However, the total conversion rate in M. tuberculosis was found to be four times greater. Examination of in vitro-generated mutants revealed that the major resistance mechanism for both species is loss of the catalase-peroxidase KatG. Analysis of lipid and protein biosynthetic profiles demonstrated that the molecular target of activated INH was identical for both species. M. avium, however, formed colonies at INH concentrations inhibitory for mycolic acid biosynthesis. These mycolate-deficient M. avium exhibited altered colony morphologies, modified cell wall ultrastructure and were 10-fold more sensitive to treatment with hydrophobic antibiotics, such as rifampin. These findings may significantly impact the design of new therapeutic regimens for the treatment of infections with atypical mycobacteria.

  17. 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

  18. [Physical activity for prevention and therapy of internal diseases in the elderly].

    PubMed

    Weisser, Burkhard; Preuss, Manuela; Predel, Hans-Georg

    2009-04-15

    There is a growing number of elderly people in Western societies. Therefore, the prevalence of age-associated diseases increases. For most of these conditions, exercise and physical activity play a major role in the prevention and therapy. However, it is well established that the level of physical activity is lowest in elderly people. Physical fitness continues to be the most important protective health factor and should be improved in the elderly population. Many exercise recommendations include only endurance programs, but strength and coordination also deliver positive therapeutic effects in cardiovascular and metabolic diseases, lung diseases, neoplasms, and many other pathologic conditions including dementia. Age-specific recommendations should be included in exercise programs for health.

  19. 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

  20. Antibody-mediated p53 protein therapy prevents liver metastasis in vivo.

    PubMed

    Hansen, James E; Fischer, Laurice K; Chan, Grace; Chang, Sophia S; Baldwin, Scott W; Aragon, Robert J; Carter, Jacqueline J; Lilly, Michael; Nishimura, Robert N; Weisbart, Richard H; Reeves, Mark E

    2007-02-15

    To evaluate the clinical efficacy of monoclonal antibody (mAb) 3E10 Fv antibody-mediated p53 protein therapy, an Fv-p53 fusion protein produced in Pichia pastoris was tested on CT26.CL25 colon cancer cells in vitro and in vivo in a mouse model of colon cancer metastasis to the liver. In vitro experiments showed killing of CT26.CL25 cells by Fv-p53 but not Fv or p53 alone, and immunohistochemical staining confirmed that Fv was required for transport of p53 into cells. Prevention of liver metastasis in vivo was tested by splenic injection of 100 nmol/L Fv-p53 10 min and 1 week after injection of CT26.CL25 cancer cells into the portal vein of BALB/c mice. Mice were sacrificed 1 week after the second injection of Fv-p53 and assigned a quantitative metastasis score. Control mice had an average metastasis score of 3.3 +/- 1.3, whereas mice treated with Fv-p53 had an average metastasis score of 0.8 +/- 0.4 (P = 0.004). These results indicate that Fv-p53 treatment had a profound effect on liver metastasis and represent the first demonstration of effective full-length p53 protein therapy in vivo. mAb 3E10 Fv has significant clinical potential as a mediator of intracellular and intranuclear delivery of p53 for prevention and treatment of cancer metastasis.

  1. Partial prevention of hepatic lipid alterations in nude mice by neonatal thymulin gene therapy.

    PubMed

    García de Bravo, Margarita M; Polo, Mónica P; Reggiani, Paula C; Rimoldi, Omar J; Dardenne, Mireille; Goya, Rodolfo G

    2006-08-01

    During adult life athymic (nude) male mice display not only a severe T-cell-related immunodeficiency but also endocrine imbalances and a moderate hyperglycemia. We studied the impact of congenital athymia on hepatic lipid composition and also assessed the ability of neonatal thymulin gene therapy to prevent the effects of athymia. We constructed a recombinant adenoviral vector, RAd-metFTS, expressing a synthetic DNA sequence encoding met-FTS, an analog of the thymic peptide facteur thymique sérique (FTS), whose Zn-bound biologically active form is known as thymulin. On postnatal day 1-2 homozygous (nu/nu) nude and heterozygous (nu/+) mice were injected with 10(8) pfu of RAd-metFTS or RAd-betagal (control vector) intramuscularly. The animals were processed at 52 d of age. Serum thymulin, glycemia, hepatic phospholipid FA composition and free and esterified cholesterol were determined. Adult homozygous male nudes were significantly (P < 0.01) hyperglycemic when compared with their heterozygous counterparts (2.04 vs. 1.40 g/L, respectively). The relative percentage of 16:0, 18:1 n-9, and 18:1n-7 FA was lower, whereas that of 18:0, 20:4n-6, and 22:6n-3 FA was higher, in hepatic phospholipid (PL) of nu/nu animals as compared with their nu/+ counterparts. Some of these alterations, such as that in the relative content of 22:6n-3 in liver PL and the unsaturation index, were completely or partially prevented by neonatal thymulin gene therapy. We conclude that the thymus influences lipid metabolism and that thymulin is involved in this modulatory activity.

  2. Antiplatelet therapy for preventing stroke in patients with chronic kidney disease.

    PubMed

    Kim, Suk Jae; Bang, Oh Young

    2013-01-01

    Chronic kidney disease (CKD), defined as reduced glomerular filtration rate and/or proteinuria, is a serious worldwide health problem. The incidence and prevalence of CKD are increasing with age, and patients with CKD are a population at very high risk for developing stroke. CKD may increase the risk for incident stroke independent of conventional stroke risk factors. A common pathological process including anemia, homocysteine, nitric oxide, oxidative stress, inflammation, and conditions promoting coagulation may be related to the development of stroke in the course of CKD. CKD can also serve as a marker of brain injury, because the cerebral microvascular system has similar hemodynamic features with the vascular beds of the kidney. CKD has been linked with markers of cerebral small artery disease including white matter lesions, lacunar infarctions, and cerebral microbleeds. CKD has been implicated with neurological deterioration during hospitalization, poor functional outcome, and hemorrhagic transformation in patients with acute stroke. Recurrence of stroke may also be higher in CKD patients compared with those having normal kidney function. However, there have been no specific recommendations for antiplatelet therapy in patients with ischemic stroke plus CKD. As CKD patients have distinct characteristics including high bleeding complications and poor response to antiplatelet agents, selecting and adjusting platelet aggregation inhibitors should be individualized. In addition, it should be noted that aspirin may aggravate renal dysfunction. Phosphodiesterase inhibitors restore endothelial dysfunction and may serve as a target for preventing stroke in CKD patients. Aside from antiplatelet therapy, other treatments including lipid control, blood pressure lowering, and renal transplantation are also important. Further studies are warranted for optimal treatment in stroke prevention in CKD patients.

  3. A case of isoniazid-resistant miliary tuberculosis in which tuberculous meningitis paradoxically developed despite systemic improvement.

    PubMed

    Ikegame, Satoshi; Wakamatsu, Kentaro; Fujita, Masaki; Nakanishi, Yoichi; Harada, Mine; Kajiki, Akira

    2011-10-01

    A 63-year-old man with chronic myelomonocytic leukemia was admitted to our hospital with miliary tuberculosis. He received anti-tuberculosis drugs: isoniazid (INH), rifampicin (RFP), ethambutol (EB), and pyrazinamide (PZA). His condition clearly and immediately improved after the therapy, but he experienced a high fever of about 38°C every day from 1 month after the initiation of the therapy. Drug-induced fever and tumor fever were suspected as causes, but the etiology could not be determined. The tuberculosis was identified as an INH-resistant strain, so INH was stopped and levofloxacin (LVFX) was introduced, with streptomycin (SM), in addition to RFP, EB, and PZA. At 2 months after the initiation of the therapy (about one week after the change in the anti-tuberculosis drug regimen), his spinal fluid was examined, given his complaints of headache and vomiting. The spinal fluid analysis revealed invasion of lymphocytic inflammatory cells and high adenosine deaminase activity; the patient was thus diagnosed with tuberculous meningitis. His condition gradually improved after the changing of the anti-tuberculosis drugs. Thus, to summarize, the tuberculous meningitis had worsened paradoxically despite his systemic improvement, although it was successfully treated by the addition of LVFX and SM. We must keep in mind that a potential cause of fever during anti-tuberculosis therapy may be INH-resistant tuberculous meningitis.

  4. 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 ...

  5. Prevention

    MedlinePlus

    ... Is Strong Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... to avoid secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  6. 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

  7. CROI 2015: Advances in Antiretroviral Therapy.

    PubMed

    Olender, Susan A; Taylor, Barbara S; Wong, Marcia; Wilkin, Timothy J

    2015-01-01

    The 2015 Conference on Retroviruses and Opportunistic Infections included new and exciting advances in the realm of antiretroviral therapy. The Temprano trial demonstrated benefits from early antiretroviral therapy and isoniazid preventive therapy. Important data on investigational antiretroviral drugs were presented, including tenofovir alafenamide fumarate and BMS-955176, an HIV-1 maturation inhibitor. Novel data on the HIV care continuum from resource-rich and -limited settings highlighted persistent sex- and race-related disparities in care engagement, and the crucial need to bring HIV testing and care into the community to improve engagement across the care continuum. Life expectancy data from resource-limited settings reveal dramatic improvements across sub-Saharan Africa, although people with HIV still live 5 years to 10 years less than those without HIV, and new cost-effectiveness research revealed that the price of antiretroviral therapy itself remains a key driver of cost and cost-effectiveness calculations. Results from the PROMISE trial showed reduced rates of mother-to-child transmission among women who received antiretroviral therapy with 3 drugs compared with women who received zidovudine monotherapy, supporting current World Health Organization guidelines.

  8. Centering prayer as an alternative to mindfulness-based cognitive therapy for depression relapse prevention.

    PubMed

    Knabb, Joshua J

    2012-09-01

    In the last two decades, mindfulness has made a significant impact on Western secular psychology, as evidenced by several new treatment approaches that utilize mindfulness practices to ameliorate mental illness. Based on Buddhist teachings, mindfulness offers individuals the ability to, among other things, decenter from their thoughts and live in the present moment. As an example, mindfulness-based cognitive therapy (MBCT) teaches decentering and mindfulness techniques to adults in an eight-session group therapy format so as to reduce the likelihood of depression relapse. Yet, some Christian adults may prefer to turn to their own religious heritage, rather than the Buddhist tradition, in order to stave off depression relapse. Thus, the purpose of this article is to present centering prayer, a form of Christian meditation that is rooted in Catholic mysticism, as an alternative treatment for preventing depression relapse in adults. I argue that centering prayer overlaps considerably with MBCT, which makes it a suitable treatment alternative for many Christians in remission from depressive episodes.

  9. Intensive insulin therapy for preventing postoperative infection in patients with traumatic brain injury

    PubMed Central

    Wang, Yan; Li, Jin-ping; Song, Ying-lun; Zhao, Qi-huang

    2017-01-01

    Abstract Objective: To assess the effect of intensive insulin therapy (IIT) for preventing postoperative infection in patients with traumatic brain injury (TBI). Methods: In total, 88 patients with TBI were randomly divided into 2 groups, 44 in each group. One group (group ITT) received IIT and the other group (group CIT) received conventional insulin therapy (CIT). This study was conducted between February 2013 and January 2016. Outcomes included infection rate, mortality, and neurological outcome (measured by the Glasgow Outcome Scale [GOS]). Results: A total of 81 patients completed the study. IIT showed greater efficacy than CIT, with a decreased infection rate in the IIT group compared to the CIT group (31.9% vs 52.3%, P = 0.03), and also a reduced duration of stay in intensive care unit (ICU) (IIT group, 4.5 ± 2.1 days vs CIT group, 5.7 ± 2.8 days, P = 0.02). In addition, a significant difference in scores on the GOS scale was observed between the 2 groups (P = 0.04). The mortality rates in hospital and at the 26-week follow-up were similar between the 2 groups. Conclusion: IIT leads to a reduced infection rate, shorter stays in ICU, and improved neurological outcome. PMID:28353579

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

    PubMed Central

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

    2008-01-01

    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

  11. 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

  12. 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.

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

    PubMed Central

    Casey, Stephanie C.; Amedei, Amedeo; Aquilano, Katia; Benencia, Fabian; Bhakta, Dipita; 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; Kerkar, Sid P.; Mohammed, Sulma I.; Niccolai, Elena; Nowsheen, Somaira; Rupasinghe, H. P. Vasantha; Samadi, Abbas; Singh, Neetu; Talib, Wamidh H.; Venkateswaran, Vasundara; Whelan, Richard; Yang, Xujuan; Felsher, Dean W.

    2015-01-01

    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 adapative 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. PMID:25865775

  14. Changing Clinician Practices and Attitudes Regarding the Use of Antiretroviral Therapy for HIV Treatment and Prevention.

    PubMed

    Buchacz, Kate; Farrior, Jennifer; Beauchamp, Geetha; McKinstry, Laura; Kurth, Ann E; Zingman, Barry S; Gordin, Fred M; Donnell, Deborah; Mayer, Kenneth H; El-Sadr, Wafaa M; Branson, Bernard

    As part of the HPTN 065 study in the Bronx, New York and Washington, the authors, we surveyed clinicians to assess for shifts in their practices and attitudes around HIV treatment and prevention. Antiretroviral therapy (ART)-prescribing clinicians at 39 HIV care sites were offered an anonymous Web-based survey at baseline (2010-2011) and at follow-up (2013). The 165 respondents at baseline and 141 respondents at follow-up had similar characteristics-almost 60% were female, median age was 47 years, two-thirds were physicians, and nearly 80% were HIV specialists. The percentage who reported recommending ART irrespective of CD4 count was higher at follow-up (15% versus 68%), as was the percentage who would initiate ART earlier for patients having unprotected sex with partners of unknown HIV status (64% versus 82%), and for those in HIV-discordant partnerships (75% versus 87%). In line with changing HIV treatment guidelines during 2010 to 2013, clinicians increasingly supported early ART for treatment and prevention.

  15. Characterization of biomodified dentin matrices for potential preventive and reparative therapies

    PubMed Central

    Bedran-Russo, Ana Karina B.; Castellan, Carina. S.; Shinohara, Mirela S.; Hassan, Lina; Antunes, Alberto

    2011-01-01

    Biomodification of existing hard tissue structures, specifically tooth dentin, is an innovative approach proposed to improve the biomechanical and biochemical properties of tissue for potential preventive or reparative/regenerative therapies. The objectives of the study were to systematically characterize dentin matrices biomodified by proanthocyanidin-rich grape seed extract (GSE) and glutaraldehyde (GD). Changes to the biochemistry and biomechanical properties were assessed by several assays to investigate the degree of interactions, biodegradation rates, proteoglycans interaction, and effect of collagen fibril orientation and environmental conditions on the tensile properties. The highest degree of agent-dentin interaction was observed with GSE which exhibited the highest denaturation temperature, regardless of the agent concentration. Biodegradation rates remarkably decreased following biomodification of dentin matrices after 24hs collagenase digestion. A significant decreased in the proteoglycans content of GSE treated samples was observed using a micro-assay for glycosaminoglycans and histological electron microscopy, while no changes were observed for GD and control. Tensile strength properties of GD biomodified dentin matrices were affected by dentin tubule orientation, most likely due to the orientation of the collagen fibrils. Higher and/or increased stability of the tensile properties of GD and GSE-treated samples were observed following exposure to collagenase and 8 month water storage. Biomodification of dentin matrices using chemical agents not only affects the collagen biochemistry; it also involves interaction with proteoglycans. Tissue biomodifiers interact differently with dentin matrices and may provide the tissue with enhanced preventive and restorative/reparative abilities. PMID:21167964

  16. The effectiveness of antioxidant therapy in aspirin resistance, diabetes population for prevention of thrombosis.

    PubMed

    Aboonabi, Anahita; Singh, Indu

    2016-10-01

    Thrombosis as the main complication of coronary heart disease (CHD) represents the primary cause of morbidity and mortality in patients with diabetes mellitus (DM). In the course of diabetes mellitus some coagulation abnormalities occur, that may result in a thrombogenic propensity. Aspirin (ASA) as a platelet-inhibiting agent through inactivation of Cyclooxygenase-1 (COX-1) is mostly used for the prevention and treatment of atherothrombotic disorders. ASA inhibits the COX-1 enzyme and therefore blocks platelet thromboxane A2 (TXA2) synthesis. However, some of the serious vascular events in high-risk vascular patients are attributable to a failure of ASA to suppress platelet aggregation. The consumption of antioxidant or antioxidant rich foods such as vitamin C, E, and polyphenols might impart anti-thrombotic and cardiovascular protective effects via their inhibition of platelet hyper-activation or aggregation similar to the action of aspirin. This review will discuss the risk of thrombosis in diabetes, what aspirin resistance means, and the effectiveness of antioxidant therapy in the prevention and possible treatment of atherothrombotic disorders.

  17. Implications of the Cancer Stem-Cell Hypothesis for Breast Cancer Prevention and Therapy

    PubMed Central

    Kakarala, Madhuri; Wicha, Max S.

    2009-01-01

    Recent research in breast biology has provided support for the cancer stem-cell hypothesis. Two important components of this hypothesis are that tumors originate in mammary stem or progenitor cells as a result of dysregulation of the normally tightly regulated process of self-renewal. As a result, tumors contain and are driven by a cellular subcomponent that retains key stem-cell properties including self-renewal, which drives tumorigenesis and differentiation that contributes to cellular heterogeneity. Advances in stem-cell technology have led to the identification of stem cells in normal and malignant breast tissue. The study of these stem cells has helped to elucidate the origin of the molecular complexity of human breast cancer. The cancer stem-cell hypothesis has important implications for early detection, prevention, and treatment of breast cancer. Both hereditary and sporadic breast cancers may develop through dysregulation of stem-cell self-renewal pathways. These aberrant stem cells may provide targets for the development of cancer prevention strategies. Furthermore, because breast cancer stem cells may be highly resistant to radiation and chemotherapy, the development of more effective therapies for this disease may require the effective targeting of this cell population. PMID:18539959

  18. 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

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

    PubMed

    Lanier, Paul; Kohl, Patricia L; Benz, Joan; Swinger, Dawn; Drake, Brett

    2014-02-01

    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.

  20. 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

  1. 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

  2. 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

  3. Molecular targets of dietary agents for prevention and therapy of cancer.

    PubMed

    Aggarwal, Bharat B; Shishodia, Shishir

    2006-05-14

    While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the molecular level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various molecular targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food.

  4. Nutritional hepatic iron overload is not prevented by parenteral hepcidin substitution therapy in mice.

    PubMed

    Sillerova, Tereza; Zivny, Jan; Vyoral, Daniel; Petrak, Jiri

    2012-11-28

    The peptide hormone hepcidin functions as a negative regulator of intestinal Fe absorption and Fe recycling. Since its discovery as a systemic negative regulator of Fe metabolism, hepcidin has attracted enormous interest as a potential drug for the treatment and/or prevention of several forms of Fe overload. We therefore tested whether multiple doses of intraperitoneally administered synthetic renatured hepcidin can prevent hepatic Fe loading in mice concurrently fed an Fe-rich diet, and whether the same treatment affects hepatic Fe stores in mice fed a normal diet. Cohorts of male mice were fed either a normal defined diet (180 parts per million Fe) or an Fe-rich diet (the same diet supplemented with 2 % carbonyl iron for 2 weeks). Concurrently, half of the animals in each diet group received 100 μg of renatured hepcidin intraperitoneally every 12 h, for the same 2-week period. The second half of the animals received PBS only. The renatured synthetic hepcidin demonstrated biological activity by significantly decreasing transferrin saturation, which lasted for up to 24 h after a single hepcidin dose. However, the 14 d intraperitoneal hepcidin therapy did not prevent hepatic Fe overload in mice fed the Fe-rich diet, nor did it affect hepatic Fe stores in mice fed the normal diet. Both hepcidin agonists and antagonists are expected to have broad therapeutic potential. The absence of an effect of biologically active hepcidin on hepatic Fe loading shows the need for thorough future studies on the hepcidin regulation of Fe absorption and tissue distribution.

  5. Successful treatment of acquired pendular elliptical nystagmus in multiple sclerosis with isoniazid and base-out prisms.

    PubMed

    Traccis, S; Rosati, G; Monaco, M F; Aiello, I; Agnetti, V

    1990-03-01

    We treated 3 multiple sclerosis patients who had pendular nystagmus with isoniazid (800 to 1,000 mg/d). Isoniazid abolished the nystagmus and relieved oscillopsia in 2 patients but was ineffective in the 3rd in whom the nystagmus was damped with convergence and vision improved with converging (base-out) prisms.

  6. Antiretroviral therapy for prevention of HIV transmission: potential role for people who inject drugs in Central Asia.

    PubMed

    McNairy, Margaret L; Deryabina, Anna; Hoos, David; El-Sadr, Wafaa M

    2013-11-01

    Interest in the use of antiretroviral therapy (ART) for prevention stems from mounting evidence from research studies demonstrating that ART is associated with a decrease in sexual HIV transmission among serodiscordant couples and, perhaps, in other populations at risk. There is paucity of data on the efficacy of ART for prevention in key populations, including persons who inject drugs (PWID). In this paper, we examine the current status of HIV services for PWID in Central Asia, the use of ART by this population and explore ART for prevention for PWID in this context. We also discuss research and implementation questions with relevance to such a strategy in the region.

  7. Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women

    PubMed Central

    Sanchez, Rafael Gabriel; Sanchez Gomez, Luis Maria; Carmona, Loreto; Figuls, Marta Roqué i; Cosp, Xavier Bonfill

    2014-01-01

    Background There is apparently compelling evidence, from observational studies, that hormone replacement therapy (HRT) may have benefits in reducing cardiovascular events in post-menopausal women. However, these observational data are subject to biases and confounding and require support from formally designed randomised controlled trials of the effects of HRT on cardiovascular disease risk. Objectives To assess the effects of HRT for the primary and secondary prevention of cardiovascular diseases in post-menopausal women. Search methods We searched MEDLINE (1998 to December 2002)), EMBASE (1998 to December 2002), the Cochrane Controlled Trials Register (CCTR) (Issue 4 2002), the National Research Register (1998 to present), ClinicalTrials.gov (1998 to present), and the database of Spanish Clinical Trials (1998 to present) and reference lists of articles. Selection criteria Randomised controlled trials comparing HRT with controls (placebo or no treatment) with a minimum follow up of 6 months for treating or preventing cardiovascular disease in postmenopausal women with or without cardiovascular disease. Data collection and analysis Three independent reviewers extracted information from the articles, solving discrepancies by consensus. All outcomes studied were dichotomous. Risk ratios and 95% confidence intervals (CI) were calculated for each study and plotted. Random effects meta-analysis was used in efficacy outcomes (cardiovascular events) and fixed-effects meta-analysis in variables regarding side effects (deep venous thrombosis). Main results No protective effect of HRT was seen for any of the cardiovascular outcomes assessed: all cause mortality, cardiovascular death, non-fatal MI, venous thromboemboli or stroke. Higher risks of venous thromboembolic events (Relative risk (RR) 2.15, 95% CI 1.61 to 2.86), pulmonary embolus (RR 2.15, 95% CI 1.41 to 3.28), and stroke (RR 1.44, 95% CI 1.10 to 1.89) was found in those randomised to HRT compared with placebo. No

  8. 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

  9. 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.

  10. [Efficiency of remaxol in preventing unwanted side effects of the antiviral therapy in patients with chronic hepatitis C].

    PubMed

    Baranova, I P; Zykova, O A; Krasnova, L I; Romantsov, M G; Nikol'skaia, M V; Aftaeva, L N

    2013-01-01

    The article briefly addresses issues pertaining to the problem of complications encountered in antiviral therapy of patients with chronic hepatitis C. Data on the effectiveness of remaxol as a means of preventing the development of complication in patients with chronic viral hepatitis C in early stages of antiviral treatment.

  11. 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…

  12. 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

  13. 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

  14. Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines

    PubMed Central

    Norris, Susan L.; Schulman, Sam; Hirsh, Jack; Eckman, Mark H.; Akl, Elie A.; Crowther, Mark; Vandvik, Per Olav; Eikelboom, John W.; McDonagh, Marian S.; Lewis, Sandra Zelman; Gutterman, David D.; Cook, Deborah J.; Schünemann, Holger J.

    2012-01-01

    Background: To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physicians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, and systematic review and guideline methodologists. Methods: Clinical areas were designated as articles, and a methodologist without important intellectual or financial conflicts of interest led a panel for each article. Only panel members without significant conflicts of interest participated in making recommendations. Panelists specified the population, intervention and alternative, and outcomes for each clinical question and defined criteria for eligible studies. Panelists and an independent evidence-based practice center executed systematic searches for relevant studies and evaluated the evidence, and where resources and evidence permitted, they created standardized tables that present the quality of the evidence and key results in a transparent fashion. Results: One or more recommendations relate to each specific clinical question, and each recommendation is clearly linked to the underlying body of evidence. Judgments regarding the quality of evidence and strength of recommendations were based on approaches developed by the Grades of Recommendations, Assessment, Development, and Evaluation Working Group. Panel members constructed scenarios describing relevant health states and rated the disutility associated with these states based on an additional systematic review of evidence regarding patient values and preferences for antithrombotic therapy. These ratings guided value and preference decisions underlying the recommendations. Each topic panel identified questions in which resource allocation issues were particularly important and, for these issues, experts in economic analysis provided additional searches and guidance. Conclusions: AT9 methodology reflects the current science of evidence

  15. Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes.

    PubMed

    Goudy, Kevin S; Johnson, Mark C; Garland, Alaina; Li, Chengwen; Samulski, R Jude; Wang, Bo; Tisch, Roland

    2011-03-15

    IL-2 and TGF-β1 play key roles in the immunobiology of Foxp3-expressing CD25(+)CD4(+) T cells (Foxp3(+)Treg). Administration of these cytokines offers an appealing approach to manipulate the Foxp3(+)Treg pool and treat T cell-mediated autoimmunity such as type 1 diabetes. However, efficacy of cytokine treatment is dependent on the mode of application, and the potent pleiotropic effects of cytokines like IL-2 may lead to severe side effects. In the current study, we used a gene therapy-based approach to assess the efficacy of recombinant adeno-associated virus vectors expressing inducible IL-2 or TGF-β1 transgenes to suppress ongoing β cell autoimmunity in NOD mice. Intramuscular vaccination of recombinant adeno-associated virus to 10-wk-old NOD female mice and a subsequent 3 wk induction of IL-2 was sufficient to prevent diabetes and block the progression of insulitis. Protection correlated with an increased frequency of Foxp3(+)Treg in the periphery as well as in the draining pancreatic lymph nodes and islets. IL-2 induced a shift in the ratio favoring Foxp3(+)Treg versus IFN-γ-expressing T cells infiltrating the islets. Induction of IL-2 had no systemic effect on the frequency or activational status of T cells and NK cells. Induction of TGF-β1 had no effect on the Foxp3(+)Treg pool or the progression of β cell autoimmunity despite induced systemic levels of activated TGF-β1 that were comparable to IL-2. These results demonstrate that inducible IL-2 gene therapy is an effective and safe approach to manipulate Foxp3(+)Treg and suppress T cell-mediated autoimmunity and that under the conditions employed, IL-2 is more potent than TGF-β1.

  16. Antimicrobial therapy of pulmonary tuberculosis*

    PubMed Central

    McDermott, Walsh

    1960-01-01

    The discovery, some nine years ago, of the highly specific antituberculous drug, isoniazid, marked an important advance in the antimicrobial therapy of tuberculosis, first practised successfully with streptomycin and p-aminosalicylic acid (PAS) in the late 'forties. Isoniazid is relatively non-toxic and, unlike streptomycin, can be administered orally, so that it is eminently suitable for use, either alone or in combination with PAS, in the domiciliary treatment of tuberculous patients. The wisdom of employing it on a large scale in home-treatment programmes, however, has been questioned on the ground that such wide-spread use might result in a spread of tubercle bacilli resistant to the drug. This controversial subject is discussed in some detail in this general review of the chemotherapy of tuberculosis. The author is convinced that, so far, the benefits of isoniazid therapy have outweighed the disadvantages and, though well aware of the possible consequences in terms of isoniazid-resistance, sees no reason at the present time for not making full use of this valuable weapon in the antituberculosis armamentarium. PMID:20604078

  17. Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis.

    PubMed

    Unissa, Ameeruddin Nusrath; Subbian, Selvakumar; Hanna, Luke Elizabeth; Selvakumar, Nagamiah

    2016-11-01

    Isoniazid (INH) is one of the most active compounds used to treat tuberculosis (TB) worldwide. In addition, INH has been used as a prophylactic drug for individuals with latent Mycobacterium tuberculosis (MTB) infection to prevent reactivation of disease. Importantly, the definition of multidrug resistance (MDR) in TB is based on the resistance of MTB strains to INH and rifampicin (RIF). Despite its simple chemical structure, the mechanism of action of INH is very complex and involves several different concepts. Many pathways pertaining to macromolecular synthesis are affected, notably mycolic acid synthesis. The pro-drug INH is activated by catalase-peroxidase (KatG), and the active INH products are targeted by enzymes namely, enoyl acyl carrier protein (ACP) reductase (InhA) and beta-ketoacyl ACP synthase (KasA). In contrast, INH is inactivated by arylamine N-acetyltransferases (NATs). Consequently, the molecular mechanisms of INH resistance involve several genes in multiple biosynthetic networks and pathways. Mutation in the katG gene is the major cause for INH resistance, followed by inhA, ahpC, kasA, ndh, iniABC,fadE, furA, Rv1592c and Rv1772. The recent association of efflux genes with INH resistance has also gained considerable attention. Interestingly, substitutions have also been observed in nat, fabD, and accD recently in resistant isolates. Understanding the mechanisms operating behind INH action and resistance would enable better detection of INH resistance. This information would aid novel drug design strategies. Herein we review all mechanisms known to potentially contribute to the complexity of INH action and mechanisms of resistance in MTB, with insights into methods for detection of INH resistance as well as their limitations.

  18. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect.

    PubMed

    Brookhart, M Alan; Patrick, Amanda R; Dormuth, Colin; Avorn, Jerry; Shrank, William; Cadarette, Suzanne M; Solomon, Daniel H

    2007-08-01

    Patients who adhere to preventive therapies may be more likely to engage in a broad spectrum of behaviors consistent with a healthy lifestyle. Because many of these behaviors cannot be measured easily, observational studies of outcomes associated with the long-term use of preventive therapies are subject to the so-called "healthy user bias." To better understand this effect, the authors examined the association between adherence to statin therapy and the use of preventive health services in a Pennsylvania cohort of 20,783 new users of statins between 1996 and 2004. After adjustment for age, gender, and various comorbid conditions, patients who filled two or more prescriptions for a statin during a 1-year ascertainment period were more likely than patients who filled only one prescription to receive prostate-specific antigen tests (hazard ratio (HR)=1.57, 95% confidence interval (CI): 1.17, 2.19), fecal occult blood tests (HR=1.31, 95% CI: 1.12, 1.53), screening mammograms (HR=1.22, 95% CI: 1.09, 1.38), influenza vaccinations (HR=1.21, 95% CI: 1.12, 1.31), and pneumococcal vaccinations (HR=1.46, 95% CI: 1.17, 1.83) during follow-up. These results suggest that patients who adhere to chronic therapies are more likely to seek out preventive health services, such as screening tests and vaccinations. Further work is needed to identify study design and analysis methods that can be used to minimize the healthy user bias in studies of preventive therapies.

  19. 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

    2014-11-25

    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.

  20. 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

  1. Cost-effectiveness of combined oral bisphosphonate therapy and falls prevention exercise for fracture prevention in the USA.

    PubMed

    Mori, T; Crandall, C J; Ganz, D A

    2017-02-01

    We developed a Markov microsimulation model among hypothetical cohorts of community-dwelling US white women without prior major osteoporotic fractures over a lifetime horizon. At ages 75 and 80, adding 1 year of exercise to 5 years of oral bisphosphonate therapy is cost-effective at a conventionally accepted threshold compared with bisphosphonates alone.

  2. Phage therapy as an approach to prevent Vibrio anguillarum infections in fish larvae production.

    PubMed

    Silva, Yolanda J; Costa, Liliana; Pereira, Carla; Mateus, Cristiana; Cunha, Angela; 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.

  3. Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms.

    PubMed

    Sinha, Dona; Sarkar, Nivedita; Biswas, Jaydip; Bishayee, Anupam

    2016-10-01

    Globally, breast cancer is the most frequently diagnosed cancer among women. The major unresolved problems with metastatic breast cancer is recurrence after receiving objective response to chemotherapy, drug-induced side effects of first line chemotherapy and delayed response to second line of treatment. Unfortunately, very few options are available as third line treatment. It is clear that under such circumstances there is an urgent need for new and effective drugs. Phytochemicals are among the most promising chemopreventive treatment options for the management of cancer. Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a non-flavonoid polyphenol present in several dietary sources, including grapes, berries, soy beans, pomegranate and peanuts, has been shown to possess a wide range of health benefits through its effect on a plethora of molecular targets.The present review encompasses the role of resveratrol and its natural/synthetic analogue in the light of their efficacy against tumor cell proliferation, metastasis, epigenetic alterations and for induction of apoptosis as well as sensitization toward chemotherapeutic drugs in various in vitro and in vivo models of breast cancer. The roles of resveratrol as a phytoestrogen, an aromatase inhibitor and in stem cell therapy as well as adjuvent treatment are also discussed. This review explores the full potential of resveratrol in breast cancer prevention and treatment with current limitations, challenges and future directions of research.

  4. 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

  5. Development of a Patient Adherence Scale for Exposure and Response Prevention Therapy

    PubMed Central

    Simpson, Helen Blair; Maher, Michael; Page, Jessica R.; Gibbons, Carly J.; Franklin, Martin E.; Foa, Edna B.

    2014-01-01

    Exposure and response prevention (EX/RP) is an evidence-based treatment for obsessive-compulsive disorder (OCD). For EX/RP to be maximally effective, it is believed that patients must adhere outside of sessions to the procedures they learn in therapy. To date, there is no standard measure of patient EX/RP adherence, despite the importance of accurately assessing EX/RP adherence in both clinical research and practice. This paper describes the development of the Patient EX/RP Adherence Scale (PEAS), which assesses the patient's between-session adherence to the therapist's EX/RP instructions, and presents initial data on the scale's reliability and validity. The scale was designed to focus on the key procedures of EX/RP and to be brief enough to be used at each treatment session. The scale demonstrates excellent interrater reliability and good face and content validity. The usefulness of the scale is considered in the context of being an important tool to researchers trying to understand and improve outcomes of EX/RP for OCD as well as to EX/RP therapists in clinical practice. Future research will need to test the scale's reliability and validity in a larger sample of patients over the course of treatment. PMID:20171325

  6. 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.

  7. 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.

  8. 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

  9. Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review.

    PubMed

    O'Donnell, Martin J; Hankey, Graeme J; Eikelboom, John W

    2008-05-01

    For patients with ischemic stroke or transient ischemic attack caused by atherothromboembolism, immediate and long-term aspirin reduces the relative risk of recurrent stroke, MI, and death attributable to vascular causes. Oral anticoagulation is not more effective than aspirin. Long-term clopidogrel reduces the relative risk of stroke, MI, or vascular death by about 9% (0.3% to 16.5%) compared with aspirin. Any long-term benefits of clopidogrel combined with aspirin, compared with aspirin or clopidogrel alone, appear to be offset by increased major bleeding. The combination of aspirin and extended-release dipyridamole reduces the relative odds of stroke, MI, or vascular death by about 18% (odds ratio 0.82, 0.74 to 0.91) compared with aspirin alone without causing more bleeding. Cilostazole reduces the risk of stroke, MI, or vascular death by 39% compared to placebo. A large clinical trial comparing clopidogrel with the combination of aspirin and dipyridamole, in >20 000 patients with recent (<120 days) atherothrombotic ischemic stroke, is expected to report in 2008. Emerging antiplatelet therapies presently being evaluated for secondary prevention of atherothromboembolism include other P(2)Y(12) ADP receptor antagonists (prasugrel, cangrelor, AZD 6140), thromboxane receptor antagonists (eg, S18886 - terutroban), and thrombin receptor (PAR-1) antagonists (eg, SCH530348).

  10. 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

  11. Crocetin: an agent derived from saffron for prevention and therapy for cancer.

    PubMed

    Gutheil, William G; Reed, Gregory; Ray, Amitabha; Anant, Shrikant; Dhar, Animesh

    2012-01-01

    Cancer is one of the leading causes of death in the United States and accounts for approximately 8 million deaths per year worldwide. Although there is an increasing number of therapeutic options available for patients with cancer, their efficacy is time-limited and non-curative. Approximately 50-60% cancer patients in the United States utilize agents derived from different parts of plants or nutrients (complementary and alternative medicine), exclusively or concurrently with traditional therapeutic regime such as chemotherapy and/or radiation therapy. The need for new drugs has prompted studies evaluating possible anti-cancer agents in fruits, vegetables, herbs and spices. Saffron, a spice and a food colorant present in the dry stigmas of the plant Crocus sativus L., has been used as an herbal remedy for various ailments including cancer by the ancient Arabian, Indian and Chinese cultures. Crocetin, an important carotenoid constituent of saffron, has shown significant potential as an anti-tumor agent in animal models and cell culture systems. Crocetin affects the growth of cancer cells by inhibiting nucleic acid synthesis, enhancing anti-oxidative system, inducing apoptosis and hindering growth factor signaling pathways. This review discusses the studies on cancer preventive potential of crocetin and its future use as an anticancer agent.

  12. 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.

  13. Crocetin: an agent derived from saffron for prevention and therapy for cancer

    PubMed Central

    Gutheil, William G.; Reed, Gregory; Ray, Amitabha; Dhar, Animesh

    2015-01-01

    Cancer is one of the leading causes of death in the United States and accounts for approximately 8 million deaths per year worldwide. Although there is an increasing number of therapeutic options available for patients with cancer, their efficacy is time-limited and non-curative. Approximately 50-60% of cancer patients in the United States utilize agents derived from different parts of plants or nutrients (complementary and alternative medicine), exclusively or concurrently with traditional therapeutic regime such as chemotherapy and/or radiation therapy. The need for new drugs has prompted studies evaluating possible anti-cancer agents in fruits, vegetables, herbs and spices. Saffron, a spice and a food colorant present in the dry stigmas of the plant Crocus sativus L., has been used as an herbal remedy for various ailments including cancer by the ancient Arabian, Indian and Chinese cultures. Crocetin, an important carotenoid constituent of saffron, has shown significant potential as an anti-tumor agent in animal models and cell culture systems. Crocetin affects the growth of cancer cells by inhibiting nucleic acid synthesis, enhancing anti-oxidative system, inducing apoptosis and hindering growth factor signaling pathways. This review discusses the studies on cancer preventive potential of crocetin and its future use as an anticancer agent. PMID:21466430

  14. Therapy and prevention of parasitic insects in veterinary medicine using imidacloprid.

    PubMed

    Mencke, Norbert; Jeschke, Peter

    2002-07-01

    Ectoparasitic insects play a major role in veterinary medicine. The flea, especially the cat flea (Ctenocephalides felis felis Bouch 1835) is the most important ectoparasite worldwide. The cat flea parasitizes not only on dogs and cats but also on other warm-blooded animals including humans. The veterinary importance of flea infestation are dermatological conditions due to allergic reactions to antigens in the flea saliva and the transmission of infectious agents like bacteria, viruses and helminths. Insecticides used in veterinary medicine today have to fulfil criteria of elimination of a existing flea infestation (therapy) and prevention (prophylaxis) of new infestation for weeks. Imidacloprid is a compound of the chemical class of CNI (chloronicotinyl insecticides syn. neonicotinoids) that fits these criteria. The high selectivity towards the site of action within insects together with the high safety margin on mammals allowed to develop imidacloprid as an insecticide for agricultural use and finally for the application as a veterinary medicine. The major features of imidacloprid chemistry, toxicology and the development and use as a veterinary medicinal remedy are described.

  15. Combined MMF and insulin therapy prevents renal injury in experimental diabetic rats.

    PubMed

    Wu, Xiaoyan; Zha, Dongqing; Xiang, Guangsheng; Zhang, Bo; Xiao, Shu-Yuan; Jia, Ruhan

    2006-12-01

    Conventional therapies for diabetic mellitus are not effective in preventing the progression from early diabetic nephropathy (DN) to end-stage renal disease. The role of inflammation in the pathogenesis of DN has been implicated both clinically and experimentally, which provides an alternative therapeutic target for DN. Anti-inflammatory impact of mycophenolate mofetil (MMF) alone and in combination with insulin had been observed in a rat model of experimental DN. In this study, the diabetic rats were subjected to different treatments. Compared to control, the expression levels of CD68, NGF, and NF-kappaB p65, as determined immunohistochemically, were elevated in diabetic rats. Treatment with combined MMF/insulin is associated with a significant reduction in renal tissue of NGF and NF-kappaB p65 expression, macrophage infiltration. It also partially improved the renal function and attenuated renal hypertrophy at early stage of DN. CD68 was found to positively correlate with urinary albumin excretion and NGF. The combined use of MMF/insulin seemed to offer more protections in rats with experimental diabetic renal injury, and the protective effects of MMF might be due to its anti-inflammatory actions through inhibition of NF-kappaB activation and reduction of T cells and macrophage infiltration and/or other kidney chemokine productions.

  16. Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review.

    PubMed

    Sangro, Bruno; Martínez-Urbistondo, Diego; Bester, Lourens; Bilbao, Jose I; Coldwell, Douglas M; Flamen, Patrick; Kennedy, Andrew; Ricke, Jens; Sharma, Ricky A

    2017-04-13

    Selective internal radiation therapy (SIRT or radioembolisation) by intraarterial injection of radioactive yttrium-90 ((90) Y)-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source so that its effects are limited to the site of delivery. However the off-target diversion of (90) Y microspheres to tissues other than the tumor may lead to complications. The most prominent ones include: radiation gastritis and gastrointestinal (GI) ulcers, cholecystitis, radiation pneumonitis, and radioembolisation-induced liver disease (REILD). Complications may occur despite careful pre-treatment planning and SIRT demands an expert multidisciplinary team (MDT) approach in order to provide comprehensive care for patients. This review provides recommendations to MDTs on the optimal medical processes in order to ensure the safe delivery of SIRT. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis and management of potential radiation injury to the liver and to other organs. This article is protected by copyright. All rights reserved.

  17. [Current role of progesterone therapy in the prevention of spontaneous abortion and in the treatment of threatened abortion].

    PubMed

    Marzetti, L; Boni, T; Fazzio, M; Giobbe, M

    2000-12-01

    Progesterone therapy is often used to prevent spontaneous abortion. In this paper the most significant studies on the benefits and risks of this treatment over the last 30 years are analyzed. None of these studies about the effects of progesterone as non-specific therapy in abortion risk and recurrent miscarriage, proved a reduced pregnancy wastage in treated patients compared with patients who received no treatment. The results concerning the use of progesterone in recurrent miscarriage for luteal phase inadequacy are more controversial, but they are still inadequate to encourage progesterone supplementation. To obtain a definitive conclusion about progesterone therapy real effectiveness, it is necessary to carry out randomized double-blind prospected trials. As regards the risks of using progesterone therapy during pregnancy, even if a possible teratologic role has certainly been reduced, it cannot be excluded completely yet. Moreover a high incidence of respiratory problems has been noticed in newborns from patients treated with progesterone, compared with control groups.

  18. Prevention

    MedlinePlus

    ... Ban For Clinicians Clinical Recognition Specimen Collection Treatment Smallpox Vaccine Guidance Infection Control: Hospital Infection Control: Home ... Mouth Infection) Poxvirus and Rabies Branch Travelers’ Health: Smallpox & Other Orthopoxvirus-Associated Infections Poxvirus Prevention Recommend on ...

  19. Lupus vulgaris responding to double antituberculous therapy.

    PubMed

    Heller, G L; Pavlidakey, G P; Hashimoto, K; Greenberg, M; Rosenberg, M

    1984-11-01

    A patient with a 3 by 4 cm ulcerated lesion on the nose and upper lip in whom previous antibiotics and antifungal treatments for a "mixed infection" were of no avail is presented. Her history revealed that she has had pulmonary and pharyngeal tuberculosis and subsequently scrofuloderma of cervical lymph nodes. She eventually responded well to isoniazid, rifampin, and pyridoxine therapy.

  20. 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

  1. Metabolism by rat hepatic microsomes of fluorinated ether anesthetics following isoniazid administration.

    PubMed

    Rice, S A; Sbordone, L; Mazze, R I

    1980-12-01

    The possibility that enflurane defluorination is increased following treatment with isoniazid was investigated in male Fischer 344 rats. The effects of various isoniazid dosage regimens on the hepatic microsomal defluorination rates of enflurane were compared with those of several other ether anesthetics, and the conditions for production of maximal enflurane defluorination rates were determined. Seven to ten days of treatment with 50 mg/kg/day isoniazid (Nydrazid) resulted in maximal rates of defluorination of methoxyflurane, enflurane, isoflurane, and sevoflurane with no overt sign of toxicity. Compared with saline treatment of control rats, isoniazid increased defluorination of enflurane 370 per cent, methoxyflurane 259 per cent, sevoflurane 283 per cent, and isoflurane 168 per cent. Previous studies have shown that while the enzyme inducer phenobarbital increased in vitro rates of methoxyflurane defluorination approximately 1000 per cent, the rate of enflurane defluorination remained unchanged or increased by 100 per cent at most. In this study, enhanced hepatic microsomal defluorination was not associated with an increase in cytochrome P-450 per mg protein. Anesthetic defluorination rates were not altered by treatment with chlorobutanol, the preservative contained in Nydrazid.

  2. The genotypic study of Mycobacterium tuberculosis complex resistant to isoniazid: Galicia, Spain (2008-2013).

    PubMed

    Pérez Del Molino, M L; Barbeito-Castiñeiras, G; Mejuto, B; Alonso, P; Fernández, A; González-Mediero, G

    2016-11-01

    Incorporation of rapid detection systems to identify mutations in M. tuberculosis complex that confer resistance to isoniazid and rifampicin has potentiated the knowledge of their distribution, given the geographical variability. We performed antibiograms of the 2,993 strains isolated in Galicia, Spain (2008-2013). In the strains resistant to isoniazid, a concentration of 0.4 mg/mL and MTBDRplus Genotype test (Hain Lifescience, Germany) were used. We found that 3.64 % of strains were resistant to isoniazid, while 0.43 % were resistant to isoniazid and rifampicin (multidrug resistant, MDR). The MTBDRplus test showed an overall sensitivity of 72.48 %, with 62.5 % sensitivity for non MDR isoniazid-resistant strains and 100 % sensitivity for MDR strains. The katG gene mutation was detected at codon 315 in 38.53 % of strains. The S315T mutation appeared in 61.54 % of MDR strains and 34.38 % of non-MDR strains. The 28.44 % had mutations in inhA, (93.55 % in C15T), and 38.46 % of MDR strains were mutated. In non-MDR strains, 37.50 % were wild-type, 35.42 % and 27.08 % had mutations in katG and inhA, respectively. The most frequent mutation in rpoβ was S531L (46.15 %). The 38.71 % and 41.9 % of strains with resistance to isoniazid and streptomycin had mutations in katG and inhA, respectively (2 strains with mutations in T8C and T8A). The distribution pattern of resistance among strains with high and low concentrations of isoniazid showed statistically significant differences in relation to the mutation in katG and wild-type. The sensitivity of the Genotype MTBDRplus test for non-MDR strains in our area was at the lower threshold described.

  3. Prevention strategies for blood‐borne viruses—in the Era of vaccines, direct acting antivirals and antiretroviral therapy

    PubMed Central

    Pfaender, Stephanie; von Hahn, Thomas; Steinmann, Joerg; Ciesek, Sandra

    2016-01-01

    Summary Blood‐borne viruses, such as hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and the facultative blood‐borne hepatitis E virus, are considered a major public health problem given that they are accountable for millions of deaths each year. Treatment options, including effective vaccine design, development of antiviral strategies and the implementation of antiretroviral therapy have improved substantially over the last couple of years and contribute to successful treatment and prevention of these infectious diseases. In this review, we summarise the current knowledge and concepts in prevention of transmission of these blood‐borne viruses. PMID:27185010

  4. 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

  5. First principles calculation on the structure and electronic properties of BNNTs functionalized with isoniazid drug molecule

    NASA Astrophysics Data System (ADS)

    Saikia, Nabanita; Pati, Swapan K.; Deka, Ramesh C.

    2012-09-01

    One-dimensional nanostructures such as nanowires and nanotubes are stimulating tremendous research interest due to their structural, electronic and magnetic properties. We perform first principles calculation using density functional theory on the structural, and electronics properties of BNNTs adsorbed with isoniazid (INH) drug via noncovalent functionalization using the GGA/PBE functional and DZP basis set implemented in SIESTA program. The band structure, density of states and projected density of states (PDOS) plots suggest that isoniazid prefers to get adsorbed at the hollow site in case of (5,5) BNNT, whereas in (10,0) BNNT it favours the bridge site. The adsorption energy of INH onto (5,5) BNNT is smaller than in (10,0) BNNT which proposes that (10,0) BNNT with a larger radius compared to (5,5) BNNT is more favourable for INH adsorption as the corresponding distortion energy will also be quite lower. Functionalization of (5,5) and (10,0) BNNTs with isoniazid displays the presence of new impurity states (dispersionless bands) within the HOMO-LUMO energy gap of pristine BNNT leading to an increase in reactivity of the INH/BNNT system and lowering of the energy gap of the BNNTs. The PDOS plots show the major contribution towards the dispersionless impurity states is from INH molecule itself rather than from BNNT near the Fermi energy region. To summarize, noncovalent functionalization of BNNTs with isoniazid drug modulates the electronic properties of the pristine BNNT by lowering its energy gap with respect to the Fermi level, as well as demonstrating the preferential site selectivity for adsorption of isoniazid onto the nanotube sidewalls of varying chirality.

  6. Non-Drug Therapy and Prevention of Diabetes Mellitus by Dalk (Massage)

    PubMed Central

    Bayat, Davood; Vakilinia, Seyed Reza; Asghari, Majid

    2016-01-01

    Background: According to WHO estimation, the number of diabetic patients would reach about 591.9 million people in 2035. The tendency towards other kinds of treatment is increasing because of the high therapeutic expenditures and current medical complications. Positive results of massage in recent articles and the prominent role of dalk in Iranian traditional medicine led us to the present study review. Methods: Studying Iranian traditional medicine textbooks, such as Canon of Ibn Sina, Kholasat Al Hekma of Aghili, Zakhireh-ye Khwarazm shahi of Jorjani, Alhavi of Razes and Kamel-al-sanaat of Ibn Abas were done on the topic of dalk discussion. Additionally, a search on “massage and diabetes mellitus” articles was done in motor search engines of PubMed, Google Scholars and the site of “Farhangestane Oloume Pezeshki”. The data were eventually compared and evaluated. Results: In Iranian traditional medicine, dalk means kneading or massage of the body. Depending on the quality and quantity of the performance, it was divided into different kinds. The mechanism of dalk is to increase the blood supply in organs and subsequently increasing organ’s warmness and metabolism that lead to increased residues expulsion. Therefore, it could be advised to healthcare system as a means of treatment. On the other hand, for different diseases such as asthma, arthritis, insomnia, paralysis, DM, and constipation the effect of massage was evaluated and its positive results were confirmed. For example, in DM, its effects in decreasing FBS and HBA1C are shown. Conclusion: According to Iranian traditional medicine and latest articles, dalk as a non-drug therapy and prevention manner is recommended. PMID:27840511

  7. Non-Drug Therapy and Prevention of Diabetes Mellitus by Dalk (Massage)

    PubMed Central

    Bayat, Davood; Vakilinia, Seyed Reza; Asghari, Majid

    2016-01-01

    Background: According to WHO estimation, the number of diabetic patients would reach about 591.9 million people in 2035. The tendency towards other kinds of treatment is increasing because of the high therapeutic expenditures and current medical complications. Positive results of massage in recent articles and the prominent role of dalk in Iranian traditional medicine led us to the present study review. Methods: Studying Iranian traditional medicine textbooks, such as Canon of Ibn Sina, Kholasat Al Hekma of Aghili, Zakhireh-ye Khwarazm shahi of Jorjani, Alhavi of Razes and Kamel-al-sanaat of Ibn Abas were done on the topic of dalk discussion. Additionally, a search on “massage and diabetes mellitus” articles was done in motor search engines of PubMed, Google Scholars and the site of “Farhangestane Oloume Pezeshki”. The data were eventually compared and evaluated. Results: In Iranian traditional medicine, dalk means kneading or massage of the body. Depending on the quality and quantity of the performance, it was divided into different kinds. The mechanism of dalk is to increase the blood supply in organs and subsequently increasing organ’s warmness and metabolism that lead to increased residues expulsion. Therefore, it could be advised to healthcare system as a means of treatment. On the other hand, for different diseases such as asthma, arthritis, insomnia, paralysis, DM, and constipation the effect of massage was evaluated and its positive results were confirmed. For example, in DM, its effects in decreasing FBS and HBA1C are shown. Conclusion: According to Iranian traditional medicine and latest articles, dalk as a non-drug therapy and prevention manner is recommended. PMID:27516677

  8. Mindfulness-Based Cognitive Therapy for Preventing Relapse in Recurrent Depression: A Randomized Dismantling Trial

    PubMed Central

    2013-01-01

    Objective: We compared mindfulness-based cognitive therapy (MBCT) with both cognitive psychological education (CPE) and treatment as usual (TAU) in preventing relapse to major depressive disorder (MDD) in people currently in remission following at least 3 previous episodes. Method: A randomized controlled trial in which 274 participants were allocated in the ratio 2:2:1 to MBCT plus TAU, CPE plus TAU, and TAU alone, and data were analyzed for the 255 (93%; MBCT = 99, CPE = 103, TAU = 53) retained to follow-up. MBCT was delivered in accordance with its published manual, modified to address suicidal cognitions; CPE was modeled on MBCT, but without training in meditation. Both treatments were delivered through 8 weekly classes. Results: Allocated treatment had no significant effect on risk of relapse to MDD over 12 months follow-up, hazard ratio for MBCT vs. CPE = 0.88, 95% CI [0.58, 1.35]; for MBCT vs. TAU = 0.69, 95% CI [0.42, 1.12]. However, severity of childhood trauma affected relapse, hazard ratio for increase of 1 standard deviation = 1.26 (95% CI [1.05, 1.50]), and significantly interacted with allocated treatment. Among participants above median severity, the hazard ratio was 0.61, 95% CI [0.34, 1.09], for MBCT vs. CPE, and 0.43, 95% CI [0.22, 0.87], for MBCT vs. TAU. For those below median severity, there were no such differences between treatment groups. Conclusion: MBCT provided significant protection against relapse for participants with increased vulnerability due to history of childhood trauma, but showed no significant advantage in comparison to an active control treatment and usual care over the whole group of patients with recurrent depression. PMID:24294837

  9. Ultra-Early Combination Antiplatelet Therapy with Cilostazol for the Prevention of Branch Atheromatous Disease: A Multicenter Prospective Study

    PubMed Central

    Kimura, Teruo; Tucker, Adam; Sugimura, Toshihide; Seki, Toshitaka; Fukuda, Shin; Takeuchi, Satoru; Miyata, Shiro; Fujita, Tsutomu; Hashizume, Akira; Izumi, Naoto; Kawasaki, Kazutsune; Katsuno, Makoto; Hashimoto, Masaaki; Sako, Kazuhiro

    2016-01-01

    Background and Purpose The optimal use of antiplatelet therapy for intracranial branch atheromatous disease (BAD) is not known. Methods We conducted a prospective multicenter, single-group trial of 144 consecutive patients diagnosed with probable BAD. All patients were treated within 12 h of symptom onset to prevent clinical progression using dual antiplatelet therapy with cilostazol plus one oral antiplatelet drug (aspirin or clopidogrel). Endpoints of progressive BAD in the dual therapy group at 2 weeks were compared with a matched historical control group of 142 patients treated with single oral antiplatelet therapy using either cilostazol, aspirin, or clopidogrel. Results Progressive motor paresis occurred in 14 patients (9.7%) in the aggressive antiplatelet group, compared with 48 (33.8%) in the matched single antiplatelet group. Multivariate logistic regression analysis revealed the following variables to be associated with a better prognosis for BAD: baseline modified Rankin Scale score, dual oral antiplatelet therapy with cilostazol, and dyslipidemia (odds ratios of 0.616, 0.445, and 0.297, respectively). Hypertension was associated with a worse prognosis for BAD (odds ratio of 1.955). Conclusions Our trial showed that clinical progression of BAD was significantly reduced with the administration of ultra-early aggressive combination therapy using cilostazol compared to treatment with antiplatelet monotherapy. PMID:27728903

  10. Neutrophil to lymphocyte ratio predicts appropriate therapy in idiopathic dilated cardiomyopathy patients with primary prevention implantable cardioverter defibrillator

    PubMed Central

    Uçar, Fatih M.; Açar, Burak

    2017-01-01

    Objectives: To investigate whether an inflammatory marker of neutrophil to lymphocyte ratio (NLR) predicts appropriate implantable cardioverter defibrillator (ICD) therapy (shock or anti tachycardia pacing) in idiopathic dilated cardiomyopathy (IDC) patients. Methods: We retrospectively examined IDC patients (mean age: 58.3 ± 11.8 years, 81.5% male) with ICD who admitted to outpatient clinic for pacemaker control at 2 tertiary care hospitals in Ankara and Edirne, Turkey from January 2013-2015. All ICDs were implanted for primary prevention. Hematological and biochemical parameters were measured prior procedure. Results: Over a median follow-up period of 43 months (Range 7-125), 68 (33.1%) patients experienced appropriate ICD therapy. The NLR was increased in patients that received appropriate therapy (4.39 ± 2.94 versus 2.96 ± 1.97, p<0.001). To identify independent risk factors for appropriate therapy, a multivariate linear regression model was conducted and age (β=0.163, p=0.013), fasting glucose (β=0.158, p=0.017), C-reactive protein (CRP) (β=0.289, p<0.001) and NLR (β=0.212, p<0.008) were found to be independent risk factors for appropriate ICD therapy. Conclusions: Before ICD implantation by using NLR and CRP, arrhythmic episodes may be predictable and better antiarrhythmic medical therapy optimization may protect these IDC patients from unwanted events. PMID:28133686

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy

    PubMed Central

    Crittenden, Marka R.; Baird, Jason; Friedman, David; Savage, Talicia; Uhde, Lauren; Alice, Alejandro; Cottam, Benjamin; Young, Kristina; Newell, Pippa; Nguyen, Cynthia; Bambina, Shelly; Kramer, Gwen; Akporiaye, Emmanuel; Malecka, Anna; Jackson, Andrew; Gough, Michael J.

    2016-01-01

    Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFb inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy. PMID:27602953

  16. Induction or prevention of intimal hyperplasia by photodynamic therapy in a porcine model

    NASA Astrophysics Data System (ADS)

    Sobeh, Mohammed S.; Greenwald, Stephen E.; Ham, Robert J.; Phypers, Barrie J.; Cross, Frank W.; Hsiang, York N.

    1995-05-01

    Photodynamic therapy (PDT) has been proposed as a treatment for intimal hyperplasia (IH). We studied the effect of PDT on the development of IH following endothelial injury, using the photosensitizer Metatetrahydroxyphenyl-chlorin (m-THPC) and 652 nm illumination. 9 mini- pigs were used in 3 groups of 3. Pigs in the first group (balloon alone; BA) were anaesthetized and the lower 4 cm of abdominal aorta was denuded using a balloon catheter through the right femoral artery. In the second group (light alone; LA) the procedure was repeated, followed by illumination of the denuded area at an energy density of 20 Jcm-2 using a transparent PDT catheter. In the third group pigs were sensitized and an intravenous injection of 0.3 mg/kg of m-THPC 4 hours prior to balloon injury and illumination (PDT Group). Animals were allowed to recover for 8 weeks before being killed and perfusion fixed with 10% formal saline. 5 sections were cut from the treated segments and stained for elastin. Specimens were measured by a computerized morphometry system and the areas of the lumen (L), intima (I) and media (M) were measured. The degree of intimal hyperplasia was expressed as (a) I/M; (b) I/(I+M) and (c) I/(I+L) to take account of changes that could have occurred to the media and the overall diameter of the vessel. We found that when compared to BA controls, the lumenal area was decreased by 46% in LA group and increased by 44% in PDT group. The changes in the medical areas were minimal. These results show that both light alone and PDT produced more intimal hyperplasia than balloon injury alone (P < 0.002 for both groups, Student's t test). When allowance is made for the large increase in lumenal area associated with PDT the degree of intimal hyperplasia I/(I+L) was significantly reduced in PDT treated vessels when compared to those treated with light and balloon alone in spite of the greater absolute area of the intima in the PDT group. We conclude that PDT under the above conditions

  17. HIV-1 Transmission during Early Antiretroviral Therapy: Evaluation of Two HIV-1 Transmission Events in the HPTN 052 Prevention Study

    PubMed Central

    Rodrigo, Allen G.; Hudelson, Sarah E.; Piwowar-Manning, Estelle; Wang, Lei; Eshleman, Susan H.; Cohen, Myron S.; Swanstrom, Ronald

    2013-01-01

    In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART). We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index) initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention. PMID:24086252

  18. 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

  19. A concurrent comparison of intermittent (twice-weekly) isoniazid plus streptomycin and daily isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis

    PubMed Central

    1964-01-01

    Previous reports from the Tuberculosis Chemotherapy Centre, Madras, have established that ambulatory treatment of pulmonary tuberculosis with the combination of isoniazid and PAS, administered daily, yields satisfactory results. However, in the usage of any unsupervised regimen, reliance must be placed on the co-operation of patients in self-administering their drugs. Irregularities in drug-taking, which are not uncommon, may lead to unfavourable therapeutic results; this might be avoided by supervised administration of the drugs. Daily supervision is clearly impracticable in developing countries but regimens in which the drug is administered intermittently—say, twice a week or less frequently—are, if effective, more likely to gain general application. This paper presents the results of a controlled study of a fully supervised intermittent regimen of isoniazid (12.5-16.1 mg/kg body-weight, orally) plus streptomycin (injected in a uniform dose of 1 g), given together twice weekly, compared with a standard, unsupervised, daily, oral regimen of isoniazid (3.7-6.3 mg/kg body-weight) plus sodium PAS (0.2-0.3 g/kg body-weight), given in two doses. The intermittent regimen was at least as effective as the standard oral regimen, and although the incidence of temporary giddiness in patients receiving this regimen was rather high, this did not appear to have any long-term importance nor did it appear unduly to affect the co-operation of the patients. These encouraging findings suggest a possible change in the orientation of drug-administration for tuberculosis in developing countries. PMID:14253243

  20. Transient Delivery of Adenosine as a Novel Therapy to Prevent Epileptogenesis

    DTIC Science & Technology

    2014-08-01

    Using silk-based brain implants engineered to release adenosine we demonstrated that reversal of epigenetic changes prevents epileptogenesis. We...biodegradable silk-based brain implants ) to prevent epileptogenesis long term. These findings constitute a novel scientific advance with direct clinical...implications. Specifically, using bioengineered silk- based brain implants we demonstrated that transient delivery of a defined focal dose of adenosine

  1. Advantages of isovolemic hemodilution-red cell exchange therapy to prevent recurrent stroke in sickle cell anemia patients.

    PubMed

    Sarode, Ravi; Matevosyan, Karén; Rogers, Zora R; Burner, James D; Rutherford, Cynthia

    2011-01-01

    Chronic simple hypertransfusion (every 3 to 4 weeks) effectively prevents secondary stroke in children with sickle cell anemia but leads to iron overload despite chelation therapy. Conventional red blood cell exchange (C-RBCx) has advantages over simple transfusion: no net iron gain and less frequent hospital visits. However, C-RBCx requires more red blood cell units, an apheresis instrument and skilled personnel; it is also more expensive. We developed a modified procedure where isovolemic hemodilution precedes RBCx (IHD-RBCx) to decrease RBC units required and to increase the interval between procedures. Twenty patients underwent IHD-RBCx over a period of 7 years. IHD-RBCx required 11% fewer RBC units and increased inter-procedure interval from 37 to 53 days compared to C-RBCx. The median number of annual procedures decreased from 9.8 to 7.0 per patient, resulting in estimated savings of more than $4.5 million over 10 years for 20 patients while providing improved care. Five patients have discontinued chelation therapy; three while on C-RBCx and two while on IHD-RBCx. No adverse events occurred related to the isovolemic hemodilution phase and no patients had recurrent stroke. IHD-RBCx is a safe, efficient, and cost effective therapy for secondary prevention of stroke in patients with sickle cell anemia.

  2. Efficacy of a Six-Month versus a 36-Month Regimen for Prevention of Tuberculosis in HIV-Infected Persons in India: A Randomized Clinical Trial

    PubMed Central

    Swaminathan, Soumya; Menon, Pradeep Aravindan; Gopalan, Narendran; Perumal, Venkatesan; Santhanakrishnan, Ramesh Kumar; Ramachandran, Ranjani; Chinnaiyan, Ponnuraja; Iliayas, Sheik; Chandrasekaran, Padmapriyadarsini; Navaneethapandian, Pooranaganga Devi; Elangovan, Thiruvalluvan; Pho, Mai Tuyet; Wares, Fraser; Paranji RamaIyengar, Narayanan

    2012-01-01

    Background The optimal duration of preventive therapy for tuberculosis (TB) among HIV-infected persons in TB-endemic countries is unknown. Methods An open-label randomized clinical trial was performed and analyzed for equivalence. Seven hundred and twelve HIV-infected, ART-naïve patients without active TB were randomized to receive either ethambutol 800 mg and isoniazid 300 mg daily for six-months (6EH) or isoniazid 300 mg daily for 36-months (36H). Drugs were dispensed fortnightly and adherence checked by home visits. Patients had chest radiograph, sputum smear and culture performed every six months, in addition to investigations if they developed symptoms. The primary endpoint was incident TB while secondary endpoints were all-cause mortality and adverse events. Survival analysis was performed on the modified intent to treat population (m-ITT) and rates compared. Findings Tuberculosis developed in 22 (6.4%) of 344 subjects in the 6EH arm and 13 (3.8%) of 339 subjects in the 36H arm with incidence rates of 2.4/100py (95%CI- 1.4–3.5) and 1.6/100py (95% CI-0.8–3.0) with an adjusted rate ratio (aIRR) of 1.6 (0.8–3.2). Among TST-positive subjects, the aIRR of 6EH was 1.7 (0.6–4.3) compared to 36H, p = 0.8. All-cause mortality and toxicity were similar in the two arms. Among 15 patients with confirmed TB, 4 isolates were resistant to isoniazid and 2 were multidrug-resistant. Interpretation Both regimens were similarly effective in preventing TB, when compared to historical incidence rates. However, there was a trend to lower TB incidence with 36H. There was no increase in isoniazid resistance compared to the expected rate in HIV-infected patients. The trial is registered at ClinicalTrials.gov, NCT00351702. PMID:23251327

  3. Electrochemical sensor for Isoniazid based on the glassy carbon electrode modified with reduced graphene oxide-Au nanomaterials.

    PubMed

    Guo, Zhuo; Wang, Ze-Yu; Wang, Hui-Hua; Huang, Guo-Qing; Li, Meng-Meng

    2015-12-01

    A sensitive electrochemical sensor has been fabricated to detect Isoniazid (INZ) using reduced graphene oxide (RGO) and Au nanocomposites (RGO-Au). RGO-Au nanocomposites were synthesized by a solution-based approach of chemical co-reduction of Au(III) and graphene oxide (GO), and were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy, and Fourier transform infrared (FT-IR). The Au nanoparticles separate the RGO sheets in the precipitate and prevent RGO sheets from aggregation upon π-π stacking interactions. RGO-Au nanocomposites were used to modify the glassy carbon electrode (GCE). The electrochemical properties of RGO-Au/GCE were investigated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), and the RGO-Au/GCE exhibited remarkably strong electrocatalytic activities towards INZ. Under the optimized conditions, there was linear relationships between the peak currents and the concentrations in the range of 1.0×10(-7)M to 1.0×10(-3)M for INZ, with the limit of detection (LOD) (based on S/N=3) of 1.0×10(-8)M for INZ.

  4. Twenty years and counting: epidemiology of an outbreak of isoniazid-resistant tuberculosis in England and Wales, 1995 to 2014

    PubMed Central

    Smith, Catherine M; Trienekens, Suzan C M; Anderson, Charlotte; Lalor, Maeve K; Brown, Tim; Story, Alistair; Fry, Hannah; Hayward, Andrew C; Maguire, Helen

    2017-01-01

    An outbreak of isoniazid-resistant tuberculosis first identified in London has now been ongoing for 20 years, making it the largest drug-resistant outbreak of tuberculosis documented to date worldwide. We identified culture-confirmed cases with indistinguishable molecular strain types and extracted demographic, clinical, microbiological and social risk factor data from surveillance systems. We summarised changes over time and used kernel-density estimation and k-function analysis to assess geographic clustering. From 1995 to 2014, 508 cases were reported, with a declining trend in recent years. Overall, 70% were male (n = 360), 60% born in the United Kingdom (n = 306), 39% white (n = 199), and 26% black Caribbean (n = 134). Median age increased from 25 years in the first 5 years to 42 in the last 5. Approximately two thirds of cases reported social risk factors: 45% drug use (n = 227), 37% prison link (n = 189), 25% homelessness (n = 125) and 13% alcohol dependence (n = 64). Treatment was completed at 12 months by 52% of cases (n = 206), and was significantly lower for those with social risk factors (p < 0.05), but increased over time for all patients (p < 0.05). The outbreak remained focused in north London throughout. Control of this outbreak requires continued efforts to prevent and treat further active cases through targeted screening and enhanced case management. PMID:28251890

  5. 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.

  6. The molecular basis of resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium tuberculosis

    PubMed Central

    Somoskovi, Akos; Parsons, Linda M; Salfinger, Max

    2001-01-01

    Multidrug-resistant (MDR) strains of Mycobacterium tuberculosis have emerged worldwide. In many countries and regions, these resistant strains constitute a serious threat to the efficacy of tuberculosis control programs. An important element in gaining control of this epidemic is developing an understanding of the molecular basis of resistance to the most important antituberculosis drugs: isoniazid, rifampin, and pyrazinamide. On the basis of this information, more exacting laboratory testing, and ultimately more appropriate and timely treatment regimens, can be developed. PMID:11686881

  7. 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.

  8. 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.

  9. To Compare the Effect of Vibration Therapy and Massage in Prevention of Delayed Onset Muscle Soreness (DOMS)

    PubMed Central

    Imtiyaz, Shagufta; Veqar, Zubia; Shareef, M.Y.

    2014-01-01

    Objectives: To compare the effects of vibration therapy and massage in prevention of DOMS. Methods: Pre-test and Post-test Control-Group Design was used, 45 healthy female non athletic Subjects were recruited and randomly distributed to the three groups (15 subject in each group). After the subject’s initial status was measured experimental groups received vibration therapy (50 Hz vibration for five minutes) or massage therapy (15 minutes) intervention and control group received no treatment, just prior to the eccentric exercise. Subjects were undergoing the following measurements to evaluate the changes in the muscle condition: muscle soreness (pain perception), Range of Motion (ROM), Maximum Isometric Force (MIF), Repetition maximum (RM), Lactate dehydrogenase (LDH) and Cretain Kinase (CK) level. All the parameters except LDH, CK and 1RM were measured before, immediately post intervention, immediately post exercise, 24 hours post exercise, 48 hours post exercise and 72 hours post exercise. LDH, CK and 1 RM were measured before and 48 hours post exercise. Result: Muscle soreness was reported to be significantly less for experimental (vibration and massage) group (p=0.000) as compared to control group at 24, 48, and 72 hours of post-exercise. Experimental and control group did not show any significant difference in MIF immediate (p=0.2898), 24 hours (p=0.4173), 48 hours (p=0.752) and 72 hours (p=0.5297) of post-exercise. Range of motion demonstrated significant recovery in experimental groups in 48 hours (p=0.0016) and 72 hours (p=0.0463). Massage therapy showed significant recovery in 1RM (p=0.000) compared to control group and vibration therapy shows significantly less LDH level (p=0.000) 48 hours of post exercise compare to control group. CK at 48 hours of post exercise in vibration group (p=0.000) and massage group showed (p=0.002) significant difference as compared to control group. Conclusion: Vibration therapy and massage are equally effective in

  10. Topological analysis of electron density and the electrostatic properties of isoniazid: an experimental and theoretical study.

    PubMed

    Rajalakshmi, Gnanasekaran; Hathwar, Venkatesha R; Kumaradhas, Poomani

    2014-04-01

    Isoniazid (isonicotinohydrazide) is an important first-line antitubercular drug that targets the InhA enzyme which synthesizes the critical component of the mycobacterial cell wall. An experimental charge-density analysis of isoniazid has been performed to understand its structural and electronic properties in the solid state. A high-resolution single-crystal X-ray intensity data has been collected at 90 K. An aspherical multipole refinement was carried out to explore the topological and electrostatic properties of the isoniazid molecule. The experimental results were compared with the theoretical charge-density calculations performed using CRYSTAL09 with the B3LYP/6-31G** method. A topological analysis of the electron density reveals that the Laplacian of electron density of the N-N bond is significantly less negative, which indicates that the charges at the b.c.p. (bond-critical point) of the bond are least accumulated, and so the bond is considered to be weak. As expected, a strong negative electrostatic potential region is present in the vicinity of the O1, N1 and N3 atoms, which are the reactive locations of the molecule. The C-H···N, C-H···O and N-H···N types of intermolecular hydrogen-bonding interactions stabilize the crystal structure. The topological analysis of the electron density on hydrogen bonding shows the strength of intermolecular interactions.

  11. 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

  12. Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 2: Prevention, Treatment, Guidelines, and Future Directions.

    PubMed

    Hamo, Carine E; Bloom, Michelle W; Cardinale, Daniela; Ky, Bonnie; Nohria, Anju; Baer, Lea; Skopicki, Hal; Lenihan, Daniel J; Gheorghiade, Mihai; Lyon, Alexander R; Butler, Javed

    2016-02-01

    Success with oncologic treatment has allowed cancer patients to experience longer cancer-free survival gains. Unfortunately, this success has been tempered by unintended and often devastating cardiac complications affecting overall patient outcomes. Cardiac toxicity, specifically the association of several cancer therapy agents with the development of left ventricular dysfunction and cardiomyopathy, is an issue of growing concern. Although the pathophysiologic mechanisms behind cardiac toxicity have been characterized, there is currently no evidence-based approach for monitoring and management of these patients. In the first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy-related cardiac dysfunction and heart failure. In this second part, we discuss the prevention and treatment aspects in these patients and conclude with highlighting the evidence gaps and future directions for research in this area.

  13. 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…

  14. Evaluating the Primary Prevention of Ischemic Stroke of Oral Antithrombotic Therapy in Head and Neck Cancer Patients with Radiation Therapy

    PubMed Central

    Hsu, Chin-Wei

    2016-01-01

    Although previous studies demonstrated the risk of ischemic stroke (IS) in patients with head and neck cancer (HNC), the impact of oral antithrombotic therapy (OAT) on this risk has not yet been assessed. We aimed to evaluate the effectiveness and safety of OAT in patients with HNC treated with RT. This retrospective cohort study was performed using the National Health Insurance Research Database of Taiwan. A total of 37,638 patients diagnosed with HNC included in the study were classified as users and nonusers of OAT. Primary outcome was IS or transient ischemic attack (TIA), and secondary outcomes were death and major bleeding. The Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). There was no significant difference in the risk of IS or TIA between patients on continuous OAT and nonusers (adjusted HR, 0.812; 95% CI, 0.199–3.309). The risk of major bleeding was not significantly different between the groups. From a national population database, we did not find an association between OAT and decreasing risk of ischemic stroke/TIA or increasing hazard of major bleeding. PMID:27990433

  15. [Hormone replacement therapy in the management of postmenopausal osteoporosis and prevention of fracture risk].

    PubMed

    Ribot, Claude; Trémollières, Florence

    2006-10-01

    The consequences to the bone of estrogen deficiency are early and irreversible. Effective prevention of postmenopausal osteoporosis at the individual level requires early screening of women at risk of fractures and their early treatment. Hormone treatment prevents bone loss and has been proven effective in preventing fractures, even in situations of low risk. The benefit/risk ratio of hormone treatment can be optimized by the choice of the 'right moment' and the 'right treatment'. HRT, administered early and for a limited period, must be integrated into a strategy of long-term osteoporosis prevention that includes using the (drug and nondrug) means most appropriate to the patient's age and clinical condition and choosing the 'right moment' and 'right treatment.'

  16. 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.

  17. [An epidemiological study on dental-periodontal pathology in a sample of the school-age population of the city of Naples. II. Prevention and periodontal therapy].

    PubMed

    Matarasso, S; Dante, G; Cecere, E; Vadalà, R; Epifania, E

    1991-04-01

    The need for periodontal prevention and therapy was quantified according to the prevention of pathologies within the framework of an epidemiological study carried out on a sample population aged between 6 and 18 years. Data were collected using the CPITN method (WHO).

  18. 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.

  19. Steroid therapy in clinically stable but serologically active systemic lupus erythematosus prevents severe disease flares.

    PubMed

    Cardiel, Mario H; Almagro, Raúl Menor

    2007-05-01

    Evaluation of: Tseng CE, Buyon JP, Kim M et al. The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 54, 3623-3632 (2006). Systemic lupus erythematosus is an autoimmune disease of unknown origin. Flares and remissions are commonly seen in clinical settings. These clinical flares can have several degrees of severity, some of which require intensive immunosuppressive treatment and/or hospitalization. Clinicians treating these patients have looked at different strategies for prevention, early detection and prompt treatment of a lupus flare. Clinical information and laboratory findings have been proposed to reach these goals and preventive steroid adjustment has even been used in some cases without convincing results. This paper presents results from a controlled, multicenter, double-blind clinical trial evaluating the effectiveness of short-term corticosteroid treatment for preventing severe flares in which elevations of C3a by 50% were accompanied by a 25% increase in the anti-double-stranded DNA titer in patients with inactive or stable/active systemic lupus erythematosus. Results suggest that this strategy can prevent severe lupus flares.

  20. 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)…

  1. Hyperbaric oxygen therapy for the prevention of arterial gas embolism in food grade hydrogen peroxide ingestion.

    PubMed

    Hendriksen, Stephen M; Menth, Nicholas L; Westgard, Bjorn C; Cole, Jon B; Walter, Joseph W; Masters, Thomas C; Logue, Christopher J

    2016-12-14

    Food grade hydrogen peroxide ingestion is a relatively rare presentation to the emergency department. There are no defined guidelines at this time regarding the treatment of such exposures, and providers may not be familiar with the potential complications associated with high concentration hydrogen peroxide ingestions. In this case series, we describe four patients who consumed 35% hydrogen peroxide, presented to the emergency department, and were treated with hyperbaric oxygen therapy. Two of the four patients were critically ill requiring intubation. All four patients had evidence on CT or ultrasound of venous gas emboli and intubated patients were treated as if they had an arterial gas embolism since an exam could not be followed. After hyperbaric oxygen therapy each patient was discharged from the hospital neurologically intact with no other associated organ injuries related to vascular gas emboli. Hyperbaric oxygen therapy is an effective treatment for patients with vascular gas emboli after high concentration hydrogen peroxide ingestion. It is the treatment of choice for any impending, suspected, or diagnosed arterial gas embolism. Further research is needed to determine which patients with portal venous gas emboli should be treated with hyperbaric oxygen therapy.

  2. Acupuncture and Traditional Herbal Medicine Therapy Prevent Deliriumin Patients with Cardiovascular Disease in Intensive Care Units.

    PubMed

    Matsumoto-Miyazaki, Jun; Ushikoshi, Hiroaki; Miyata, Shusaku; Miyazaki, Nagisa; Nawa, Takahide; Okada, Hideshi; Ojio, Shinsuke; Ogura, Shinji; Minatoguchi, Shinya

    2017-02-23

    The aim of this study was to determine the effect of combination therapy consisting of acupuncture and traditional herbal medicine (Kampo medicine) for reducing the incidence rate of delirium in patients with cardiovascular (CV) disease in ICUs. Twenty-nine patients who had been urgently admitted to the ICU in the control period were treated with conventional intensive care. Thirty patients in the treatment period received conventional therapy plus a combination therapy consisting of acupuncture and herbal medicine. Acupuncture treatment was performed once a day, and the herbal formula was administered orally three times a day during the first week of the ICU stay. The standard acupuncture points were GV20, Ex-HN3, HT7, LI4, Liv3, and KI3, and the main herbal preparation was Kamikihito. The incident rates of delirium, assessed using the confusion assessment method for ICU, in the treatment and control period were compared. The incidence rate of delirium was significantly lower in the treatment group than in the control group (6.6% vs. 37.9%, [Formula: see text]). Moreover, sedative drugs and non-pharmacological approaches against aggressive behavior of patients who were delirious were used less in the treatment group than in the control group. No serious adverse events were observed in the treatment group. Combination therapy consisting of acupuncture and herbal medicine was found to be effective in lowering the incidence of delirium in patients with CV disease in ICUs. Further studies with a large sample size and parallel randomized controlled design would be required to establish the effects of this therapy.

  3. A prospective, randomized, double-blind study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the continuation phase of tuberculosis treatment.

    PubMed

    Bock, Naomi N; Sterling, Timothy R; Hamilton, Carol D; Pachucki, Connie; Wang, Yong-Cheng; Conwell, Donna S; Mosher, Ann; Samuels, Mary; Vernon, Andrew

    2002-06-01

    Once-weekly rifapentine 600 mg plus isoniazid (INH) during the continuation phase treatment of tuberculosis is associated with a relapse rate higher than that of twice-weekly rifampin plus INH. The safety and tolerability of higher rifapentine doses need to be determined. We conducted a prospective, randomized, double-blind trial of rifapentine at three doses (600, 900, and 1,200 mg) plus INH 15 mg/kg once weekly in the continuation phase treatment of culture-positive tuberculosis in 150 human immunodeficiency virus-seronegative adults. Outcome measures were discontinuation of therapy for any reason and adverse events on therapy. Treatment was discontinued in 3 of 52 (6%), 2 of 51 (4%), and 3 of 47 (6%) in the rifapentine 600-, 900-, and 1,200-mg treatment arms, respectively. Only one discontinuation, in the rifapentine 1,200-mg arm, was due to an adverse event possibly associated with study therapy. There was a trend toward more adverse events, possibly associated with study therapy, in the highest-dose arms (p = 0.051). Rifapentine 900-mg, once-weekly dosing appears to be safe and well tolerated and is being evaluated in Phase III efficacy trials of treatment of latent tuberculosis. Further evaluation of the safety and tolerability of rifapentine 1,200 mg is warranted.

  4. 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.

  5. [Physiokinetic therapy in the prevention of cervical disk arthrosis in helicopter personnel].

    PubMed

    Lanciani, P; La Verde, R; Losani, F; Guicciardi, M

    1983-08-25

    Helicopter pilots subjected to "chronic microtraumatism" related to the constant vibration present in this type of aircraft are considered. The most suitable physiokinetic treatment in the prevention of cervical spondylodiscarthrosis is discussed. Spondylodiscarthrosis is the most common and debilitating problem affecting helicopter personnel.

  6. Early traditional Chinese medicine bundle therapy for the prevention of sepsis acute gastrointestinal injury in elderly patients with severe sepsis

    PubMed Central

    Wang, Yifei; Zhang, Yunhua; Jiang, Ronglin

    2017-01-01

    This study aimed to study the effect of early traditional Chinese medicine bundle therapy on the prevention of sepsis-associated acute gastrointestinal injury (AGI). This was a multicenter, prospective, observational, non-randomized cohort study of 296 consecutive patients with severe sepsis during 2013/3 and 2014/11; 150 patients received standard treatments (controls) and 146 received traditional Chinese medicine bundle therapy (intervention group) (herbal decoction gavage based on syndrome differentiation, Chinese acupuncture, application of mirabilite, and defecation mixture). D-lactic acid, diamine oxidase, endotoxin, gastrin, motilin, and intra-abdominal pressure were measured. AGI was categorized into four levels. Compared with controls, D-lactic acid, diamine oxidase, endotoxin, gastrin, and intra-abdominal pressure in the intervention group were decreased, and motilin was increased on day 7. AGI incidence in the intervention group was lower than in controls. GIF scores of the intervention AGI II and III groups were lower than in controls. The APACHE II scores of the intervention AGI II, III, and IV groups were lower than in controls. Compared with controls, mechanical ventilation time and ICU stay in the intervention group were shorter, and 28-day overall and AGI-attributed mortality were lower. For elderly patients with severe sepsis, early traditional Chinese medicine bundle therapy could decrease AGI incidence and improve prognosis. PMID:28382954

  7. Gene therapy for haemophilia: prospects and challenges to prevent or reverse inhibitor formation.

    PubMed

    Scott, David W; Lozier, Jay N

    2012-02-01

    Monogenic hereditary diseases, such as haemophilia A and B, are ideal targets for gene therapeutic approaches. While these diseases can be treated with protein therapeutics, such as factor VIII (FVIII) or IX (FIX), the notion that permanent transfer of the genes encoding these factors can cure haemophilia is very attractive. An underlying problem with a gene therapy approach, however, is the patient's immune response to the therapeutic protein (as well as to the transmission vector), leading to the formation of inhibitory antibodies. Even more daunting is reversing an existing immune response in patients with pre-existing inhibitors. In this review, we will describe the laboratory and clinical progress, and the challenges met thus far, in achieving the goal of gene therapy efficacy, with a focus on the goal of tolerance induction.

  8. Adjuvant pamidronate therapy prevents the development of bone metastases in breast cancer patients with four or more positive nodes.

    PubMed

    Kokufu, Ikuo; Kohno, Norio; Yamamoto, Masayuki; Takao, Shintaro

    2010-03-01

    Bisphosphonates are strongly efficacious in inhibiting osteoclast bone resorption and have beneficial effects on bone metastasis. Due to their mechanism of action, bisphosphonates are expected to prevent the development of bone metastases in breast cancer patients. Pamidronate is a potent inhibitor of osteoclast activity. We examined whether pamidronate was able to prevent the development of bone metastases in breast cancer patients at high risk for bone metastasis. Between 1997 and 2001, 90 patients with primary breast cancer with ≥4 positive nodes were assigned to receive 45 mg pamidronate 4 times every 2 weeks (33 patients) or standard follow-up (57 patients) based on patient self-preference. Patients underwent surgery and adjuvant therapy. The characteristics of the patients in the two groups were well-balanced. The median follow-up period was 5 years. Bone metastases were detected in 12.1% of patients in the pamidronate group and 40.4% in the control group (p=0.005). Distant metastases (36.4 vs. 56.1%, p=0.071) and non-osseous metastases (33.3 vs. 52.6%, p=0.077) were detected at a lower frequency in the pamidronate group. Thus, the rate of bone metastasis-free survival was significantly higher in the pamidronate group (85.9 vs. 64.0% at 5 years, p=0.023). Overall and disease-free survival rates did not differ between the two groups. In the pamidronate group, the incidence of bone metastases was significantly reduced and bone metastasis-free survival was significantly higher. Adjuvant pamidronate therapy therefore prevents the development of bone metastases in breast cancer patients with ≥4 positive nodes.

  9. 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. |

  10. Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD

    PubMed Central

    Jacob, Noam; Targan, Stephan R

    2016-01-01

    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

  11. 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.

  12. Any role for probiotics in the therapy or prevention of autoimmune diseases? Up-to-date review.

    PubMed

    Özdemir, Öner

    2013-08-06

    Probiotic use as capable preventive and therapeutic strategy in different diseases varying from allergic to autoimmune disease (AD) has been recently reported. Three interacting factors including an aberrant intestinal microbiota, a "leaky" intestinal mucosal barrier, and altered intestinal immune responsiveness have been suggested to be able to create a "perfect environment" for AD development. Regulation of intestinal microflora composition by probiotics offers the possibility to influence the development of mucosal/systemic immunity besides ADs. Moreover, with various strains of probiotics, development and/or stimulation of T helper type 2 (Th2)-mediated immune responses causing exacerbation of atopic disease have been described. Similarly, certain probiotics are known to stimulate Th1 immunity, which has been suggested as one of the mechanisms by which they can suppress Th2-mediated allergic diseases. Consequently, this presumed that excessive immunostimulation might aggravate or induce Th1-mediated immune responses and diseases such as type 1 diabetes, multiple sclerosis, and it might cause an additional safety issue. Although there is a large amount of conflicting data on the preventive/therapeutic effects of probiotics in ADs, there is fairly promising evidence to recommend as well. Thus, probiotic use cannot be generally recommended for primary prevention and therapy of ADs for now.

  13. 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

  14. [Chemotherapy and NSAIDs in neoplastic disease. Role of anti-secretory preventive therapy].

    PubMed

    Annibale, Bruno; Panzuto, Francesco

    2003-11-01

    The patients treated by chemotherapy should be considered at high-risk for developing serious lesions of upper gastrointestinal tract. Several factors should be considered during the initial management of these patients, such as the presence and the staging of the malignancy, the cytotoxic effects of the antiblastic drugs, the co-administration of NSAIDs and corticosteroids, and the possible co-existence of Helicobacter pylori infection, hiatal hernia, and gastro-esophageal reflux. In order to prevent gastro-duodenal damage, the optimal approach first has to include an accurate clinical and pharmacological evaluation. The upper gastrointestinal endoscopy should also be performed in neoplastic patients undergoing chemotherapy before starting treatment. Proton pump inhibitors can play a major role in these patients to prevent gastro-duodenal damages, and to relieve dyspeptic symptoms.

  15. Recent advances in RNAi-based strategies for therapy and prevention of HIV-1/AIDS.

    PubMed

    Swamy, Manjunath N; Wu, Haoquan; Shankar, Premlata

    2016-08-01

    RNA interference (RNAi) provides a powerful tool to silence specific gene expression and has been widely used to suppress host factors such as CCR5 and/or viral genes involved in HIV-1 replication. Newer nuclease-based gene-editing technologies, such as zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, also provide powerful tools to ablate specific genes. Because of differences in co-receptor usage and the high mutability of the HIV-1 genome, a combination of host factors and viral genes needs to be suppressed for effective prevention and treatment of HIV-1 infection. Whereas the continued presence of small interfering/short hairpin RNA (si/shRNA) mediators is needed for RNAi to be effective, the continued expression of nucleases in the gene-editing systems is undesirable. Thus, RNAi provides the only practical way for expression of multiple silencers in infected and uninfected cells, which is needed for effective prevention/treatment of infection. There have been several advances in the RNAi field in terms of si/shRNA design, targeted delivery to HIV-1 susceptible cells, and testing for efficacy in preclinical humanized mouse models. Here, we comprehensively review the latest advances in RNAi technology towards prevention and treatment of HIV-1.

  16. Migraines with and without aura and their response to preventive therapy with topiramate.

    PubMed

    Reuter, U; Del Rio, M S; Diener, H-C; Allais, G; Davies, B; Gendolla, A; Pfeil, J; Schwalen, S; Schäuble, B; van Oene, J

    2010-05-01

    Data from the Prolonged Migraine Prevention (PROMPT) with Topiramate trial were evaluated post hoc to determine whether topiramate could prevent migraine auras, and whether its efficacy in preventing migraine headaches was similar in patients with (MA; n = 269) and without (MoA; n = 542) aura. Migraines and auras were recorded during prospective baseline, 6-month open-label (OL) topiramate and 6-month double-blind (DB), placebo-controlled phases. In the last 28 OL days, migraines without aura and migraine auras decreased by 43.1% and 54.1%, respectively, in MA patients. MoA patients experienced a 44.3% reduction in migraines. In the DB phase, increases in migraines with placebo vs. topiramate were similar to the full study, but were generally not statistically significant, probably due to lack of power in the subgroup analysis. Similarly, there were no statistically significant changes in number of auras between groups. Thus, topiramate appears to reduce migraine auras in parallel with headache reductions, which are similar in patients with and without aura.

  17. In vivo efficiency of targeted norfloxacin against persistent, isoniazid-insensitive, Mycobacterium bovis BCG present in the physiologically hypoxic mouse liver.

    PubMed

    Balazuc, A M; Lagranderie, M; Chavarot, P; Pescher, P; Roseeuw, E; Schacht, E; Domurado, D; Marchal, G

    2005-06-01

    Persistence of Mycobacterium tuberculosis is a hypoxia-inducible state in which the bacteria are phenotypically insensitive to currently available antituberculous drugs. In humans, persistent M. tuberculosis is found in granulomatous lesions, either inside macrophages or in necrotic tissue, where the partial oxygen pressure (pO(2)) is very low. Persistent bacteria can remain silent for decades before overt tuberculosis develops. Due to insensitivity to classical drugs, M. tuberculosis persistence prevents rapid and definitive clearance of bacteria. Consequently, therapeutic molecules are required that are both active against persistent bacilli and able to reach their intramacrophagic location. In contrast to its native form, norfloxacin is active in vivo against Mycobacterium bovis BCG present in the lungs when temporarily linked to a macromolecular carrier targeted to macrophages. To study the efficiency of this macromolecular prodrug targeted to persistent mycobacteria confined inside macrophages, we established a short-term in vivo model based on the physiological pO(2) differences between lungs, spleen and liver. Whereas lungs and spleen are well oxygenated, the liver has a low pO(2) due to its portal irrigation. Therefore, studying mycobacteria in the liver yields information about in vivo persistent bacilli exposed to low pO(2). To our knowledge, no similar short-term in vivo model has been published to date. Using this model, we demonstrated the insensitivity to isoniazid of M. bovis BCG present in hypoxic sites, and showed that norfloxacin given as a mannosylated macrophage-targeted prodrug was able to kill these isoniazid-insensitive mycobacteria. This demonstrates that intracellular persistent mycobacteria are amenable to antibiotic treatment.

  18. A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy

    PubMed Central

    Block, Keith I.; Gyllenhaal, Charlotte; Lowe, Leroy; Amedei, Amedeo; Amin, A.R.M. Ruhul; Amin, Amr; Aquilano, Katia; Arbiser, Jack; Arreola, Alexandra; Arzumanyan, Alla; Ashraf, S. Salman; Azmi, Asfar S.; Benencia, Fabian; Bhakta, Dipita; Bilsland, Alan; Bishayee, Anupam; Blain, Stacy W.; Block, Penny B.; Boosani, Chandra S.; Carey, Thomas E.; Carnero, Amancio; Carotenuto, Marianeve; Casey, Stephanie C.; Chakrabarti, Mrinmay; Chaturvedi, Rupesh; Chen, Georgia Zhuo; Chen, Helen; Chen, Sophie; Chen, Yi Charlie; Choi, Beom K.; Ciriolo, Maria Rosa; Coley, Helen M.; Collins, Andrew R.; Connell, Marisa; Crawford, Sarah; Curran, Colleen S.; Dabrosin, Charlotta; Damia, Giovanna; Dasgupta, Santanu; DeBerardinis, Ralph J.; Decker, William K.; Dhawan, Punita; Diehl, Anna Mae E.; Dong, Jin-Tang; Dou, Q. Ping; Drew, Janice E.; Elkord, Eyad; El-Rayes, Bassel; Feitelson, Mark A.; Felsher, Dean W.; Ferguson, Lynnette R; Fimognari, Carmela; Firestone, Gary L.; Frezza, Christian; Fujii, Hiromasa; Fuster, Mark M.; Generali, Daniele; Georgakilas, Alexandros G.; Gieseler, Frank; Gilbertson, Michael; Green, Michelle F.; Grue, Brendan; Guha, Gunjan; Halicka, Dorota; Helferich, William G.; Heneberg, Petr; Hentosh, Patricia; Hirschey, Matthew D.; Hofseth, Lorne J.; Holcombe, Randall F.; Honoki, Kanya; Hsu, Hsue-Yin; Huang, Gloria S.; Jensen, Lasse D.; Jiang, Wen G.; Jones, Lee W.; Karpowicz, Phillip A.; Keith, W Nicol; Kerkar, Sid P.; Khan, Gazala N.; Khatami, Mahin; Ko, Young H.; Kucuk, Omer; Kulathinal, Rob J.; Kumar, Nagi B.; Kumara, H.M.C. Shantha; Kwon, Byoung S.; Le, Anne; Lea, Michael A.; Lee, Ho-Young; Lichtor, Terry; Lin, Liang-Tzung; Locasale, Jason W.; Lokeshwar, Bal L.; Longo, Valter D.; Lyssiotis, Costas A.; MacKenzie, Karen L.; Malhotra, Meenakshi; Marino, Maria; Martinez-Chantar, Maria L.; Matheu, Ander; Maxwell, Christopher; McDonnell, Eoin; Meeker, Alan K.; Mehrmohamadi, Mahya; Mehta, Kapil; Michelotti, Gregory A.; Mohammad, Ramzi M.; Mohammed, Sulma I.; Morre, D. James; Muqbil, Irfana; Muralidhar, Vinayak; Murphy, Michael P.; Nagaraju, Ganji Purnachandra; Nahta, Rita; Niccolai, Elena; Nowsheen, Somaira; Panis, Carolina; Pantano, Francesco; Parslow, Virginia R.; Pawelec, Graham; Pedersen, Peter L.; Poore, Brad; Poudyal, Deepak; Prakash, Satya; Prince, Mark; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Rathmell, W. Kimryn; Ray, Swapan K.; Reichrath, Jörg; Rezazadeh, Sarallah; Ribatti, Domenico; Ricciardiello, Luigi; Robey, R. Brooks; Rodier, Francis; Rupasinghe, H.P. Vasantha; Russo, Gian Luigi; Ryan, Elizabeth P.; Samadi, Abbas K.; Sanchez-Garcia, Isidro; Sanders, Andrew J.; Santini, Daniele; Sarkar, Malancha; Sasada, Tetsuro; Saxena, Neeraj K.; Shackelford, Rodney E; Sharma, Dipali; Shin, Dong M.; Sidransky, David; Siegelin, Markus David; Signori, Emanuela; Singh, Neetu; Sivanand, Sharanya; Sliva, Daniel; Smythe, Carl; Spagnuolo, Carmela; Stafforini, Diana M.; Stagg, John; Subbarayan, Pochi R.; Sundin, Tabetha; Talib, Wamidh H.; Thompson, Sarah K.; Tran, Phuoc T.; Ungefroren, Hendrik; Vander Heiden, Matthew G.; Venkateswaran, Vasundara; Vinay, Dass S.; Vlachostergios, Panagiotis J.; Wang, Zongwei; Wellen, Kathryn E.; Whelan, Richard L.; Yang, Eddy S.; Yang, Huanjie; Yang, Xujuan; Yaswen, Paul; Yedjou, Clement; Yin, Xin; Zhu, Jiyue; Zollo, Massimo

    2016-01-01

    Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a

  19. Combination Therapy for Ulcerative Colitis: Orally Targeted Nanoparticles Prevent Mucosal Damage and Relieve Inflammation

    PubMed Central

    Xiao, Bo; Zhang, Zhan; Viennois, Emilie; Kang, Yuejun; Zhang, Mingzhen; Han, Moon Kwon; Chen, Jiucun; Merlin, Didier

    2016-01-01

    Combination therapy is an emerging strategy that is under intensive preclinical investigation for the treatment of various diseases. CD98 is highly overexpressed on the surfaces of epithelial cells and macrophages in the colon tissue with ulcerative colitis (UC), which is usually associated with mucosal damage and inflammation. We previously proved that CD98 siRNA (siCD98)-induced down-regulation of CD98 in colitis tissue decreased the severity of UC to a certain extent. In an effort to further improve the therapeutic efficacy, we aim to simultaneously deliver siCD98 in combination with a potent anti-inflammatory agent, curcumin (CUR), using hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant spherical HA-siCD98/CUR-NPs are featured by a desirable particle size (∼246 nm) and slightly negative zeta potential (∼-14 mV). The NPs functionalized with HA are able to guide the co-delivery of drugs to the targeted cells related to UC therapy (colonic epithelial cells and macrophages). Compared to either siCD98- or CUR-based monotherapy, co-delivery of siCD98 and CUR by HA-functionalized NPs can exert combinational effects against UC by protecting the mucosal layer and alleviating inflammation both in vitro and in vivo. This study shows the promising capability of the co-delivered siCD98 and CUR for boosting the conventional monotherapy via this novel nanotherapeutic agent, which offers a structurally simple platform for orally administered delivery of drugs to target cells in UC therapy. PMID:27924161

  20. [Relapse prevention program consisting of coping skills training, cue exposure treatment, and letter therapy for Japanese alcoholic men who relapsed after standard cognitive-behavioral therapy].

    PubMed

    Yokoyama, Akira; Matsushita, Sachio; Toyama, Tomomi; Nakayama, Hideki; Takimura, Tsuyoshi; Kimura, Mitsuru; Yoneda, Junichi; Maesato, Hitoshi; Mizukami, Takeshi; Higuchi, Susumu; Yokoyama, Tetsuji

    2015-04-01

    Coping skills training (CST) and cue exposure treatment (CET) have yielded favorable outcomes when used to treat alcoholics. We conducted 6-week inpatient programs that consisted of 9 CST group sessions (n = 117) during 2005-2009 and 9 CST group sessions plus 4 CET group sessions (n = 49) during 2009-2011 and subsequent 1-year letter therapy for Japanese alcoholic men who had relapsed and been readmitted after standard cognitive-behavioral inpatient therapy. When patients received a letter containing encouraging words every 2 weeks, they were asked to reread their CST and CET records and to respond to the letter by marking drinking days on a calendar and naming the skills on a list of the 9 CST themes and CET that were useful for maintaining abstinence during that 2-week period. The estimated percentages of achievement of 30 or fewer drinking days during the one year of letter therapy were 36.1 - 45.8%. 'Non-smoking', '2nd admission', and 'After age-limit job retirement' were significant factors in achieving good outcomes. The 'usefulness' responses for 'Increasing pleasant activities', 'CET', 'Anger management', ' Managing negative thinking', 'Problem solving', and ' Seemingly irrelevant decisions' as percentages of overall responses to the letters were significantly higher, in order of decreasing percentages, in the achiever group than in the non-achiever group, but the differences between the groups in ' Managing urges to drink', ' Drink refusal skills', ' Planning for emergencies', and ' Receiving criticism about drinking' were not significant. The odds ratios for achievement of 30 or fewer drinking days during the 1-year period increased significantly by 1.15 -1.31 fold per 10% increment in the 'usefulness' ratio for 'Increasing pleasant activities'. The difference in percentage achievement between the group treated by CST alone and the group treated by CST plus CET was not significant. In conclusion, some coping skills were more useful for relapse prevention

  1. [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.

  2. DIMETHPYRINDENE—Use in High Dosage Hyposensitization Therapy; Prevention of Constitutional and Excessive Local Reactions

    PubMed Central

    Hartman, Milton M.

    1962-01-01

    To give larger doses of antigen for hyposensitization, yet hold down constitutional reactions and excessive local reactions, the antigen was mixed with epinephrine, ephedrine and dimethpyrindene, the latter a new antihistamine, just before subcutaneous injection. Dimethpyrindene, a potent antihistamine with minimal side effects, was also administered orally. The incidence of constitutional reactions and excessive local reactions was considerably diminished. Larger doses of antigens were tolerated and longer intervals between treatments were possible, a point of particular significance in maintenance therapy. There was less pain and discomfort at the site of injection and clinical results were improved. PMID:13905021

  3. [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

  4. 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

  5. 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.

  6. 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.

  7. A medicated polycarboxylate cement to prevent complications in composite resin therapy

    SciTech Connect

    Okamoto, Y.; Shintani, H.; Yamaki, M. )

    1990-01-01

    Preparative treatment is the preferred method to protect the dentin and pulp from complications in composite resin therapy. This study investigated the in vivo effects of the polycarboxylate cement containing zinc fluoride and tannic acid in composite resin restorations. Scanning electron micrographs established that the composite resin failed to contact the axial wall. The gaps varied from 10 to 60 microns. However, this polycarboxylate cement was shown to provide excellent adaptation to dentin when used as a base and its chemical adhesion allowed it to make close contact with the unetched dentin. The newly developed electron probe x-ray microanalyzer revealed that the in vivo penetration of fluoride and zinc occurred through the dentinal tubules. When this polycarboxylate cement was used, the orifices of dentinal tubules were partially occluded, possibly with the smear layer fixed by tannic acid. In addition, by releasing the components, this polycarboxylate cement adds acid resistance to dentin and increases the resistance of dentin collagen to proteolytic enzymes. As such this polycarboxylate cement offers advantages as a base to composite resin therapy.

  8. 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

  9. Experiences of a long-term randomized controlled prevention trial in a maiden environment: Estonian Postmenopausal Hormone Therapy trial

    PubMed Central

    Hovi, Sirpa-Liisa; Veerus, Piret; Rahu, Mati; Hemminki, Elina

    2008-01-01

    Background Preventive drugs require long-term trials to show their effectiveness or harms and often a lot of changes occur during post-marketing studies. The purpose of this article is to describe the research process in a long-term randomized controlled trial and discuss the impact and consequences of changes in the research environment. Methods The Estonian Postmenopausal Hormone Therapy trial (EPHT), originally planned to continue for five years, was planned in co-operation with the Women's International Study of Long-Duration Oestrogen after Menopause (WISDOM) in the UK. In addition to health outcomes, EPHT was specifically designed to study the impact of postmenopausal hormone therapy (HT) on health services utilization. Results After EPHT recruited in 1999–2001 the Women's Health Initiative (WHI) in the USA decided to stop the estrogen-progestin trial after a mean of 5.2 years in July 2002 because of increased risk of breast cancer and later in 2004 the estrogen-only trial because HT increased the risk of stroke, decreased the risk of hip fracture, and did not affect coronary heart disease incidence. WISDOM was halted in autumn 2002. These decisions had a major influence on EPHT. Conclusion Changes in Estonian society challenged EPHT to find a balance between the needs of achieving responses to the trial aims with a limited budget and simultaneously maintaining the safety of trial participants. Flexibility was the main key for success. Rapid changes are not limited only to transiting societies but are true also in developed countries and the risk must be included in planning all long-term trials. The role of ethical and data monitoring committees in situations with emerging new data from other studies needs specification. Longer funding for preventive trials and more flexibility in budgeting are mandatory. Who should prove the effectiveness of an (old) drug for a new preventive indication? In preventive drug trials companies may donate drugs but they take a

  10. 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

  11. Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy.

    PubMed

    Žiberna, Lovro; Šamec, Dunja; Mocan, Andrei; Nabavi, Seyed Fazel; Bishayee, Anupam; Farooqi, Ammad Ahmad; Sureda, Antoni; Nabavi, Seyed Mohammad

    2017-03-16

    Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5' adenosine monophosphate-activated protein kinase, extracellular signal-regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

  12. Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy

    PubMed Central

    Žiberna, Lovro; Šamec, Dunja; Mocan, Andrei; Nabavi, Seyed Fazel; Bishayee, Anupam; Farooqi, Ammad Ahmad; Sureda, Antoni; Nabavi, Seyed Mohammad

    2017-01-01

    Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5′ adenosine monophosphate-activated protein kinase, extracellular signal–regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical. PMID:28300756

  13. 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

  14. 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.

  15. Therapy and Prevention of Postoperative Urosepsis of Ureter Endoscopic Lithotripsy for Non-infection.

    PubMed

    Shen, Jun; Sun, Fa; Chen, Fang-Min; Wu, Zhi-Ping; Li, Sheng-Wen

    2016-03-20

    Objective To analyze the risk factors causing postoperative urosepsis in ureter endoscopic lithotripsy without infection preoperatively, in order to make a more effective and safer preventive and therapeutic strategy.Methods From January 2010 to January 2015, 5 ureteral calculus patients undergoing ureter endoscopic lithotripsy with holmium laser were retrospectively enrolled in this clinical study. These patients suffered urosepsis postoperatively confirmed by the clinical presentations and laboratory Results, while they had no infection in their blood and urine preoperatively. Without delay, 5 patients were treated by anti-inflammation and anti-shock.Results The vasopressor drug was stopped gradually after 12-36 hours. The body temperature was recovered to normal in 2 or 3 days, and the blood and urine test Results were not abnormal in 7 days. At last, 5 patients were all cured.Conclusions Stone and operation themselves are potential factors to cause urosepsis after ureter endoscopic lithotripsy. Especially for patients who had not presented infection preoperatively, careful preparation preoperatively, corrective manipulation, low pressure irrigation, drainage and controlling time during operation, and early diagnosis, appropriate treatment postoperatively are the key to cure and prevent urosepsis.

  16. New nutrition, proteomics, and how both can enhance studies in cancer prevention and therapy.

    PubMed

    Kim, Helen

    2005-11-01

    The increased application of MS technologies to nutrition and cancer prevention research has enabled unique insights into the health benefits of polyphenols. Polyphenols are phytochemicals that appear to have chemical properties that provide valuable health benefits when ingested. In particular, experiments have suggested that grape seed proanthocyanidins, oligomers of the catechin family of polyphenols, may have health benefits, possibly due to their capacity to be oxidized. Two-dimensional gel proteomics technology identified specific rat brain proteins that were differentially affected after ingestion of grape seed extract. Beneficial changes in the expression of these proteins were observed relative to changes seen in the brains of Alzheimer disease patients at autopsy and of transgenic mouse models of dementia. These findings were consistent with the hypothesis that grape seed polyphenols may have neuroprotective activity. Previous experiments showed that grape seed extract was significantly chemopreventive in a rat model of breast cancer, but this depended on the specific diet in which the grape seed was administered. Thus, phytochemicals such as polyphenols may have health benefits in mammalian tissues unrelated to classical nutritional deficiency models. This report illustrates how experimental approaches that combine proteomics technologies with a dietary intervention with specific phytochemicals in normal animals can enhance studies on cancer prevention and treatment.

  17. [Comparative efficacy and tolerability of paroxetine and amitriptiline in long-term therapy preventing depressive recurrences].

    PubMed

    Mosolov, S N; Kostiukova, E G; Gorodnichev, A V; Timofeev, I V

    2005-01-01

    An open comparative randomized study of paroxetine (selective inhibitor of serotonin re-uptake) and tricyclic antidepressant amitriptiline has been conducted. These drugs were used for the treatment of 43 patients with recurrent depression (RD) with frequent relapses (ICD-10 F33.0-F33.2) during 12 months. There were 2 groups matched for demographic and clinical data, one included 21 patients treated by paroxetine and the other 22 patients switched to amitriptiline. Basing on clinical records and scores on a number of scales, i.e. HAM-D, CGI, quality of life, high efficacy of the drugs was confirmed, being estimated as 90,5% responders in the paroxetine group and 69,2% in the amitriptiline one, with the marked advantage of the former medication. The better tolerability, possibility of single intake and absence of severe side-effects argue for preferable use of paroxetine during long-term therapy in RD patients with frequent relapses.

  18. Bilayered negative-pressure wound therapy preventing leg incision morbidity in coronary artery bypass graft patients

    PubMed Central

    Yu, Yongchao; Song, Zhigang; Xu, Zhiyun; Ye, Xiaofei; Xue, Chunyu; Li, Junhui; Bi, Hongda

    2017-01-01

    Abstract Backgrounds: The harvesting of great saphenous veins for coronary artery bypass graft (CABG) patients may result in significant complications, including lymphorrhagia, lymphoedema, incision infection, wound dehiscence, and skin flap necrosis. We investigated the function of a self-designed bilayered negative pressure wound therapy (b-NPWT) for reducing the above-mentioned complications using a clinical randomized controlled trial. Methods: A single-center, pilot randomized controlled trial was conducted. From December 2013 to March 2014, a total of 72 coronary heart disease patients (48 men and 24 women) received CABG therapy, with great saphenous veins were selected as grafts. Patients were equally randomized into a treatment and a control group. After the harvesting of the great saphenous veins and direct closure of the wound with sutures, b-NPWT was used for the thigh incision in the treatment group for 5 days (treatment thigh). Traditional surgical pads were applied to both the shank incisions of the treatment group patients (treatment shank) and the entire incisions of the control group (control thigh, control shank). Postoperative complications were recorded and statistically analyzed based on outcomes of thigh treatment, shank treatment, thigh control, and shank control groups. Results: The incidence rates of early complications, such as lymphorrhagia, lymphoedema, infection, wound dehiscence, and skin flap necrosis, of the vascular donor site in the thigh treatment group was significantly lower than those in the 3 other groups. Conclusions: The self-designed b-NPWT can effectively reduce postoperative complications, such as lymphedema, incision infection, wound dehiscence, and skin flap necrosis, in CABG patients who underwent great saphenous veins harvesting. Trial registration: ClinicalTrials.gov. The unique registration number is NCT02010996. PMID:28099357

  19. 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.

  20. 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

  1. Prevention and treatment of bone loss in patients with nonmetastatic breast or prostate cancer who receive hormonal ablation therapy.

    PubMed

    Limburg, Connie; Maxwell, Cathy; Mautner, Beatrice

    2014-04-01

    Hormone ablation therapy is a mainstay in the treatment of breast and prostate cancers. However, aromatase inhibitors (AIs) used in postmenopausal women with breast cancer and androgen-deprivation therapy (ADT) used in men with prostate cancer contribute to substantial bone loss, thereby increasing the risk of osteoporotic fractures. Evidence-based guidelines, therefore, urge oncology practices to screen these patients for bone loss and, if needed, provide treatment to maintain bone health. In addition to lifestyle modification and calcium or vitamin D supplementation, bone protection strategies include treatment with bisphosphonates and denosumab, a monoclonal antibody against RANK ligand. Identification of patients at greater risk for bone loss and fracture and proper interventions can reduce fracture rates. Oncology nurses can play an important role in screening these patients. The purpose of this article is to inform oncology nurses about the effects of cancer treatment on bone health, review current prevention and treatment options for cancer treatment-induced bone loss, and discuss recommendations for identifying high-risk individuals.

  2. 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.

  3. Concise Review: Next-Generation Cell Therapies to Prevent Infections in Neutropenic Patients

    PubMed Central

    Brunck, Marion E. G.

    2014-01-01

    High-dose chemotherapy is accompanied by an obligate period of neutropenia. Resulting bacterial and fungal infections are the leading cause of morbidity and mortality in neutropenic patients despite prophylactic antimicrobials and hematopoietic growth factor supplements. Replacing neutrophils in the patient through transfusion of donor cells is a logical solution to prevent fulminant infections. In the past, this strategy has been hampered by poor yield, inability to store collected cells, and possible donor morbidity caused by granulocyte colony-stimulating factor injections and apheresis. Today, neutrophil-like cells can be manufactured in the laboratory at the clinical scale from hematopoietic stem and progenitor cells enriched from umbilical cord blood. This article reviews the rationale for focusing research efforts toward ex vivo neutrophil production and explores clinical settings for future trials. PMID:24598780

  4. Pentecostalism and AIDS treatment in Mozambique: creating new approaches to HIV prevention through anti-retroviral therapy.

    PubMed

    Pfeiffer, James

    2011-01-01

    Pentecostal fervor has rapidly spread throughout central and southern Mozambique since the end of its protracted civil war in the early 1990s. In the peri-urban bairros and septic fringes of Mozambican cities African Independent Churches (AICs) with Pentecostal roots and mainstream Pentecostals can now claim over half the population as adherents. Over this same period another important phenomenon has coincided with this church expansion: the AIDS epidemic. Pentecostalism and HIV have travelled along similar vectors and been propelled by deepening inequality. Recognising this relationship has important implications for HIV/AIDS prevention and treatment strategies. The striking overlap between high HIV prevalence in peri-urban populations and high Pentecostal participation suggests that creative strategies, to include these movements in HIV/AIDS programming, may influence the long-term success of HIV care and the scale-up of anti-retroviral treatment (ART) across the region. The provision of ART has opened up new possibilities for engaging with local communities, especially Pentecostals and AICS, who are witnessing the immediate benefits of ARV therapy. Expanded treatment may be the key to successful prevention as advocates of a comprehensive approach to the epidemic have long argued.

  5. [Kinetic therapy for therapy and prevention of post-traumatic lung failure. Results of a prospective study of 111 polytrauma patients].

    PubMed

    Stiletto, R; Gotzen, L; Goubeaud, S

    2000-12-01

    The effects of kinetic therapy on the oxygenation in the injured lung of 111 polytrauma patients were analysed in an open prospective study. The patient collective comprised 82 men and 29 women. For the total group, the average age was 38.3 years (+/- 16.1). The initial ISS was 39.3 points (+/- 18.9), and the APACHE II evaluated 24 h after including the patient into the study was 13.1 (+/- 5.2). The data of 3 treatment groups were evaluated: 1, acute respiratory disease (ARDS, n = 42); 2, acute lung injury (ALI, n = 36); and 3, prophylaxis (n = 33, a group of prophylactically treated patients with a PaO2/FiO2 ratio > or = 300 and an ISS > or = 15). Positioning therapy was administered in group 3 in order to prevent atelectases, and respirator-induced lung injuries during a foreseeable, relatively long period in the intensive care unit in view of the severity of the trauma. The mean treatment time in the kinetic bed was 6.3 days (+/- 3.9), the time on respirator 18.5 days (+/- 15.4). The patients stayed in the ICU 22.4 days (+/- 15.4) and left the hospital after 35.1 days (+/- 27.7). For scoring the severity of respiratory failure, the lung injury score (LIS) according to Murray and the SOFA score lung (sepsis-related organ failure assessment) according to Vincent were evaluated. The LIS at time of recruitment into the study was 2.2 (+/- 1.0), the SOFA score lung 3.0 (+/- 0.9). In the ALI and ARDS groups a significant improvement in oxygenation was observed (p < 0.0001). No patient of the prophylaxis group developed an ALI or ARDS. The mortality rate in the total group of 10.8% was relatively low in comparison with other published data. Consistent kinetic therapy integrated in a standardised treatment regimen contributes towards improving the negative outcome to date of patients with severe respiratory failure after major trauma.

  6. Antioxidant treatment improves neonatal survival and prevents impaired cardiac function at adulthood following neonatal glucocorticoid therapy

    PubMed Central

    Niu, Youguo; Herrera, Emilio A; Evans, Rhys D; Giussani, Dino A

    2013-01-01

    Glucocorticoids are widely used to treat chronic lung disease in premature infants but their longer-term adverse effects on the cardiovascular system raise concerns. We reported that neonatal dexamethasone treatment in rats induced in the short term molecular indices of cardiac oxidative stress and cardiovascular tissue remodelling at weaning, and that neonatal combined antioxidant and dexamethasone treatment was protective at this time. In this study, we investigated whether such effects of neonatal dexamethasone have adverse consequences for NO bioavailability and cardiovascular function at adulthood, and whether neonatal combined antioxidant and dexamethasone treatment is protective in the adult. Newborn rat pups received daily i.p. injections of a human-relevant tapering dose of dexamethasone (D; n= 8; 0.5, 0.3, 0.1 μg g−1) or D with vitamins C and E (DCE; n= 8; 200 and 100 mg kg−1, respectively) on postnatal days 1–3 (P1–3); vitamins were continued from P4 to P6. Controls received equal volumes of vehicle from P1 to P6 (C; n= 8). A fourth group received vitamins alone (CCE; n= 8). At P100, plasma NO metabolites (NOx) was measured and isolated hearts were assessed under both Working and Langendorff preparations. Relative to controls, neonatal dexamethasone therapy increased mortality by 18% (P < 0.05). Surviving D pups at adulthood had lower plasma NOx concentrations (10.6 ± 0.8 vs. 28.0 ± 1.5 μm), an increased relative left ventricular (LV) mass (70 ± 2 vs. 63 ± 1%), enhanced LV end-diastolic pressure (14 ± 2 vs. 8 ± 1 mmHg) and these hearts failed to adapt output with increased preload (Δcardiac output: 2.9 ± 2.0 vs. 10.6 ± 1.2 ml min−1) or afterload (Δcardiac output: −5.3 ± 2.0 vs.1.4 ± 1.2 ml min−1); all P < 0.05. Combined neonatal dexamethasone with antioxidant vitamins improved postnatal survival, restored plasma NOx and protected against cardiac dysfunction at adulthood. In conclusion, neonatal dexamethasone therapy promotes

  7. SU-F-BRD-11: A Virtual Simulator Designed for Collision Prevention in Proton Therapy

    SciTech Connect

    Jung, H; Kum, O; Park, H; Choi, D; Han, Y

    2015-06-15

    Purpose: In proton therapy, collisions between patient and nozzle potentially occur in attaining minimal air gap due to the large nozzle structure. Thus, we developed software predicting the collisions of the nozzle and patient by simulating treatments. Methods: 3D modeling of a gantry inner-floor, nozzle and robotic-couch was done by using the SolidWorks based on the manufacturer’s machine data. To obtain patient body information, a 3D-scanner was utilized to scan a patient right before CT scanning. From 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 for 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 gantry, nozzle and couch, in real scale. Collision, if any, was examined both in static mode and dynamic mode. The static mode checks only at fixed positions of the machine’s components while dynamic mode examines while one component is in motion. Collision was notified if any voxel of two components, for example a nozzle and a patient or couch, overlapped when calculating volume locations. The event and collision point are visualized and colliding volumes are reported. Results: All components were successfully assembled and the motions could be accurately controlled. The 3D-shape of a phantom agreed with CT images within a deviation of 2 mm. Collision situations can be simulated within minutes and the results are displayed and reported. Conclusion: The developed software will be useful in improving patient safety and clinical efficiency for proton therapy. This work was supported by the National Research Foundation of Korea funded by Ministry of Science, ICT & Future Planning (2012M3A9B6055201, 2013M2A2A7043507), and Samsung Medical Center grant (GFO1130081)

  8. 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

  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. 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.

  11. 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

  12. 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.

  13. Bioactive compounds as an alternative for drug co-therapy: overcoming challenges in cardiovascular disease prevention.

    PubMed

    Scolaro, Bianca; Soo Jin Kim, Hellen; Castro, Inar Alves de

    2016-11-10

    Different pharmacological interventions have been applied with success to reduce the progression of atherosclerosis. However, many patients are not good responders or must interrupt treatment due to adverse effects. Bioactive compounds such as omega-3 fatty acids (n-3 FA), plant sterol esters (PSE) and phenolic compounds (PHC) are natural molecules with great potential to reduce the atherosclerosis burden by reducing inflammation, LDL cholesterol (LDL-C) and oxidative stress, respectively. Although their physiological effects on biomarkers are much lower than those expected by drugs used for the same purpose, bioactive compounds can easily be incorporated into the daily diet and present no adverse effects. However, little is known about the combination of n-3 FA, PSE, PHC and drugs in atherosclerosis progression. This review article summarizes potential effects of co-therapies involving n-3 FA, PSE and PHC combined with major hypolipidemic drugs on atherosclerosis biomarkers and clinical outcomes. Evidence of additive and/or complementary effects regarding drugs action reveals possible roles for bioactive compounds in disease management. Pharmaceutical companies, physicians and food scientists should be prepared to better understand this type of interaction and its consequences in terms of efficacy and life quality.

  14. 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.

  15. Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy.

    PubMed

    Rooney, Jachinta E; Gurpur, Praveen B; Burkin, Dean J

    2009-05-12

    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The alpha(7)beta(1)-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the alpha(7)-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate alpha(7)-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for alpha(7)-integrin expression. We show that laminin-111 (alpha(1), beta(1), gamma(1)), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased alpha(7)-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of alpha(7)-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.

  16. 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.

  17. 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

  18. Simultaneous chemometric determination of pyridoxine hydrochloride and isoniazid in tablets by multivariate regression methods.

    PubMed

    Dinç, Erdal; Ustündağ, Ozgür; Baleanu, Dumitru

    2010-08-01

    The sole use of pyridoxine hydrochloride during treatment of tuberculosis gives rise to pyridoxine deficiency. Therefore, a combination of pyridoxine hydrochloride and isoniazid is used in pharmaceutical dosage form in tuberculosis treatment to reduce this side effect. In this study, two chemometric methods, partial least squares (PLS) and principal component regression (PCR), were applied to the simultaneous determination of pyridoxine (PYR) and isoniazid (ISO) in their tablets. A concentration training set comprising binary mixtures of PYR and ISO consisting of 20 different combinations were randomly prepared in 0.1 M HCl. Both multivariate calibration models were constructed using the relationships between the concentration data set (concentration data matrix) and absorbance data matrix in the spectral region 200-330 nm. The accuracy and the precision of the proposed chemometric methods were validated by analyzing synthetic mixtures containing the investigated drugs. The recovery results obtained by applying PCR and PLS calibrations to the artificial mixtures were found between 100.0 and 100.7%. Satisfactory results obtained by applying the PLS and PCR methods to both artificial and commercial samples were obtained. The results obtained in this manuscript strongly encourage us to use them for the quality control and the routine analysis of the marketing tablets containing PYR and ISO drugs.

  19. 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.

  20. Cystoman® and calculi: a good alternative to standard therapies in preventing stone recurrence.

    PubMed

    Proietti, S; Giannantoni, A; Luciani, L G; Sortino, G; Graziotti, P; Giusti, G

    2014-08-01

    To assess the efficacy and tolerability of D-mannose-containing product (Cystoman(®)) in preventing recurrence in patients who underwent surgical treatment for infection related urinary stones. From January 2011 to February 2013 we have enrolled all consecutive patients affected by staghorn calculi and recurrent urinary tract infections (UTIs). All patients recommended for surgery were scheduled for percutaneous nephrolithotomy. The study agent was administered daily for 5 months after surgical procedure. At baseline and 5-month follow-up all patients underwent abdominal Computed Tomography (CT) scan and they also completed Medical Outcomes Study short-form, 36-item questionnaire (SF-36). They performed urine and urine culture monthly. The primary endpoints were the assessment of the efficacy with regard to infection-related urinary stone recurrence and the tolerability of Cystoman(®). The secondary endpoint was the evaluation of quality-of-life symptoms. During the study period, a total of 27 patients were included in the study. The data from 25 patients were analyzable. Seventeen patients (68%) did not report UTIs during follow-up. Eight patients (32%) remained infected and the average number of UTIs was 2.6 ± 1.6 in 5 months. At 5-month follow-up 17 (68%) patients were free from stones recurrence; in 8 (32%) cases CT scan revealed stone recurrence with an average stone diameter of 1.1 ± 0.4 cm. In nonrecurring patients, 2 (11.7%) reported an average of 1.5 ± 0.7 UTIs episodes; in recurring patients, 6 (75%) showed 3 ± 1.67 of UTIs episodes. Statistically significant differences were seen in the occurrence of UTIs episodes were detected between nonrecurring stone patients and recurring patients (p < 0.05). Moreover, statistically significant changes were detected in SF-36 scores from baseline to month 5 in the categories of physical functioning and energy/fatigue (p < 0.05). Cystoman(®) is effective in preventing infection-related urinary stones.

  1. 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 Central

    Enas, Enas A.; Kuruvila, Arun; Khanna, Pravien; Pitchumoni, C.S.; Mohan, Viswanathan

    2013-01-01

    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. PMID:24434254

  2. 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.

  3. 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

  4. 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.

  5. 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."

  6. Histomonosis in poultry: previous and current strategies for prevention and therapy.

    PubMed

    Liebhart, D; Ganas, P; Sulejmanovic, T; Hess, M

    2017-02-01

    Histomonosis is a parasitic disease of poultry with worldwide prevalence. The disease can cause morbidity and mortality in chicken and turkey flocks entailing severe economic losses. In the first half of the last century, there was a high demand to control histomonosis as the turkey industry was severely affected by the disease. Consequently, numerous chemical compounds were tested for their efficacy against Histomonas meleagridis with varying outcomes, that are summarized and specified in this review. At the same time, preliminary attempts to protect birds with cultured histomonads indicated the possibility of vaccination. Several years ago antihistomonal drugs were banned in countries with tight regulations on pharmaceuticals in order to comply with the demand of consumer protection. As a consequence, outbreaks of histomonosis in poultry flocks increased and the disease became endemic again. New approaches to prevent and treat histomonosis are, therefore, needed and recently performed studies focused on various areas to combat the disease, from alternative chemotherapeutic substances to plant-derived compounds until vaccination, altogether reviewed here. Considering existing regulations and the overall outcome of experimental studies, it can be concluded that vaccination is very promising, despite the fact that various challenges need to be addressed until the first ever developed vaccine based upon live flagellates in human or bird medicine can be marketed.

  7. 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

  8. F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy.

    PubMed

    Le Grand, Bruno; Letienne, Robert; Dupont-Passelaigue, Elisabeth; Lantoine-Adam, Frédérique; Longo, Frédéric; David-Dufilho, Monique; Michael, Georghia; Nishida, Kunihiro; Catheline, Daniel; Legrand, Philippe; Hatem, Stéphane; Nattel, Stanley

    2014-07-01

    Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989 ± 111 s in the vehicle group to 79 ± 59 s with F 16915, P < 0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P < 0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6 ± 7.4 %, n = 9 vs 17.6 ± 3.4 %, n = 9 in the vehicle group, P < 0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure.

  9. [Intravascular irradiation in the combined therapy and prevention of restenosis. Overview].

    PubMed

    Baumgart, D; Quast, U; Erbel, R

    1997-12-01

    Despite numerous efforts in catheter technology and procedural approaches the problem of restenosis in interventional cardiology persists. Although the implantation of coronary stents has significantly reduced restenosis rates based on the inhibition of elastic recoil, intimal proliferation as the second major mechanism for postinterventional restenosis could not effectively be suppressed. Intimal proliferation is the response to vessel injury following interventional procedure, e.g. balloon angioplasty. It results in the adhesion of mono- and lymphocytes which themselves trigger the colonisation of myofibroblasts. Intracoronary irradiation seeks to prevent this proliferative process as it destroys or irreversibly alters DNA structures of cells at the site of balloon injury. The antiproliferative effect depends on the irradiation dosis, the timing and the cell cycle phase. Mainly beta- and gamma-radiation is used for intracoronary irradiation. Beta-emitters are characterized by a sharp decline of dose rate within millimeters from the actual source. The exposure to surrounding tissue as well the catheter staff can be kept to a minimum. The high intensity of beta-emitters allow a short treatment period of minutes to gain an effective radiation dose to the target. In contrast, gamma-emitters have a low radial dose distribution resulting in high dosage even centimeters away from the source. These emitters require additional shielding in the catheter laboratory and lead to excessive whole body doses. To achieve a sufficient dose in the target tissue, irradiation times of more than 20 minutes are necessary which prolongs the interventional procedure substantially. At present, catheter based systems or radioactive implantable stents are available to deliver the required dose. Catheter based systems seem more flexible in a number of considerations. On the other hand they require a substantial amount of hardware. Beta-emitting stents are implanted via a conventional stent

  10. Potential of tocotrienols in the prevention and therapy of Alzheimer's disease.

    PubMed

    Xia, Weiming; Mo, Huanbiao

    2016-05-01

    Currently there is no cure for Alzheimer's disease (AD); clinical trials are underway to reduce amyloid generation and deposition, a neuropathological hallmark in brains of AD patients. While genetic factors and neuroinflammation contribute significantly to AD pathogenesis, whether increased cholesterol level is a causative factor or a result of AD is equivocal. Prenylation of proteins regulating neuronal functions requires mevalonate-derived farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The observation that the levels of FPP and GGPP, but not that of cholesterol, are elevated in AD patients is consistent with the finding that statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, reduce FPP and GGPP levels and amyloid β protein production in preclinical studies. Retrospective studies show inverse correlations between incidence of AD and the intake and serum levels of the HMG CoA reductase-suppressive tocotrienols; tocopherols show mixed results. Tocotrienols, but not tocopherols, block the processing and nuclear localization of sterol regulatory element binding protein-2, the transcriptional factor for HMG CoA reductase and FPP synthase, and enhance the degradation of HMG CoA reductase. Consequently, tocotrienols deplete the pool of FPP and GGPP and potentially blunt prenylation-dependent AD pathogenesis. The antiinflammatory activity of tocotrienols further contributes to their protection against AD. The mevalonate- and inflammation-suppressive activities of tocotrienols may represent those of an estimated 23,000 mevalonate-derived plant secondary metabolites called isoprenoids, many of which are neuroprotective. Tocotrienol-containing plant foods and tocotrienol derivatives and formulations with enhanced bioavailability may offer a novel approach in AD prevention and treatment.

  11. Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis.

    PubMed

    Forte, Trudy M; Sharma, Vineeta; Ryan, Robert O

    2016-03-01

    Apolipoprotein (apo) A-V is a novel member of the class of exchangeable apo's involved in triacylglycerol (TG) homeostasis. Whereas a portion of hepatic-derived apoA-V is secreted into plasma and functions to facilitate lipoprotein lipase-mediated TG hydrolysis, another portion is recovered intracellularly, in association with cytosolic lipid droplets. Loss of apoA-V function is positively correlated with elevated plasma TG and increased risk of cardiovascular disease. Single nucleotide polymorphisms (SNP) in the APOA5 locus can affect transcription efficiency or introduce deleterious amino acid substitutions. Likewise, rare mutations in APOA5 that compromise functionality are associated with increased plasma TG and premature myocardial infarction. Genetically engineered mouse models and human population studies suggest that, in certain instances, supplementation with wild type (WT) apoA-V may have therapeutic benefit. It is hypothesized that individuals that manifest elevated plasma TG owing to deleterious APOA5 SNPs or rare mutations would respond to WT apoA-V supplementation with improved plasma TG clearance. On the other hand, subjects with hypertriglyceridemia of independent origin (unrelated to apoA-V function) may not respond to apoA-V augmentation in this manner. Improvement in the ability to identify individuals predicted to benefit, advances in gene transfer technology and the strong connection between HTG and heart disease, point to apoA-V supplementation as a viable disease prevention / therapeutic strategy. Candidates would include individuals that manifest chronic TG elevation, have low plasma apoA-V due to an APOA5 mutation/polymorphism and not have deleterious mutations/polymorphisms in other genes known to influence plasma TG levels.

  12. 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

  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. 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

  15. Short-Course Therapy with Daily Rifapentine in a Murine Model of Latent Tuberculosis Infection

    PubMed Central

    Zhang, Tianyu; Zhang, Ming; Rosenthal, Ian M.; Grosset, Jacques H.; Nuermberger, Eric L.

    2009-01-01

    Rationale: Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin+pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less. Objectives: To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens. Methods: Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very low-dose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 104 CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin+isoniazid, rifampin+pyrazinamide) or test (rifapentine alone, rifapentine+isoniazid, rifapentine+pyrazinamide, rifapentine+isoniazid+pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment. Measurements and Main Results: M. tuberculosis CFU counts remained stable around 3.65 log10 in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin+isoniazid cured 0 and 53% of mice and rifampin+pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin+isoniazid and indistinguishable from rifampin+pyrazinamide. Conclusions: In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin+pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks. PMID:19729664

  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. Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm In Hdl Therapy (Vascular Disease Prevention, In Press.).

    PubMed

    White, C Roger; Datta, Geeta; Mochon, Paulina; Zhang, Zhenghao; Kelly, Ollie; Curcio, Christine; Parks, Dale; Palgunachari, Mayakonda; Handattu, Shaila; Gupta, Himanshu; Garber, David W; Anantharamaiah, G M

    2009-01-01

    Anti-atherogenic effects of high density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) are principally thought to be due to their ability to mediate reverse cholesterol transport. These agents also possess anti-oxidant properties that prevent the oxidative modification of low density lipoprotein (LDL) and anti-inflammatory properties that include inhibition of endothelial cell adhesion molecule expression. Results of the Framingham study revealed that a reduction in HDL levels is an independent risk factor for coronary artery disease (CAD). Accordingly, there has been considerable interest in developing new therapies that specifically elevate HDL cholesterol. However, recent evidence suggests that increasing circulating HDL cholesterol levels alone is not sufficient as a mode of HDL therapy. Rather, therapeutic approaches that increase the functional properties of HDL may be superior to simply raising the levels of HDL per se. Our laboratory has pioneered the development of synthetic, apolipoprotein mimetic peptides which are structurally and functionally similar to apoA-I but possess unique structural homology to the lipid-associating domains of apoA-I. The apoA-I mimetic peptide 4F inhibits atherogenic lesion formation in murine models of atherosclerosis. This effect is related to the ability of 4F to induce the formation of pre-β HDL particles that are enriched in apoA-I and paraoxonase. 4F also possesses anti-inflammatory and anti-oxidant properties that are independent of its effect on HDL quality per se. Recent studies suggest that 4F stimulates the expression of the antioxidant enzymes heme oxygenase and superoxide dismutase and inhibits superoxide anion formation in blood vessels of diabetic, hypercholesterolemic and sickle cell disease mice. The goal of this review is to discuss HDL-dependent and -independent mechanisms by which apoA-I mimetic peptides reduce vascular injury in experimental animal models.

  19. A standardized method of preventing and managing emergencies within the context of evidence-based therapy implementation.

    PubMed

    Urgelles, Jessica; Donohue, Brad; Wilks, Chelsey; Van Hasselt, Vincent B; Azrin, Nathan H

    2012-07-01

    Families served within child welfare settings evidence a wide range of emergencies or unexpected crises or circumstances that may lead to danger and make it difficult for them to focus on treatment planning. Mental health treatment providers are often unprepared to effectively manage emergencies during implementation of evidence-based prescribed therapy sessions. In this study, the authors empirically developed a standardized intervention to assist mental health providers in emergency prevention and management (EPM) with their clients. EPM includes assessment of emergent conditions and a self-control procedure that may be utilized by consumers to prevent or resolve emergencies. EPM responses of 26 mothers referred by Child Protective Services for 6 months of evidence-supported treatment were examined. Relevant to clinical utility, the results indicated that providers implemented EPM in a little more than half (56.9%) of their treatment sessions, and all emergencies assessed in EPM were endorsed by at least 8% of the sample throughout their treatment. EPM was implemented with fidelity according to service providers, and corroborated by blind raters. Participants were found to be compliant and satisfied with EPM. The average number of emergencies endorsed over the course of EPM administrations was negatively correlated with the frequency of EPM administrations, suggesting that EPM may have helped reduce emergencies. Pretreatment factors (e.g., household income, child abuse potential, family functioning, parental stress, child behavior problems, number of days child removed from home) and hard drug use (but not marijuana or alcohol) during treatment were associated with the number of emergencies reported by participants.

  20. 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

  1. 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

  2. Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice.

    PubMed

    Song, S; Goudy, K; Campbell-Thompson, M; Wasserfall, C; Scott-Jorgensen, M; Wang, J; Tang, Q; Crawford, J M; Ellis, T M; Atkinson, M A; Flotte, T R

    2004-01-01

    Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic beta cells. Although the exact immunologic processes underlying this disease are unclear, increasing evidence suggests that immunosuppressive, immunoregulatory and anti-inflammatory agents can interrupt the progression of the disease. Alpha 1 antitrypsin (AAT) is a multifunctional serine proteinase inhibitor (serpin) that also displays a wide range of anti-inflammatory properties. To test the ability of AAT to modulate the development of type I diabetes, we performed a series of investigations involving recombinant adeno-associated virus vector (rAAV)-mediated gene delivery of human alpha-1 antitrypsin (hAAT) to nonobese diabetic (NOD) mice. Recombinant AAV-expressing hAAT (rAAV2-CB-AT) was administered intramuscularly to 4-week-old female NOD mice (1 x 10(10) i.u./mouse). A single injection of this vector reduced the intensity of insulitis, the levels of insulin autoantibodies, and the frequency of overt type I diabetes (30% (3/10) at 32 weeks of age versus 70% (7/10) in controls). Transgene expression at the injection sites was confirmed by immunostaining. Interestingly, antibodies against hAAT were present in a majority of the vector-injected mice and circulating hAAT was undetectable when assessed 10 weeks postinjection. This study suggests a potential therapeutic role for AAT in preventing type I diabetes as well as the ability of AAV gene therapy-based approaches to ameliorate disease effectively.

  3. New Strategies for Prevention and Therapy of Cytomegalovirus Infection and Disease in Solid-Organ Transplant Recipients

    PubMed Central

    Sia, Irene G.; Patel, Robin

    2000-01-01

    In the past three decades since the inception of human organ transplantation, cytomegalovirus (CMV) has gained increasing clinical import because it is a common pathogen in the immunocompromised transplant recipient. Patients may suffer from severe manifestations of this infection along with the threat of potential fatality. Additionally, the dynamic evolution of immunosuppressive and antiviral agents has brought forth changes in the natural history of CMV infection and disease. Transplant physicians now face the daunting task of recognizing and managing the changing spectrum of CMV infection and its consequences in the organ recipient. For the microbiology laboratory, the emphasis has been geared toward the development of more sophisticated detection assays, including methods to detect emerging antiviral resistance. The discovery of novel antiviral chemotherapy is an important theme of clinical research. Investigations have also focused on preventative measures for CMV disease in the solid-organ transplant population. In all, while much has been achieved in the overall management of CMV infection, the current understanding of CMV pathogenesis and therapy still leaves much to be learned before success can be claimed. PMID:10627493

  4. NF-kappaB, a mediator for lung carcinogenesis and a target for lung cancer prevention and therapy

    PubMed Central

    Chen, Wenshu; Li, Zi; Bai, Lang; Lin, Yong

    2011-01-01

    Lung cancer ranks as the first malignant tumor killer worldwide. Despite the knowledge that carcinogens from tobacco smoke and the environment constitute the main causes of lung cancer, the mechanisms for lung carcinogenesis are still elusive. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to cancer development. As a major cell survival signal, nuclear factor-kappaB (NF-kappaB) is involved in multiple steps in carcinogenesis and in cancer cell’s resistance to chemo- and radiotherapy. Recent studies with animal models and cell culture systems have established the links between NF-kappaB and lung carcinogenesis, highlighting the significance of targeting the NF-kappaB signaling pathway for lung cancer treatment and chemoprevention. In this review, we summarize progresses in understanding the NF-kappaB pathway in lung cancer development as well as in modulating NF-kappaB for lung cancer prevention and therapy. PMID:21196225

  5. Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes.

    PubMed

    Bateman, D Nicholas; Page, Colin B

    2016-03-01

    Some toxins cause their effects by affecting physiological processes that are fundamental to cell function or cause systemic effects as a result of cellular interaction. This review focuses on four examples, coumarin anticoagulants, isoniazid, methotrexate and thyroxine from the context of management of overdose as seen in acute general hospitals. The current basic clinical pharmacology of the toxin, the clinical features in overdose and evidence base for specific antidotes are discussed. The treatment for this group is based on an understanding of the toxic mechanism, but studies to determine the optimum dose of antidote are still required in all these toxins except thyroxine, where treatment dose is based on symptoms resulting from the overdose.

  6. Molecular characterisation of isoniazid- and rifampicin-resistant Mycobacterium tuberculosis in Central Tunisia.

    PubMed

    Ben Kahla, I; Marzouk, M; Henry, M; Bedotto, M; Cohen-Bacrie, S; Ben Selma, W; Boukadida, J; Drancourt, M

    2011-12-01

    The aim of our study was to genotypically characterise isoniazid (INH) and rifampicin (RMP) resistant Mycobacterium tuberculosis isolates in Sousse, Central Tunisia, using DNA sequencing and multispacer sequence typing (MST). The results show that 27/28 (96.4%) and 1/28 (3.6%) INH-resistant isolates yielded respectively the kat G S315T and the inh A - 15C → T mutations. Two-thirds of RMP-resistant isolates yielded the rpo B D516V mutation and one sixth yielded either H526D or S531L mutations. Genotyping analysis revealed the multiclonal spread of drug-resistant isolates in Central Tunisia. Data presented here complete the previously published map of resistant M. tuberculosis isolates and highlight their regional disparity in Tunisia.

  7. Synthesis and characterization of a series of isoniazid hydrazones. Spectroscopic and theoretical study

    NASA Astrophysics Data System (ADS)

    Ferraresi-Curotto, Verónica; Echeverría, Gustavo A.; Piro, Oscar E.; Pis-Diez, Reinaldo; González-Baró, Ana C.

    2017-04-01

    A family of hydrazones of isoniazid and a group of hydroxybenzalaldehydes (vanillin, 5-bromovanillin, 5-chlorosalicylaldehyde and 5-bromosalicylaldehyde) were obtained and fully characterized. The results, including theoretical data, are comparatively analyzed along with the already reported hydrazone of o-vanillin. The crystal structures of three compounds were determined. The hydrazones obtained from halogenated aldehydes are isomorphic and chiral to each other. Structures are further stabilized by (pyr)NH+⋯Cl- and OwH⋯Cl- bonds. The vanillin hydrazone shows a conformer that differs from the previously reported. Neighboring molecules are linked to each other through OH⋯N(pyr) bonds, giving rise to a nearly planar polymeric structure. The conformational space was searched and geometries were optimized both in the gas phase and including solvent effects by DFT. Results are extended to describe the 5-bromovanillin hydrazone. FTIR, NMR and electronic spectra were measured and assigned with the help of computational calculations.

  8. Synthesis and in vitro antifungal activity of isoniazid-derived hydrazones against Coccidioides posadasii.

    PubMed

    Cordeiro, Rossana de Aguiar; de Melo, Charlline Vládia Silva; Marques, Francisca Jakelyne de Farias; Serpa, Rosana; Evangelista, Antônio José de Jesus; Caetano, Erica Pacheco; Mafezoli, Jair; de Oliveira, Maria da Conceição Ferreira; da Silva, Marcos Reinaldo; Bandeira, Tereza de Jesus Pinheiro Gomes; Moreira, José Luciano Bezerra; Brilhante, Raimunda Sâmia Nogueira; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa

    2016-09-01

    Coccidioidomycosis is a potentially severe infection caused by dimorphic fungi Coccidioides immitis and Coccidioides posadasii. Although guidelines are well established, refractory disease is a matter of concern in the clinical management of coccidioidomycosis. In the present study three isoniazid-derived hydrazones N'-[(E)-1-(4-methoxyphenyl)ethylidene]pyridine-4-carbohydrazide, N'-[(E)-1-(4-methylphenyl)ethylidene]pyridine-4-carbohydrazide, and N'-[(E)-1-(phenyl)ethylidene]pyridine-4-carbohydrazide were synthesized and evaluated for antifungal activity against C. posadasii. Susceptibility assays were performed by macrodilution testing. Interactions between the hydrazones and amphotericin B or itraconazole were evaluated by the checkerboard method. We also investigated the impairment of such compounds on cell ergosterol and membrane integrity. The synthesized molecules were able to inhibit C. posadasii in vitro with MIC values that ranged from 25 to 400 μg/mL. Drug interactions between synthesized molecules and amphotericin B proved synergistic for the majority of tested isolates; regarding itraconazole, synergism was observed only when strains were tested against N'-[(E)-1-(phenyl)ethylidene]pyridine-4-carbohydrazide. Reduction of cellular ergosterol was observed when strains were challenged with the hydrazones alone or combined with antifungals. Only N'-[(E)-1-(4-methylphenyl)ethylidene]pyridine-4-carbohydrazide altered membrane permeability of C. posadasii cells. Isoniazid-derived hydrazones were able to inhibit C. posadasii cells causing reduction of ergosterol content and alterations in the permeability of cell membrane. This study confirms the antifungal potential of hydrazones against pathogenic fungi.

  9. The IDEAL DVT study, individualised duration elastic compression therapy against long-term duration of therapy for the prevention of post-thrombotic syndrome: protocol of a randomised controlled trial

    PubMed Central

    ten Cate-Hoek, Arina J; Bouman, Annemieke C; Joore, Manuela A; Prins, Martin; ten Cate, Hugo

    2014-01-01

    Introduction Post-thrombotic syndrome (PTS) is a serious complication of deep vein thrombosis (DVT) of the leg that affects 20–50% of patients. Once a patient experiences PTS there is no treatment that effectively reduces the debilitating complaints. Two randomised controlled trials showed that elastic compression stocking (ECS) therapy after DVT for 24 months can reduce the incidence of PTS by 50%. However, it is unclear whether all patients benefit to the same extent from ECS therapy or what the optimal duration of therapy for individual patients should be. ECS therapy is costly, inconvenient, demanding and sometimes even debilitating. Tailoring therapy to individual needs could save substantial costs. The objective of the IDEAL DVT study, therefore, is to evaluate whether tailoring the duration of ECS therapy on signs and symptoms of the individual patient is a safe and effective method to prevent PTS, compared with standard ECS therapy. Methods and analysis A multicentre, single-blinded, allocation concealed, randomised, non-inferiority trial. A total of 864 consecutive patients with acute objectively documented proximal DVT of the leg are randomised to either standard duration of 24 months or tailored duration of ECS therapy following an initial therapeutic period of 6 months. Signs and symptoms of PTS are recorded at regular clinic visits. Furthermore, quality of life, costs, patient preferences and compliance are measured. The primary outcome is the proportion of patients with PTS at 24 months. Ethics and dissemination Based on current knowledge the standard application of ECS therapy is questioned. The IDEAL DVT study will address the central questions that remain unanswered: Which individual patients benefit from ECS therapy and what is the optimal individual treatment duration? Primary ethics approval was received from the Maastricht University Medical Centre. Results Results of the study will be disseminated via peer-reviewed publications and

  10. Polygenic Risk Score Identifies Subgroup with Higher Burden of Atherosclerosis and Greater Relative Benefit from Statin Therapy in the Primary Prevention Setting.

    PubMed

    Natarajan, Pradeep; Young, Robin; Stitziel, Nathan O; Padmanabhan, Sandosh; Baber, Usman; Mehran, Roxana; Sartori, Samantha; Fuster, Valentin; Reilly, Dermot F; Butterworth, Adam S; Rader, Daniel J; Ford, Ian; Sattar, Naveed; Kathiresan, Sekar

    2017-02-21

    Background -Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of two randomized controlled primary prevention trials (ASCOT and JUPITER), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we sought to confirm this observation in a third primary prevention randomized controlled trial. Additionally, we assessed if those at high genetic risk had a greater burden of subclinical coronary atherosclerosis. Methods -We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS, n=4,910) and two observational cohort studies (CARDIA and BioImage, n=1,154 and 4,392). For each participant, we calculated a polygenic risk score (PRS) derived from up to 57 common DNA sequence variants previously associated with coronary heart disease (CHD). We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of PRS) versus all others (WOSCOP)S as well as the association between the PRS and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage). Results -Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% CI, 22%-60%; P < 0.001) whereas in all others, relative risk reduction was 24% (95% CI 8%-37%; P = 0.004) despite similar LDL cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others (P for heterogeneity = 0.05). Across all three studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0%-5.1%) among those in the high genetic risk group and was 1.3% (95% CI, 0.6%-1.9%) in all others. Each standard deviation increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of

  11. 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

  12. 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

  13. 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

  14. 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. |

  15. 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

  16. 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.

  17. Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda

    PubMed Central

    Peltier, Cécile-Alexandra; Ndayisaba, Gilles-François; Lepage, Philippe; Van Griensven, Johan; Leroy, Valériane; Omes, Christine; Ndimubanzi, Patrick-C; Courteille, Olivier

    2009-01-01

    Objective To assess the nine-month HIV-free survival of children with two strategies to prevent HIV mother-to-child transmission. Design Non-randomized interventional cohort study. Setting Four public health centers in Rwanda. Participants Between May 2005 and January 2007, all consenting HIV-infected pregnant women were included. Intervention Women could choose the mode of feeding for their infant: breastfeeding (BF) with maternal highly active antiretroviral therapy (HAART) for six months or formula feeding (FF). All received HAART from 28 weeks of gestation. Nine-month cumulative probabilities of HIV transmission and HIV-free survival were determined using the Kaplan-Meier method, and compared using the log-rank test. Determinants were analyzed using a Cox model analysis. Results Of the 532 first-live born infants, 227 (43%) were BF and 305 (57%) were FF. Overall, seven (1.3%) children were HIV-infected of whom six were infected in utero. Only one child in the BF group became infected between month 3 and month 7, corresponding to a 9-month cumulative risk of postnatal infection of 0.5% (95% CI 0.1–3.4%; P=0.24) with BF. Nine-month cumulative mortality was 3.3% (95% CI 1.6–6.9%) in the BF arm group and 5.7% (95% CI 3.6–9.2%) for the FF group (P=0.20). HIV-free survival by nine months was 95% (95% CI 91–97%) in the BF group and 94% (95% CI 91–96%) for the FF group (P=0.66), with no significant difference in the adjusted analysis (adjusted hazard ratio for BF: 1.2 (95% CI 0.5–2.9%). Conclusions Maternal HAART while BF could be a promising alternative strategy in resource-limited countries. PMID:19730349

  18. 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

  19. 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

  20. Oral Gentamicin Gut Decontamination for Prevention of KPC-Producing Klebsiella pneumoniae Infections: Relevance of Concomitant Systemic Antibiotic Therapy

    PubMed Central

    Tascini, Carlo; Sbrana, Francesco; Flammini, Sarah; Tagliaferri, Enrico; Arena, Fabio; Leonildi, Alessandro; Ciullo, Ilaria; Amadori, Francesco; Di Paolo, Antonello; Ripoli, Andrea; Lewis, Russell; Rossolini, Gian Maria

    2014-01-01

    Gut colonization represents the main source for KPC-producing Klebsiella pneumoniae (KPC-Kp) epidemic dissemination. Oral gentamicin, 80 mg four times daily, was administered to 50 consecutive patients with gut colonization by gentamicin-susceptible KPC-Kp in cases of planned surgery, major medical intervention, or need for patient transfer. The overall decontamination rate was 68% (34/50). The median duration of gentamicin treatment was 9 days (interquartile range, 7 to 15 days) in decontaminated patients compared to 24 days (interquartile range, 20 to 30 days) in those with persistent colonization (P < 0.001). In the six-month period of follow-up, KPC-Kp infections were documented in 5/34 (15%) successfully decontaminated patients compared to 12/16 (73%) persistent carriers (P < 0.001). The decontamination rate was 96% (22/23) in patients receiving oral gentamicin only, compared to 44% (12/27) of those treated with oral gentamicin and concomitant systemic antibiotic therapy (CSAT) (P < 0.001). The multivariate analysis confirmed CSAT and KPC-Kp infection as the variables associated with gut decontamination. In the follow-up period, KPC-Kp infections were documented in 2/23 (9%) of patients treated with oral gentamicin only and in 15/27 (56%) of those also receiving CSAT (P = 0.003). No difference in overall death rate between different groups was documented. Gentamicin-resistant KPC-Kp strains were isolated from stools of 4/16 persistent carriers. Peak gentamicin blood levels were below 1 mg/liter in 12/14 tested patients. Oral gentamicin was shown to be potentially useful for gut decontamination and prevention of infection due to KPC-Kp, especially in patients not receiving CSAT. The risk of emergence of gentamicin-resistant KPC-Kp should be considered. PMID:24419337

  1. Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis.

    PubMed

    Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Fan, Bo; Kang, Lin; Gao, Zhonggao

    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.

  2. Zoledronic Acid for Prevention of Bone Loss in Patients Receiving Primary Therapy for Lymphomas: A Prospective, Randomized Controlled Phase III Trial

    PubMed Central

    Westin, Jason R.; Thompson, Michael A.; Cataldo, Vince D.; Fayad, Luis E.; Fowler, Nathan; Fanale, Michelle A.; Neelapu, Saatva; Samaniego, Felipe; Romaguera, Jorge; Shah, Jatin; McLaughlin, Peter; Pro, Barbara; Kwak, Larry W.; Sanjorjo, Perpetua; Murphy, William A.; Jimenez, Camillo; Toth, Bela; Dong, Wenli; Hagemeister, Fredrick B.

    2013-01-01

    In patients with newly diagnosed lymphoma, low bone mineral density (BMD) is common at diagnosis and worsens with therapy. Our randomized phase III trial demonstrates that 2 doses of zoledronic acid (ZA) and supplementation with calcium and vitamin D effectively prevent further bone loss. Background Patients with lymphoma are at risk of development of bone mineral density (BMD) loss from therapy with high-dose corticosteroids and alkylating agents. Zoledronic acid (ZA), a bisphosphonate, may prevent this complication of therapy. We evaluated the effect of ZA on the change in BMD and surrogate biomarkers in patients with lymphoma receiving initial chemotherapy. Patients and Methods Our phase III trial randomized 74 patients with newly diagnosed lymphoma and a baseline BMD of ≥ −2.0 to receive oral calcium and vitamin D daily with or without ZA at enrollment and at 6 months after enrollment. BMD was evaluated at baseline and 1 year after enrollment. Secondary biomarker endpoints were collected at baseline and at 3, 6, 9, and 12 months after enrollment. Results Forty-three percent of patients had baseline osteopenia. Fifty-three patients were evaluable for response: 24 received ZA and had stable BMD during the observation period, whereas 29 patients in the control group had decreased BMD (P < .05 at lumbar spine and bilateral femoral neck). Twenty-one randomized patients were not evaluable for response because of lymphoma progression or death, withdrawn consent/incomplete testing, or ineligibility. Bone biomarkers were higher in the control group at all intervals after treatment (P < .001). No fractures or intervention-related toxicities were observed during this trial. Conclusions Newly diagnosed patients with lymphoma are at risk of low BMD, which may worsen with therapy. Treatment with ZA effectively stabilizes BMD and prevents bone loss. Our data suggest that BMD testing and prophylaxis should be considered as an early intervention for a preventable problem

  3. Low Concentrations of HIV-1 DNA at Birth Delays Diagnosis, Complicating Identification of Infants for Antiretroviral Therapy to Potentially Prevent the Establishment of Viral Reservoirs

    PubMed Central

    Mitchell, Caroline; Dross, Sandra; Beck, Ingrid A.; Micek, Mark A.; Frenkel, Lisa M.

    2014-01-01

    Among infants exposed to human immunodeficiency virus type 1 (HIV-1), detection of viral infection at birth was increased by 39% (95% confidence interval, 19%–47%) by increasing DNA input from dried blood spots into polymerase chain reaction. Infants with low concentrations of HIV-1 at birth may be the best target population to evaluate whether immediate antiretroviral therapy can prevent long-term infection. PMID:24501389

  4. Low concentrations of HIV-1 DNA at birth delays diagnosis, complicating identification of infants for antiretroviral therapy to potentially prevent the establishment of viral reservoirs.

    PubMed

    Mitchell, Caroline; Dross, Sandra; Beck, Ingrid A; Micek, Mark A; Frenkel, Lisa M

    2014-04-01

    Among infants exposed to human immunodeficiency virus type 1 (HIV-1), detection of viral infection at birth was increased by 39% (95% confidence interval, 19%-47%) by increasing DNA input from dried blood spots into polymerase chain reaction. Infants with low concentrations of HIV-1 at birth may be the best target population to evaluate whether immediate antiretroviral therapy can prevent long-term infection.

  5. Evaluation of Direct Colorimetric MTT Assay for Rapid Detection of Rifampicin and Isoniazid Resistance in Mycobacterium tuberculosis

    PubMed Central

    Woldemeskel, Dawit; Gessesse, Amare

    2016-01-01

    With the spread of multidrug-resistant tuberculosis (MDR-TB) strains there is an increasing need for new accurate and cost-effective methods for a rapid diagnostic and drug susceptibility testing (DST), particularly in low-income countries where tuberculosis is hyperendemic. A colorimetric assay using 3-(4, 5-dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT) has been suggested as a promising method for DST, especially to rifampicin. In this study, we standardized and evaluated the MTT assay for a rapid direct detection of rifampicin and isoniazid resistant Mycobacterium tuberculosis strains from sputum specimens using Lowenstein-Jensen (LJ) culture medium as a gold standard. The MTT assay sensitivity, specificity, positive and negative predictive values for rifampicin were 100%, 86%, 100%, 99%, respectively. For isoniazid, the MTT assay had a 100% sensitivity, specificity, positive and negative predictive values. Interestingly, the MTT assay gave interpretable results within two weeks for 94% of the samples compared to 7–14 weeks for LJ media. Overall, an excellent agreement was observed between MTT assay and LJ proportion method (Kappa, 0.91 for rifampicin and 1.00 for isoniazid). In conclusion, the direct colorimetric MTT assay simultaneously detects susceptible and resistant strains of M. tuberculosis within three weeks. It significantly shortens the time required to obtain a DST result and could be a reliable alternative method for rapid detection of drug-resistant TB strains in high-TB-burden resource-limited settings. PMID:28030634

  6. Implementation of co-trimoxazole preventive therapy policy for malaria in HIV-infected pregnant women in the public health facilities in Tanzania

    PubMed Central

    Kamuhabwa, Appolinary AR; Gordian, Richard; Mutagonda, Ritah F

    2016-01-01

    Background In 2011, Tanzania adopted a policy for provision of daily co-trimoxazole prophylaxis to HIV-infected pregnant women for prevention of malaria and other opportunistic infections. As per the policy, HIV-infected pregnant women should not be given sulfadoxine-pyrimethamine (SP) for intermittent preventive therapy. The challenges associated with this policy change and the extent to which the new policy for prevention of malaria in pregnant women coinfected with HIV was implemented need to be assessed. Aim To assess the implementation of malaria-preventive therapy policy among HIV-infected pregnant women in the public health facilities in Dar es Salaam, Tanzania. Methodology The study was conducted in Kinondoni Municipality, Dar es Salaam, Tanzania, from January 2015 to July 2015. Three hundred and fifty-three HIV-infected pregnant women who were attending antenatal clinics (ANCs) and using co-trimoxazole for prevention of malaria were interviewed. Twenty-six health care workers working at the ANCs were also interviewed regarding provision of co-trimoxazole prophylaxis to pregnant women. A knowledge scale was used to grade the level of knowledge of health care providers. Focus group discussions were also conducted with 18 health care workers to assess the level of implementation of the policy and the challenges encountered. Results Twenty-three (6.5%) pregnant women with known HIV serostatus were using co-trimoxazole for prevention of opportunistic infections even before they became pregnant. Out of the 353 HIV-infected pregnant women, eight (2.5%) were coadministered with both SP and co-trimoxazole. Sixty (16.7%) pregnant women had poor adherence to co-trimoxazole prophylaxis. Out of the 26 interviewed health care providers, 20 had high level of knowledge regarding malaria-preventive therapy in HIV-infected pregnant women. Lack of adequate supply of co-trimoxazole in health facilities and inadequate training of health care providers were among the factors

  7. 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

  8. 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.

  9. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)--can C-reactive protein be used to target statin therapy in primary prevention?

    PubMed

    Mora, Samia; Ridker, Paul M

    2006-01-16

    The most important action of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is their ability to lower levels of low-density lipoprotein (LDL) cholesterol. Statins have proved highly effective in reducing the risk of cardiovascular events in both primary and secondary prevention studies. However, the magnitude of risk reduction associated with statins is greater than that predicted on the basis of LDL cholesterol lowering alone. A likely explanation for this effect is the anti-inflammatory action of statins. Following the observation that high-sensitivity C-reactive protein (hs-CRP) is a powerful predictor of cardiovascular events, investigators in the Cholesterol and Recurrent Events (CARE) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) trials demonstrated that the magnitude of risk reduction associated with statin therapy was higher among those with elevated hs-CRP levels. In addition, there is accumulating evidence that statins lower plasma levels of hs-CRP in a manner largely independent of LDL cholesterol lowering. In contrast, little benefit has been demonstrated for statin therapy in the absence of both hyperlipidemia and inflammation. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a large multinational, long-term, double-blind, placebo-controlled, randomized clinical trial designed to assess directly whether statin therapy (rosuvastatin 20 mg/day) should be given to apparently healthy individuals with low LDL cholesterol levels but elevated hs-CRP levels--a critical issue for the prevention of cardiovascular disease. Support for the concept behind the JUPITER trial is also now available from several recent trials comparing different intensities of statin therapy on disease progression as well as clinical end points. These studies indicate that the hs-CRP level achieved after initiation of statin therapy may be as important as the LDL

  10. A qualitative study of participant adherence in a randomized controlled trial of herpes suppressive therapy for HIV prevention in Tanzania.

    PubMed

    Plummer, Mary L; Watson-Jones, Deborah; Lees, Shelley; Baisley, Kathy; Matari, Salma; Changalucha, John; Clayton, Tim; Mugeye, Kokugonza; Tanton, Clare; Weiss, Helen A; Ross, David A; Hayes, Richard J

    2010-04-01

    Poor participant adherence to treatment may contribute to lack of impact in some biomedical HIV prevention trials. This qualitative study explored adherence in a randomized controlled trial of herpes suppressive therapy to reduce HIV acquisition and infectivity among 1305 Tanzanian women. The trial found participants completed 72% of visits on treatment; 52-56% of women on treatment had > or = 90% adherence by pill count estimate; and between six and nine months 30/86 (35%) of urine samples from acyclovir recipients tested acyclovir negative, and 7/86 (8%) from placebo recipients tested acyclovir positive. Twenty in-depth interviews (IDIs) were conducted after 30 months with respondents randomly selected from "acyclovir negative" acyclovir recipients and "acyclovir positive" placebo recipients, or by preliminary pill count adherence categories ("under users," "good users," and "over users"). Almost all respondents reported appropriate adherence and positive trial attitudes, e.g., trusting staff, appreciating services, perceiving pills as beneficial. Fourteen understood placebo use, and six understood the trial purpose. Notably, 5/9 acyclovir recipients and 1/11 placebo recipients believed their pills had treated pre-existing sexually transmitted infections. Limited understanding did not negatively affect reported adherence. Reported adherence problems usually related to illness, travel, and/or family obligations (e.g., husband's disapproval). "Acyclovir positive" placebo recipients denied taking other participants' pills. The IDIs also did not resolve discrepant reports of pill loss or theft. Biomedical HIV interventions often have strong behavioral components that require close attention during intervention development, trial design, and process and impact evaluation. This study identified topics which warrant further consideration, including: information reinforcement and comprehension assessment throughout a trial for long-term participant understanding

  11. In search of the "vulnerable plaque": can it be localized and will focal regional therapy ever be an option for cardiac prevention?

    PubMed

    Ambrose, John A

    2008-04-22

    The search to find the location of future plaque ruptures or plaque erosions leading to myocardial infarction (so-called "vulnerable plaques") is an important area of cardiovascular research. Systemic therapy, including use of statins, targets the vulnerable patient. However, adverse events cannot be completely eliminated with the appropriate application of systemic therapies and thus has given rise to the possibility of local or regional therapy of "vulnerable plaques" to prevent future events. Until now, no criteria have been developed for consideration of this therapy. For such a strategy to work, there should be several prerequisites. These involve the identification of susceptible lesions, the number of lesions, their natural history, and proof that an interventional technique is preferable to medical therapy alone. The greatest deficiency relates to the fact that until the natural history of presumed "vulnerable plaques" is known one can never truly identify what constitutes a "vulnerable plaque." Much work needs to be done in this area, but ongoing and new trials should provide important information that could potentially change drastically how coronary artery disease is diagnosed and treated.

  12. 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.

  13. Isoniazid proliposome powders for inhalation-preparation, characterization and cell culture studies.

    PubMed

    Rojanarat, Wipaporn; Changsan, Narumon; Tawithong, Ekawat; Pinsuwan, Sirirat; Chan, Hak-Kim; Srichana, Teerapol

    2011-01-01

    The aims of this study were to develop proliposome powders containing isoniazid (INH) in a dry powder aerosol form. INH-proliposome powders were prepared by a spray drying method. Proliposome physicochemical properties were determined using cascade impactor, X-ray diffraction and differential scanning calorimetry. The toxicity of proliposomes to respiratory-associated cell lines and its potential to provoke immunological responses from alveolar macrophages (AM) were determined. Free INH and INH-proliposome bioactivities were tested in vitro and in AM infected with Mycobacterium bovis (M. bovis). Aerosolization properties of INH-proliposome powders at 60 L/min, the powders showed mass median aerodynamic diameters of 2.99-4.92 μm, with fine particle fractions (aerosolized particles less than 4.4 μm) of 15-35%. Encapsulation of INH was 18-30%. Proliposome formulations containing INH to mannitol ratios of 4:6 and 6:4 exhibited the greatest overlapping peak between the drug and mannitol. INH-proliposomes were evidently nontoxic to respiratory-associated cells, and did not activate AM to produce inflammatory mediators-including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide-at a toxic level. The efficacy of INH-proliposome against AM infected with M. bovis was significantly higher than that of free INH (p < 0.05). INH-proliposomes are potential candidates for an alternative tuberculosis treatment.

  14. 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

  15. 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

  16. [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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. Simultaneous Spectrophotometric Determination of Rifampicin, Isoniazid and Pyrazinamide in a Single Step

    PubMed Central

    Asadpour-Zeynali, Karim; Saeb, Elhameh

    2016-01-01

    Three antituberculosis medications are investigated in this work consist of rifampicin, isoniazid and pyrazinamide. The ultra violet (UV) spectra of these compounds are overlapped, thus use of suitable chemometric methods are helpful for simultaneous spectrophotometric determination of them. A generalized version of net analyte signal standard addition method (GNASSAM) was used for determination of three antituberculosis medications as a model system. In generalized net analyte signal standard addition method only one standard solution was prepared for all analytes. This standard solution contains a mixture of all analytes of interest, and the addition of such solution to sample, causes increases in net analyte signal of each analyte which are proportional to the concentrations of analytes in added standards solution. For determination of concentration of each analyte in some synthetic mixtures, the UV spectra of pure analytes and each sample were recorded in the range of 210 nm-550 nm. The standard addition procedure was performed for each sample and the UV spectrum was recorded after each addition and finally the results were analyzed by net analyte signal method. Obtained concentrations show acceptable performance of GNASSAM in these cases. PMID:28243267

  4. Potentiation by isoniazid of relaxation induced by nitrovasodilators in rat aorta.

    PubMed

    Vidrio, H; Fernández, G

    1998-09-01

    The influence of isoniazid (ISO) preincubation on the relaxant effects of a group of nitrovasodilators was examined in norepinephrine-contracted rat aortic rings with and without endothelium. ISO displaced to the left the dose-response curves to all nitrovasodilators and increased the negative logarithm of their median effective concentration (EC50) values. Potentiation was minimal with sodium nitrite and increased progressively with sodium nitroprusside, nitroglycerin (NTG), and isosorbide dinitrate. The phenomenon occurred in rings with and without endothelium and was not seen with the nitric oxide-releasing agent acetylcholine or with the nonspecific vasodilator hydralazine. These results confirm previous observations of potentiation of NTG vasorelaxation by ISO and extend them to other nitrovasodilators. Potentiation is attributed to the previously postulated inhibition by ISO of pyridoxal-requiring enzymes involved in the breakdown of homocysteine, leading to its intracellular accumulation. Increased availability of this sulfhydryl donor would lead in turn to enhanced bioactivation and vasorelaxant effects of nitrovasodilators. The different degrees of potentiation observed would be related to the sulfhydryl requirement of each compound for bioactivation. Alternatively, enhanced bioactivation of the nitrovasodilators could be due to induction by ISO of P-450 enzymes involved in this process.

  5. 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.

  6. The effectiveness and cost effectiveness of dark chocolate consumption as prevention therapy in people at high risk of cardiovascular disease: best case scenario analysis using a Markov model

    PubMed Central

    Zomer, Ella; Owen, Alice; Magliano, Dianna J; Liew, Danny

    2012-01-01

    Objective To model the long term effectiveness and cost effectiveness of daily dark chocolate consumption in a population with metabolic syndrome at high risk of cardiovascular disease. Design Best case scenario analysis using a Markov model. Setting Australian Diabetes, Obesity and Lifestyle study. Participants 2013 people with hypertension who met the criteria for metabolic syndrome, with no history of cardiovascular disease and not receiving antihypertensive therapy. Main outcome measures Treatment effects associated with dark chocolate consumption derived from published meta-analyses were used to determine the absolute number of cardiovascular events with and without treatment. Costs associated with cardiovascular events and treatments were applied to determine the potential amount of funding required for dark chocolate therapy to be considered cost effective. Results Daily consumption of dark chocolate (polyphenol content equivalent to 100 g of dark chocolate) can reduce cardiovascular events by 85 (95% confidence interval 60 to 105) per 10 000 population treated over 10 years. $A40 (£25; €31; $42) could be cost effectively spent per person per year on prevention strategies using dark chocolate. These results assume 100% compliance and represent a best case scenario. Conclusions The blood pressure and cholesterol lowering effects of dark chocolate consumption are beneficial in the prevention of cardiovascular events in a population with metabolic syndrome. Daily dark chocolate consumption could be an effective cardiovascular preventive strategy in this population. PMID:22653982

  7. Therapy with the Combination of Amlodipine and Irbesartan Has Persistent Preventative Effects on Stroke Onset Associated with BDNF Preservation on Cerebral Vessels in Hypertensive Rats.

    PubMed

    Hasegawa, Yu; Nakagawa, Takashi; Uekawa, Ken; Ma, Mingjie; Lin, Bowen; Kusaka, Hiroaki; Katayama, Tetsuji; Sueta, Daisuke; Toyama, Kensuke; Koibuchi, Nobutaka; Kim-Mitsuyama, Shokei

    2016-02-01

    Although calcium channel blockers, angiotensin II receptor blockers, and combination therapy are effective for hypertensive patients, the significant differences among them against stroke onset are undetermined. In this study, we investigated the significant beneficial effects of the combination therapy using amlodipine and irbesartan against stroke onset in hypertensive rats. The animals were fed an 8% sodium diet and assigned to (1) vehicle, (2) amlodipine (2 mg/kg/day), (3) irbesartan (20 mg/kg/day), and (4) amlodipine + irbesartan groups. The drugs were given orally until 35 days, and incidences of stroke-related signs and mortality and blood pressure (BP) were monitored. Cerebral blood flow (CBF), brain water content, weight of the brain and left ventricle, and histological evaluations were conducted for the treated groups at 42 days after the start of the high-salt diet. Amlodipine and the combination therapy significantly reduced BP compared with the vehicle. Although the rates of stroke-related signs and mortality were high in the vehicle group, the rats in the treatment groups were mostly healthy until 35 days. After all drugs were discontinued, stroke onset was frequently seen in the monotherapy groups until 42 days, but no signs were observed in the combination therapy group. Although there were no significant differences in CBF or brain edema, the combination therapy reduced blood-brain barrier disruption, white matter injury, and reactive astrocytes compared with irbesartan, and the combination also inhibited left ventricular hypertrophy and preserved brain-derived neurotrophic factor (BDNF) expression on cerebral vessels compared to the monotherapies. These data suggest that the combination therapy had a persistent preventive effect on stroke onset in hypertensive rats, and the effects might be associated with BDNF preservation on cerebral vessels.

  8. 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

  9. Flavonoids and Their Glycosides as Anti-amyloidogenic Compounds: Aβ1-42 Interaction Studies to Gain New Insights into Their Potential for Alzheimer's Disease Prevention and Therapy.

    PubMed

    Guzzi, Cinzia; Colombo, Laura; Luigi, Ada De; Salmona, Mario; Nicotra, Francesco; Airoldi, Cristina

    2017-01-03

    Combining NMR spectroscopy, transmission electron microscopy, biochemical and in vitro toxicity assays, we characterized the effect of flavonoid glycosylation, a chemical modification found very frequently in nature, on their ability to recognize and bind Aβ1-42 oligomers, preventing their aggregation and their neurotoxicity. Our data allow the elucidation of their structure-activity relationships, showing that glycosylation has a modest impact on flavonoid affinity for Aβ oligomers but, at the same time, increases both solubility and chemical stability, thus promoting their beneficial properties against Alzheimer's disease (AD). As flavonoids and their glycosides are widely available in natural foods, our results provide important information for the evaluation of the role of a flavonoid-rich diet for the prevention of AD. In addition, the structural data collected can be exploited for the rational design of more potent Aβ oligomer inhibitors, useful for the development of new therapies against AD.

  10. Denosumab for the treatment of cancer therapy-induced bone loss and prevention of skeletal-related events in patients with solid tumors.

    PubMed

    Lipton, Allan; Balakumaran, Arun

    2012-07-01

    Development of bone metastasis is common among patients with advanced cancer. Improvements in chemotherapeutic agents have allowed these patients to live longer with metastatic-stage disease. Thus, treatments to prevent skeletal complications of metastatic bone disease, such as skeletal-related events and pain, are increasingly important. As the skeletal damage with bone metastases is largely caused by increased osteoclast activity, antiresorptive agents (denosumab or bisphosphonates) are recommended for use in these patients. Denosumab, a fully human monoclonal antibody to RANKL, a key mediator of osteoclast activity, was shown to be superior to zoledronic acid for the prevention of skeletal-related events in patients with solid tumors and bone metastases. In addition, denosumab is the only agent currently approved for the treatment of bone loss in patients with breast or prostate cancer receiving hormone-ablation therapy. Denosumab is also being evaluated in several other indications, including adjuvant treatment of breast cancer and giant cell tumor of the bone.

  11. 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

  12. Design and Recruitment for a Randomized Controlled Trial of Problem Solving Therapy to Prevent Depression among Older Adults with Need for Supportive Services

    PubMed Central

    Albert, Steven M.; King, Jennifer; Dew, Mary Amanda; Begley, Amy; Anderson, Stewart; Karp, Jordan; Gildengers, Ari; Butters, Meryl; Reynolds, Charles F.

    2015-01-01

    Background Addressing subthreshold depression (indicated prevention) as well as vulnerabilities that increase the risk of major depression or anxiety disorders (selective prevention) is important for protecting mental health in old age. The Depression-Agency Based Collaborative is a prevention trial involving older adults recruited from aging services sites (home care agencies, senior housing senior centers) who meet criteria for subthreshold depression and disability. Objective To examine (i) the effectiveness of partnerships with aging services sites for recruiting at-risk older adults, (ii) the quality of recruitment and acceptability of the Dep-ABC assessment and intervention, and (iii) the baseline status of participants. Methods Dep-ABC is a single-blind randomized controlled prevention trial set in aging services settings but with centralized screening, randomization, in-home assessments, and follow-up. Its intervention arm involves 6–8 sessions of problem-solving therapy, in which older adults aged 60+ learn to break down problems that affect wellbeing and develop strategies to address them. We examined participation rates to assess quality of recruitment across sites and level of disability according to service use. Results Dep-ABC randomized 104 participants, 68.4% of eligible older adults. Screening using self-reported disability successfully netted a sample in which 74% received home care agency services, with remaining participants similarly impaired in structured self-reports of impairment and on observed performance tests. Conclusions Direct outreach to aging services providers is an effective way to identify older adults with service needs at high risk of major depression. Problem solving therapy is acceptable to this population and can be added to current services. PMID:26706911

  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. Characterisation of the membrane affinity of an isoniazide peptide conjugate by tensiometry, atomic force microscopy and sum-frequency vibrational spectroscopy, using a phospholipid Langmuir monolayer model.

    PubMed

    Hill, Katalin; Pénzes, Csanád Botond; Schnöller, Donát; Horváti, Kata; Bosze, Szilvia; Hudecz, Ferenc; Keszthelyi, Tamás; Kiss, Eva

    2010-10-07

    Tensiometry, sum-frequency vibrational spectroscopy, and atomic force microscopy were employed to assess the cell penetration ability of a peptide conjugate of the antituberculotic agent isoniazide. Isoniazide was conjugated to peptide (91)SEFAYGSFVRTVSLPV(106), a functional T-cell epitope of the immunodominant 16 kDa protein of Mycobacterium tuberculosis. As a simple but versatile model of the cell membrane a phospholipid Langmuir monolayer at the liquid/air interface was used. Changes induced in the structure of the phospholipid monolayer by injection of the peptide conjugate into the subphase were followed by tensiometry and sum-frequency vibrational spectroscopy. The drug penetrated lipid films were transferred to a solid support by the Langmuir-Blodgett technique, and their structures were characterized by atomic force microscopy. Peptide conjugation was found to strongly enhance the cell penetration ability of isoniazide.

  15. Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

    PubMed Central

    Seng, Kok-Yong; Hee, Kim-Hor; Soon, Gaik-Hong; Chew, Nicholas; Khoo, Saye H.

    2015-01-01

    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. PMID:26282412

  16. 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